Burixafor is a potent and selective chemokine CXCR4 antagonist developed by TaiGen Biotechnology (www.taigenbiotech.com.tw).
The SDF1/CXCR4 pathway plays key roles in homing and mobilization of hematopoietic stem cells and endothelial progenitor cells. In a mouse model, burixafor efficiently mobilizes stem cells (CD34+) and endothelial progenitor cells (CD133+) from bone marrow into peripheral circulation. It can be used in hematopoietic stem cell transplantation, chemotherapy sensitization and other ischemic diseases.
Because TaiGen has filed an IND (CXHL1200371) for burixafor as a chemotherapy sensitizer in October 2012, the new application (CXHL1400844) may supplement a new indication. Phase II clinical trials (NCT02104427) are currently underway in the US, with Phase IIa (NCT01018979, NCT01458288) already completed.
TaiGen plans to initiate clinical trials of burixafor as a chemotherapy sensitizer in China shortly. Burixafor’s annual sales are estimated at $1.1 billion by consultancy company JSB. This compound is protected by patent WO2009131598.
英文名称Burixafor
TG-0054
(2-{4-[6-amino-2-({[(1r,4r)-4-({[3-(cyclohexylamino)propyl]amino}methyl)cyclohexyl]methyl}amino)pyrimidin-4-yl]piperazin-1-yl}ethyl)phosphonic acid
[2-[4-[6-Amino-2-[[[trans-4-[[[3-(cyclohexylamino)propyl]amino]methyl]cyclohexyl]methyl]amino]pyrimidin-4-yl]piperazin-1-yl]ethyl]phosphonic acid
1191448-17-5
C27H51N8O3P, 566.7194
chemokine CXCR 4 receptor antagonist;
| Taigen Biotechnology Co., Ltd. |
ScinoPharm to Provide Active Pharmaceutical Ingredient to F*TaiGen for Novel Stem Cell Drug
MarketWatch
The drug has received a Clinical Trial Application from China’s FDA for the initiation of … In addition, six products have entered Phase III clinical trials.
read at
TAINAN, June 8, 2014 — ScinoPharm Taiwan, Ltd. (twse:1789) specializing in the development and manufacture of active pharmaceutical ingredients, and TaiGen Biotechnology (4157.TW; F*TaiGen) jointly announced today the signing of a manufacturing contract for the clinical supply of the API of Burixafor, a new chemical entity discovered and developed by TaiGen. The API will be manufactured in ScinoPharm’s plant in Changshu, China. This cooperation not only demonstrates Taiwan’s international competitive strength in new drug development, but also sees the beginning of a domestic pharmaceutical specialization and cooperation mechanisms, thus establishing a groundbreaking milestone for Taiwan’s pharmaceutical industry.
Dr. Jo Shen, President and CEO of ScinoPharm said, “This cooperation with TaiGen is of representative significance in the domestic pharmaceutical companies’ upstream and downstream cooperation and self-development of new drugs, and indicates the Taiwanese pharmaceutical industry’s cumulative research and development momentum is paving the way forward.” Dr. Jo Shen emphasized, “ScinoPharm’s Changshu Plant provides high-quality API R&D and manufacturing services through its fast, flexible, reliable competitive advantages, effectively assisting clients of new drugs in gaining entry into China, Europe, the United States, and other international markets.”
According to Dr. Ming-Chu Hsu, Chairman and CEO of TaiGen, “R&D is the foundation of the pharmaceutical industry. Once a drug is successfully developed, players at all levels of the value chain could reap the benefit. Burixafor is a 100% in-house developed product that can be used in the treatment of various intractable diseases. The cooperation between TaiGen and ScinoPharm will not only be a win-win for both sides, but will also provide high-quality novel dug for patients from around the world.”
Burixafor is a novel stem cell mobilizer that can efficiently mobilize bone marrow stem cells and tissue precursor cells to the peripheral blood. It can be used in hematopoietic stem cell transplantation, chemotherapy sensitization and other ischemic diseases. The results of the ongoing Phase II clinical trial in the United States are very impressive. The drug has received a Clinical Trial Application from China’s FDA for the initiation of a Phase II clinical trial in chemotherapy sensitization under the 1.1 category. According to the pharmaceutical consultancy company JSB, with only stem cell transplant and chemotherapy sensitizer as the indicator, Burixafor’s annual sales are estimated at USD1.1 billion.
ScinoPharm currently has accepted over 80 new drug API process research and development plans, of which five new drugs have been launched in the market. In addition, six products have entered Phase III clinical trials. Through the Changshu Plant’s operation in line with the latest international cGMP plant equipment and quality management standards, the company provides customers with one stop shopping services in professional R&D, manufacturing, and outsourcing, thereby shortening the customer development cycle of customers’ products and accelerating the launch of new products to the market.
TaiGen’s focus is on the research and development of novel drugs. Besides Burixafor, the products also include anti-infective, Taigexyn®, and an anti-hepatitis C drug, TG-2349. Taigexyn® is the first in-house developed novel drug that received new drug application approval from Taiwan’s FDA. TG-2349 is intended for the 160 million global patients with hepatitis C with huge market potential. TaiGen hopes to file one IND with the US FDA every 3-4 years to expand TaiGen’s product line.
About ScinoPharm
ScinoPharm Taiwan, Ltd. is a leading process R&D and API manufacturing service provider to the global pharmaceutical industry. With research and manufacturing facilities in both Taiwan and China, ScinoPharm offers a wide portfolio of services ranging from custom synthesis for early phase pharmaceutical activities to contract services for brand companies as well as APIs for the generic industry. For more information, please visit the Company’s website at http://www.scinopharm.com
About TaiGen Biotechnology
TaiGen Biotechnology is a leading research-based and product-driven biotechnology company in Taiwan with a wholly-owned subsidiary in Beijing, China. The company’s first product, Taigexyn®, have already received NDA approval from Taiwan’s FDA. In addition to Taigexyn®, TaiGen has two other in-house discovered NCEs in clinical development under IND with US FDA: TG-0054, a chemokine receptor antagonist for stem cell transplantation and chemosensitization, in Phase 2 and TG-2349, a HCV protease inhibitor for treatment of chronic hepatitis infection, in Phase 2. Both TG-0054 and TG-2349 are currently in clinical trials in patients in the US.
SOURCE ScinoPharm Taiwan Ltd.
TG-0054 is a potent and selective chemokine CXCR4 (SDF-1) antagonist in phase II clinical studies at TaiGen Biotechnology for use in stem cell transplantation in cancer patients. Specifically, the compound is being developed for the treatment of stem cell transplantation in multiple myeloma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and myocardial ischemia.
Preclinical studies had also been undertaken for the treatment of diabetic retinopathy, critical limb ischemia (CLI) and age-related macular degeneration. In a mouse model, TG-0054 efficiently mobilizes stem cells (CD34+) and endothelial progenitor cells (CD133+) from bone marrow into peripheral circulation.
BACKGROUND
Chemokines are a family of cytokines that regulate the adhesion and transendothelial migration of leukocytes during an immune or inflammatory reaction (Mackay C.R., Nat. Immunol, 2001, 2:95; Olson et al, Am. J. Physiol. Regul. Integr. Comp. Physiol, 2002, 283 :R7). Chemokines also regulate T cells and B cells trafficking and homing, and contribute to the development of lymphopoietic and hematopoietic systems (Ajuebor et al, Biochem. Pharmacol, 2002, 63:1191). Approximately 50 chemokines have been identified in humans. They can be classified into 4 subfamilies, i.e., CXC, CX3C, CC, and C chemokines, based on the positions of the conserved cysteine residues at the N-terminal (Onuffer et al, Trends Pharmacol ScI, 2002, 23:459). The biological functions of chemokines are mediated by their binding and activation of G protein-coupled receptors (GPCRs) on the cell surface.
Stromal-derived factor- 1 (SDF-I) is a member of CXC chemokines. It is originally cloned from bone marrow stromal cell lines and found to act as a growth factor for progenitor B cells (Nishikawa et al, Eur. J. Immunol, 1988, 18:1767). SDF-I plays key roles in homing and mobilization of hematopoietic stem cells and endothelial progenitor cells (Bleul et al, J. Exp. Med., 1996, 184:1101; and Gazzit et al, Stem Cells, 2004, 22:65-73). The physiological function of SDF-I is mediated by CXCR4 receptor. Mice lacking SDF-I or CXCR4 receptor show lethal abnormality in bone marrow myelopoiesis, B cell lymphopoiesis, and cerebellar development (Nagasawa et al, Nature, 1996, 382:635; Ma et al, Proc. Natl. Acad. ScI, 1998, 95:9448; Zou et al, Nature, 1998, 393:595; Lu et al, Proc. Natl. Acad. ScI, 2002, 99:7090). CXCR4 receptor is expressed broadly in a variety of tissues, particularly in immune and central nervous systems, and has been described as the major co-receptor for HIV- 1/2 on T lymphocytes. Although initial interest in CXCR4 antagonism focused on its potential application to AIDS treatment (Bleul et al, Nature, 1996, 382:829), it is now becoming clear that CXCR4 receptor and SDF-I are also involved in other pathological conditions such as rheumatoid arthritis, asthma, and tumor metastases (Buckley et al., J. Immunol., 2000, 165:3423). Recently, it has been reported that a CXCR4 antagonist and an anticancer drug act synergistically in inhibiting cancer such as acute promuelocutic leukemia (Liesveld et al., Leukemia
Research 2007, 31 : 1553). Further, the CXCR4/SDF-1 pathway has been shown to be critically involved in the regeneration of several tissue injury models. Specifically, it has been found that the SDF-I level is elevated at an injured site and CXCR4-positive cells actively participate in the tissue regenerating process.
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http://www.google.com/patents/WO2009131598A1?cl=en
Compound 52
Example 1 : Preparation of Compounds 1
1-1 1-Ii 1-m
^ ^–\\ Λ xCUNN H ‘ ‘22.. P rdu/’C^ ^. , Λ>\V>v
Et3N, TFAA , H_, r [ Y I RRaanneeyy–NNiicckkeell u H f [ Y | NH2
CH2CI2, -10 0C Boc^ ‘NNA/ 11,,44–ddιιooxxaannee B Boocer”1^”–^^ LiOH, H2O, 50 0C
1-IV 1-V
Water (10.0 L) and (BoC)2O (3.33 kgg, 15.3 mol) were added to a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (compound 1-1, 2.0 kg, 12.7 mol) and sodium bicarbonate (2.67 kg, 31.8 mol). The reaction mixture was stirred at ambient temperature for 18 hours. The aqueous layer was acidified with concentrated hydrochloric acid (2.95 L, pH = 2) and then filtered. The resultant solid was collected, washed three times with water (15 L), and dried in a hot box (60 0C) to give trα/?5-4-(tert-butoxycarbonylamino-methyl)-cyclo-hexanecarboxylic acid (Compound l-II, 3.17 kg, 97%) as a white solid. Rf = 0.58 (EtOAc). LC-MS m/e 280 (M+Na+). 1H NMR (300 MHz, CDCl3) δ 4.58 (brs, IH), 2.98 (t, J= 6.3 Hz, 2H), 2.25 (td, J = 12, 3.3 Hz, IH), 2.04 (d, J= 11.1 Hz, 2H), 1.83 (d, J= 11.1 Hz, 2H), 1.44 (s, 9H), 1.35-1.50 (m, 3H), 0.89-1.03 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 181.31, 156.08, 79.12, 46.41, 42.99, 37.57, 29.47, 28.29, 27.96. M.p. 134.8-135.0 0C. A suspension of compound l-II (1.0 kg, 3.89 mol) in THF (5 L) was cooled at
-10 0C and triethyl amine (1.076 L, 7.78 mol) and ethyl chloroformate (0.441 L, 4.47 mol) were added below -10 0C. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then cooled at -100C again and NH4OH (3.6 L, 23.34 mol) was added below -10 0C. The reaction mixture was stirred at ambient temperature for 18 hours and filtered. The solid was collected and washed three times with water (10 L) and dried in a hot box (6O0C) to give trans-4- (tert-butoxycarbonyl-amino-methyl)-cyclohexanecarboxylic acid amide (Compound l-III, 0.8 kg, 80%) as a white solid. Rf= 0.23 (EtOAc). LC-MS m/e 279, M+Na+. 1H NMR (300 MHz, CD3OD) δ 6.63 (brs, IH), 2.89 (t, J= 6.3 Hz, 2H), 2.16 (td, J = 12.2, 3.3 Hz, IH), 1.80-1.89 (m, 4H), 1.43 (s, 9H), 1.37-1.51 (m, 3H), 0.90-1.05 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 182.26, 158.85, 79.97, 47.65, 46.02, 39.28, 31.11, 30.41, 28.93. M.p. 221.6-222.0 0C.
A suspension of compound l-III (1.2 kg, 4.68 mol) in CH2Cl2 (8 L) was cooled at -1O0C and triethyl amine (1.3 L, 9.36 mol) and trifluoroacetic anhydride (0.717 L, 5.16 mol) were added below -10 0C. The reaction mixture was stirred for 3 hours. After water (2.0 L) was added, the organic layer was separated and washed with water (3.0 L) twice. The organic layer was then passed through silica gel and concentrated. The resultant oil was crystallized by methylene chloride. The crystals were washed with hexane to give £rαns-(4-cyano-cyclohexylmethyl)-carbamic acid tert-butyl ester (Compound 1-IV, 0.95 kg, 85%) as a white crystal. Rf = 0.78 (EtOAc). LC-MS m/e 261, M+Na+. 1H NMR (300 MHz, CDCl3) δ 4.58 (brs, IH), 2.96 (t, J = 6.3 Hz, 2H), 2.36 (td, J= 12, 3.3 Hz, IH), 2.12 (dd, J= 13.3, 3.3 Hz, 2H), 1.83 (dd, J = 13.8, 2.7 Hz, 2H), 1.42 (s, 9H), 1.47-1.63 (m, 3H), 0.88-1.02 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 155.96, 122.41, 79.09, 45.89, 36.92, 29.06, 28.80, 28.25, 28.00. M.p. 100.4~100.6°C.
Compound 1-IV (1.0 kg, 4.196 mol) was dissolved in a mixture of 1 ,4-dioxane (8.0 L) and water (2.0 L). To the reaction mixture were added lithium hydroxide monohydrate (0.314 kg, 4.191), Raney-nickel (0.4 kg, 2.334 mol), and 10% palladium on carbon (0.46 kg, 0.216 mol) as a 50% suspension in water. The reaction mixture was stirred under hydrogen atmosphere at 5O0C for 20 hours. After the catalysts were removed by filtration and the solvents were removed in vacuum, a mixture of water (1.0 L) and CH2Cl2 (0.3 L) was added. After phase separation, the organic phase was washed with water (1.0 L) and concentrated to give £rα/?s-(4-aminomethyl- cyclohexylmethyl)-carbamic acid tert- butyl ester (compound 1-V, 0.97 kg, 95%) as pale yellow thick oil. Rf = 0.20 (MeOH/EtOAc = 9/1). LC-MS m/e 243, M+H+. 1H NMR (300 MHz, CDCl3) δ 4.67 (brs, IH), 2.93 (t, J= 6.3 Hz, 2H), 2.48 (d, J= 6.3 Hz, 2H), 1.73-1.78 (m, 4H), 1.40 (s, 9H), 1.35 (brs, 3H), 1.19-1.21 (m, IH), 0.77-0.97 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 155.85, 78.33, 48.27, 46.38, 40.80, 38.19, 29.87, 29.76, 28.07. A solution of compound 1-V (806 g) and Et3N (1010 g, 3 eq) in 1-pentanol
(2.7 L) was treated with compound 1-VI, 540 g, 1 eq) at 900C for 15 hours. TLC showed that the reaction was completed. Ethyl acetate (1.5 L) was added to the reaction mixture at 25°C. The solution was stirred for 1 hour. The Et3NHCl salt was filtered. The filtrate was then concentrated to 1.5 L (1/6 of original volume) by vacuum at 500C. Then, diethyl ether (2.5 L) was added to the concentrated solution to afford the desired product 1-VII (841 g, 68% yield) after filtration at 250C .
A solution of intermediate 1-VII (841 g) was treated with 4 N HCl/dioxane (2.7 L) in MeOH (8.1 L) and stirred at 25°C for 15 hours. TLC showed that the reaction was completed. The mixture was concentrated to 1.5 L (1/7 of original volume) by vacuum at 500C. Then, diethyl ether (5 L) was added to the solution slowly, and HCl salt of 1-VIII (774 g) was formed, filtered, and dried under vacuum (<10 torr). For neutralization, K2CO3 (2.5 kg, 8 eq) was added to the solution of HCl salt of 1-VIII in MeOH (17 L) at 25°C. The mixture was stirred at the same temperature for 3 hours (pH > 12) and filtered (estimated amount of 1-VIII in the filtrate is 504 g). Aldehyde 1-IX (581 g, 1.0 eq based on mole of 1-VII) was added to the filtrate of 1-VIII at 0-100C. The reaction was stirred at 0-100C for 3 hours. TLC showed that the reaction was completed. Then, NaBH4 (81 g, 1.0 eq based on mole of 1-VII) was added at less than 100C and the solution was stirred at 10-150C for Ih. The solution was concentrated to get a residue, which then treated with CH2Cl2 (15 L). The mixture was washed with saturated aq. NH4Cl solution (300 mL) diluted with H2O (1.2 L). The CH2Cl2 layer was concentrated and the residue was purified by chromatography on silica gel (short column, EtOAc as mobile phase for removing other components; MeOH/28% NH4OH = 97/3 as mobile phase for collecting 1-X) afforded crude 1-X (841 g). Then Et3N (167 g, leq) and BoC2O (360 g, leq) were added to the solution of
1-X (841 g) in CH2Cl2 (8.4 L) at 25°C. The mixture was stirred at 25°C for 15 hours. After the reaction was completed as evidenced by TLC, the solution was concentrated and EtOAc (5 L) was added to the resultant residue. The solution was concentrated to 3L (1/2 of the original volume) under low pressure at 500C. Then, n-hexane (3 L) was added to the concentrated solution. The solid product formed at 500C by seeding to afford the desired crude product 1-XI (600 g, 60% yield) after filtration and evaporation. To compound 1-XI (120.0 g) and piperazine (1-XII, 50.0 g, 3 eq) in 1- pentanol (360 niL) was added Et3N (60.0 g, 3.0 eq) at 25°C. The mixture was stirred at 1200C for 8 hours. Ethyl acetate (480 mL) was added to the reaction mixture at 25°C. The solution was stirred for Ih. The Et3NHCl salt was filtered and the solution was concentrated and purified by silica gel (EtOAc/MeOH = 2:8) to afforded 1-XIII (96 g) in a 74% yield.
A solution of intermediate 1-XIII (100 mg) was treated with 4 N HCl/dioxane (2 mL) in CH2Cl2 (1 mL) and stirred at 25°C for 15 hours. The mixture was concentrated to give hydrochloride salt of compound 1 (51 mg). CI-MS (M+ + 1): 459.4
Example 2: Preparation of Compound 2
Compound 2 Intermediate 1-XIII was prepared as described in Example 1.
To a solution of 1-XIII (120 g) in MeOH (2.4 L) were added diethyl vinyl phosphonate (2-1, 45 g, 1.5 eq) at 25°C. The mixture was stirred under 65°C for 24 hours. TLC and HPLC showed that the reaction was completed. The solution was concentrated and purified by silica gel (MeOH/CH2Cl2 = 8/92) to get 87 g of 2-11 (53% yield, purity > 98%, each single impurity <1%) after analyzing the purity of the product by HPLC.
A solution of 20% TFA/CH2C12 (36 mL) was added to a solution of intermediate 2-11 (1.8 g) in CH2Cl2 (5 mL). The reaction mixture was stirred for 15 hours at room temperature and concentrated by removing the solvent to afford trifluoracetic acid salt of compound 2 (1.3 g). CI-MS (M+ + 1): 623.1
Example 3 : Preparation of Compound 3
TMSBr H H
s U
Intermediate 2-11 was prepared as described in Example 2. To a solution of 2-11 (300 g) in CH2Cl2 (1800 mL) was added TMSBr (450 g, 8 eq) at 10-150C for 1 hour. The mixture was stirred at 25°C for 15 hours. The solution was concentrated to remove TMSBr and solvent under vacuum at 400C.
CH2Cl2 was added to the mixture to dissolve the residue. TMSBr and solvent were removed under vacuum again to obtain 36O g crude solid after drying under vacuum (<1 torr) for 3 hours. Then, the crude solid was washed with 7.5 L IPA/MeOH (9/1) to afford compound 3 (280 g) after filtration and drying at 25°C under vacuum (<1 torr) for 3 hours. Crystallization by EtOH gave hydrobromide salt of compound 3 (19Og). CI-MS (M+ + 1): 567.0.
The hydrobromide salt of compound 3 (5.27 g) was dissolved in 20 mL water and treated with concentrated aqueous ammonia (pH=9-10), and the mixture was evaporated in vacuo. The residue in water (30 mL) was applied onto a column (100 mL, 4.5×8 cm) of Dowex 50WX8 (H+ form, 100-200 mesh) and eluted (elution rate, 6 mL/min). Elution was performed with water (2000 mL) and then with 0.2 M aqueous ammonia. The UV-absorbing ammonia eluate was evaporated to dryness to afford ammonia salt of compound 3 (2.41 g). CI-MS (M+ + 1): 567.3.
The ammonia salt of compound 3 (1.5 g) was dissolved in water (8 mL) and alkalified with concentrated aqueous ammonia (pH=l 1), and the mixture solution was applied onto a column (75 mL, 3×14 cm) of Dowex 1X2 (acetate form, 100-200 mesh) and eluted (elution rate, 3 mL/min). Elution was performed with water (900 mL) and then with 0.1 M acetic acid. The UV-absorbing acetic acid eluate was evaporated, and the residue was codistilled with water (5×50 mL) to afford compound 3 (1.44 g). CI-MS (M+ + 1): 567.4. Example 4: Preparation of Compound 4
Compound 4
Intermediate 1-XIII was obtained during the preparation of compound 1. To a solution of diethyl vinyl phosphonate (4-1, 4 g) in CH2Cl2 (120 mL) was added oxalyl chloride (15.5 g, 5 eq) and the mixture was stirred at 300C for 36 hours. The mixture were concentrated under vacuum on a rotatory evaporated to give quantitatively the corresponding phosphochloridate, which was added to a mixture of cyclohexyl amine (4-II, 5.3 g, 2.2 eq), CH2Cl2 (40 mL), and Et3N (6.2 g, 2.5 eq). The mixture was stirred at 35°C for 36 hours, and then was washed with water. The organic layer was dried (MgSO4), filtered, and evaporated to afford 4-III (4.7 g, 85% yield) as brown oil.
Compound 4-III (505 mg) was added to a solution of intermediate 1-XIII (500 mg) in MeOH (4 mL). The solution was stirred at 45°C for 24 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/ MeOH = 4: 1) to afford intermediate 4-IV (420 mg) in a 63% yield.
A solution of HCl in ether (5 mL) was added to a solution of intermediate 4- IV (420 mg) in CH2Cl2 (1.0 mL). The reaction mixture was stirred for 12 hours at room temperature and concentrated by removing the solvent. The resultant residue was washed with ether to afford hydrochloride salt of compound 4 (214 mg). CI-MS (M+ + 1): 595.1
Preparation of compound 51
TMSBr
Intermediate l-II was prepared as described in Example 1. To a suspension of the intermediate l-II (31.9 g) in toluene (150 mL) were added phosphorazidic acid diphenyl ester (51-1, 32.4 g) and Et3N (11.9 g) at 25°C for 1 hour. The reaction mixture was stirred at 800C for 3 hours and then cooled to 25°C. After benzyl alcohol (51-11, 20 g) was added, the reaction mixture was stirred at 800C for additional 3 hours and then warmed to 1200C overnight. It was then concentrated and dissolved again in EtOAc and H2O. The organic layer was collected. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with 2.5 N HCl, saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (EtOAc/Hexane = 1 :2) to give Intermediate 51-111 (35 g) in a 79% yield. A solution of intermediate 51-111 (35 g) treated with 4 N HCl/dioxane (210 rnL) in MeOH (350 mL) was stirred at room temperature overnight. After ether (700 mL) was added, the solution was filtered. The solid was dried under vacuum. K2CO3 was added to a suspension of this solid in CH3CN and ώo-propanol at room temperature for 10 minutes. After water was added, the reaction mixture was stirred at room temperature for 2 hours, filtered, dried over anhydrous MgSO4, and concentrated. The resultant residue was purified by column chromatography on silica gel (using CH2Cl2 and MeOH as an eluant) to give intermediate 51-IV (19 g) in a 76% yield. Intermediate 1-IX (21 g) was added to a solution of intermediate 51-IV (19 g) in CH2Cl2 (570 mL). The mixture was stirred at 25°C for 2 hours. NaBH(OAc)3 (23 g) was then added at 25°C overnight. After the solution was concentrated, a saturated aqueous NaHCO3solution was added to the resultant residue. The mixture was then extracted with CH2Cl2. The solution was concentrated and the residue was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 51-V (23.9 g) in a 66% yield.
A solution of intermediate 51-V (23.9 g) and BoC2O (11.4 g) in CH2Cl2 (200 mL) was added to Et3N (5.8 mL) at 25°C for overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (using EtOAc and Hexane as an eluant) to give intermediate 51-VI (22 g) in a 77% yield.
10% Pd/C (2.2 g) was added to a suspension of intermediate 51-VI (22 g) in MeOH (44 mL). The mixture was stirred at ambient temperature under hydrogen atmosphere overnight, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 51-VII (16.5 g) in a 97% yield.
Intermediate 51-VII (16.5 g) and Et3N (4.4 mL) in 1-pentanol (75 mL) was allowed to react with 2,4-dichloro-6-aminopyrimidine (1-VI, 21 g) at 1200C overnight. The solvent was then removed and the residue was purified by column chromatography on silica gel (using EtOAc and hexane as an eluant) to afford intermediate 51-VIII (16.2 g) in a 77% yield.
A solution of intermediate 51-VIII (16.2 g) and piperazine (1-XII, 11.7 g) in 1-pentanol (32 mL) was added to Et3N (3.3 mL) at 1200C overnight. After the solution was concentrated, the residue was treated with water and extracted with CH2Cl2. The organic layer was collected and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc/ MeOH to 28% NH40H/Me0H as an eluant) to afford Intermediate 51-IX (13.2 g) in a 75% yield. Diethyl vinyl phosphonate (2-1) was treated with 51-IX as described in
Example 3 to afford hydrobromide salt of compound 51. CI-MS (M+ + 1): 553.3
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Preparation of Compound 1
Water (10.0 L) and (Boc)2O (3.33 kgg, 15.3 mol) were added to a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (compound 1-I, 2.0 kg, 12.7 mol) and sodium bicarbonate (2.67 kg, 31.8 mol). The reaction mixture was stirred at ambient temperature for 18 hours. The aqueous layer was acidified with concentrated hydrochloric acid (2.95 L, pH=2) and then filtered. The resultant solid was collected, washed three times with water (15 L), and dried in a hot box (60° C.) to give trans-4-(tert-butoxycarbonylamino-methyl)-cyclo-hexanecarboxylic acid (Compound 1-II, 3.17 kg, 97%) as a white solid. Rf=0.58 (EtOAc). LC-MS m/e 280 (M+Na+). 1H NMR (300 MHz, CDCl3) δ 4.58 (brs, 1H), 2.98 (t, J=6.3 Hz, 2H), 2.25 (td, J=12, 3.3 Hz, 1H), 2.04 (d, J=11.1 Hz, 2H), 1.83 (d, J=11.1 Hz, 2H), 1.44 (s, 9H), 1.35˜1.50 (m, 3H), 0.89˜1.03 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 181.31, 156.08, 79.12, 46.41, 42.99, 37.57, 29.47, 28.29, 27.96. M.p. 134.8˜135.0° C.
A suspension of compound 1-II (1.0 kg, 3.89 mol) in THF (5 L) was cooled at 10° C. and triethyl amine (1.076 L, 7.78 mol) and ethyl chloroformate (0.441 L, 4.47 mol) were added below 10° C. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then cooled at 10° C. again and NH4OH (3.6 L, 23.34 mol) was added below 10° C. The reaction mixture was stirred at ambient temperature for 18 hours and filtered. The solid was collected and washed three times with water (10 L) and dried in a hot box (60° C.) to give trans-4-(tert-butoxycarbonyl-amino-methyl)-cyclohexanecarboxylic acid amide (Compound 1-III, 0.8 kg, 80%) as a white solid. Rf=0.23 (EtOAc). LC-MS m/e 279, M+Na+. 1H NMR (300 MHz, CD3OD) δ 6.63 (brs, 1H), 2.89 (t, J=6.3 Hz, 2H), 2.16 (td, J=12.2, 3.3 Hz, 1H), 1.80˜1.89 (m, 4H), 1.43 (s, 9H), 1.37˜1.51 (m, 3H), 0.90˜1.05 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 182.26, 158.85, 79.97, 47.65, 46.02, 39.28, 31.11, 30.41, 28.93. M.p. 221.6˜222.0° C.
A suspension of compound 1-III (1.2 kg, 4.68 mol) in CH2Cl2 (8 L) was cooled at 10° C. and triethyl amine (1.3 L, 9.36 mol) and trifluoroacetic anhydride (0.717 L, 5.16 mol) were added below 10° C. The reaction mixture was stirred for 3 hours. After water (2.0 L) was added, the organic layer was separated and washed with water (3.0 L) twice. The organic layer was then passed through silica gel and concentrated. The resultant oil was crystallized by methylene chloride. The crystals were washed with hexane to give trans-(4-cyano-cyclohexylmethyl)-carbamic acid tent-butyl ester (Compound 1-IV, 0.95 kg, 85%) as a white crystal. Rf=0.78 (EtOAc). LC-MS m/e 261, M+Na+. 1H NMR (300 MHz, CDCl3) δ 4.58 (brs, 1H), 2.96 (t, J=6.3 Hz, 2H), 2.36 (td, J=12, 3.3 Hz, 1H), 2.12 (dd, J=13.3, 3.3 Hz, 2H), 1.83 (dd, J=13.8, 2.7 Hz, 2H), 1.42 (s, 9H), 1.47˜1.63 (m, 3H), 0.88˜1.02 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 155.96, 122.41, 79.09, 45.89, 36.92, 29.06, 28.80, 28.25, 28.00. M.p. 100.4˜100.6° C.
Compound 1-IV (1.0 kg, 4.196 mol) was dissolved in a mixture of 1,4-dioxane (8.0 L) and water (2.0 L). To the reaction mixture were added lithium hydroxide monohydrate (0.314 kg, 4.191), Raney-nickel (0.4 kg, 2.334 mol), and 10% palladium on carbon (0.46 kg, 0.216 mol) as a 50% suspension in water. The reaction mixture was stirred under hydrogen atmosphere at 50° C. for 20 hours. After the catalysts were removed by filtration and the solvents were removed in vacuum, a mixture of water (1.0 L) and CH2Cl2 (0.3 L) was added. After phase separation, the organic phase was washed with water (1.0 L) and concentrated to give trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (compound 1-V, 0.97 kg, 95%) as pale yellow thick oil. Rf=0.20 (MeOH/EtOAc=9/1). LC-MS m/e 243, M+H+. 1H NMR (300 MHz, CDCl3) δ 4.67 (brs, 1H), 2.93 (t, J=6.3 Hz, 2H), 2.48 (d, J=6.3 Hz, 2H), 1.73˜1.78 (m, 4H), 1.40 (s, 9H), 1.35 (brs, 3H), 1.19˜1.21 (m, 1H), 0.77˜0.97 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 155.85, 78.33, 48.27, 46.38, 40.80, 38.19, 29.87, 29.76, 28.07.
A solution of compound 1-V (806 g) and Et3N (1010 g, 3 eq) in 1-pentanol (2.7 L) was treated with compound 1-VI, 540 g, 1 eq) at 90° C. for 15 hours. TLC showed that the reaction was completed.
Ethyl acetate (1.5 L) was added to the reaction mixture at 25° C. The solution was stirred for 1 hour. The Et3NHCl salt was filtered. The filtrate was then concentrated to 1.5 L (1/6 of original volume) by vacuum at 50° C. Then, diethyl ether (2.5 L) was added to the concentrated solution to afford the desired product 1-VII (841 g, 68% yield) after filtration at 25° C.
A solution of intermediate 1-VII (841 g) was treated with 4 N HCl/dioxane (2.7 L) in MeOH (8.1 L) and stirred at 25° C. for 15 hours. TLC showed that the reaction was completed. The mixture was concentrated to 1.5 L (1/7 of original volume) by vacuum at 50° C. Then, diethyl ether (5 L) was added to the solution slowly, and HCl salt of 1-VIII (774 g) was formed, filtered, and dried under vacuum (<10 ton). For neutralization, K2CO3 (2.5 kg, 8 eq) was added to the solution of HCl salt of 1-VIII in MeOH (17 L) at 25° C. The mixture was stirred at the same temperature for 3 hours (pH>12) and filtered (estimated amount of 1-VIII in the filtrate is 504 g).
Aldehyde 1-IX (581 g, 1.0 eq based on mole of 1-VII) was added to the filtrate of 1-VIII at 0-10° C. The reaction was stirred at 0-10° C. for 3 hours. TLC showed that the reaction was completed. Then, NaBH4 (81 g, 1.0 eq based on mole of 1-VII) was added at less than 10° C. and the solution was stirred at 10-15° C. for 1 h. The solution was concentrated to get a residue, which then treated with CH2Cl2 (15 L). The mixture was washed with saturated aq. NH4Cl solution (300 mL) diluted with H2O (1.2 L). The CH2Cl2 layer was concentrated and the residue was purified by chromatography on silica gel (short column, EtOAc as mobile phase for removing other components; MeOH/28% NH4OH=97/3 as mobile phase for collecting 1-X) afforded crude 1-X (841 g).
Then Et3N (167 g, 1 eq) and Boc2O (360 g, 1 eq) were added to the solution of 1-X (841 g) in CH2Cl2 (8.4 L) at 25° C. The mixture was stirred at 25° C. for 15 hours. After the reaction was completed as evidenced by TLC, the solution was concentrated and EtOAc (5 L) was added to the resultant residue. The solution was concentrated to 3 L (1/2 of the original volume) under low pressure at 50° C. Then, n-hexane (3 L) was added to the concentrated solution. The solid product formed at 50° C. by seeding to afford the desired crude product 1-XI (600 g, 60% yield) after filtration and evaporation.
To compound 1-XI (120.0 g) and piperazine (1-XII, 50.0 g, 3 eq) in 1-pentanol (360 mL) was added Et3N (60.0 g, 3.0 eq) at 25° C. The mixture was stirred at 120° C. for 8 hours. Ethyl acetate (480 mL) was added to the reaction mixture at 25° C. The solution was stirred for 1 h. The Et3NHCl salt was filtered and the solution was concentrated and purified by silica gel (EtOAc/MeOH=2:8) to afforded 1-XIII (96 g) in a 74% yield.
To a solution of 1-XIII (120 g) in MeOH (2.4 L) were added diethyl vinyl phosphonate (1-XIV, 45 g, 1.5 eq) at 25° C. The mixture was stirred under 65° C. for 24 hours. TLC and HPLC showed that the reaction was completed. The solution was concentrated and purified by silica gel (MeOH/CH2Cl2=8/92) to get 87 g of 1-XV (53% yield, purity>98%, each single impurity<1%) after analyzing the purity of the product by HPLC.
A solution of 20% TFA/CH2Cl2 (36 mL) was added to a solution of intermediate 1-XV (1.8 g) in CH2Cl2 (5 mL). The reaction mixture was stirred for 15 hours at room temperature and concentrated by removing the solvent to afford trifluoracetic acid salt of compound 1 (1.3 g).
CI-MS (M++1): 623.1.
(2) Preparation of Compound 2
Intermediate 1-XV was prepared as described in Example 1.
To a solution of 1-XV (300 g) in CH2Cl2 (1800 mL) was added TMSBr (450 g, 8 eq) at 10-15° C. for 1 hour. The mixture was stirred at 25° C. for 15 hours. The solution was concentrated to remove TMSBr and solvent under vacuum at 40° C. CH2Cl2 was added to the mixture to dissolve the residue. TMSBr and solvent were removed under vacuum again to obtain 360 g crude solid after drying under vacuum (<1 torr) for 3 hours. Then, the crude solid was washed with 7.5 L IPA/MeOH (9/1) to afford compound 2 (280 g) after filtration and drying at 25° C. under vacuum (<1 ton) for 3 hours. Crystallization by EtOH gave hydrobromide salt of compound 2 (190 g). CI-MS (M++1): 567.0.
The hydrobromide salt of compound 2 (5.27 g) was dissolved in 20 mL water and treated with concentrated aqueous ammonia (pH=9-10), and the mixture was evaporated in vacuo. The residue in water (30 mL) was applied onto a column (100 mL, 4.5×8 cm) of Dowex 50WX8 (H+ form, 100-200 mesh) and eluted (elution rate, 6 mL/min). Elution was performed with water (2000 mL) and then with 0.2 M aqueous ammonia. The UV-absorbing ammonia eluate was evaporated to dryness to afford ammonia salt of compound 2 (2.41 g). CI-MS (M++1): 567.3.
The ammonia salt of compound 2 (1.5 g) was dissolved in water (8 mL) and alkalified with concentrated aqueous ammonia (pH=11), and the mixture solution was applied onto a column (75 mL, 3×14 cm) of Dowex 1×2 (acetate form, 100-200 mesh) and eluted (elution rate, 3 mL/min). Elution was performed with water (900 mL) and then with 0.1 M acetic acid. The UV-absorbing acetic acid eluate was evaporated, and the residue was codistilled with water (5×50 mL) to afford compound 2 (1.44 g). CI-MS (M++1): 567.4.
(3) Preparation of Compound 3
Intermediate 1-XIII was obtained during the preparation of compound 1.
To a solution of diethyl vinyl phosphonate (3-I, 4 g) in CH2Cl2 (120 mL) was added oxalyl chloride (15.5 g, 5 eq) and the mixture was stirred at 30° C. for 36 hours. The mixture were concentrated under vacuum on a rotatory evaporated to give quantitatively the corresponding phosphochloridate, which was added to a mixture of cyclohexyl amine (3-II, 5.3 g, 2.2 eq), CH2Cl2 (40 mL), and Et3N (6.2 g, 2.5 eq). The mixture was stirred at 35° C. for 36 hours, and then was washed with water. The organic layer was dried (MgSO4), filtered, and evaporated to afford 3-III (4.7 g, 85% yield) as brown oil.
Compound 3-III (505 mg) was added to a solution of intermediate 1-XIII (500 mg) in MeOH (4 mL). The solution was stirred at 45° C. for 24 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH=4:1) to afford intermediate 3-IV (420 mg) in a 63% yield.
A solution of HCl in ether (5 mL) was added to a solution of intermediate 3-IV (420 mg) in CH2Cl2 (1.0 mL). The reaction mixture was stirred for 12 hours at room temperature and concentrated by removing the solvent. The resultant residue was washed with ether to afford hydrochloride salt of compound 3 (214 mg).
CI-MS (M++1): 595.1.
(4) Preparation of Compound 4
Compound 4 was prepared in the same manner as that described in Example 2 except that sodium 2-bromoethanesulfonate in the presence of Et3N in DMF at 45° C. was used instead of diethyl vinyl phosphonate. Deportations of amino-protecting group by hydrochloride to afford hydrochloride salt of compound 4.
CI-MS (M++1): 567.3
(5) Preparation of Compound 5
Compound 5 was prepared in the same manner as that described in Example 2 except that diethyl-1-bromopropylphosphonate in the presence of K2CO3 in CH3CN was used instead of diethyl vinyl phosphonate.
CI-MS (M++1): 581.4
(6) Preparation of Compound 6
Compound 6 was prepared in the same manner as that described in Example 5 except that 1,4-diaza-spiro[5.5]undecane dihydrochloride was used instead of piperazine.
CI-MS (M++1): 649.5
(7) Preparation of Compound 7
Intermediate 1-II was prepared as described in Example 1.
To a suspension of the intermediate 1-II (31.9 g) in toluene (150 mL) were added phosphorazidic acid diphenyl ester (7-I, 32.4 g) and Et3N (11.9 g) at 25° C. for 1 hour. The reaction mixture was stirred at 80° C. for 3 hours and then cooled to 25° C. After benzyl alcohol (7-II, 20 g) was added, the reaction mixture was stirred at 80° C. for additional 3 hours and then warmed to 120° C. overnight. It was then concentrated and dissolved again in EtOAc and H2O. The organic layer was collected. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with 2.5 N HCl, saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (EtOAc/Hexane=1:2) to give Intermediate 7-III (35 g) in a 79% yield.
A solution of intermediate 7-III (35 g) treated with 4 N HCl/dioxane (210 mL) in MeOH (350 mL) was stirred at room temperature overnight. After ether (700 mL) was added, the solution was filtered. The solid was dried under vacuum. K2CO3 was added to a suspension of this solid in CH3CN and iso-propanol at room temperature for 10 minutes. After water was added, the reaction mixture was stirred at room temperature for 2 hours, filtered, dried over anhydrous MgSO4, and concentrated. The resultant residue was purified by column chromatography on silica gel (using CH2Cl2 and MeOH as an eluant) to give intermediate 7-IV (19 g) in a 76% yield.
Intermediate 1-IX (21 g) was added to a solution of intermediate 7-IV (19 g) in CH2Cl2 (570 mL). The mixture was stirred at 25° C. for 2 hours. NaBH(OAc)3(23 g) was then added at 25° C. overnight. After the solution was concentrated, a saturated aqueous NaHCO3 solution was added to the resultant residue. The mixture was then extracted with CH2Cl2. The solution was concentrated and the residue was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 7-V (23.9 g) in a 66% yield.
A solution of intermediate 7-V (23.9 g) and Boc2O (11.4 g) in CH2Cl2 (200 mL) was added to Et3N (5.8 mL) at 25° C. for overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (using EtOAc and Hexane as an eluant) to give intermediate 7-VI (22 g) in a 77% yield. 10% Pd/C (2.2 g) was added to a suspension of intermediate 7-VI (22 g) in MeOH (44 mL). The mixture was stirred at ambient temperature under hydrogen atmosphere overnight, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford intermediate 7-VII (16.5 g) in a 97% yield.
Intermediate 7-VII (16.5 g) and Et3N (4.4 mL) in 1-pentanol (75 mL) was allowed to react with 2,4-dichloro-6-aminopyrimidine (1-VI, 21 g) at 120° C. overnight. The solvent was then removed and the residue was purified by column chromatography on silica gel (using EtOAc and hexane as an eluant) to afford intermediate 7-VIII (16.2 g) in a 77% yield.
A solution of intermediate 7-VIII (16.2 g) and piperazine (1-XII, 11.7 g) in 1-pentanol (32 mL) was added to Et3N (3.3 mL) at 120° C. overnight. After the solution was concentrated, the residue was treated with water and extracted with CH2Cl2. The organic layer was collected and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc/MeOH to 28% NH4OH/MeOH as an eluant) to afford Intermediate 7-IX (13.2 g) in a 75% yield.
Diethyl vinyl phosphonate (2-I) was treated with 7-IX as described in Example 3 to afford hydrobromide salt of compound 7.
CI-MS (M++1): 553.3
(8) Preparation of Compound 8
Cis-1,4-cyclohexanedicarboxylic acid (8-I, 10 g) in THF (100 ml) was added oxalyl chloride (8-II, 15.5 g) at 0° C. and then DMF (few drops). The mixture was stirred at room temperature for 15 hours. The solution was concentrated and the residue was dissolved in THF (100 ml). The mixture solution was added to ammonium hydroxide (80 ml) and stirred for 1 hour. The solution was concentrated and filtration to afford crude product 8-III (7.7 g).
Compound 8-III (7.7 g) in THF (200 ml) was slowly added to LiAlH4 (8.6 g) in THF (200 ml) solution at 0° C. The mixture solution was stirred at 65° C. for 15 hours. NaSO4.10H2O was added at room temperature and stirred for 1 hours. The resultant mixture was filtered to get filtrate and concentrated. The residue was dissolved in CH2Cl2 (100 ml). Et3N (27 g) and (Boc)2O (10 g) were added at room temperature. The solution was stirred for 15 h, and then concentrated to get resultant residue. Ether was added to the resultant residue. Filtration and drying under vacuum afforded solid crude product 8-IV (8.8 g).
A solution of compound 8-IV (1.1 g) and Et3N (1.7 g) in 1-pentanol (10 ml) was reacted with 2,4-dichloro-6-aminopyrimidine (1-VI, 910 mg) at 90° C. for 15 hours. TLC showed that the reaction was completed. Ethyl acetate (10 mL) was added to the reaction mixture at 25° C. The solution was stirred for 1 hour. The Et3NHCl salt was removed. The filtrate was concentrated and purified by silica gel (EtOAc/Hex=1:2) to afford the desired product 8-V (1.1 g, 65% yield).
A solution of intermediate 8-V (1.1 g) was treated with 4 N HCl/dioxane (10 ml) in MeOH (10 ml) and stirred at 25° C. for 15 hours. TLC showed that the reaction was completed. The mixture was concentrated, filtered, and dried under vacuum (<10 ton). For neutralization, K2CO3 (3.2 g) was added to the solution of HCl salt in MeOH (20 ml) at 25° C. The mixture was stirred at the same temperature for 3 hours (pH>12) and filtered. Aldehyde 1-IX (759 mg) was added to the filtrate at 0-10° C. The reaction was stirred at 0-10° C. for 3 hours. TLC showed that the reaction was completed. Then, NaBH4 (112 mg) was added at less than 10° C. and the solution was stirred at 10-15° C. for 1 hour. The solution was concentrated to get a residue, which was then treated with CH2Cl2 (10 mL). The mixture was washed with saturated NH4Cl (aq) solution. The CH2Cl2 layer was concentrated and the residue was purified by chromatography on silica gel (MeOH/28% NH4OH=97/3) to afford intermediate 8-VI (1.0 g, 66% yield).
Et3N (600 mg) and Boc2O (428 mg) were added to the solution of 8-VI (1.0 g) in CH2Cl2 (10 ml) at 25° C. The mixture was stirred at 25° C. for 15 hours. TLC showed that the reaction was completed. The solution was concentrated and purified by chromatography on silica gel (EtOAc/Hex=1:1) to afford intermediate 8-VII (720 mg, 60% yield).
To a solution compound 8-VII (720 mg) and piperazine (1-XII, 1.22 g) in 1-pentanol (10 mL) was added Et3N (1.43 g) at 25° C. The mixture was stirred at 120° C. for 24 hours. TLC showed that the reaction was completed. Ethyl acetate (20 mL) was added at 25° C. The solution was stirred for 1 hour. The Et3NHCl salt was removed and the solution was concentrated and purified by silica gel (EtOAc/MeOH=2:8) to afford 8-VIII (537 mg) in 69% yield.
To a solution of 8-VIII (537 mg) in MeOH (11 ml) was added diethyl vinyl phosphonate (2-I, 201 mg) at 25° C. The mixture was stirred under 65° C. for 24 hours. TLC and HPLC showed that the reaction was completed. The solution was concentrated and purified by silica gel (MeOH/CH2Cl2=1:9) to get 8-IX (380 mg) in a 57% yield.
To a solution of 8-IX (210 mg) in CH2Cl2 (5 ml) was added TMSBr (312 mg) at 10-15° C. for 1 hour. The mixture was stirred at 25° C. for 15 hours. The solution was concentrated to remove TMSBr and solvent under vacuum at 40° C., then, CH2Cl2 was added to dissolve the residue. Then TMSBr and solvent were further removed under vacuum and CH2Cl2 was added for four times repeatedly. The solution was concentrated to get hydrobromide salt of compound 8 (190 mg).
CI-MS (M++1): 566.9
To do a job well is one thing, but to consistently deliver a product that is nearly flawless is quite a different challenge. For its new molecule burixafor, the Taiwanese drug discovery firm TaiGen Biotechnology instructed its contract manufacturing partners to achieve 99.8% purity in the production of the active pharmaceutical ingredient (API).
Discovered in TaiGen’s labs in 2006, burixafor is in Phase II clinical trials in both the U.S. and China for use in stem cell transplants and cancer chemotherapy. Avecia, a unit of Japan’s Nitto Denko, manufactures the drug substance in the U.S., where burixafor was tested for the first time on human patients. When TaiGen later initiated clinical trials in China, it chose the Taiwanese firm ScinoPharm to produce the drug at its plant in Changshu, near Shanghai. Under Chinese law, only drugs made domestically can be tested in China.
NITTO DENKO Avecia Inc.
It is rare for a drug discovery firm to select two companies to scale up the production of a new molecule. TaiGen went one step further by paying both contract manufacturers to reach an extremely high level of purity.
“We are trying to avoid any unwanted side effects during the trials,” says C. Richard King, TaiGen’s senior vice president of research. Drug regulators in the U.S. and China “need very tight specifications these days for new drugs,” he adds.
TaiGen registered burixafor with the U.S. Food & Drug Administration in 2007. When it contracted Girindus America (bought by Avecia in 2013) to manufacture it that year, TaiGen specified purification by column chromatography, a cumbersome and relatively expensive procedure when carried out on a large scale. “Our process development efforts were racing against the clinical trials launch schedule,” King recalls. Column chromatography, he points out, is a “tedious approach, but it works.”
By the time ScinoPharm was hired last year, TaiGen’s process development team had come up with a simpler and more elegant process. But its purity demands hadn’t changed.
“Usually, clients are satisfied with a purity level of 98% to 99%,” says Koksuan Tang, head of operations at ScinoPharm’s Changshu plant. “To go from 99% to 99.8% is very different.” The manufacturing of burixafor, he adds, involves five chemical steps and two purification steps. Upstream of the API, ScinoPharm also produces burixafor’s starting material.
Purity level aside, burixafor is not a particularly difficult compound to make, Tang says. Nonetheless, the process supplied by TaiGen had to be adjusted for larger-scale production. “If you heat up 10 g in the lab, it takes two minutes, but in a plant, it could take as long as two hours,” he says.
Although, while hydrogen chloride gas can be controlled effectively when making minute quantities of a compound in the lab, it’s another challenge to handle large volumes of the toxic substance at the plant level. To safely execute one reaction step, ScinoPharm dissolved HCl in a special solvent that does not affect the purity profile of burixafor.
TaiGen selected ScinoPharm as its China contractor after a careful process that involved two visits to Changshu by TaiGen’s senior managers, Tang recalls. ScinoPharm’s track record of meeting regulatory requirements in different countries, including China, was a plus, Tang believes. Its ability to produce both for clinical trials and in larger quantities after commercial launch was also decisive.
Operational since 2012, ScinoPharm’s Changshu site can deliver products under Good Manufacturing Practices in quantities ranging from grams to kilograms. It employs 220 people.
“Moving from the single-kilogram quantities we make now to hundreds of kilograms will require some adjustment to the process, but we believe we can deliver,” says Tang’s colleague Sing Ping Lee, senior director of product technical support in Changshu. One thing to keep in mind, he notes, is that Chinese regulatory standards for drug production are actually more restrictive than those in the U.S. or Europe, going so far as specifying what equipment manufacturers need to use.
Other than complying with Chinese regulators, one reason TaiGen needed to carefully select its China contractor is that the two companies could well be long-term partners, since TaiGen believes it has the ability to market the drug on its own in China, Taiwan, and Southeast Asia. In the event of approvals elsewhere, TaiGen plans to license the compound to a large drug company, which may or may not stick with ScinoPharm or Avecia.
Relatively unknown outside Taiwan, TaiGen was formed in 2001 by Ming-Chu Hsu, the founder of the Division of Biotechnology & Pharmaceutical Research at Taiwan’s National Health Research Institutes. The holder of a Ph.D. in biochemistry from the University of Illinois, Urbana-Champaign, she headed oncology and virology research at Roche for more than 10 years before returning to Taiwan in 1998.
Ming-Chu Hsu, Chairman & CEO, TaiGen Biotechnology, Taiwan
TaiGen employs about 80 people, three-quarters of whom are in R&D. The company develops its own drugs in-house and also in-licenses molecules that are in early stages of development. The company licenses out the molecules for the European Union and U.S. markets but seeks to retain Asian marketing rights. Burixafor was discovered in TaiGen’s own labs in Taipei. To come up with it, researchers used a high-throughput screening approach that involved 130,000 compounds, including the design and synthesis of 1,500 new compounds. “It went back and forth between chemistry and biology many times,” recalls King, TaiGen’s research head.
A so-called CXCR4 chemokine receptor antagonist, burixafor mobilizes hematopoietic stem cells and endothelial progenitor cells in human bone marrow and channels them into the peripheral blood within three hours of ingestion, according to results of Phase I and Phase II trials.
In the U.S., burixafor is undergoing clinical trials for use during stem cell transplantation in patients with multiple myeloma, non-Hodgkin’s lymphoma, or Hodgkin’s disease. In China, TaiGen is testing it as a chemotherapy sensitizer in relapsed or refractory adult acute myeloid leukemia.
Owing to its activity on CXCR4 chemokine receptors, the drug could also fight age-related macular degeneration and diabetic retinopathy diseases, as well as find use in tissue repair, King says. For clinical trials in the U.S., TaiGen has partnered with Michael W. Schuster, a medical doctor who conducts research at Stony Brook University Hospital in New York.
Dr. Michael Schuster is Gift of Life’s Medical Director, as well as the Director of the Hematopoietic Stem Cell Transplantation Program and Hematologic Malignancy Program of Stony Brook University Hospital in New York
Typical structure of a chemokine receptor
TaiGen sees particular potential for burixafor in stem cell applications. For example, patients undergoing hematopoietic stem cell transplantation often must take a granulocyte colony-stimulating factor plus a Sanofi drug called Mozobil to stimulate stem cell production. TaiGen says burixafor could accomplish this goal on its own in multiple myeloma patients. It cites one consulting firm forecast that puts eventual sales at more than $1 billion per year.
Sanofi drug called Mozobil to stimulate stem cell production
With that kind of potential, the company is counting on significant interest among licensors, any one of which might want to engage its own contract producer of burixafor. If that happens, a third manufacturer will have to learn to reach 99.8% purity.
TaiGen Biotechnology Co., Ltd.
7F,138 Shin Ming Rd. Neihu Dist., Taipei, Taiwan 114 R.O.C
Tel: 886-2-81777072 | 886-2-27901861
Fax: 886-2-27963606
Taipei Railway Station front
Taipei Songshan Airport
Scinopharm
ScinoPharm is currently expanding its manufacturing and process development capabilities by adding significant production and technical capacity in Mainland China at its new Changshu site.
ScinoPharm Changshu is located in the Changshu Economic Development Zone (CEDZ), near Suzhou City, Jingsu Province, China on a 6.6-hectare site.
The facilities will include a R&D centre and production plants fully compliant with U.S. and international GMP standards. The Changshu plant, slated to be fully completed by 2012, will be used for the production of GMP grade pharmaceutical intermediates initially, and later be equipped to handle API production. China’s market for better quality APIs has grown considerably, and local formulation companies are encouraged to utilize APIs from companies having DMFs filed in advanced countries. ScinoPharm had closed its site in Kunshan and relocated the production and R&D groups to Changshu in the 4th quarter of 2011. These groups will continue to be expanded to meet growing demand for ScinoPharm products by both multinational and local formulation companies.
The small and medium-sized production units had been operational in the 4th quarter of 2011. The large production Bays plus a peptide purification unit, a high potency unit and a physical property processing facility will be operational by the end of 2012. Using advanced engineering designs, this site will also have the capability to process high potency, injectable grade products.
ScinoPharm Changshu will adopt the same quality systems as ScinoPharm Taiwan, and will therefore comply with ICH guidelines and FDA 21 CFR Parts 210 & 211.
TAIPEI
Old street in Taipei. 2013
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| Nickname(s): The City of Azaleas | |||
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 Satellite image of Taipei City |
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Coordinates:  25°02′N 121°38′E |
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NARINGENIN
Naringenin; CAS: 480-41-1
Aldrich Library of 13C and 1H FT NMR Spectra, 1992, 2, 915C
TERUTROBAN
Terutroban is an antiplatelet agent developed by Servier Laboratories. as of|2008, it is tested for the secondaryprevention of acute thrombotic complications in the Phase III clinical trial PERFORM.
Method of action
Terutroban is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced plateletaggregation and vasoconstriction.
DOI: 10.1039/C4OB02302A
![3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid NMR spectra analysis, Chemical CAS NO. 165538-40-9 NMR spectral analysis, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid H-NMR spectrum](http://pic11.molbase.net/nmr/nmr_image/2014-11-09/001/775/1775661_1h.png)
![3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid NMR spectra analysis, Chemical CAS NO. 165538-40-9 NMR spectral analysis, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid C-NMR spectrum](http://pic11.molbase.net/nmr/nmr_image/2014-11-09/001/775/1775661_13c.png)
Terutroban is an antiplatelet agent developed by Servier Laboratories. It has been tested for the secondary prevention of acute thrombotic complications in the Phase III clinical trial PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack).[1] The study was prematurely stopped and thus it could not be determined whether terutroban has a better effect than aspirin.
Terutroban is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced platelet aggregation andvasoconstriction.[2][3]
…………………..
10.1358/dof.2006.031.10.1038241
Thromboxane A2 (TxA2) is an unstable metabolite of arachidonic acid formed by the cyclooxygenase pathway and released from activated platelets, monocytes and damaged vessel walls, causing irreversible platelet aggregation, vasoconstriction and smooth muscle cell proliferation. From efforts to discover novel compounds that could block the deleterious actions of TxA2, the 2-aminotetralin derivative terutroban sodium (S-18886) emerged as a potent, orally active, long-acting, selective antagonist of thromboxane (TP) receptors. The agent was able to inhibit TP agonist-induced platelet aggregation and vasoconstriction and was selected for further development as an antiplatelet and antithrombotic agent. Terutroban has been shown to be effective in animal models of thrombosis, atherosclerosis and diabetic nephropathy and is currently undergoing phase III development for the secondary prevention of acute thrombotic complications of atherosclerosis.
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| Systematic (IUPAC) name | |
|---|---|
| 3-((6R)-6-{[(4-Chlorophenyl)sulfonyl]amido}-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid | |
| Clinical data | |
| Legal status |
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| Routes | Oral |
| Pharmacokinetic data | |
| Half-life | 6–10 hours |
| Identifiers | |
| CAS number | 165538-40-9  609340-89-8 (sodium salt) |
| ATC code | None |
| PubChem | CID 9938840 |
| ChemSpider | 8114465 |
| UNII | A6WX9391D8 |
| Chemical data | |
| Formula | C20H22ClNO4S |
| Molecular mass | 407.911 g/mol |
Chief Scientist & Head, Division of Natural Products Chemistry, CSIR- Indian Institute of Chemical Technology
Chandrasekhar obtained his Bachelor’s and Master’s degrees in 1982 and 1985 respectively, from Osmania University, Hyderabad and excelled in the same with distinction. He then joined A. V. Rama Rao’s group at CSIR–IICT and earned his doctorate in 1991, also from Osmania University. Between 1991 and 1994 he was associated with J. R. Falck (University of Texas Southwestern Medical Center) as a postdoctoral student. In 1994, Chandrasekhar joined his parent institute (CSIR–IICT) as a scientist
srivaric@gmail.com
READ………..http://www.currentscience.ac.in/Volumes/108/02/0160.pdf
)/Images/CSIRlogo.gif) |
Council of Scientific and Industrial Research Ministry of Science and Technology, Government of India |
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CSIR-IICT CSIR-Indian Institute of Chemical Technology |
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DR AV RAMA RAO
Professor J. R. Falck
Professor L. F. Tietze
Srivari Chandrasekhar, senior scientist, Organic Chemistry Division, Indian Institute of Chemical Technology (IICT), has been conferred Fellow of Indian Academy of Sciences, Bangalore.
According to a press release here on Tuesday, Dr. Chandrasekhar has been conferred the honour for his significant contribution in organic chemistry and medicinal chemistry.
The major contributions include synthesis of complex natural products, especially of marine origin with anti-cancer and anti-depressant properties, green chemistry and automation chemistry to make large number of new chemicals.
He has produced 25 Ph.D. students and published more than 200 papers in international journals. He is also a fellow of National Academy of Sciences.
India has achieved many prizes in 2014. Before the year ends IICT scientist Srivari Chandrasekhar has added one more prize, he wins Infosys Prize. The scientist who has made important contributions in potential drug developments. Srivari Chandrasekhar from CSIR-IICT , Hyderabad, was announced the winner of the Infosys Prize 2014 in Physical Sciences. The award includes a purse of Rs. 55 lakh, a 22 carat gold medal and citation. The award will be presented by The President on January 5 in Kolkata. The prize is awarded annually by the Infosys Foundation.
He had won the CSIR Technology award-2014 along with his team member
Chandrasekhar’s current contribution is to develop a technology for manufacturing Misoprostal, an abortive drug also used in the treatment of ulcers. Now we can easily get rid of Ulcer.
He has successfully prepared some important drug molecules such as bedaquiline for multi-drug resistant TB, Galantamine for Alzheimer’s disease, Sertraline for treatment of depression, Nebivolol for hypertension and marine natural products such as Eribulin, Azumamide, Arenamide and Bengazole which are scarce to get from nature, with potent biological activities.
As he moves on achieving his target , he has made contributions in synthesizing complex and scarcely available natural products in the laboratory using easily available chemicals.
Chandrasekhar has over 250 publications in national and international journals to his credit.
Prof. Chandrasekhar has displayed an exceptional flair for identifying and synthesizing molecules of biological relevance, topical synthetic interest and utility to industry. His research efforts, with an impressive degree of innovations and enterprise, have led to the synthesis of complex and scarcely available natural products and new molecular entities for affordable healthcare. His endeavors have provided cost-effective technologies to chemical industry through identification of new reagents / solvents for specific transformations. Chandrasekhar’s group has synthesized several classes of complex natural products in optically pure form employing chiral pool precursors and catalytic asymmetric reactions and his syntheses of pladienolide, azumamide, bengazole etc., bear testimony to the efficacy of such approaches.
His passion and commitment to topical health related problems is through provisioning for better and affordable access to important drugs. Mention may be made of hissynthesis of bedaquiline, the first drug approved by FDA after a gap of over 40 years for the treatment of multi-drug resistant TB through simpler transformations and higher yields to ensure ready availability. He along with a team atIICT has developed a scalable synthetic route for misoprostol (a hormone like biologically important synthetic prostaglandin) used to prevent gastric ulcer, induce labor and / or abortion (particularly for safe termination of unwanted pregnancies), which has already been commercialized.
D. Srinivasa Reddy of CSIR-National Chemical Laboratory Pune devised (J. Org. Chem. 2013, 78, 8149. DOI: 10.1021/jo401033j) a cascade protocol of Diels-Alder cycloaddition of 8 to the diene 7 followed by intramolecular aldol condensation, to give the enone 9. Oxidative manipulation followed by methylenation completed the synthesis of the commercially important grapefruit flavor Nootkatone (10).
A simple and efficient synthesis of functionalized cis-hydrindanes and cis-decalins was achieved using a sequential Diels–Alder/aldol approach in a highly diastereoselective manner. The scope of this method was tested with a variety of substrates and was successfully applied to the synthesis of two natural products in racemic form. The highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.
(4R*,4aS*,6R*)-4,4a-Dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaph thaen-2(3H)-one ((±)-Nootkatone 20)
(±)-Nootkatone 20 (19 mg, 65%). IRυmax(film) 2923, 1668, 1606, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1 H), 4.74 (s, 1 H), 4.72(s, 1 H), 2.50 (ddt, J = 15.3, 5.0, 1.8 Hz, 1 H), 2.40–2.24 (m, 4 H), 2.04–1.89 (m, 3 H),1.74 (s, 3 H), 1.40–1.29 (m, 2 H), 1.11 (s, 3 H), 0.96 (d, J = 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.9, 170.7, 149.3, 124.8, 109.4, 44.0, 42.2, 40.6, 40.5, 39.5, 33.2, 31.7, 21.0, 17.0, 15.0.
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| Names | |
|---|---|
| IUPAC name
4-α,5-Dimethyl-1,2,3,4,4α,5,6,7-octahydro-7-keto-3-isopropenylnaphthalene
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| Other names
(+)-nootkatone
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| Identifiers | |
| CAS number | 4674-50-4  |
| ChEMBL | ChEMBL446299 |
| ChemSpider | 1064812 |
| Jmol-3D images | Image |
| KEGG | C17914 |
| PubChem | 1268142 |
| Properties | |
| C15H22O | |
| Molar mass | 218.33 g·mol−1 |
| Appearance | Viscous yellow in its liquid form |
| Density | 0.968 g/mL |
| Melting point | 36 °C (97 °F; 309 K) |
| Boiling point | 170 °C (338 °F; 443 K) |
| Hazards | |
| S-phrases | S23 S24 S25 |
| Flash point | ~ 100 °C (212 °F) |
Nootkatone is a natural organic compound and is the most important and expensive aromatic of grapefruit.[1] It is a sesquiterpeneand a ketone.
Nootkatone was previouslythought to be one of the main chemical components of the smell and flavour of grapefruits. In its solid form it is usually found as crystals. As a liquid, it is viscous and yellow. Nootkatone is typically extracted from grapefruit, but can also be manufactured with genetically modified organisms, or through the chemical or biochemical oxidation of valencene. It is also found in Alaska yellow cedar trees[2] and vetiver grass.[3]
Nootkatone in spray form has been shown as an effective repellent/insecticide against deer ticks[3][4][5] and lone star ticks.[4][5] It is also an effective repellent/insecticide against mosquitos, and may repel bed bugs, head lice and other insects.[6] It is environmentally friendly insecticide, because it is a volatile essential oil that does not persist in the environment.[6] It is nontoxic to humans, is an approved food additive,[6] and “is commonly used in foods, cosmetics, and pharmaceuticals”.[3]
The CDC has licensed patents to two companies to produce an insecticide and an insect repellant.[6] Allylix, of San Diego, CA, is one of these licensees [7] and has developed an enzyme fermentation process that will produce nookatone more cost effectively.[8]
https://www.linkedin.com/pub/d-srinivasa-reddy-dsreddy/1/75a/139
Our group research interests are broadly in total synthesis of biologically active compounds and medicinal chemistry. Current projects include the total synthesis of bioactive natural products such as antiinflammatory agents, antibacterial agents, antimalarial compounds and anti-cancer agents. Targets are chosen for their interesting biological activity and moderate complexity, which drives our creative solutions to their synthesis. Our ability to achieve an efficient synthesis enables us to access sufficient quantities of target molecule for biological profiling and ready access to different analogs that may prove to be more selective and efficacious as a drug-like molecule. We have plans to divert our total synthesis projects into medicinal chemistry projects by simplifying the complex structures. In medicinal chemistry front, our main interest is to use “silicon-switch approach” to discover novel drugs or drug-like molecules with improved pharmacokintetic (PK) and pharmacodynamic (PD) properties.
DEC2014 NCL PUNE INDIA
DR ANTHONY WITH DR REDDY
Tomas Hudlicky
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada
E-mail: thudlicky@brocku.ca
Chemoenzymatic synthesis of complex natural and unnatural products: morphine, pancratistatin, and their analogs
Tomas Hudlicky
ARKIVOC 2006 (vii) 276-291
pp. 276 – 291
http://www.arkat-usa.org/get-file/23149/
Organic synthesis, biocatalysis, electrochemistry, asymmeric catalysis
Our group is engaged in a variety of projects ranging from total synthesis to investigations of new reactions and the design of enzyme inhibitors. In total synthesis, we work on implementing reliable and efficient routes to target molecules. Our ventures are exact and logical pursuits, yet serendipity, intuition, and art all form an integral part of designing a total synthesis.
We have exploited the biooxidation of aromatic compounds in an exhaustive approach to the synthetic design of carbohydrates and their derivatives. Our guiding principles are symmetry, simplicity, and precise order of operations so that any derivative or stereoisomer with a sugar backbone can be constructed. These products are tested for glycosidase inhibition, a process important in viral expression. In addition, carbocyclic sugars can act as cell messengers, and their availability through synthesis allows greater understanding of cellular communication. Oligomers of inositols can also be exploited in a rational design of templates for asymmetric synthesis and in the design of chiral polymers.
Morphine, pancratistatin, and taxol are other important molecules in which our group has invested much synthetic effort. Their total synthesis permits the investigation of new reactions and mechanistic pathways, which can then be applied in subsequent syntheses. Current effort is focused on designing a practical synthesis of morphine and analogs and in probing the active pharmacophore of pancratistatin in hopes of designing a more bio-available anti-tumor agent.
To address environmentally benign manufacturing, or Green Chemistry, we are exploiting organic electrochemistry as replacement technology for metal-based oxidizing and reducing agents.
Finally we are devoting some effort to studies in the mechanism of prokaryotic oxygenase enzymes. Our ultimate goal is the design of a synthetic enzyme mimic that can be used as a chiral reagent for aromatic cis-hydroxylation.
Research: organic synthesis, green chemistry, chemoenzymatic synthesis, biomanufacturing, biocatalysis
When people are trying to find Brock University they are often told to use the Schmon Tower, which can be seen throughout Niagara, as their guide. In the world of organic chemistry, Tomas Hudlicky, a Canada Research Chair in Biocatalysis, has earned the same sort of status.
The goal of Hudlicky’s research is the practical and efficient synthesis of new medicinal agents by asymmetric synthesis and total synthesis of natural products. His work related to the total synthesis of morphine and the anticancer drug pancratistatin is concerned with refinements and production of the alkaloids in a more efficient and environmentally benign manner. Analogs of both compounds are also being synthesized and evaluated for biological activities.
Hudlicky also conducts research in the area of organic electrochemistry, which provides “green” alternatives to oxidation and reduction methodology. His current research has led to several patent applications and licensing agreements with the Johnson & Johnson subsidiary Noramco. He has also developed a new, simpler route to Tamiflu, one of the few compounds effective against the illness known as H5N1 virus or bird flu.
Recognized as a “green” scientist, Hudlicky converts pharmaceutical waste into a variety of desirable pharmaceutical compounds. His research is responsible for giving the harmful waste of the past a new life as analgesic and anti-tumour products, specifically compounds used in the treatment of cancer, bio-infection and diabetes.
Hudlicky receives daily requests from across the globe to join his research team. The Cairns Family Health and Bioscience Research Complex will greatly improve the size and capacity of Hudlicky’s research facilities, allowing him to accept more graduate students to study with his group.
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| Systematic (IUPAC) name | |
|---|---|
| (1R,2S,3S,4S,4aR,11bR)-1,2,3,4,7-pentahydroxy-2,3,4,4a,5,11b-hexahydro-1H-[1,3]dioxolo[4,5-j]phenanthridin-6-one | |
| Clinical data | |
| Legal status |
?
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| Identifiers | |
| CAS number | 96281-31-1 |
| ATC code | ? |
| PubChem | CID 441597 |
| ChemSpider | 390265 |
| Chemical data | |
| Formula | C14H15NO8 |
| Molecular mass | |
Pancratistatin (PST) is a natural compound initially extracted from Spider Lily,[1] a Hawaiian native plant, belonging to the familyAmaryllidaceae[2] (AMD).
Pancratistatin occurs naturally in Hawaiian Spider Lily, a flowering plant within the Amaryllidaceae family. Pancratistatin is mostly found in the bulb tissues of Spider Lilies. It has been shown that the enrichment of atmospheric CO2 can enhance the production ofantiviral secondary metabolites, including Pancratistatin, in these plants.[3] Pancratistatin can be isolated from the tropical bulbs ofHymenocallis littoralis in the order of 100 to 150 mg/kg when bulbs are obtained from the wild type in Hawaii. However, the compound has to be commercially extracted from field- and greenhouse-grown bulbs or from tissue cultures cultivated, for example, in Arizona, which generate lower levels of Pancratistatin (a maximum of 22 mg/kg) even in the peak month of October. After October, when the bulb becomes dormant, levels of Pancratistatin drop, down to only 4 mg/kg by May. Field-grown bulbs, which show monthly changes in Pancratistatin content, generate somewhat smaller amounts (2–5 mg/kg) compared to those grown in greenhouses cultivated over the same period.[4] There are about 40 different Spider Lily species worldwide and they are mainly native to theAndes of South America.
Schoals Spider Lilly
Spider Lily
Pancratistatin is thought to have potential as a basis for the development of new pharmaceuticals,[5] particularly in the field of cancer treatment.[6]
Although there may not be a precise elucidation of Pancratistatin biological synthesis, there have been speculations on biosynthesis ofNarciclasine and Lycoricidine that are very similar to Pancratistatin in terms of structure. The biosynthesis is accomplished via synthesis from O-methylnorbelladine 4 by para-para phenol coupling to obtain vittatine 5 as an intermediate. Subsequent elimination of two carbon atoms and hydroxylations of compound 5 (vittatine) then leads to narciclasine.[7]
Pancratistatin-like biosynthesis using Narciclasine as a model.
The first total synthesis of racemic (+/-) Pancratistatin was proposed by Samuel Danishefsky and Joung Yon Lee, which involved a very complex and long (40 steps) total synthesis. According to both Danishefsky and Joung, there were several weak steps in this synthesis that gave rise to a disappointing low synthetic yield. Amongst the most challenging issues, the Moffatt transposition and theorthoamide problem, which required a blocking maneuver to regiospecifically distinguish the C, hydroxyl group for rearrangement were considered to be the severe cases. However, both Danishevsky and Yon Lee stated that their approach towards the PST total synthesis was not out of merit and believed that their work would interest other medicinal scientists to construct a much more practical and efficient way for PST total synthesis.[8][9]
The work of Danishevsky and Joung provided the foundation for another total synthesis of PST, which was propounded by Li,M. in 2006. This method employed a more sophisticated approach, starting out with the pinitol 30 that its stereocenters are exactly the same as the ones in the C-ring of Pancratistatin.[10] Protection of the diol functions of compound 30 gave compound 31. The free hydroxyl of this was subsequently substituted by an azide to give 32. After removal of the silyl function, a cyclic sulfate was installed to obtain product 33. The Staudinger reaction gave the free amine 34 from azide 33. The coupling reaction between 34 and 35 gave compound 36 with a moderate yield. Methocymethyl protection of both the amide and the free phenol gave compound 37. Treatment of this latter product with t-BuLi followed by addition of cerium chloride gave compound 38. Full deprotection of 38 by BBr3 and methanol afforded pancratistatin 3 in 12 steps from commercially available pinitol with an overall yield of 2.3% 20.
a: TIPDSCl2, imidazole, DMAP, DMF, 24%. b: DMP, p-TsOH, acetone, 81%. c: PPh3, DEAD, CH3SO3H, CH2Cl2, 0 °C to r.t. then NaN3, DMF, 60 °C, 72%. d: TBAF, THF, 0 °C to r.t., 100%. e: SOCl2, Et3N, CH2Cl2, 0 °C. f: NaIO4, RuCl3, aq CH3CN, 87% (more than two steps). g: PPh3, aq THF, 0 °C to r.t., 94%. h: Et2O, 35, 0 °C, 64%. i: K2CO3, MOMCl,DMF, 84%. j: t-BuLi, CeCl3, ultrasound, THF, −78 °C to r.t., 72%. k: BBr3, CH2Cl2, −78 °C to 0 °C, 1 hour then MeOH, −78 °C to 0 °C, 2 hours, 52%.
Total Synthesis of racemic Pancratistatin CLICK ON PICTURE
The abstract of the Stereocontrolled synthesis of Pancratistatin
Pancratistatin and Narciclasine
Streocontrolled synthesis of pancratistatin
A very recent approach to a stereocontrolled Pancratistatin synthesis was accomplished by Sanghee Kim from the National University of Seoul, in which claisen rearrangement of dihydropyranethlyene and a cyclic sulfate elimination reaction were employed 21. This reaction has proven to be very highly efficient as it produced an 83% overall synthetis yield. (Proved by H and 13C NMR).
The B ring of the phenanthridone (three membered nitrogen hetrocyclic ring) is formed using the Bischler-Napieralski reaction. The n precursor 3 with its stereocenters in the C ring is stereoselectively synthesized from the cis-disubstituted cyclohexene 4. The presence of unsaturated carbonyl in compound 4 suggested the use of a Claisen rearrangement of 3,4-dihydro-2H-pyranylethylene.[11]
The synthesis starts with the treatment of 6 with excess trimethyl phosphate. This reaction provides phosphate 7 in 97% yield. Using Honer-Wadsworth-Emmons reaction between 7 ands acrolein dimmer 8 in the presence of LHMDS in THF forms (E)-olefin 5 with very high stereoselectivity in 60% yield. Only less than 1% of (Z)-olefin was detected in the final product. The Claisen rearrangement of dihydropyranethylene forms the cis-distributed cyclohexene as a single isomer in 78% yield.
The next step of the synthesis involves the oxidation of aldehyde of compound 4 using NaClO2 to the corresponding carboxylic acid 9 in 90% yield. Iodolactonization of 9 and subsequent treatment with DBU in refluxing benzene gives rise to the bicyclic lacytone in 78% yield. Mthanolysis of lactone 10 with NaOMe forms a mixture of hydroxyl ester 11 and its C-4a epimer (Pancratistatin numbering). Saponification of the methyl ester 11 with LiOH was followed by a Curtius rearrangement of the resulting acid 12 with diphenylphosphoryl azide in refluxing toluene to afford isocyanate intermediate, which its treatment with NaOMe/MeOH forms the corresponding carbamate 13 in 82% yield.
The next steps of the synthesis involve the regioselevtive elimination of C-3 hydroxyl group and subsequent unsaturation achieved by cyclic sulfate elimination. Diol 16 needs to be treated with thionyl chloride and further oxidation with RuCl3 provides the cyclic sulfate 17 in 83% yield.[12] Treatment of cyclic sulfate with DBU yields the desired allylic alcohol 18 (67% yield).
Reaction with OsO4 forms the single isomerlization 19 in 88% yield. Peracetylation of 19 (77% yield) accompanied by Banwell’s modified Bischler-Napieralski forms the compound 20 with a little amount of isomer 21 ( 7:1 regioselectivity). The removal of protecting groups with NaOMe/MeOH forms Pancratistatin in 83%.
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Cheon-Gyu Cho of Hanyang University added (Org. Lett. 2013, 15, 5806. DOI: 10.1021/ol4028623) the activated dienophile 4 to the dienyl lactone to give, after oxidation, the dibromide 5. Debromination followed by oxidation led to the antineoplastic lactam Pancratistatin (6).
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KAIXIN
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CHINA
MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878
MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878
MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878\
: Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE) plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS) and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension.
– See more at: http://www.mdpi.com/1660-3397/8/4/1080/htm#sthash.B8fUm0Hw.dpuf
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE
amcrasto@gmail.com
Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin
Feb 2015….India-based drugmaker Lupin has signed an agreement with Polish biopharmaceutical firm Celon Pharma to develop a fluticasone / salmeterol dry powder inhaler (DPI).
Under the deal, Lupin will take the responsibility for commercialisation of the product, which is a generic version of GlaxoSmithKline’s (GSK) Advair Diskus.
Lupin CEO Vinita Gupta said: “We are very pleased to partner with Celon given their experience in the development and manufacturing of fluticasone/salmeterol DPI in Europe…………..http://www.pharmaceutical-technology.com/news/newslupin-celon-pharma-partner-generic-version-gsks-advair-diskus-4514718?WT.mc_id=DN_News
Ms. Vinita Gupta is the CEO of Lupin Pharmaceuticals Inc, USA, (LPI) and Group President, Director on the board of Lupin Limited and a Director on the Board of Lupin’s Japanese subsidiary Kyowa Pharmaceuticals. Ms. Gupta is responsible for the North American and European business of the company.
Ms. Gupta joined Lupin in 1992 and developed Lupin’s entry strategy into US and Europe. Under her leadership Lupin has emerged as a leader in the US generic market as well as the only company from India to have a successful brand business in the US. As part of her responsibility she built the entire management team for the US and European business and supervised the development of the company’s pipeline.
Ms. Gupta holds a Bachelor’s degree in Pharmacy from the University of Mumbai and MBA from J L Kellogg Graduate School of Management, Northwestern University.
“A good year” is how Vinita Gupta, Group President and CEO at Lupin Pharmaceuticals, describes her company’s performance at a time when unsettling news was the key takeaway for pharma companies. Lupin grew by an impressive 35.9 per cent globally and 24 per cent in India. New product launches helped it grow its generics business by 52 per cent, making it the sixth-largest generics pharmaceutical company globally by market capitalisation and the third-largest Indian pharmaceutical company by revenues. “I can’t think of any challenges that affected Lupin’s performance during the last fiscal year,” says Gupta, 44. The company’s strategy now is to focus strongly on building its branded business globally.
Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin, is based in the United States, but has been in India a lot in the past one year.
With an expanding role in Lupin’s universe, Vinita has been spending more time outside the US, at times taking her six-year-old son, Krish with her. “He is getting exposure at a much younger age,” she says. Gupta herself was exposed to business at the age of 11 by her father Desh Bandhu Gupta, Lupin’s founder and Chairman.
“We almost had a family board at home, discussing work,” she says. Currently work goes well indeed, with Gupta taking new initiatives in India and also making the business more global. “I am focusing on drivers for growth in our business for the next five years,” she says.
Gupta is married to US-based businessman Brij Sharma.
She was 13 when she travelled to Switzerland with her father, to watch him position the family-run Lupin Limited, to negotiate and to strategise. It was enough to get her hooked. Enough for her to move away from a childhood fascination for art and enter the world of pharmaceuticals. Group president and CEO, Lupin Pharmaceuticals, and director on the board of Lupin Limited, Vinita Gupta has never regretted that decision. The 41-year-old is responsible for creating a substantial international presence for the company that was born in Mumbai in 1968 and named after a leguminous flower.
The Lupin group produces affordable generic and branded formulations in the world with a significant presence in cardiovasculars, diabetes, asthma, pediatrics and anti-infectives. But Desh Bandhu Gupta, her father, wanted the company to make an impact in the western market.
It was a challenge that seemed perfect for Gupta who graduated in pharmacy from the University of Mumbai and then spent a year working at the company in Mumbai. She then moved to the US for an MBA from the J.L. Kellogg Graduate School of Management at Northwestern University, following it with a brief stint in a US pharma company. But she didn’t want to be a mere “cog in the wheel”, returning to India to take up that initial challenge-to create a business strategy that would allow Lupin to enter American and European markets.
Today, Lupin is the ninth largest generics company in the US. It is also one of India’s top five pharmaceutical players and one of the fastest growing top 10 generic players in Japan and South Africa. The US arm of the business, Gupta’s baby, contributes to over 30 per cent of Lupin’s revenues, a company that clocked in close to Rs.4,000 crore in 2008-2009. Nine out of the 23 generic products Lupin has in the US market are at the number one position giving consistent competition to larger US pharma companies.
With brother NileshThe beginning however was difficult. After all, India wasn’t very well known in the US market. “We realised that we had the aspirations but not the infrastructure in the form of facilities to meet US and European requirements and standards,” she remembers. So she spent three years building the infrastructure, creating a process that would be acceptable to these regulated markets. The break came with Suprax, a pediatric antiinfective drug that was valued at nearly $60 million in the US market. Gupta had already filed for a generic of the brand. “Suddenly, we had the opportunity to brand the generic, so we licensed the brand name from the innovator as he had left the market,” she remembers. It was a three-person team with 40 outsourced sales people.
Today, the product’s sales are at $74 million. It has been satisfying, she says. “The innovator was in the market with a sales force of 300 people. We are 60.” The aim, she says, has always been to balance branded products as well as generic. The success, her father and chairman of the company, Desh Bandhu Gupta, says, stems not just from her determination. “It’s also her intimate understanding of the entire pharma spectrum with the motivation to see it through,” he says.
This determination became obvious when she managed to persuade the dean at Kellogg to give her admission, even though she was 19 and perhaps the youngest in her class. It was a challenging time as she learned to balance her work and household chores. “At that time in India, everything was handwritten. I had to do every single thing using the computer,” says Gupta who often bribed her friends with homemade Indian food to type out her projects. It taught her to be independent.
But it was perhaps, two months ago, when Gupta a bigger challenge. A deal that made tough seem an understatement. For Antara, an anti-cholesterol drug. “It was very much like Suprax, that was serendipity,” says Gupta. It was a large product with high potential. But the company was in bankruptcy. “I was sure we could do things differently with the product,” she says.
Gupta says Lupin was the first to file for the generic brand. But they couldn’t own the generic and the brand. She had six weeks to sell the generic, win the bid in the US bankruptcy court and buy the brand. She did it. At $38 million, one-third its market value. It’s a deal that Nilesh, her brother and group president and executive director, believes displayed his sister’s meticulous calibre. “There were three sets of negotiations going on at the same time. And while there were others involved, this deal was Vinita all the way,” he says.
Kamal Sharma, managing director, Lupin Limited, has watched Gupta transform from a teenager learning the ropes of a business to the successful go-getter that she is today. “She values, teaches and encourages her people to deliver consistent results year after year,” he says. It’s an attitude that is apparent from the get-go.
(L-R) With Richa, Kavita, Anuja and NileshAt the Trident, Mumbai, for the photo shoot, Gupta is comfortable surrounded by people, even though she is a little hesitant in front of the camera. It’s here that she actually seems to shed the image of an ultimate powerhouse, a businesswoman driven to succeed. It is here that she becomes the Mumbaikar who prefers a masala chai over brewed coffee and a plain tee over a designer label. In some ways, she is still the girl who grew up in a housing society near the airport in Vile Parle, Mumbai. It’s the kind of place where people still keep their doors open and where one can walk into a neighbour’s house without having to knock. Things weren’t handed to her on a golden platter, she admits. In fact, she says, their father taught them that, “as a family we would have to work harder to earn and deserve our right more than what other professionals do.”
As a child, she remembers sharing a room with her four siblings, Kavita, Anuja, Nilesh and Richa. She didn’t like that very much. “But now, when I think of it, I feel it was an amazing life,” she says. Her father adds that he always took his children to different countries, either on work or otherwise. It was his way of showing them the world and different experiences.
But a different side emerges as Gupta talks of the pharma industry. “I dreamed of taking what Dad had built and adding value to it in the western markets,” she says. “This is what I had always prepared myself for. I am living the dream.” And it isn’t as if there aren’t any downs. Six months ago, she remembers, the company received a warning letter from the Food and Drug Administration. She spent that time working to resolve their concerns. “And then three months later, we made one of our most attractive acquisitions. The industry is so quick changing, so dynamic. It always keeps you thinking,” she says.
For Nilesh though, Gupta is his sounding board, the eldest sister with whom he shares a relationship that complements their work profiles. And while Nilesh says with a laugh, Gupta doesn’t pull the bigsister act with him at work, home is a different story. Gupta admits with a mock sigh, “You can’t posture with your siblings. You can posture with anyone else, but not your siblings.”
With husband Brij and son KrishThe obvious downside, however, is family. Her work keeps her busy, sees her up and in office by 8 am, back just in time to spend about an hour with her four-year-old son Krish. “He was a very easy child till some time ago, but lately he has become very demanding,” she says with a smile. Just as Gupta was leaving her home in Baltimore, Maryland for her current trip to India, Krish demanded they go leaf-picking in their backyard. “More than anything, I loved watching the expression on his face while we were picking leaves. His smile brightens up my day,” she says.
As much as her job is a passion she tries to spend time with Krish and husband Brij Sharma, a businessman whom she met in the US. “My husband is a very good listener. I keep talking whenever I am with him and he listens even today,” she says with a laugh. A workout is a must, however, as Gupta heads to the gym every day, spinning the cycle even when she was eight months pregnant.
“My husband jokes that’s the reason why Krish thinks and behaves ahead of his age,” laughs Gupta. But biking near the waterfront with her son and spending time on her husband’s boat is an activity that wins hands down. As does time spent with her two sisters Anuja and Richa, who live in Chicago. While Anuja is a pediatric cardiologist, Anuja is into public health. They do plan vacations together, but she often discovers that her brother Nilesh refuses to talk to her over the weekend. “Probably because I always end up talking about work,” she says with a laugh. “It has become so much a part of our lives,” she says.
In June2012 , Vinita Gupta, CEO of Lupin Pharmaceuticals Inc, the Indian drug maker’s US unit, received the “Entrepreneur of the Year” award from Ernst & Young in the health services and technology category for Maryland state of the US. Over the past year, the US business of Lupin crossed the $500 million mark.
DB Gupta (centre) Chairman, Vinita Gupta (right) CEO and Nilesh Gupta
