AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

 spectroscopy, SYNTHESIS  Comments Off on One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases
Dec 252016
 

Graphical abstract: One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03023H, Communication
P. Matzel, M. Gand, M. Hohne
Imine reductases (IREDs) show great potential as catalysts for reductive amination of ketones to produce chiral secondary amines.

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

Imine reductases (IREDs) show great potential as catalysts for reductive amination of ketones to produce chiral secondary amines. In this work, we explored this potential and synthesized the pharmaceutically relevant (R)-rasagiline in high yields (up to 81%) and good enantiomeric excess (up to 90% ee) from the ketone precursor. This one-step approach in aqueous medium represents the shortest synthesis route from achiral starting materials. Furthermore, we demonstrate for the first time that tertiary amines also can be accessed by this route, which provides new opportunities for eco-friendly enzymatic asymmetric syntheses of these important molecules.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03023H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

P. Matzel,a   M. Gandb and   M. Höhne*a  
*Corresponding authors
aInstitute of Biochemistry, Greifswald University, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
E-mail: Matthias.Hoehne@uni-greifswald.de
bBiocenter Klein Flottbek, University of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03023H

str0 str1 str2 str3 str4

////////////One-step, asymmetric synthesis,  (R)- ,  (S)-rasagiline,  reductive amination,  imine reductases

Share

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol , Furofuranol

 Uncategorized  Comments Off on (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol , Furofuranol
Dec 232016
 

str1

CAS : 156928-09-5
Molecular Formula: C6H10O3
Molecular Weight: 130.144
  • Furo[2,3-b]furan-3-ol, hexahydro-, [3R-(3α,3aβ,6aβ)]-
  • (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol
  • 3R,3AS,6aR-hexahydrofuro[2,3-b]furan-3-ol
  • R,S,R-Bisfuran alcohol

WO2012075122  SP ROT= -13.2/1G/100ML, METHANOL

PATENT

http://www.google.com.ar/patents/WO2012070057A1?cl=en

The overall synthesis of the present invention is shown in the scheme 1:

Figure imgf000005_0003

Yet another aspect of present invention is to provide a process for the preparation of compound formula I as per below scheme 2.

Figure imgf000006_0001

str1

 

str2

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (7) as clear oil (7.8 g, 96.8 A% purity by GC-MS, 55.7 mmol, 74% yield). C6H10O3, GC-MS (EI): m/z 100 (M- H2CO).

1H NMR (CDCl3): 1.88 (m, 1H), 2.08 (bd, 1H, −OH), 2.31 (m, 1H), 2.87 (m, 1H), 3.64 (dd, J = 9.2, 7.0 Hz, 1H), 3.87–4.02 (abx system, 3H), 4.45 (m, 1H), 5.70 (d, J = 5.2 Hz, 1H).

13C NMR (CDCl3): 109.54, 73.15, 71.00, 69.90, 46.58, 24.86.

Diastereomeric ratio of 7 to 12 = 98.2:1.8.

GC retention time of 7= 3.20 min; 12 = 3.09 min.

Abstract Image

A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol—a key intermediate in the synthesis of darunavir—from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound’s ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS. Key to the success of this process was identifying an optimal amide that allowed for complete reaction and successful product isolation. N-Methyl aniline amide was identified as the most suitable substrate for the reduction and the subsequent cyclization to the desired product. Thus, the side chain is produced in 55% overall yield from monopotassium isocitrate.

Practical Synthesis of the Bicyclic Darunavir Side Chain: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol from Monopotassium Isocitrate

Clinton Health Access Initiative, 800 North Five Points Road, West Chester, Pennsylvania 19380, United States
Org. Process Res. Dev., Article ASAP
1H NMR PREDICT
str1 str2
13C NMR PREDICT
str1 str2
 PATENT

In particular, the following synthetic scheme (1) illustrates the present commercial method of synthesizing compound (I) . This synthesis is disclosed in detail in A.K. Ghosh et al . , Tetra- hedron Letters, 36 (4) , pp. 505-508 (1995), incorporated herein by reference. Also see, A.K. Ghosh et al., J. Med. Chem . , 39, pp. 3278-3290 (1996) for the synthesis of compound (I) and a related compound of structural formula (II) (i.e., (3S, 3aR, 7aS) -3- hydroxyhexahydrofuro [2, 3-b] pyran) .

Figure imgf000004_0001

Scheme 1 (prior art)

Figure imgf000004_0002

(91%)

Cobaloxime (catalytic) , NaBH4, EtOH

Figure imgf000004_0003
Figure imgf000005_0001

Alternatively,

-OAc

0 Immobilized Lipase 30

0- pH 7 buffer 23°C, 24 h

(+)

Figure imgf000005_0002

R=Ac

MeLi, THF

^ R=H (Compound (I))

The present method of synthesizing bis-THF is summarized as follows:

Figure imgf000007_0002
Figure imgf000008_0001

<

(78-100%;

Figure imgf000008_0002

(70-90%)

Figure imgf000008_0003

(65-80%;

Figure imgf000008_0004

2. NaBH4, EtOH (65-75%) -15°C, 1-3 h Compound (I) (bis-THF) Another aspect of the present invention is to provide a method of preparing a compound having a structure

Figure imgf000009_0001

then utilizing the benzyl-protected 5-hydroxymethyl- 5H-furan-2-one in the synthesis of compound (I) .

Another aspect of the present invention is to provide a method of preparing compounds related to bis-THF by using a starting material having a following structure:

Figure imgf000009_0002
Figure imgf000009_0003

X

I

R R

The synthesis of bis-THF (compound (I) ) is summarized below:

Figure imgf000012_0001

(1) (2)

Figure imgf000012_0002

(3)

Figure imgf000012_0003

15) (6)

Figure imgf000013_0001

(I)

(3R, 3aS , 6aR) -3-Hydroxyhexahydrofuro [2 , 3-b] uran (I)

Figure imgf000030_0001

(3R, 3aS, 6aR) -3-Hydroxyhexahydrofuxo [2, 3- b] furan (I) : To a solution containing 250 mg (1.95 mmol) (3aS, 6aR) -3-oxyhexahydrofuro [2, 3-b] furan (6) in EtOH (25 mL) was added ’89 mg (2.35 mmol) NaBH4 at -18 °C. The reaction mixture was stirred at -18 °C for 2.5 hours, then the reaction was quenched with saturated NH4C1 solution (5 mL) and warmed to room temperature. The resulting mixture was concentrated under reduced pressure, and then 10 mL water was added. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and a solution of 70% CHC13, 20% MeOH, and 10% water (3 x 50 mL) . The combined organic extracts were dried over Na2S04. Column chromatography (silica gel 80 g, MeOH in CHC13 7%) gave compound (I) (178 mg. 70%) as a colorless solid, Rf=0.3, [α]25 D -12.4°, c 1.3, MeOH. IR (neat) 2951, 1641, 1211 cm“1; XH-NMR (400 MHz CDC13) δ: 1.85 (mc, IH) , 1.94 (bs, IH) , 2.27 (mc, IH) , 2.84 (mc, IH) , 3.63 (dd, IH, J=7.1 Hz, J=9.2 Hz), 3.89 (mc, IH) , 3.97 (mc, IH) , 4.43 (dd, IH, J=6.8 Hz, J=14.5 ” Hz), 5.68 (d, IH, J=5.2 Hz). 13C-NMR (125.8 MHz, CDC13, Dept) δ‘: 25.27 (-) , 46.97 (+) , 70.31 (-) , . 71.26 (-), 73.50 (+) , 109.93. (+) . C6H10O3; Exact Mass: 130.06; Mol. Wt . : 130.14; C, 55.37, H, 7.74, 0, 36.88.

Experimentals :

l-(Benzyloxy)-but-3-en-2-ol (±)-(8): To a solution of vinylmagnesium bromide (1 M in THF, 40 mL, 40 mmol) in THF (10 mL) at 0°C was added benz- yloxyacetaldehyde (7) (5 g, 33.3 mmol) dropwise. The mixture was stirred for 10 min at 0°C, and the reaction then was quenched with 20 L of saturated NaHC03 solution. The layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 20 mL) , and the combined organic extracts were dried over sodium sulfate. Evaporation of solvent under reduced pressure, followed by column chromatography on silica gel (20% EtOAc in hexanes as the eluent) yielded alcohol (±)-8 (5.22 g, 88%) as a yellow oil, Rf=0.40 (30% EtOAc in hexanes); 1H-NMR (400 MHz, CDC13) δ: a 2.79 (bs, IH) , 3.39 (dd, IH, J=1.7, 7.85 Hz), 3.55 (dd, IH, J=3.35, 6.3 Hz), 4.35 (m, IH) , 4.58 (s, IH) , 5.21 (dt, IH, J=7.75, 1.4 Hz), 5.38 (dt, IH, J=14.18, 1.4 Hz), 5.84 (m, IH) , 7.30-7.38 (m, 5H) ; 13C-NMR (100.6 MHz, CDC13) δ: 71.52, 73.37, 74.02, 116.49, 127.85, 128.49, 136.58, 137.81. (S)-l-(Benzyloxy) -but-3-en-2-ol (9) and (R) -1- (benzyloxy) -but-3-en-2-oyl acetate (10):

A: To a solution of alcohol (±)-(8) (5.21 g, 29.3 mmol) in acetic anhydride (14 mL, 147 mmol) and tert-butyl methyl ether (70 mL, 586 mmol) was added immobilized lipase PS-30 (5.3 g ) on Celite 521 (Aldrich) . The mixture was stirred at room temperature for 20 h, and then filtered through Celite. Removal of solvent under reduced pressure followed, by column chromatography on silica gel (10 and 15% EtOAc in hexanes as the eluents) yielded acetate (10) (3.81 g, 54%) Rf=0.57 (30% EtOAc in hexanes) as a clear oil, [of]25 D -2° (c 1, CHC13) ; NMR (500 MHz, CDC13) δ: 2.10 (s, 3H) , 3.55-3.59 (m, 2H) , 4.56 (q, 2H, J=12.2, 14.0 Hz), 5.24 (d, IH, J-10.6 Hz), 5.32 (d, IH, J=17.3 Hz), 5.50 (m, IH) , 5.84 (m, IH) , 7.25-7.36 (m, 5H) ; 13C-NMR (125.8 MHz, CDC13) δ: 21.62, 71.67, 73.57, 73.59, 118.39, 128.14, 128.84, 133.77, 138.32, 170.63; alcohol 9 (2.34 g, 45%) as a yellow oil, Rf=0.40 (30% EtOAc in hexanes), [α]25 D– 8.3° (c 1.06, MeOH) .

B: To a solution of alcohol (±)-(8) (3.92 g, 22.0 mmol) in vinyl acetate (46 mL, 499 mmol) and ethylene glycol dimethyl ether (46 mL, 440 mmol) was added immobilized lipase PS-30 (4 g ) on Celite-545 (Aldrich) . The mixture was stirred at room temperature for 28 h, and then filtered through celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (10 and 15% EtOAc in hexanes as the eluents) yielded acetate

(10) (2.20 g, 45%) Rf=0.57 (30% EtOAc in hexanes) as a clear oil, [ ]25 D -2.7° (c 1.35, MeOH); alcohol (9) (2.00 g, 51%) as a yellow oil, Rf=0.40 (30% EtOAc in hexanes), [α]25 D -11.4° (c 1.6, MeOH).

C: To a solution of alcohol (+)-(8) (30 mg, 0.168 mmol) in isopropenyl acetate (375 μL, 3.36 mmol) and ethylene glycol dimethyl ether (375 μL, 3.61mmol) was added immobilized lipase PS-30 (35 mg) on Celite-545 (Aldrich) . The mixture was stirred at room temperature for 23 h, and then filtered through celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (10) and 15% EtOAc in hexanes as the eluents) yielded acetate 10 (20.3 mg, 54%) as an oil, Rf=0.57 (30% EtOAc in hexanes), [α]25 D -1.4° (c 1.02, MeOH); alcohol (9) (13 mg, 43%) as a yellow oil, Rf=0.40

(30% EtOAc in hexanes), [ ]25 D -13.5° (c 1.3, MeOH). (R) -1- (Benzyloxy) -but-3-en-2-ol (11): To a solution of acetate (10) (3.7 g, 16.9 mmol) in methanol (20 mL) was added K2C03 (7 g, 50.6 mmol). The mixture was stirred at room temperature for 35 min. Methanol then was removed under reduced pressure. The resulting solid residue was dissolved in ethyl acetate, washed with saturated NH4C1 solution and brine, and dried over sodium sulfate. Removal of ethyl acetate under reduced pressure yielded the crude alcohol (11) (3 g, 100%) as a yellow oil, Rf=0.40 (30% EtOAc in hexanes), [α]25 D 8.3° (c 1.06, MeOH) .

(S)-l- (Benzyloxy) -but-3-en-2-ol (9) from (11): To a solution of crude alcohol (5) (2 g, 11.2 mmol), triphenylphosphine (5.88 g , 22.4 mmol), and 4-nitrobenzoic acid (2.81 g, 16.8 mmol) in benzene (35 mL) was added at room temperature diisopropyl azodicarboxylate (4.35 mL, 22.4 mmol) dropwise. The mixture was stirred for 40 min, followed by the re- moval of solvent under reduced pressure. All of the crude ester then was dissolved in a mixture of MeOH:Et3N:H20 (20ml) in the ratio of 4:3:1 and reacted with LiOH (1.64 g, 39.3 mmol) at room temperature. The mixture was stirred for 2 h, followed by the removal of solvent. Column chromatography on silica gel (15% EtOAc in hexanes as the eluent) yielded alcohol (3) (1.64 g, 82%) as a yellow oil, Rf=0.40 (30% EtOAc in hexanes), [o;]25 D -7.3° (c 0.82, MeOH) . (S) -1- (Benzyloxy) -but-3-en-2-yl acrylate

(12): To a solution of alcohol (3) (1 g, 5.61 mmol) in CH2C12 (20 L) was added acryloyl chloride (685 μL, 8.41 mmol) dropwise, followed by the addition of Et3N (1.56 mL, 11.2 mmol). The resulting mixture was stirred for 10 min, and the solvent then was removed under reduced pressure. Filtration of the concentrated crude acrylate through a pad of silica gel using 15% EtOAc in hexanes, followed by the removal of solvent, yielded acrylate (12) (1.19 g, 92%) as a colorless oil, Rf=0.57 (30% EtOAc in hexanes), [α]25 D -5.7° (c 1.09, CHC13) ; 1H-NMR (500 MHz, CDC13) δ: 3.59-3.65 (m, 2H) , 4.56 (q, 2H, J=12.2, 14.65 Hz), 5.25 (d, IH, J=10.6 Hz), 5.33 (d, IH, J=16.8 Hz), 5.57 (m, IH) , 5.84-5.91 (m, 2H) , 6.17 (dd, IH, J=6.9, 10.4 Hz), 6.44 (dd, IH, J=1.3, 16.2 Hz), 7.27-7.36 (m, 5H) ; 13C-NMR (125.8 MHz, CDC13) δ: 71 . 62 , 73 . 58 , 73 . 77 , 118 . 49 , 128 . 05 , 128 . 85 , 131 . 52 , 133 . 62 , 138 . 31 , 165 . 79 .

(5S) -5- (Benzyloxymethyl) -5H-furan-2-one (13): To a solution of acrylate (12) (1.87 g, 8.05 mmol) in CH2C12 (700 mL) was added second generation Grubbs’ catalyst (4 mol %, 170 mg, 0.322 mmol). The reaction mixture was refluxed for 5 hours, and the solvent then was removed under reduced pressure. Column chromatography on silica gel (30% EtOAc in hexanes as the eluent) yielded the furanone (13)

(1.62 g, 98%) as a brown oil, Rf=0.15 (30% EtOAc in hexanes), [α]25 D -81.3° (c 1.09, MeOH); αH-NMR (500 MHz, CDC13) δ: 3.66 (dd, IH, J=5.0, 5.5 Hz), 3.71 (dd, IH, J=5.0, 5.2 Hz), 4.57 (s, 2H) , 5.17 (m, IH) , 6.16 (dd, IH, J=1.9, 3.8 Hz), 7.29-7.37 (m, 5H) , 7.48 (dd, IH, J=1.4, 4.3 Hz); 13C-NMR (125.8 MHz, CDC13) δ: a 69.86, 74.18, 82.61, 123.03, 128.42, 128.95, 137.69, 154.32, 173.19.

(4S ,5S) -5- (Benzyloxymethyl) -4- [1 , 3] di- oxolan-2-yldihydrofuran-2-one (14) : A solution of furanone (13) (1.2 g, 5.88 mmols) and benzophenone

(108 mg, 0.588 mmols) in [1, 3] -dioxolane (108 mg) was degassed for 40 min in a stream of argon. The mixture then was irradiated using one 450 watt ACE glass medium pressure mercury lamp, from a distance of 15 cm, for 9 hours. Progress of this reaction was observed via 1H-NMR. As the reaction mixture was degassed, and throughout all of the irradiation time, the reaction flask was held in a water cooled cooling mantel. The temperature of the cooling water was constantly maintained near 0°C. Upon completion of the reaction, solvent was removed under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent), yielding the title compound (1.34 g, 82%) as a clear oil, Rf=0.14 (30% EtOAc in hexanes), [α]25 D 16.5° (c 1.2, CHC13) ; 1H-NMR (500 MHz, CDC13) δ: 2.50 (dd, IH, J=3.9, 12.9 Hz), 2.70-2.79 (m, 2H) , 3.58 (dd, IH, J=3.5, 7.2 Hz), 3.75 (dd, IH, J=2.8, 7.9 Hz), 3.87-3.92 (m, 2H) , 3.97-4.00 ( , 2H) , 4.51 (d, IH, J=11.9 Hz), 4.57-4.61 (m, 2H) , 4.88 (d, IH, J=3.6 Hz), 7.26-7.36 (m, 5H) ; 13C-NMR (125.8 MHz, CDC13) δ: 30.39, 40.53, 65.77, 71.74, 73.99, 79.52, 104.14, 128.00, 128.89, 138.07, 176.79.

(4S,5S) -4-[l,3]Dioxolan-2-yl-5-hydroxy- methyldihydrofuran-2-one (15) : To a solution of dihydrofuranone (14) (0.5 g, 1.79 mmol) in MeOH (30 mL) was added Pd/C (25 mg) . The mixture was stirred at room temperature under an H2 balloon for 24 hours, and then filtered over Celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent) yielded the compound (15) (301 mg, 89%) as a white solid, Rf=0.28 (50% EtOAc in hexanes), [ ]25 D 22° (c 1.32, CHC13) ; XH-NMR (500 MHz, CDC13) δ: 2.54 (dd, IH, J=6.0, 11.4 Hz), 2.68-2.81 (m, 2H) , 3.66

(dd, IH, J=3.9-8.5 Hz), 3.88-3.95 (m, 3H) , 3.97-4.02 (m, 2H) , 4.53 (m, IH) , 4.91 (d, IH, J=3.9 Hz); 13C- NMR (125.8 MHz, CDC13) δ: 30.68, 40.12, 64.36, 65.77, 81.07, 103.94, 176.83. (3S , 3aS , 6aR) -3-Hydroxyhexahydrofuro [2 , 3- b] furan (5) : To a solution of lithium aluminum hydride (76 mg, 1.98 mmols) in THF (10 ml) at 0°C was added dihydrofuranone 15 (275 mg , 1.46 mmol) in THF (30 mL ) dropwise. Upon completion of the reduction after 4 hours, the reaction was quenched with a saturated aqueous sodium sulfate solution at 0°C. The solvent then was decanted and the remaining residue was washed with THF (3x) , EtOAc (3x) , and CHC13 (3x) . The organic extracts were combined and the solvent was removed under reduced pressure, yielding a crude (2S, 3S) -3- [1, 3] dioxolan-2- ylpentane-1, 2, 5-triol, which was immediately used in the next reaction.

The crude triol was dissolved in a mixture of THF:H20 (8ml) in the ratio of a 5:1. This solu- tion then was acidified at room temperature to pH 2- 3 with 1 N hydrochloric acid, and was stirred for 40 hours. Removal of solvent with the aid of benzene under reduced pressure, followed by column chromatography purification on silica gel (5% MeOH in CHCI3 as the eluent) yielded the compound (5) (145 mg,

77%) as a white solid, Rf=0.40 (15% MeOH in CHC13) , [α]25 D -25.1° (c 1.05, CHC13) ; XH-NMR (500 MHz, CDCI3) δ: 1.67 ( , IH) , 2.13 (m, IH) , 2.31 (bs, IH) , 2.79 (m, IH) , 3.80-3.88 (m, 3H) , 3.95 (dd, IH, J=3.2, 7.1 Hz), 4.20 (d, IH, J=3.1 Hz), 5.86 (d, IH, J=4.9 Hz). Preparation of bis-THF derivative (I) (by Mitsunobu inversion of compound (5) ) : To a stirred solution of alcohol (5) (400 mg, 3.07 mmol), tri- phenylphosphine (1.6 g, 61.4 mmol), and p-nitroben- zoic acid (770 mg, 4.61 mmol) in dry benzene (30 mL) at 23 °C was added diisoproylazodicarboxylate (DIAD, 1.2 L, 6.14 mmol) dropwise. After 1.5 hours, the mixture was concentrated in vacuo, and the crude ester was dissolved in a (4:3:1) mixture of MeOH:Et3N:H20 (24 mL) , then treated with LiOH (450 mg, 10.7 mmol) . The solution was stirred at room temperature for 2 h. The mixture then was concentrated under reduced pressure and the residue was chromatographed over silica gel to provide the bis-

THF (I) (326 mg, 82%); [ ]25 D -12.4 (c 1.16 , MeOH)

In particular, the following synthetic scheme (1) illustrates the present commercial method of synthesizing compound (I). This synthesis is disclosed in detail in A.K. Ghosh et al., Tetra. hedron Letters, 36 (4) , pp. 505-508 (1995), incorporated herein by reference. Also see, A.K. Ghosh et al., J. Med. Chem . , 39, pp. 3278-3290 (1996) for the synthesis of compound (I) and a related compound of structural formula (II) (i.e., (3S, 3aR, 7aS) -3-hydroxyhexahydrofuro [2, 3-b] pyran).

The present method of synthesizing bis-THF is summarized as follows:

The synthesis of bis-THF (compound (I) ) is summarized below:

previously.

REF

//////////(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, furofuranol, DARUNAVIR

O[C@H]1CO[C@H]2OCC[C@@H]12

Share

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

 Uncategorized  Comments Off on Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process
Dec 222016
 

Abstract Image

The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety.

 

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

† Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067 CEDEX 2 Orléans, France
‡ ISOCHEM, 4 Rue Marc Sangnier, BP 16729, 45300 Pithiviers, France
§ Institut de Combustion, Aérothermique, Réactivité, et Environnement (ICARE), 1c, Avenue de la Recherche Scientifique, 45071 CEDEX 2 Orléans, France
Org. Process Res. Dev., Article ASAP

str1

1H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, Har), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, Har), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, Har).

2,5-Dichloro-1,3-benzoxazole (33)

The reaction was carried out as described in general procedure B using 2-Amino-5-chlorobenzoxazole (221 mg, 1.31 mmol). After purification with silica flash chromatography (EP 100%), the product was isolated as a yellow oil (62 mg, 25%).
CAS number 3621-81-6.
1H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, Har), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, Har), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, Har).
str1
13C NMR (101 MHz, Chloroform-d) δ 152.27 (C), 150.12 (C), 142.06 (C), 130.79 (C), 125.85 (CH), 119.78 (CH), 111.16 (CH).
HRMS [M + H]+ (EI) calcd for C7H4Cl2NO: 187.9664, found: 187.9663.

1H NMR PREDICT

str1 str2

13 C NMR PREDICT

str1 str2

/////////////

Share

EMA issues new Guideline on “Chemistry of Active Substances”

 EMA, regulatory  Comments Off on EMA issues new Guideline on “Chemistry of Active Substances”
Dec 222016
 

Image result for active substances

The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.

http://www.gmp-compliance.org/enews_05704_EMA-issues-new-Guideline-on-%22Chemistry-of-Active-Substances%22_15982,15721,S-WKS_n.html

A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document  entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued on 21 November.

The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline “already existing” ingredients are those that are used in a product already authorized in the EU.

In detail the information and data regarding the substance have to be included in the following chapters of the CTD:

3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.

3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.

3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.

3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.

3.2.S.2.5: Information on Process Validation

3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.

3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.

3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance’s specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance’s specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.

3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia – counting as completely qualified reference standards – are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.

3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance’s quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.

3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.

The Guideline’s provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a “traditional” way or according to the “enhanced” approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.

The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.

The Guideline “Guideline on the chemistry of active substances” (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.

///////////////EMA, Guideline,  chemistry of active substances

Share

5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one

 Uncategorized  Comments Off on 5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one
Dec 212016
 

str00

 COSY PREDICT

str0

                      

1H NMR PREDICT

 

str1

str1

                      

 

str1

1H NMR (DMSO-d6, 400 MHz): δH 0.95 (3H, d, H4), 3.09–3.23 (2H, m, H2), 3.29–3.49 (5H, m, H14, H11, H3), 3.94–4.04 (2H, m, H5), 8.14 (1H, s, H8), 8.02 (1H, s, H9).

 

 

                      

13C NMR PREDICT

str1 str2

                      

str2

13C NMR (DMSO-d6, 100 MHz): δC 50.54 (C2), 54.33 (C3), 11.28 (C4), 52.31 (C5), 166.81 (C6), 147.15 (C7), 128.95 (C8), 135.96 (C9), 147.07 (C10), 51.93 (C11, C14), 172.41 (C12, C13);

str3 str4

 

str1 str2

                      

 

Figure

Houben-Weyl methods of organic chemistry, 4th ed.; Vol. E 9c Hetarenes III part 3; p 279.

5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one (Impurity A)

M.p.: 252.09 °C.
1H NMR (DMSO-d6, 400 MHz): δH 0.95 (3H, d, H4), 3.09–3.23 (2H, m, H2), 3.29–3.49 (5H, m, H14, H11, H3), 3.94–4.04 (2H, m, H5), 8.14 (1H, s, H8), 8.02 (1H, s, H9).
13C NMR (DMSO-d6, 100 MHz): δC 50.54 (C2), 54.33 (C3), 11.28 (C4), 52.31 (C5), 166.81 (C6), 147.15 (C7), 128.95 (C8), 135.96 (C9), 147.07 (C10), 51.93 (C11, C14), 172.41 (C12, C13);
                       
str3
HRMS (ESI) calcd for C13H17O3N6: 305. 13338 ([M + H]+), found; 305.13566([M + H]+).
IR (KBr, cm–1): 3248.13 (NH), 2970.38 and 2931.80 (CH), 1705.07 and 1689.64 (C═O), 1564.27 (NH bending), 1512.19 (C═N).

                       

Study on the Isolation and Chemical Investigation of Potential Impurities in Dexrazoxane Using 2D-NMR and LC-PDA-MS

§ Centre for Chemical Science & Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University, Hyderabad 500085, Telangana, India
†Gland Pharma Ltd, Research and Development, D.P.Pally, Hyderabad 500043, Telangana, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00219
Publication Date (Web): December 7, 2016
Copyright © 2016 American Chemical Society
*E-mail: venkatesan@glandpharma.com. Phone: 040-30510999 Ext: 280. Fax: 30510800., *E-mail: maheshk@glandpharma.com. Phone: 040-30510999 Ext: 280. Fax: 30510800.
guvvala vinodh
Abstract Image

A chemical investigation of process related impurities associated with the synthesis of dexrazoxane was performed. The degradation product of dexrazoxane is known in the literature; however, the information related to process impurities is not available. For the first time, two process related impurities were isolated, characterized, and confirmed by their individual chemical synthesis. The present study describes the isolation methods of the impurities and their structural elucidation using IR, 1H, 13C, 2D NMR, and mass spectrometry. The identification of these impurities would be highly valuable for the quality control during the production of the dexrazoxane drug substance

The U.S. Food and Drug Administration (FDA)(5) and the European Medicine Agency (EMA)(6) require analytical characterization not only for the active pharmaceutical ingredient (API), but also for its key starting materials and advanced intermediates. The determination of a drug substance impurity profile, including especially known pharmacopeial impurities, as well as other unknown impurities, could have a significant impact on the quality and the safety of the drug products. The health implications of the impurities could be significant because of their potential mutagenic or carcinogenic effects. Therefore, the International Conference on Harmonization (ICH) has set a high standard for the purity of drug substances.(7) If the dose is less than 2 g/day, then impurities over 0.10% are expected to be identified, qualified, and controlled. If the dose exceeds 2 g/day, then the qualification threshold is lowered to 0.05%. It is therefore essential to monitor and control the impurities in both the drug substance (API) and the drug products.

  1. 5 Guidance for Industry on Abbreviated New Drug Applications: Impurities in Drug Substances; Availability;Fed. Regist. 2009, 74, 34359– 34360.

  2. 6.The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Impurities in New Drug Substances Q3A (R2); IGH: Geneva, Switzerland, 2006.

  3. 7.International Conference on Harmonization; revised guidance on Q3A impurities in new drug Substances; Availability; Fed. Regist. 2003, 68, 6924– 6925.

//////////5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one

O=C1Nc3ncncc3N(C1)[C@@H](C)CN2CC(=O)NC(=O)C2

Share

Synthesis of (E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline

 spectroscopy, SYNTHESIS, Uncategorized  Comments Off on Synthesis of (E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline
Dec 212016
 

str1

Cas 1204588-48-6
MF C21 H20 N4 O4
MW 392.41
Benzenamine, 2,​4-​dinitro-​N-​[(2E,​4E)​-​4-​phenyl-​5-​(1-​pyrrolidinyl)​-​2,​4-​pentadien-​1-​ylidene]​-​, [N(E)​]​-
(E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline
str1

 

 

Molbank 2009, 2009(3), M604; doi:10.3390/M604

http://www.mdpi.com/1422-8599/2009/3/M604/htm
Synthesis of (E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline
Nosratollah Mahmoodi 1,*, Manuchehr Mamaghani 1, Ali Ghanadzadeh 2, Majid Arvand 3 and Mostafa Fesanghari 1
1Laboratory of Organic Chemistry, Faculty of Science, University of Guilan, P.O.Box 1914, Rasht, Iran,
2Departments of Physical Chemistry, Faculty of Science, University of Guilan, P.O.Box 1914, Rasht, Iran
3Departments of Analytical Chemistry, Faculty of Science, University of Guilan, P.O.Box 1914, Rasht, Iran
*Author to whom correspondence should be addressed
mahmoodi@guilan.ac.ir, m-chem41@guilan.ac.ir, aggilani@guilan.ac.ir, arvand@guilan.ac.ir, nosmahmoodi@gmail.com

Abstract:

(E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene) aniline dye was prepared in one pot by reaction of premade N-2,4-dinitrophenyl-3-phenylpyridinium chloride (DNPPC) and pyrrolidine in absolute MeOH.
Keywords:

N-2,4-dinitrophenyl-3-phenylpyridinium chloride (DNPPC); photochromic; pyridinium salt

N-2,4-Dinitrophenyl-3-phenylpyridinium chloride (DNPPC) 1 was prepared according to the literature method [1,2,3,4,5,6,7]. Recently, we became interested in the synthesis of photochromic compounds [8,9,10]. The UV-Vis spectra under irradiation of UV light of dye 2 indicate photochromic properties for this molecule. The salt 1 was premade and typically isolated and purified by recrystallization and characterized. To a solution of 1-chloro-2,4-dinitrobenzene (1.42 g, 7.01 mmol) in acetone (10 mL) was added 3-phenylpyridine (1.0 mL, 6.97 mmol). The reaction was heated at reflux for 48 h. The solvent was removed under reduced pressure and the red residue was stirred in hexanes. The precipitated product was collected by vacuum filtration to afford pure pyridinium salt 1 as a reddish brown solid (2.23 g, 6.25 mmol, 90%). 1H NMR (CDCl3, 500 MHz): δ (ppm) 9.9 (s, 1H), 9.4 (d, J = 6.0 Hz, 1H), 9.3 (d, J = 8.3 Hz, 1H), 9.2 (d, J = 2.2 Hz, 1H), 9.0 (dd, J = 8.7, 2.4 Hz, 1H), 8.5-8.6 (m, 2H), 8.0 (d, J = 7.3 Hz, 2H), 7.6- 7.7 (m, 3H); 13C NMR (CDCl3, 125 MHz): δ (ppm) 149.2, 145.6, 144.3, 144.2, 143.0, 139.2, 138.7, 132.5, 132.3, 130.6, 130.2, 129.6, 128.0, 127.6, 121.3; IR (KBr pellet) 3202, 3129, 2994, 2901, 1609 cm-1; m. p. = 182-183 °C; HRMS m/z Calcd for C17H12N3O4+ (M)+ 322.0828, found 322.0836.
Molbank 2009 m604 i001
Reaction of pyrrolidine with salt (1) leads to the opening of the pyridinium ring and formation of dye 2. This dye was prepared from reaction of salt 1 (0.5 g, 1.4 mmol) in 5 mL absolute MeOH after cooling a reaction mixture to -10oC and keeping at this temperature for 15 min. To this was added pyrrolidine (0.1 g, 1.4 mmol) in 3 mL absolute MeOH over a period of 10 min. The prepared solid was filtered, washed with CH2Cl2, dried and recrystallized from n-hexane to yield 68% (0.37 g, 0.95 mmol) of pure metallic greenish-brown 2,
m.p. = 146 oC.
IR (KBr): 3040, 2950, 1616, 1514, 1492, 1469, 1321, 1215, 1170, 1105, 956, 904, 862, 727 cm-1.
1H NMR (500 MHz, CDCl3): δ (ppm) 8.7 (d, J = 2.4 Hz, 1H) 8.3 (dd, J = 2.4, 8.84 Hz, 1H), 8.0 (s, 1H), 7.5 (d, J = 7.4 Hz, 2H), 7.4-7.5 (t, J = 7.5 Hz, 2H), 7.3-7.4 (m, 1H), 7.2 (d, J = 12.5 Hz, 1H), 7.1 (d, J = 8.9 Hz, 1H), 7.0 (d, J = 12.1 Hz, 1H), 5.4 (t, J = 12.2 Hz, 1H), 3.3 (br, 4H), 2.0 (br, 4H);
13C NMR (125 MHz, CDCl3): δ (ppm) 22.0, 55.6, 114.7, 117.4, 120.0, 124.1, 126.4, 128.7, 128,8, 129.0, 132.7, 137.1, 137.3, 142.9, 147.8, 150.2, 163.8.
Anal. Calcd for C21H20N4O4: %C = 64.28, %H = 5.14, %N = 14.28. Found: %C = 64.08, %H = 5.11, %N = 14.07.

str1

 

 

1H NMR PREDICT

str0

ACTUAL….

1H NMR (500 MHz, CDCl3): δ (ppm) 8.7 (d, J = 2.4 Hz, 1H) 8.3 (dd, J = 2.4, 8.84 Hz, 1H), 8.0 (s, 1H), 7.5 (d, J = 7.4 Hz, 2H), 7.4-7.5 (t, J = 7.5 Hz, 2H), 7.3-7.4 (m, 1H), 7.2 (d, J = 12.5 Hz, 1H), 7.1 (d, J = 8.9 Hz, 1H), 7.0 (d, J = 12.1 Hz, 1H), 5.4 (t, J = 12.2 Hz, 1H), 3.3 (br, 4H), 2.0 (br, 4H);

str0

 

13 C NMR PREDICT

 

str1

ACTUAL…….13C NMR (125 MHz, CDCl3): δ (ppm) 22.0, 55.6, 114.7, 117.4, 120.0, 124.1, 126.4, 128.7, 128,8, 129.0, 132.7, 137.1, 137.3, 142.9, 147.8, 150.2, 163.8.

str3

////////////Synthesis, (E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline

[O-][N+](=O)c3ccc(\N=C\C=C\C(=C/N1CCCC1)c2ccccc2)c([N+]([O-])=O)c3

Share

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

 spectroscopy, SYNTHESIS, Uncategorized  Comments Off on Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
Dec 202016
 
str1
2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
1-Piperazineacetic acid, 4-(4-chlorophenyl)-α,α-dimethyl-, ethyl ester
2-[4-(4-Chlorophényl)-1-pipérazinyl]-2-méthylpropanoate d‘éthyle
Ethyl 2-[4-(4-chlorophenyl)-1-piperazinyl]-2-methylpropanoate
Ethyl-2-[4-(4-chlorphenyl)-1-piperazinyl]-2-methylpropanoat
1206769-44-9
2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester (en)
AGN-PC-0JIRMK
AKOS016034964
ethyl 2-[4-(4-chlorophenyl)piperazin-1-yl]-2-methylpropanoate
MWt310.819
MFC16H23ClN2O2
Image result for MOM CAN TEACH YOU NMRNMR IS EASY
1H NMR PREDICT
 str0
ACTUAL VALUES……..1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
str1
13C NMR PREDICT
str2
ACTUAL VALUES……..13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
str3
Paper

To a solution of 4-(4-chlorophenyl)piperazine dihydrochloride 1 (5.0 g, 0.0185 mol) in DMSO (30 ml), anhydrous cesium carbonate (30.0 g, 0.0925 mol), sodium iodide (1.39 g, 0.0093 mol) and ethyl 2-bromo-2-methylpropanoate 2 (3.97 g, 0.02 mol) were added. The resulting mixture was stirred at 25-30oC for 12 hours. The reaction mass was diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate (10.0 g) and concentrated under vacuum. The crude product thus obtained was purified by column chromatography (stationary phase silica gel 60-120 mesh; mobile phase 10% ethyl acetate in hexane). The title compound 3 was obtained as a white solid (4.73 g, 82 %).

Molbank 2009 m607 i001
Melting Point: 56oC.
EI-MS m/z (rel. int. %): 311 (100) [M+1]+, 236(40), 197(60), 154(45).
IR ν max (KBr) cm-1: 2839-2996 (C-H aliphatic); 1728 (C=O), 1595, 1505 (C=C aromatic), 1205 (C-O bending), 758 (C-Cl bending).
1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
Elemental analysis: Calculated for C16H23ClN2O2: C, 61.83%, H, 7.46%, N, 9.01%; Found: C, 61.90%, H, 7.44%, N, 8.98%.
Molbank 2009, 2009(3), M607; doi:10.3390/M607
http://www.mdpi.com/1422-8599/2009/3/M607

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

Hari N. Pati 1,* ,Bijay K. Mishra 1 andVijay S. Satam 2
1Department of Chemistry, Sambalpur University, JyotiVihar-768019, Orissa, India
2Institute of Chemical Technology (ICT), Matunga, Mumbai-400019, Maharashtra, India
*Author to whom correspondence should be addressed.
Received: 17 May 2009 / Accepted: 30 June 2009 / Published: 27 July 2009
Bijay K Mishra

Professor at Sambalpur University, Chemistry Department

Abstract

The title compound was synthesized by N-alkylation of 4-(4-chlorophenyl)piperazine with ethyl 2-bromo-2-methylpropanoate and its IR, 1H NMR, 13C NMR and Mass spectroscopic data are reported.

Keywords: 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropionic acid; N-alkylation; 4-(4-Chlorophenyl)piperazine

 

/////////

CCOC(=O)C(N1CCN(CC1)c1ccc(cc1)Cl)(C)C

Share

Citarinostat

 phase 1  Comments Off on Citarinostat
Dec 192016
 

2D chemical structure of 1316215-12-9

str0

Citarinostat

Treatment of Hematological Malignancies, 

Molecular Formula, C24-H26-Cl-N5-O3, Molecular Weight, 467.9544,
RN: 1316215-12-9
UNII: 441P620G3P

  • 2-[(2-Chlorophenyl)phenylamino]-N-[7-(hydroxyamino)-7-oxoheptyl]-5-pyrimidinecarboxamide

2-((2-Chlorophenyl)phenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-5-pyrimidinecarboxamide

5-Pyrimidinecarboxamide, 2-((2-chlorophenyl)phenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-

ACY-241; HDAC-IN-2

Histone deacetylase-6 inhibitor

Acute myelogenous leukemia; Cancer; Mantle cell lymphoma; Multiple myeloma

Image result for ACY 241

  • Mechanism of ActionHDAC6 protein inhibitors

Highest Development Phases

  • Phase IIMultiple myeloma
  • Phase IMalignant melanoma; Non-small cell lung cancer; Solid tumours

Most Recent Events

  • 12 Dec 2016Chemical structure information added
  • 04 Dec 2016Efficacy and safety data from a phase Ia/Ib clinical trial in Multiple myeloma released by Acetylon
  • 03 Jun 2016Phase-II clinical trials in Multiple myeloma in USA (PO)

In December 2016, citarinostat was reported to be in phase 1 clinical development. The drug appears to be first disclosed in WO2011091213, claiming reverse amide derivatives as HDAC-6 inhibitors useful for treating multiple myeloma, Alzheimers disease and psoriasis.

HDAC-IN-2.png

Duzer John H. Van, Ralph Mazitschek, Walter Ogier, James Elliott Bradner, Guoxiang Huang, Dejian Xie, Nan Yu, Less «
Applicant Acetylon Pharmaceuticals

 

The identification of small organic molecules that affect specific biological functions is an endeavor that impacts both biology and medicine. Such molecules are useful as therapeutic agents and as probes of biological function. Such small molecules have been useful at elucidating signal transduction pathways by acting as chemical protein knockouts, thereby causing a loss of protein function. (Schreiber et al, J. Am. Chem. Soc, 1990, 112, 5583; Mitchison, Chem. and Biol., 1994, 15 3) Additionally, due to the interaction of these small molecules with particular biological targets and their ability to affect specific biological function (e.g. gene transcription), they may also serve as candidates for the development of new therapeutics.

One biological target of recent interest is histone deacetylase (HDAC) (see, for example, a discussion of the use of inhibitors of histone deacetylases for the treatment of cancer: Marks et al. Nature Reviews Cancer 2001, 7,194; Johnstone et al. Nature Reviews Drug Discovery 2002, 287). Post-translational modification of proteins through acetylation and deacetylation of lysine residues plays a critical role in regulating their cellular functions. HDACs are zinc hydrolases that modulate gene expression through deacetylation of the N-acetyl-lysine residues of histone proteins and other transcriptional regulators (Hassig et al Curr. Opin. Chem. Biol. 1997, 1, 300-308). HDACs participate in cellular pathways that control cell shape and differentiation, and an HDAC inhibitor has been shown effective in treating an otherwise recalcitrant cancer (Warrell et al J. Natl. Cancer Inst. 1998, 90, 1621-1625). At this time, eleven human HDACs, which use Zn as a cofactor, have been identified (Taunton et al. Science 1996, 272, 408-411 ; Yang et al. J. Biol. Chem. 1997, 272, 28001-28007. Grozinger et al. Proc. Natl. Acad. Sd. U.S.A. 1999, 96, 4868-4873; Kao et al. Genes Dev. 2000, 14, 55-66. Hu et al J. Biol. Chem. 2000, 275, 15254-15264; Zhou et al. Proc. Natl. Acad. Scl U.S.A. 2001, 98, 10572-10577; Venter et al. Science 2001, 291, 1304-1351) these members fall into three classes (class I, II, and IV). An additional seven HDACs h ave been identified which use NAD as a cofactor. To date, no small molecules are known that selectively target any particular class or individual members of this family ((for example ortholog- selective HDAC inhibitors have been reported: (a) Meinke et al. J. Med. Chem. 2000, 14, 4919-4922; (b) Meinke, et al Curr. Med. Chem. 2001, 8, 211-235). There remains a need for preparing structurally diverse HDAC and tubulin deacetylase (TDAC) inhibitors particularly ones that are potent and/or selective inhibitors of particular classes of HDACs or TDACs and individual HDACs and TDACs.

Recently, a cytoplasmic histone deacetylase protein, HDAC6, was identified as necessary for aggresome formation and for survival of cells following ubiquitinated misfolded protein stress. The aggresome is an integral component of survival in cancer cells. The mechanism of HDAC6-mediated aggresome formation is a consequence of the catalytic activity of the carboxy-terminal deacetylase domain, targeting an uncharacterized non-histone target. The present invention also provides small molecule inhibitors of HDAC6. In certain embodiments, these new compounds are potent and selective inhibitors of HDAC6.

The aggresome was first described in 1998, when it was reported that there was an appearance of microtubule-associated perinuclear inclusion bodies in cells over- expressing the pathologic AF508 allele of the cystic fibrosis transmembrane conductance receptor (CFTR). Subsequent reports identified a pathologic appearance of the aggresome with over-expressed presenilin-1 (Johnston JA, et al. J Cell Biol. 1998;143:1883-1898), parkin (Junn E, et al. J Biol Chem. 2002; 277: 47870-47877), peripheral myelin protein PMP22 (Notterpek L, et al. Neurobiol Dis. 1999; 6: 450-460), influenza virus nucleoprotein (Anton LC, et al. J Cell Biol. 1999;146:113-124), a chimera of GFP and the membrane transport protein pi 15 (Garcia- Mata R, et al. J Cell Biol. 1999; 146: 1239-1254) and notably amyloidogenic light chains (Dul JL, et al. J Cell Biol. 2001;152:705-716). Model systems have been established to study ubiquitinated (AF508 CFTR) (Johnston JA, et al. J Cell Biol. 1998;143:1883-1898) and non-ubiquitinated (GFP -250) (Garcia-Mata R, et al. J Cell Biol. 1999;146:1239-1254) protein aggregate transport to the aggresome. Secretory, mutated, and wild-type proteins may assume unstable kinetic intermediates resulting in stable aggregates incapable of degradation through the narrow channel of the 26S proteasome. These complexes undergo active, retrograde transport by dynein to the pericentriolar aggresome, mediated in part by a cytoplasmic histone deacetylase, HDAC6 (Kawaguchi Y, et al. Cell. 2003;1 15:727-738).

Histone deacetylases are a family of at least 11 zinc -binding hydrolases, which

catalyze the deacetylation of lysine residues on histone proteins. HDAC inhibition results in hyperacetylation of chromatin, alterations in transcription, growth arrest, and apoptosis in cancer cell lines. Early phase clinical trials with available nonselective HDAC inhibitors demonstrate responses in hematologic malignancies including multiple myeloma, although with significant toxicity. Of note, in vitro synergy of conventional chemotherapy agents (such as melphalan) with bortezomib has been reported in myeloma cell lines, though dual proteasome-aggresome inhibition was not proposed. Until recently selective HDAC inhibitors have not been realized.

HDAC6 is required for aggresome formation with ubiquitinated protein stress and is essential for cellular viability in this context. HDAC6 is believed to bind ubiquitinated proteins through a zinc finger domain and interacts with the dynein motor complex through another discrete binding motif. HDAC6 possesses two catalytic deacetylase domains. It is not presently known whether the amino-terminal histone deacetylase or the carboxy-terminal tubulin deacetylase (TDAC) domain mediates aggresome formation.

Aberrant protein catabolism is a hallmark of cancer, and is implicated in the stabilization of oncogenic proteins and the degradation of tumor suppressors (Adams J. Nat Rev Cancer. 2004;4:349-360). Tumor necrosis factor alpha induced activation of nuclear factor kappa B (NFKB) is a relevant example, mediated by NFKB inhibitor beta (1KB) proteolytic degradation in malignant plasma cells. The inhibition of 1KB catabolism by proteasome inhibitors explains, in part, the apoptotic growth arrest of treated myeloma cells (Hideshima T, et al. Cancer Res. 2001;61:3071-3076). Multiple myeloma is an ideal system for studying the mechanisms of protein degradation in cancer. Since William Russell in 1890, cytoplasmic inclusions have been regarded as a defining histological feature of malignant plasma cells. Though the precise composition of Russell bodies is not known, they are regarded as ER-derived vesicles containing aggregates of monotypic immunoglobulins

(Kopito RR, Sitia R. EMBO Rep. 2000; 1 :225-231) and stain positive for ubiquitin (Manetto V, et al. Am J Pathol. 1989;134:505-513). Russell bodies have been described with CFTR over-expression in yeast (Sullivan ML, et al. J. Histochem. Cytochem. 2003;51 :545-548), thus raising the suspicion that these structures may be linked to overwhelmed protein catabolism, and potentially the aggresome. The role of the aggresome in cancer remains undefined.

Aberrant histone deacetylase activity has also been linked to various neurological and neurodegenerative disorders, including stroke, Huntington’s disease, Amyotrophic Lateral Sclerosis and Alzheimer’s disease. HDAC inhibition may induce the expression of antimitotic and anti-apoptotic genes, such as p21 and HSP-70, which facilitate survival. HDAC inhibitors can act on other neural cell types in the central nervous system, such as reactive astrocytes and microglia, to reduce inflammation and secondary damage during neuronal injury or disease. HDAC inhibition is a promising therapeutic approach for the treatment of a range of central nervous system disorders (Langley B et al., 2005, Current Drug Targets— CNS & Neurological Disorders, 4: 41-50).

Histone deacetylase is known to play an essential role in the transcriptional machinery for regulating gene expression, induce histone hyperacetylation and to affect the gene expression. Therefore, it is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression such as inflammatory disorders, diabetes, diabetic

complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections, tumors, etc.

Thus, there remains a need for the development of novel inhibitors of histone deacetylases and tubulin histone deacetylases. In particular, inhibitors that are more potent and/or more specific for their particular target than known HDAC and TDAC inhibitors. HDAC inhibitors specific for a certain class or member of the HDAC family would be particularly useful both in the treatment of proliferative diseases and protein deposition disorders and in the study of HDACs, particularly HDAC6. Inhibitors that are specific for HDAC versus TDAC and vice versa are also useful in treating disease and probing biological pathways. The present invention provides novel compounds, pharmaceutical compositions thereof, and methods of using these compounds to treat disorders related to HDAC6 including cancers, inflammatory, autoimmune, neurological and neurodegenerative disorders

Image result for ACY 241

Rocilinostat (ACY-1215)

Image result for ACY 241

PATENT

WO2011091213

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011091213

Patent

US20160355486

WO 2013013113

WO 2015061684

WO 2015054474

US 20150099744

PATENT

CITARINOSTAT BY ACTYLON

WO-2016200919

Crystalline forms of a histone deacetylase inhibitor

Novel crystalline polymorphic forms of citarinostat, useful for treating cancer, eg multiple myeloma, mantle cell lymphoma or acute myelogenous leukemia. Also claims a method for preparing the crystalline form of citarinostat. Acetylon is developing citarinostat, a next generation selective inhibitor of HDAC6, for treating multiple myeloma and solid tumors, including melanoma.

Provided herein are crystalline forms of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide (CAS No. 1316215-12-9), shown as Compound (I) (and referred to herein as “Compound (I)”):

Compound (I) is disclosed in International Patent Application No.

PCT/US2011/021982 and U.S. Patent No. 8,609,678, the entire contents of which are incorporated herein by reference.

Accordingly, provided herein are crystalline forms of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide. In particular, provided herein are the following crystalline forms of Compound (I): Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, and Form IX. Each of these forms have been characterized by XRPD analysis. In an embodiment, the crystalline form of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide can be a hydrate or solvate (e.g., dichloromethane or methanol).

EXAMPLES

Example 1: Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7- oxoheptyl)pyrimidine-5-carboxamide (Compound (I))

I. Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide:

Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), compound 1 (7.5 g, 40 mmol), and K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to r.t. and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml χ 3). The organic layers were separated and dried over Na2S04, evaporated to dryness and purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).

Synthesis of Intermediate 3: A mixture of compound 2 (6.2 g, 25 mmol), iodobenzene (6.12 g, 30 mmol), Cul (955 mg, 5.0 mmol), Cs2C03 (16.3 g, 50 mmol) in TEOS (200 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 14 hrs. After cooling to r.t., the residue was diluted with EtOAc (200 ml). 95% EtOH (200 ml) and H4F-H20 on silica gel [50g, pre-prepared by the addition of H4F (lOOg) in water (1500 ml) to silica gel (500g, 100-200 mesh)] was added, and the resulting mixture was kept at r.t. for 2 hrs. The solidified materials were filtered and washed with EtOAc. The filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give a yellow solid (3 g, 38%).

Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2 χ 200 ml), and the organic layers were separated, washed with water (2 χ 100 ml), brine (2 χ 100 ml), and dried over Na2S04. Removal of the solvent gave a brown solid (2.5 g, 92 %).

Synthesis of Intermediate 6: A mixture of compound 4 (2.5 g, 8.58 mmol), compound 5 (2.52 g, 12.87 mmol), HATU (3.91 g, 10.30 mmol), and DIPEA (4.43 g, 34.32 mmol) was stirred at r.t. overnight. After the reaction mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 2/1) to give a brown solid (2 g, 54 %).

Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for 10 min. Hydroxylamine (50%) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48%).

II. Synthetic Route 1 : 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptvDpyrimidine-5-carboxamide

Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), ethyl 2-chloropyrimidine-5-carboxylate 1 (7.5 g, 40 mmol), K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to rt and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml x 3). The organic layer was separated and dried over Na2S04, evaporated to dryness and purified by silica gel

chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).

Synthesis of Intermediate 3: A mixture of compound 2 (69.2 g, 1 equiv.), l-chloro-2-iodobenzene (135.7 g, 2 equiv.), Li2C03 (42.04 g, 2 equiv.), K2C03 (39.32 g, 1 equiv.), Cu (1 equiv. 45 μπι) in DMSO (690 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 36 hours. Work-up of the reaction gave compound 3 at 93 % yield.

Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of the compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HC1 to give a white precipitate. The suspension was extracted with EtOAc (2 x 200 ml), and the organic layer was separated, washed with water (2 x 100 ml), brine (2 x 100 ml), and dried over Na2S04. Removal of solvent gave a brown solid (2.5 g, 92 %).

Synthesis of Intermediate 5: A procedure analogous to the Synthesis of Intermediate 6 in Part I of this Example was used.

Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A procedure analogous to the Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide in Part I of this Example was used.

III. Synthetic Route 2: 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide

(I)

Step (1): Synthesis of Compound 11: Ethyl 2-chloropyrimidine-5-carboxylate (7.0 Kgs), ethanol (60 Kgs), 2-Chloroaniline (9.5 Kgs, 2 eq) and acetic acid (3.7 Kgs, 1.6 eq) were charged to a reactor under inert atmosphere. The mixture was heated to reflux. After at least 5 hours the reaction was sampled for HPLC analysis (method TM-113.1016). When analysis indicated reaction completion, the mixture was cooled to 70 ± 5 °C and N,N-Diisopropylethylamine (DIPEA) was added. The reaction was then cooled to 20 ± 5°C and the mixture was stirred for an additional 2-6 hours. The resulting precipitate is filtered and washed with ethanol (2 x 6 Kgs) and heptane (24 Kgs). The cake is dried under reduced pressure at 50 ± 5 °C to a constant weight to produce 8.4 Kgs compound 11 (81% yield and 99.9% purity.

Step (2): Synthesis of Compound 3: Copper powder (0.68 Kgs, 1 eq, <75 micron), potassium carbonate (4.3 Kgs, 1.7 eq), and dimethyl sulfoxide (DMSO, 12.3 Kgs) were added to a reactor (vessel A). The resulting solution was heated to 120 ± 5°C. In a separate reactor (vessel B), a solution of compound 11 (2.9 Kgs) and iodobenzene (4.3 Kgs, 2 eq) in DMSO (5.6 Kgs) was heated at 40 ± 5°C. The mixture was then transferred to vessel A over 2-3 hours. The reaction mixture was heated at 120 ± 5°C for 8-24 hours, until HPLC analysis (method TM-113.942) determined that < 1% compound 11 was remaining.

Step (3): Synthesis of Compound 4: The mixture of Step (2) was cooled to 90-100 °C and purified water (59 Kgs) was added. The reaction mixture was stirred at 90-100 °C for 2-8 hours until HPLC showed that <1% compound 3 was remaining. The reactor was cooled to 25 °C. The reaction mixture was filtered through Celite, then a 0.2 micron filter, and the filtrate was collected. The filtrate was extracted with methyl t-butyl ether twice (2 x 12.8 Kgs). The aqueous layer was cooled to 0-5 °C, then acidified with 6N hydrochloric acid (HC1) to pH 2-3 while keeping the temperature < 25°C. The reaction was then cooled to 5-15 °C. The precipitate was filtered and washed with cold water. The cake was dried at 45-55 °C under reduced pressure to constant weight to obtain 2.2 kg (65% yield) compound 4 in 90.3% AUC purity.

Step (4): Synthesis of Compound 5: Dichloromethane (40.3 Kgs), DMF (33g, 0.04 eq) and compound 4 (2.3 Kg) were charged to a reaction flask. The solution was filtered through a 0.2 μπι filter and was returned to the flask. Oxalyl chloride (0.9 Kgs, 1 eq) was added via addition funnel over 30-120 minutes at < 30 °C. The batch was then stirred at < 30°C until reaction completion (compound 4 <3 %) was confirmed by HPLC (method TM-113.946. Next, the dichloromethane solution was concentrated and residual oxalyl chloride was removed under reduced pressure at < 40 °C. When HPLC analysis indicated that < 0.10% oxalyl chloride was remaining, the concentrate was dissolved in fresh dichloromethane (24 Kgs) and transferred back to the reaction vessel (Vessel A).

A second vessel (Vessel B) was charged with Methyl 7-aminoheptanoate

hydrochloride (Compound Al, 1.5 Kgs, 1.09 eq), DIPEA (2.5 Kgs, 2.7 eq), 4

(Dimethylamino)pyridine (DMAP, 42g, 0.05 eq), and DCM (47.6 Kgs). The mixture was cooled to 0-10 °C and the acid chloride solution in Vessel A was transferred to Vessel B while maintaining the temperature at 5 °C to 10 °C. The reaction is stirred at 5-10 °C for 3 to 24 hours at which point HPLC analysis indicated reaction completion (method TM-113.946, compound 4 <5%). The mixture was then extracted with a 1M HC1 solution (20 Kgs), purified water (20 Kgs), 7% sodium bicarbonate (20 Kgs), purified water (20 Kgs), and 25% sodium chloride solution (20 Kgs). The dichloromethane was then vacuumdistilled at < 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that <1 mol% DCM was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (6.4 Kgs). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 2.2 Kgs (77% yield) was isolated in 95.9% AUC purity method and 99.9 wt %.

Step (5): Synthesis of Compound (I): Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 °C and 25% sodium methoxide (11.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 °C. Once the addition was complete, the reaction was mixed at 20 °C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5°C.

Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-113.964, compound 5 < 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 – 9 using 6N HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/ Pattern D.

The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IP A, 27.1 Kg). The slurry was heated to 75±5 °C to dissolve the solids. The solution was seeded with crystals of Compound (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at 45-55°C to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) (Form I/Pattern A) in 85% yield and 99.5% purity (AUC%, HPLC method TM-113.941).

HPLC Method 113.941

Column Zorbax Eclipse XDB-C18, 4.6 mm x 150 mm, 3.5 μπι

Column Temperature 40°C

UV Detection Wavelength Bandwidth 4 nm, Reference off, 272 nm

Flow rate 1.0 mL/min

Injection Volume 10 μΐ. with needle wash

Mobile Phase A 0.05% trifluoroacetic acid (TFA) in purified water

Mobile Phase B 0.04% TFA in acetonitrile

Data Collection 40.0 min

Run Time 46.0 min

Gradient Time (min) Mobile Phase A Mobile Phase B

0.0 98% 2%

36.0 0% 100%

40.0 0% 100%

40.1 98% 2%

46.0 98% 2%

Example 2: Summary of Results and Analytical Techniques

Table 1. Summary of the Isolated Crystalline Forms of Compound (I)

Patent ID Patent Title Submitted Date Granted Date
US2016030458 TREATMENT OF LEUKEMIA WITH HISTONE DEACETYLASE INHIBITORS 2015-07-06 2016-02-04
US2015176076 HISTONE DEACETYLASE 6 (HDAC6) BIOMARKERS IN MULTIPLE MYELOMA 2014-12-19 2015-06-25
US2015150871 COMBINATIONS OF HISTONE DEACETYLASE INHIBITORS AND IMMUNOMODULATORY DRUGS 2014-12-03 2015-06-04
US2015119413 TREATMENT OF POLYCYSTIC DISEASES WITH AN HDAC6 INHIBITOR 2014-10-24 2015-04-30
US2015105358 COMBINATIONS OF HISTONE DEACETYLASE INHIBITORS AND IMMUNOMODULATORY DRUGS 2014-10-07 2015-04-16
US2015105383 HDAC Inhibitors, Alone Or In Combination With PI3K Inhibitors, For Treating Non-Hodgkin’s Lymphoma 2014-10-08 2015-04-16
US2015105384 PYRIMIDINE HYDROXY AMIDE COMPOUNDS AS HISTONE DEACETYLASE INHIBITORS 2014-10-09 2015-04-16
US2015105409 HDAC INHIBITORS, ALONE OR IN COMBINATION WITH BTK INHIBITORS, FOR TREATING NONHODGKIN’S LYMPHOMA 2014-10-07 2015-04-16
US2015099744 COMBINATIONS OF HISTONE DEACETYLASE INHIBITORS AND EITHER HER2 INHIBITORS OR PI3K INHIBITORS 2014-10-06 2015-04-09
US2015045380 REVERSE AMIDE COMPOUNDS AS PROTEIN DEACETYLASE INHIBITORS AND METHODS OF USE THEREOF 2014-10-22 2015-02-12
Patent ID Patent Title Submitted Date Granted Date
US2014378385 Histone Deacetylase 6 Selective Inhibitors for the Treatment of Bone Disease 2012-07-20 2014-12-25
US2014142117 REVERSE AMIDE COMPOUNDS AS PROTEIN DEACETYLASE INHIBITORS AND METHODS OF USE THEREOF 2013-11-11 2014-05-22
US8609678 Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof 2012-04-02 2013-12-17
US8148526 Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof 2011-12-02 2012-04-03
US2011300134 REVERSE AMIDE COMPOUNDS AS PROTEIN DEACETYLASE INHIBITORS AND METHODS OF USE THEREOF 2011-12-08

 

Acetylon Crafts New Buyout Deal With Celgene, Spins Out Startup Regenacy

Acetylon Crafts New Buyout Deal With Celgene, Spins Out Startup Regenacy

December 2nd, 2016

Earlier this year, Celgene passed on an exclusive option to buy Acetylon Pharmaceuticals. But surprisingly, the two companies have come up with a new deal instead. Celgene agreed Friday to acquire just a portion of the assets of the Boston company, which will spin the rest of its assets into a new startup called Regenacy Pharmaceuticals.

In the deal, Summit, NJ-based Celgene (NASDAQ: CELG) will get partial rights to two drug candidates developed by Acetylon: citarinostat (also known as ACY-241), and ricolinostat (ACY-1215). Specifically, Celgene will get worldwide rights to develop both drugs for cancer, neurodegenerative diseases, and autoimmune diseases, but nothing else.

Regenacy meanwhile, will also have partial rights to these two drugs, but only for other disease types, such as nerve pain. It also gets access to other preclinical drugs Acetylon has been developing for blood diseases like sickle cell disease and beta-thalassemia.

[Updated w/comments from CEO] Acetylon CEO Walter Ogier—who will be the president and CEO of Regenacy—said via e-mail that Celgene was only interested in the parts of Acetylon that fit with its current portfolio. Acetylon’s shareholders and executives, meanwhile, wanted to push the rest of the company’s experimental products forward. So the two companies let the original deal expire and came up with the new transaction.

“The remaining assets are exciting enough to create a new company to advance,” Ogier said.

Other “key members” of Acetylon’s executive team will switch over to the new company as well, according to the announcement. Ogier said Regenacy has acquired Acetylon’s remaining cash in the deal—he didn’t say how much—to get itself started.

Both citarinostat and ricolinostat interfere with what are known as histone deacetylases (HDACs), enzymes that help regulate gene expression and are implicated in a number of cancers. HDACs are a well-known molecular target, but Acetylon’s drugs are part of a newer breed of HDAC-blocking agents meant to be more precise, and thus less toxic, than their predecessors. Acetylon’s lead drug ricolinostat, for instance, is meant to block only the specific enzyme HDAC6. Citarinostat is a pill version of ricolinostat,

With Celgene’s help, Acetylon has been developing these drugs as potential treatments for breast cancer and the blood cancer multiple myeloma. It has been testing the drug in combination with Celgene’s own experimental drugs, like the myeloma drug pomalidomide (Pomalyst) and the breast cancer drug nab-paclitaxel (Abraxane).

[Updated w/CEO comments] Citarinostat, for instance, is being tested as a multiple myeloma treatment in a Phase 1b trial in combination with pomalidamide and dexamethasome in multiple myeloma. Acetylon and Celgene just reported early data at the American Society of Hematology’s annual meeting. Ricolinostat is in a mid-stage study in multiple myeloma as well as several investigator-sponsored studies in lymphoma, chronic lymphocytic leukemia, and ovarian and breast cancer, according to Ogier.

Regenacy will take ricolinostat into a Phase 2 trial in peripheral neuropathy next year, he says.

The two companies aren’t disclosing the terms of the deal. Co-founder and chairman Marc Cohen said in a statement that the deal is a “favorable outcome” for Acetylon’s shareholders—an unusual mix of private financiers, non-profits, public companies, and federal grant sources including Celgene itself, Kraft Group (the holding company founded by New England Patriots owner Robert Kraft), Cohen, and the Leukemia & Lymphoma Society. (All of those shareholders aside from Celgene will be the owners of Regenacy.)

But it’s a different outcome than Acetylon and Celgene anticipated when they signed a broad deal in 2013. At that time, Celgene paid Acetylon $100 million for the option to buy it outright for at least an additional $500 million (the actual price was to be tied to an independent valuation). The deal included another $1.1 billion in “bio-bucks,” future payments tied to clinical progress that may or may not materialize. All told, that meant the Celgene deal could have been worth $1.7 billion to Acetylon and its shareholders. Acetylon raised $55 million from shareholders before it struck that deal with Celgene.

Celgene extended its partnership with Acetylon in the summer of 2015, but that included a contingency that the relationship would end in May 2016 if it didn’t buy Acetylon. A regulatory filing in July showed that’s exactly what happened: the collaboration between the two companies ended this year, and that Celgene was no longer on the hook for any future payments related to 2013 deal.

Though that deal is now history, Acetylon shareholders were at least able to generate some type of return—and take another shot on some of the same assets. Ogier said these shareholders have “ample capacity” to make further investments in Regenacy, though the company will try to find new partners to help move its programs forward as well.

“We are excited to continue Acetylon’s legacy through the receipt of rights to many of Acetylon’s most promising compounds and the continued advancement of these clinical and preclinical programs in disease indications outside of Celgene’s areas of strategic focus, where we believe patients may especially benefit from selective HDAC inhibition,” he said in a statement.

REFERENCES

http://www.acetylon.com/docs/ACE-MM-200_Poster_Final%20Draft.pdf

References:
[1].  Quayle SN, Almeciga-Pinto I, Tamang D, et al. Selective HDAC inhibition by ricolinostat (ACY-1215) or ACY-241 synergizes with IMiD® immunomodulatory drugs in Multiple Myeloma (MM) and Mantle Cell Lymphoma (MCL) cells. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, 2015, Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5380.
[2].  Huang P, Almeciga-Pinto I, Jordan M, et al. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. In: Proceedings of the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, Massachusetts. Philadelphia (PA): AACR

NMR

str0

HPLC

str0

////////////ACY-241,  HDAC-IN-2, PHASE 1, CITARINOSTAT, 1316215-12-9

ONC(=O)CCCCCCNC(=O)c1cnc(nc1)N(c2ccccc2)c3ccccc3Cl

Share

How to Extend the Life of a Patent

 PATENTS  Comments Off on How to Extend the Life of a Patent
Dec 182016
 

Image result for WIKI HOW

ALL CREDIT TO WIKIHOW

How to Extend the Life of a Patent

Three Methods:

Determining Eligibility

Extending Your Patent

Contacting Congress

A patent ensures that an inventor is able to profit from his or her invention by preventing others from making, using, selling, or importing it without consent. Once the patent expires, the invention is free for the public to use without paying you. If you meet certain requirements, you may wish to extend your patent.Take advantage of this opportunity to have extra time added to your patent term and keep your invention out of the public domain longer.

1

Determining EligibilityImage titled Get a Patent Step 3

  1. Determine the status of your patent. The United States Patent and Trademark Office (USPTO) keeps a website database of patent information. Access the USPTO database to check on your patent status. If you can’t find all the information you are looking for in the text-based display, then look at the patent image in PDF format.

    • You can also look up European patents here.
    • Or check Google Patents.
    • Patents cannot be renewed and you can’t get the rights to an expired patent. [1]
  2. Image titled Patent an Idea Step 7
    Know what kind of patent you have. In the US, 2 main types of patents are given: utility patents or design patents. Utility patents cover the function of an invention and design patents protect the way an invention looks. Utility patents generally last 20 years, while design patents last 14 years or 15 years for those filed on or after May 13, 2015. There are also 20 year long plant patents for inventors who asexually reproduce a newly discovered or invented variety of plant.[2]
  3. Image titled Do Research Step 14
    Find out if you qualify. Patent extensions are sometimes granted if there are government regulatory delays or if newer laws extend the length of a patent. Sometimes, with very strong justification, you can try to get Congress to pass a bill to extend your patent. If you fall into one of these categories, then you may be able to get your patent extended.
  4. Image titled Interrogate Someone Step 16
    Be aware that extensions may not be an option. For most inventions, the given term for your patent will stand. Recognize that you may not be able to extend your patent for this particular invention. Focus, instead, on developing a new invention that you can then get a new patent for.
 2
Extending Your Patent
  1. Image titled Calculate Profit Step 12
    Get a term adjustment. If you filed your patent after May 29, 2000 and your patent was delayed because the USPTO was taking longer than normal to process the paperwork, you may be eligible to file for an extension. The extension will cover the time lost from your patent term for the delay. The length of the extension you are approved for will depend on the delay time frame, but will not be longer than 5 years.
  2. Image titled Buy a Stock Without a Stockbroker Step 5
    Increase your original patent term. If you were initially granted less time than later legislation allows, you may be eligible to request an extension on your patent for the newer patent term. Under the Uruguay Rounds Agreements Act, utility patents granted before June of 1995 may be given an extension to 20 years instead of the original 17 years. This does not apply to design patents.
  3. Image titled Be a Successful Entrepreneur Step 2
    Get an extension under the Hatch-Waxman Act. A patent term restoration under the Hatch-Waxman Act is sometimes given to those who qualify.This applies to those whose products or processes, such as medications, medical devices, food and color additives, require testing and approval by the Food and Drug Administration’s (FDA) before they can be marketed. The period of time that you were unable to sell your product because you were awaiting FDA approval may be restored as an extension to the original patent. [3]
  4. Image titled Patent an Idea Step 11

    File for an extension with the United States Patent and Trademark Office (USPTO). All application forms for patent extensions can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Know that there are filing fees associated with this application.The process for filing for the extension depends upon which reason for extension the patent falls under.

    • Generally, the application for extension must be in writing, include the identifying information for the patent, information about why the applicant is entitled to an extension, relevant dates to determine the length of the extension, copies of the patent documents, etc.
    • Be sure to check with the USPTO for the exact amount of the fee (around $1,000) and the proper procedure for requesting the extension for your case.
  5. Image titled Delegate Step 11
    Wait to hear back from the USPTO. It can take up to several months for the USPTO to process your request. As with any government process, patience is best. If you are eligible and have a good reason for an extension, then there’s a chance you could be approved so waiting is worth it.
  6. Image titled Get a Patent Step 9

    Request an administrative hearing. If your extension request is denied, you have the right to appeal your denied request. Appeal forms can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Reasons for denial include defects in the paperwork you submitted to the USPTO asking for the extension and your invention being ineligible for extension. File an appeal and address any of the issues that your extension was denied in your written appeal.

    • The appeals process begins with your Notice of Appeal and fee payment. It will continue through various steps until it reaches the Patent Trial and Appeal Board. The board will make a decision on your case and complete the appeals process.
  7. Image titled Announce Your Retirement Step 3
    Meet with an intellectual property lawyer. It could be very beneficial to consult with an attorney to review your options, especially if your request is denied. Your lawyer may be able to offer suggestions and ways to supplement your application. Filing for a patent extension can be complex and your lawyer can ensure that it is done correctly.
 3

Contacting Congress

  1. Image titled Develop Critical Thinking Skills Step 18

    Be realistic. This is the least common form of attempting to extend a patent. Congress may not grant your request unless you have very convincing evidence for doing so. You also may need strong support from the community or a special interest group with persuasive lobbyists on your side.

    • Congress extended the copyright of works to 95 years over the original 75 in 1998. This was due mainly to influential corporations like the Walt Disney Company lobbying for the modification.[4] Keep the kind of influence you may require in mind when you decide to send a bill requesting a patent extension through Congress on your behalf.
  2. Image titled Get a Job Fast Step 1
    Find a representative. Do some research on representatives in your area or someone you think would want to sponsor you in extending your patent. You will need to convince him or her that there is a very important reason you must extend your patent. It is best if they have a record of supporting the type of invention you have or are connected in some way to that field.
    • Only a member of Congress can propose private legislation to the legislative body.
  3. Image titled Do Research Step 10
    Draft a bill. It’s a good idea to do as much of the legwork as possible before approaching your representative. Your bill should be written in legal language and go over the reasons your patent should be granted an extension. You can check existing bills on the Congress website to get an idea what a bill looks like. It might be helpful to consult with a patent attorney when you’re writing this as legalese can be difficult to master.[5]
    • Create a preamble. This is an introduction and general overview about your patent, the date it will expire and an explanation of why you need an extension on your patent.
    • Write up a body clause. This is the meat of your biIl and contains clauses that show what action needs to be taken—in this case, you want your patent to be extended.
    • Finish with an enactment clause. This tells when you want the bill to take effect. This will be the day your patent is due to expire.
    • Know that bills which need to take effect in 90 days or less will need 2/3 majority vote, while those that take effect after that time period will only require a majority vote. Send your bill in as early as possible.[6]
  4. Image titled Write a Grant Proposal Step 22
    Submit your bill to your potential sponsor. Contact your representative by phone or email. Many have websites where you can fill out a form to submit your case. Be sure to ask what the process is like and when you can expect to hear back.
  5. Image titled Communicate Effectively Step 9
    Get a lobbyist to represent you. If your patent is important to certain groups or not extending it could cause harm, then look for someone with contacts to represent you. Lobbyist groups can put pressure on Congress to extend your patent. In order to do this, you need to have a good cause with far-reaching effects if your patent is not extended.
  6. Image titled Excel in a Retail Job Step 2
    Be patient. The legislative process can take time. It must go through multiple committees before the house will vote on it. After that, it must be signed in. The length of time this will take varies and is something you should discuss with your sponsor.
Tips
  • It is best to file for an extension as soon as possible, as the USPTO generally takes months to process most filings.
 Warnings
  • The request for patent extension should be made 3 months prior to the date on which the patent is set to expire.

Sources and Citations

  1. ↑ http://www.bpmlegal.com/patqa.html#2
  2. ↑ http://www.uspto.gov/patents-getting-started/patent-basics/types-patent-applications/general-information-about-35-usc-161
  3. ↑ http://corporate.findlaw.com/intellectual-property/patent-term-extensions-and-restoration-under-the-hatch-waxman-act.html#sthash.xuVfZJXF.dpuf
Share

Selection and justification of starting materials: new Questions and Answers to ICH Q11 published

 regulatory  Comments Off on Selection and justification of starting materials: new Questions and Answers to ICH Q11 published
Dec 082016
 

 

The ICH Q11 Guideline describing approaches to developing and understanding the manufacturing process of drug substances was finalised in May 2012. Since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experience has shown that there is some need for clarification. Thus the Q11 Implementation Working Group recently issued a Questions and Answers Document.

http://www.gmp-compliance.org/enews_05688_Selection-and-justification-of-starting-materials-new-Questions-and-Answers-to-ICH-Q11-published_15619,15868,S-WKS_n.html

str0

The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.

On 30 November 2016 the ICH published a Questions and Answers document “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)” which was developed by the Q11 Implementation Working Group. This document aims at addressing the most important ambiguities with respect to starting materials and at promoting a harmonised approach for their selection and justification as well as the information that should be provided in marketing authorisation applications and/or Drug Master Files.

In the following some examples of questions and answers from this document:

Question:
ICH Q11 states that “A starting material is incorporated as a significant structural fragment into the structure of the drug substance.” Why then are intermediates used late in the synthesis, which clearly contain significant structural fragments, often not acceptable as starting materials?

Answer:
The selection principle about “significant structural fragment” has frequently been misinterpreted as meaning that the proposed starting material should be structurally similar to the drug substance. However, as stated in ICH Q11, the principle is intended to help distinguish between reagents, catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the molecular structure of the drug substance) from materials that do. … The presence of a “significant structural fragment” should not be the sole basis for of starting material selection. Starting materials justified solely on the basis that they are a “significant structural fragment” probably will not be accepted as starting materials by regulatory authorities, as the other principles for the appropriate selection of a proposed starting material also require consideration.

Question:
Do the ICH Q11 general principles for selection of starting materials apply to processes where multiple chemical transformations are run without isolation of intermediates?

Answer:
Yes. The ICH Q11 general principles apply to processes where multiple chemical transformations are run without isolation of intermediates. In the absence of such isolations (e.g., crystallization, precipitations), other unit operations (e.g., extraction, distillation, the use of scavenging agents) should be in place to adequately control impurities and be described in the application. The drug substance synthetic process should include appropriate unit operations that purge impurities.
The ICH Q11 general principles also apply for sequential chemical transformations run continuously. Non isolated intermediates are generally not considered appropriate starting materials.

Question:
Is a “starting material” as described in ICH Q11 the same as an “API starting material” as described in ICH Q7?

Answer:
Yes. ICH Q11 states that the Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch of the drug substance manufacturing process beginning with the first use of a “starting material”. ICH Q7 states that appropriate GMP (as defined in that guidance) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process … . Because ICH Q11 sets the applicability of ICH Q7 as beginning with the “starting material”, and ICH Q7 sets the applicability of ICH Q7 as beginning with the “API starting material”, these two terms are intended to refer to the same material.
ICH Q7 states that an “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API. ICH Q7 provides guidance regarding good manufacturing practices for the drug substance; however, it does not provide specific guidance on the selection and justification of starting materials. When a chemical, including one that is also a drug substance, is proposed to be a starting material, all ICH Q11 general principles still need to be considered.

With the recent publication of this draft Q&A Document with the complete title “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers (regarding the selection and justification of starting materials)” on the ICH website it reached Step 2b of the ICH Process and now enters the consultation period.  Comments may be provided by e-mailing to the ICH Secretariat at admin@ich.org.

Image result for ICH Q11

Image result for ICH Q11

extra info…………
A PRESENTATION

 

 

 

QbD Takes a Step Forward with ICH Q11

Ever since the FDA issued its landmark guidance Pharmaceutical GMPs-A Risk Based Approach in 2004, the industry has been struggling with how to demonstrate process understanding as a basis for quality. Bolstered by guidance from ICH, specifically Q6-Q10, the pieces have long been in place to build a solution that is philosophically consistent with these best practice principles. Even so, the evolution to process understanding as a basis for quality has been slow. Pressure to accelerate this transformation spiked in 2011 when the FDA issued its new guidance on process validation that basically mandated the core components of ICH Q6-10 as part of Stages 1 and 2. To be fair, enforcement has been uneven and that fact has further impeded adoption, with the compliance inspectors themselves struggling to acquire the necessary skills to fully evaluate statistical arguments of process control and predictability.

One area debated since 2008 is the application of GMPs and demonstration of control for drug substances. Drug substance suppliers and drug product manufacturers have used the tenets of ICH Q7A as the foundation for deciding where GMPs can be reasonably implemented, to establish the final intermediate (FI) and the regulatory starting material (RSM). However, the ability to support the quality of the drug substance has a profound impact on the ability to defend the drug product quality. In the last few years it has become apparent that it was not reasonable to apply the same requirements for drug products to drug substances because the processes can be markedly different. In response to this need, the ICH issued a new guidance; Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). The key ICH documents that impact Q11 are shown in Figure 1.


Figure 1. Guidances Impacting ICH Q11.

The FDA formally adopted ICHQ11 in November 2012 and its purpose is two-fold. First, it offers guidance on the information to provide in Module 3 of the Common Technical Document (CTD) Sections 3.2.S.2.2 – 3.2.S.2.6 (ICH M4Q). Second, and perhaps most importantly, it attempts to clarify the concepts defined in the ICH guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9), and Pharmaceutical Quality System (Q10) as they pertain to the development and manufacture of drug substances.

What makes ICH Q11 so important is its emphasis on control strategy. This concept was introduced in ICH Q10 as “a planned set of controls, derived from current product and process understanding that assures process performance and product quality.”

Within the drug product world, the control strategy concept has been elusive as industry grapples with moving from a sample-and-test concept of quality to one of process understanding and behavior. This concept is even more removed for drug substance manufacturers and, in some cases, is more difficult to implement. But Q11 is much more than a mere framework for control strategy. The guidance is structured very similarly to the concepts discussed in the new 2011 Process Validation guidance. Looking closely, Q11 addresses:
• Product Design/Risk Assessment/CQA Determination
• Defining the Design Space and establishing a control strategy
• Process validation and analysis
• Information required for Sections 3.2.S.2.2 – 3.2.S.2.6 of the eCTD
• Lifecycle management

Product design/Risk assessment/CQA determination

Within the context of process development, the guidance defines similar considerations to those defined in the Stage 1 activity of Process Validation. Understanding the quality linkage between the drug substance’s physical, chemical, and microbiological characteristics, and the final drug products’ Quality Target Product Profile (QTPP), is the primary objective of the product and process design phase. The product’s QTPP is comprised of the final product Critical to Quality Attributes (CQAs). Identifying the raw material characteristics of the drug substance that can impact the drug product is a critical first step in developing a defensible control strategy. Employing risk analysis tools at the outset can help focus the process development activities upon the unit operations that have the potential to impact the final product’s CQAs. In the case of biological drug substances, any knowledge regarding mechanism of action and biological characterization, such as studies that evaluate structure-function relationships, can contribute to the assessment of risk for some product attributes.

Drug substance CQAs typically include those properties or characteristics that affect identity, purity, biological activity, and stability of the final drug product. In the case of biotechnological/biological products, most of the CQAs of the drug product are associated with the drug substance and thus are a direct result of the design of the drug substance or its manufacturing process. When considering CQAs for the drug substance, it is important to not overlook the impact of impurities because of their potential impact on drug product safety. For chemical entities, these include organic impurities (including potentially mutagenic impurities), inorganic impurities such as metal residues, and residual solvents.

For biotechnological/biological products, impurities may be process-related or product-related (see ICH Q6B). Process-related impurities include: cell substrate-derived impurities (e.g., Host Cell Proteins [HCP] and DNA); cell culture-derived impurities (e.g., media components); and downstream-derived impurities (e.g., column leachable). Determining CQAs for biotechnology/biological products should also include consideration of contaminants, as defined in Q6B, including all adventitiously introduced materials not intended to be part of the manufacturing process (e.g., viral, bacterial, or mycoplasma contamination).

Defining the design space and establishing a control strategy

ICH Q8 describes a tiered approach to establishing final processing conditions that consists of moving from the knowledge space to the process design space and finally the control space. ICH Q8 and Q11 define the Design Space as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.” In the drug product world the terminology typically applied to the design space is the Proven Acceptable Range (PAR) that used to equate to the validated range.

Here is why this is important: the ability to accurately assess the significance and effect of the variability of material attributes and process parameters on drug substance CQAs, and hence the limits of a design space, depends on the extent of process and product understanding. The challenge with drug substance processes is where to apply the characterization. ICH Q7A recognizes that upstream of the RSM does not require GMP control. The design space can be developed based on a combination of prior knowledge, first principles, and/or empirical understanding of the process. A design space might be determined per unit operation (e.g., reaction, crystallization, distillation, purification), or a combination of selected unit operations should generally be selected based on their impact on CQAs.

In developing a control strategy, both upstream and downstream factors should be considered. Starting material characteristics, in-process testing, and critical process parameters variation control are the key elements in a defensible control strategy. For in-process and release testing criteria the resolution of the measurement tool should be considered before making any conclusions.

Process validation

ICH Q11’s description of process validation mimics the same description in ICH Q7A but offers up an alternative for continuous verification that mirrors the concepts in ICH Q8 and the new process validation guidance. As mentioned, the enforcement of the new guidance by the FDA has been uneven, but positioning the process validation to satisfy the new guidance requires the drug substance manufacturer to formally implement characterization and validation standards, just as a drug product manufacturer would be required to do.

Life-cycle management

The quality system elements and management responsibilities described in ICH Q10 are intended to encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual improvement across the entire product lifecycle. There should be a systematic approach to managing knowledge related to both drug substance and its manufacturing process throughout the lifecycle. This knowledge management should include but not be limited to process development activities, technology transfer activities to internal sites and contract manufacturers, process validation studies over the lifecycle of the drug substance, and change management activities.

Conclusion

The new ICH Q11 guidance represents the most recent example of the FDA’s commitment to the principles of QbD to define an integrated framework for implementing the principles of ICH Q6-Q10. Although the guidance does not mandate adopting ICH Q8, the considerations required to create a defensible control strategy require a much higher level of process understanding than the conventional approach of sample and test, once the foundation of product development. Defining the requirements is another example of where the FDA is going in terms of expectations for drug substance and drug product understanding. If effectively enforced, this can be a significant step forward, pushing the industry toward a QbD philosophy for process and product development.

/////////Selection, justification, starting materials,  ICH Q11 , ich, qbd

Share
 Older Entries  Newer Entries
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: