Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

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Jun 052017

The first continuous flow synthesis of C₈–C₁₆ alkane fuel precursors from biobased platform molecules is reported. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) was found to be a recyclable and highly efficient organic base catalyst for the aldol condensation of furfural with carbonyl compounds, and the selectivity of mono- or difuryl product can be easily regulated by adjusting the molar ratio of substrates. By means of flow technique, a shorter reaction time, satisfactory output, and continuous preparation are achieved under the present procedure, representing a significant advance over the corresponding batch reaction conditions.

Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

Tao Shen^†^‡, Jingjing Tang^†^‡, Chenglun Tang^†^‡, Jinglan Wu^†^‡, Linfeng Wang^∥, Chenjie Zhu^*^†^‡^§

, and Hanjie Ying^†^‡^§

^† College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China

^‡National Engineering Technique Research Center for Biotechnology, Nanjing 211816, China

^§Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing 211816, China

^∥State Key Laboratory of Motor Vehicle Biofuel Technology, Nanyang 473000, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00141

*E-mail: zhucj@njtech.edu.cn. Phone/Fax: +86 25 58139389.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00141

1-(furan-2-yl)-2-methylpent-1-en-3-one

3-pentanone (100 mmol, 8.6 g) and furfural (100 mmol, 9.6 g) were diluted with MeOH-H2O to 40 mL in stream 1, catalyst TBD (10 mmol, 1.39 g) were diluted with MeOH-H2O (v/v = 1/1) to 40 mL in stream 2, the two streams was purged in a 0.2 mL/min speed into slit plate mixer and at the 353 K passed tubing reactor. Finally, the product was extracted with EtOAc and water, the obtained organic layer was evaporated and purified by silica gel flash chromatography (25:1 hexane-EtOAc) to provide the analytically pure product for further characterization, the aqueous phase was collected and reused.According to the general procedure afforded 14.92 g (91%) of product 1a, isolated as pale yellow oil;

1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 1.4 Hz, 1H), 7.29 (s, 1H), 6.71 (d, J = 3.5 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 2.71 (q, J = 7.3 Hz, 2H), 2.05 (s, 3H), 1.04 (t, J = 7.3 Hz, 3H).

13C NMR (100 MHz, CD3OD) δ 203.5, 153.0, 145.8, 133.8, 126.8, 116.6, 113.3, 31.1, 13.2, 9.2.

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Guest blogger, Dr Pravin Patil, Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-Diaryloxazoles

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Jun 042017

University of Louisville

Chemistry building and Shumaker building

Department of Chemistry, University of Louisville

Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-Diaryloxazoles

Pravin C. Patil and Frederick A. Luzzio*

Department of Chemistry, University of Louisville, 2320South Brook Street, Louisville, Kentucky 40292

Faluzz01@louisville.edu

*Corresponding Author: Email: faluzz01@louisville.edu

J Org. Chem., 2016, 81(21), pp 10521–10526.

Publication Date (Web): July 21, 2016 (Note)

DOI: 10.1021/acs.joc.6b01280

Frederick A. Luzzio

Professor, Organic Chemistry: Organic and Medicinal Chemistry

str0

STR2

Typical Procedure for Aluminum/HgCl2-Mediated Desulfonylation for Synthesis of 4 (Eq. 1) and 18 (Table 2). To a solution of the alkylated 2-(sulfonylethyl)-4,5-diphenyloxazole 5 (0.12 mmol, 1.0 equiv) and crystals of mercuric chloride (0.034 mmol, 0.3 equiv), in methanol (15 mL), was added an excess of food-grade aluminum foil (2.32 mmol, 20 equiv) with vigorous stirring under a nitrogen atmosphere. The resulting heterogeneous mixture was heated at reflux until the metal disappeared. The reaction mixture was then allowed to cool to room temperature and filtered through a Celite bed followed by washing with methanol (2 x 15mL). The filtrate was concentrated to a crude residue which was submitted to gravity-column chromatography on silica gel to provide 2-methyl-4,5-diphenyloxazole 4 (96%) or 2-ethyl-4,5-diphenyloxazole 18 (97%).

General procedure for Magnesium/HgCl2-Mediated Desulfonylation of Alkylated Sulfones 5-17. To a stirred solution of an alkylated 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole (0.12 mmol, 1.0 equiv. from Table 1) in methanol (5 mL) was added magnesium turnings (1.73 mmol, 15 equiv) and crystals of mercuric chloride (0.012 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at room temperature (2 h) while monitoring the reaction progress by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite bed followed by washing with methanol (2 x 10 mL). The filtrate was concentrated and the resultant crude residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate) to afford the pure products 18–27 listed in Table 2.

Typical procedure: Synthesis of Oxaprozin

Ethyl 3-(4,5-diphenyloxazol-2-yl)-3-(phenylsulfonyl)propanoate (28). To a prechilled solution of 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole 3 (100 mg, 0.27 mmol) in dry THF (15 mL) was added potassium tert-butoxide (33 mg, 0.29 mmol) under a nitrogen atmosphere. The resulting yellow solution was stirred (5°C) for 30 min. To the reaction mixture was slowly added ethyl bromoacetate (49 mg, 32.4 μL, 0.29 mmol) and stirring was continued (16 h) at room temperature. Upon completion of reaction as indicated by TLC, the reaction mixture was quenched with cold water (20 mL) and extracted with dichloromethane (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to obtain a crude oily residue. The residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate, 4:1) afford pure ethyl 3-(4,5-diphenyloxazol-2-yl)-3-(phenylsulfonyl)propanoate 28 as off-white solid ( 88 mg, 72%).

Ethyl 3-(4,5-diphenyloxazol-2-yl)acrylate (29). To a cooled (5°C) solution of sulfonyloxazole ester 28 (225 mg, 0.49 mmol) in dry THF was added potassium tert-butoxide (60.2 mg, 0.54 mmol) under nitrogen and the reaction mixture was then stirred at 5-10°C (2 h) while monitoring by TLC. After completion of the reaction, the reaction mixture was extracted with dichloromethane (2 x 25 mL) followed by washing the extracts with water and brine then drying over anhydrous Na2SO4. Removal of the drying agent and concentration of the filtrate gave a crude residue which was submitted to gravity-column chromatography (hexane/ethylacetate, 4:1) to provide unsaturated oxazole ester 29 as a colorless oil (100 mg, 65%).

Ethyl 3-(4,5-diphenyloxazol-2-yl)propanoate (30).17 The unsaturated oxazole ester 30 (160 mg, 0.50 mmol) was dissolved in methanol (25 mL) then 10% Pd/C (16 mg, 10% wt/wt) was added at room temperature. The reaction mixture was purged with nitrogen while stirring followed by the addition of hydrogen gas (balloon) and then stirring was continued (16 h) under an atmosphere of hydrogen. Upon completion of reaction, the reaction mixture was filtered through a bed of Celite while washing with methanol (2 x 30 mL). The combined filtrates were concentrated and the crude residue was submitted to gravity-column chromatography (hexane/ethyl acetate, 4:1) to afford 30 as an off-white solid (129 mg, 80%).

Methyl 3-(4,5-diphenyloxazol-2-yl)propanoate (31).13 To a clear solution of sulfonyloxazole ester 28 (80 mg, 0.173 mmol) in methanol (10 mL) was added magnesium turnings (63 mg, 2.60 mmol) followed by solid mercuric chloride (4.7 mg, 0.017 mmol) at room temperature. The resulting reaction mixture was stirred (2 h) while monitoring the reaction progress by TLC. After completion of the reaction, the heterogeneous mixture was then filtered through a Celite bed followed by washing with methanol (2 x 15 mL). The methanolic filtrates were combined and concentrated to afford a crude residue. The residue was submitted to gravity-column chromatography (hexane/ethylacetate, 4:1) to provide ester 31 as an off-white solid (52 mg, 97%).

3-(4,5-Diphenyloxazol-2-yl)propanoic acid (Oxaprozin) (32).13 Ethyl ester 30 (128 mg, 0.39 mmol) or methyl ester 31 (65 mg, 0.21 mmol) and 20% aquous NaOH solution (3 mL) was stirred overnight at room temperature. Upon completion of reaction as indicated by TLC, the reaction mixture was slowly acidified to pH 3-4 using conc. HCl (3 mL) at room temperature and stirring was continued (3 h). After the neutralization was complete the reaction mixture was diluted with cold water (15 mL) and extracted with dichloromethane (2 x 15 mL). The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated to give a white solid residue. The residue was submitted to gravity-column chromatography (chloroform/methanol, 9:1) to afford pure Oxaprozin 32 as white solid (80 mg, 68%, from the ethyl ester 30) or (60 mg, 97%, from the methyl ester 31).

ABOUT GUEST BLOGGER

Dr. Pravin C. Patil

Postdoctoral Research Associate at University of Louisville

see…….http://oneorganichemistoneday.blogspot.in/2017/04/dr-pravin-patil.html

Dr. Pravin C Patil completed his B.Sc. (Chemistry) at ASC College Chopda (Jalgaon, Maharashtra, India) in 2001 and M.Sc. (Organic Chemistry) at SSVPS’S Science College Dhule in North Maharashtra University (Jalgaon, Maharashtra, India) in year 2003. After M.Sc. degree he was accepted for summer internship training program at Bhabha Atomic Research Center (BARC, Mumbai) in the laboratory of Prof. Subrata Chattopadhyay in Bio-organic Division. In 2003, Dr. Pravin joined to API Pharmaceutical bulk drug company, RPG Life Science (Navi Mumbai, Maharashtra, India) and worked there for two years. In 2005, he enrolled into Ph.D. (Chemistry) program at Institute of Chemical Technology (ICT), Matunga, Mumbai, aharashtra, under the supervision of Prof. K. G. Akamanchi in the department of Pharmaceutical Sciences and Technology.

After finishing Ph.D. in 2010, he joined to Pune (Maharashtra, India) based pharmaceutical industry, Lupin Research Park (LRP) in the department of process development. After spending two years at Lupin as a Research Scientist, he got an opportunity in June 2012 to pursue Postdoctoral studies at Hope College, Holland, MI, USA under the supervision of Prof. Moses Lee. During year 2012-13 he worked on total synthesis of achiral anticancer molecules Duocarmycin and its analogs. In 2014, he joined to Prof. Frederick Luzzio at the Department for Chemistry, University of Louisville, Louisville, KY, USA to pursue postdoctoral studies on NIH sponsored project “ Structure based design and synthesis of Peptidomimetics targeting P. gingivalis.

During his research experience, he has authored 23 international publications in peer reviewed journals and inventor for 4 patents.

Prof K. G. Akamanchi

Prof. K. G. Akamanchi

Professor, Pharmaceutical Sciences and Technology

Email ID : kg.akamanchi@ictmumbai.edu.in

Reseach Area : Development of Novel Methodologies, Hypervalent Iodine Chemistry, Synthesis of drug and drug intermediates, Design and Synthesis of Potential bioactive molecules, Protein Isolation and Bioassay

ICT Mumbai

SEE…………

About

The long term goals of our research are focused at the interface of chemistry and biology. We are interested in solving problems in biomedicine using the techniques and application of synthetic organic, medicinal and natural products chemistry. Toward our goals in biomedicine we concentrate our efforts in the following three areas of organic chemistry: (1) the development of new methods and strategy which are applicable to the synthesis of biologically active compounds; (2) the total synthesis of a wide range of complex molecules including natural products, pharmaceutical leads and their analogues; and (3) the isolation and discovery of biologically active compounds from natural sources. Within our objectives in item 1 (above), we have had a long-term collaboration with the Clinical Pharmacology Section of the National Cancer Institute in which we have synthesized metabolites and analogues of thalidomide, a small-molecule immunomodulator and angiogenesis inhibitor. The derivatives and analogues of thalidomide were stereospecifically synthesized in order to ascertain the mode of action and the molecular target of this small molecule. Ultimately, the synthetic studies are leading to analogues of thalidomide which are more potent, but which have less undesirable side effects than the parent compound. In the neurosciences area we have completed an enantioselective synthesis of both optical isomers of a key intermediate in preparing the histrionicotoxins, a group of compounds which are isolated for the neurotoxic Amazon “poison dart” frogs. One of our present natural products projects (under item 3,above) entails the isolation, neurotoxicity assays and synthesis of a series of naturally-occurring compounds called acetogenins from the North American paw paw tree Asimina triloba. The isolation, purification and structural confirmation of the natural products has been conducted in collaboration with the Neurosciences Department within the University of Louisville School of Medicine. In the area of anti-infectives (under 1), we are designing and synthesizing an array of nitrogen and nitrogen/oxygen heterocyclic scaffolds bearing acetylenic and azido groups for use in the so-called “click reaction.” The multiply-connected scaffolds have proven to be effective for inhibiting micro-organisms working in tandem to produce biofilms necessary for their establishment and survival.

Education

1976   B.S.   Vanderbilt University
1979   M.S. Tufts University
1982   Ph.D. Tufts University
1982-1985 Postdoctoral Fellow, Harvard University

Current Service

Executive Committee/Treasurer, International Society of Heterocyclic Chemistry HETCHEM@louisville.edu

Links

Gordon Research Conferences on Natural Products 2009

The Natural Products Gordon Conference. 1951-2011

International Society of Heterocyclic Chemistry

Organic Links

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Tegafur

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Jun 012017

Tegafur

CAS 17902-23-7

2,4(1H,3H)-Pyrimidinedione, 5-fluoro-1-(tetrahydro-2-furanyl)-

Molecular Weight,200.17, MF C₈ H₉ F N₂ O₃
172-173 °C

Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, 29(11), PG 3181-90

Uracil, 5-fluoro-1-(tetrahydro-2-furyl)-

Utefos

Venoterpine

WY1559000

YR0450000

5-fluoro-1-tetrahydrofuran-2-ylpyrimidine-2,4(1H,3H)-dione

Carzonal

N1-(2′-Furanidyl)-5-fluorouracil

Synonyms:Ftorafur
ATC:L01BC03

EINECS:241-846-2
LD₅₀:800 mg/kg (M, i.v.); 775 mg/kg (M, p.o.);
685 mg/kg (R, i.v.); 930 mg/kg (R, p.o.);
34 mg/kg (dog, p.o.)

Derivatives, monosodium salt

Formula:C₈H₈FN₂NaO₃
MW:222.15 g/mol
CAS-RN:28721-46-2

Tegafur (INN, BAN, USAN) is a chemotherapeutic prodrug of 5-flourouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.^[1]

Medical uses

As a prodrug to 5-FU it is used in the treatment of the following cancers:^[2]

Stomach (when combined with gimeracil and oteracil)
Breast (with uracil)
Gallbladder
Lung (specifically adenocarcinoma, typically with uracil)
Colorectal (usually when combined with gimeracil and oteracil)
Head and neck
Liver (with uracil)^[3]
Pancreatic

It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil.^[2] These agents achieve this by inhibiting the enzyme dihydropyrimidine dehydrogenase (uracil/gimeracil) or orotate phosphoribosyltransferase (oteracil).^[2]

Image result for tegafur

Adverse effects

The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea).^[2] Gastrointestinal toxicity is the dose-limiting side effect of tegafur.^[2] Central neurotoxicity is more common with tegafur than with fluorouracil.^[2]

Image result for tegafur

Pharmacogenetics

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.^[4] Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency.^[4]^[5] Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome.^[4]^[5]

Mechanism of action

It is a prodrug to 5-FU, which is a thymidylate synthase inhibitor.^[2]

Pharmacokinetics

It is metabolised to 5-FU by CYP2A6.^[6]^[7]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

The interactive pathway map can be edited at WikiPathways: “FluoropyrimidineActivity_WP1601”.

Image result for tegafur

Image result for tegafur SYNTHESIS

MASS SPECTRUM

1H NMR

13C NMR

RAMAN

Synthesis

Image result for tegafur SYNTHESIS

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
58138-78-6	C₁₀H₁₉FN₂O₂Si₂	1,3-bis(trimethylsilyl)fluorouracil	2,4(1H,3H)-Pyrimidinedione, 5-fluoro-1,3-bis(trimethylsilyl)-
13369-70-5	C₄H₇ClO	2-chlorotetrahydrofuran	Furan, 2-chlorotetrahydro-
1191-99-7	C₄H₆O	2,3-dihydrofuran	Furan, 2,3-dihydro-
51-21-8	C₄H₃FN₂O₂	5-fluorouracil	2,4(1H,3H)-Pyrimidinedione, 5-fluoro-

Image result for tegafur

ChemSpider 2D Image | Tegafur | C8H9FN2O3

SYN1

CN 106397416

SYN 2

Advanced Synthesis & Catalysis, 356(16), 3325-3330; 2014

PATENTS

CN 106397416

CN 104513230

CN 103159746

PATENT

CN 102285972

tegafur is a derivative of 5-fluorouracil, and in 1967, Hiller of the former Soviet Union synthesized tegafur (SA Hiller, RA Zhuk, M. Yu. Lidak, et al. Substituted Uracil [ P, British Patent, 1168391 (1969)). In 1974, it was listed in Japan. China was successfully developed by Shandong Jinan Pharmaceutical Factory in 1979. Its present origin is Shanghai and Shandong provinces and cities. The anti-cancer effect of tegafur is similar to that of 5-fluorouracil and is activated in vivo by 5-fluorouracil through liver activation. Unlike 5-fluorouracil, tegafur is fat-soluble, has good oral absorption, maintains high concentrations in the blood for a long time and easily passes through the blood-brain barrier. Clinical and animal experiments show that tegafur on gastrointestinal cancer, breast cancer is better, the role of rectal cancer than 5-fluorouracil good, less toxic than 5-fluorouracil. Teflon has a chemotherapy index of 2-fold for 5-fluorouracil and only 1 / 4-1 / 7 of toxicity. So the addition of fluoride is widely used in cancer patients with chemotherapy.

[0003] The first synthesis of tegafur is Hiller ([SA Hiller, RA Zhuk, Μ. Yu. Lidak, et al. Substituted Uracil [P], British Patent, 1168391 (1969)]. 5-fluorouracil or 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-Fu, 1) and 2-chlorotetrahydrofuran (Thf-Cl), and it is reported that this synthesis must be carried out at low temperature (- 20 to -40 ° C), because Thf-Cl is unstable, and excess Thf-Cl results in a decomposition reaction, thereby reducing the yield of Thf-Fu.

[0004] Earl and Townsend also prepared 1_ (tetrahydro-2-furyl) uracil using Thf-Cl and 2,4-bis (trimethylsilyl) uracil, and then using trifluoromethyl fluorite to product Fluorination. Mitsugi Yasurnoto reacts with the Friedel-Crafts catalyst in the presence of 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-U, 1) 2-acetoxytetrahydrofuran (Thf-OAc, 2) (Kazu Kigasawa et al., 2-tert-Butoxy), & lt; RTI ID = 0.0 & gt;, & lt; / RTI & gt; (K. Kigasawa, M. Hiiragi, K. ffakisaka, et al. J. Heterocyclic Chem. 1977, 14: 473-475) was reacted with 5-Fu at 155-160 ° C. Reported in the literature for the fluoride production route there are the following questions: 1, high energy consumption. In the traditional synthesis method, in order to obtain the product, the second step of the reaction needs to continue heating at 160 ° C for 5-6 hours, high energy consumption; 2, difficult to produce, low yield: 5-fluorouracil as a solid powder The reaction needs to be carried out at a high temperature (160 ° C), which requires the use of a high boiling solvent N, N-dimethylformamide (DMF). But it is difficult to completely remove the fluoride from the addition of fluoride, because DMF can form hydrogen bonds with the fluoride molecules, difficult to separate from each other; 3, in order to unreacted 5-fluorouracil and tegafur separation and recycling , The use of carcinogenic solvent chloroform as a extractant in the conventional method to separate 5-fluorouracil and tegafur. However, the main role of chloroform on the central nervous system, with anesthesia, the heart, liver, kidney damage; the environment is also harmful to the water can cause pollution. Therefore, the use of volatile solvent chloroform, even if the necessary measures to reduce its volatilization, will still cause harm to human health and the environment; 4, low yield. Since both NI and N-3 in the 5-fluorouracil molecule react with 2-tert-butoxytetrahydrofuran, the addition of tegafur is also the addition of 1,3-bis (tetrahydro-2-furyl) -5 – Fluorouracil. Therefore, the improvement of the traditional production process of tegafur is a significant and imminent task.

Example 1 (for example, the best reaction conditions):

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 10. 0 mg CuCl2, microwave irradiation 250W at 25 ° C reaction 0. 6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), and microwave irradiation at 400 ° C for 100 ° C. After distilling off the low boiling solvent, the oil was obtained. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give 1.34349 g of product. Melting point: 160-165 ° C. The yield was 75%.

[0011] Example 2

Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 3.8 g (100 mmol) of ethanol were added to a single-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 5mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), microwave irradiation 400W, reaction temperature 60 ° C under the reaction pool. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give the product 0. 46 g. Melting point: 160-165 ° C. The yield was 15%.

[0012] Example 3

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 20mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1301: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give the product 1.81 g. Melting point: 160-165 ° C. The yield was 61%.

[0013] Example 4

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran and 19 g (500 mmol) of ethanol were added to a single-necked flask. To this was added 20 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give product U6g. Melting point: 160-165 ° C. The yield was 43%.

[0014] Example 5

Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 9.5 g (250 mmol) of ethanol were added to a single-necked flask. To this was added 30 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 6001, reaction temperature 1001: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give 1.15 g of product. Melting point: 160-165 ° C. The yield was 38%.

[0015] Example 6

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 25 ml of tetrahydrofuran (THF). And then weighed 15mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 5001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give product 2.10 g. Melting point: 160-165 ° C. The yield was 70%.

Paper

A novel protocol for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the 1,8-diazabicycloundec-7-ene-mediated alkylation of 5-fluorouracil with 2-acetoxytetrahydrofuran at 90 °C, followed by treatment of the prepurified mixture of the alkylation products with aqueous ethanol at 70 °C. The yield of the two-step process is 72%.

Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions

Aleksandra Zasada, Ewa Mironiuk-Puchalska, and Mariola Koszytkowska-Stawińska ^*

Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00103

*E-mail: mkoszyt@ch.pw.edu.pl.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00103

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00103/suppl_file/op7b00103_si_001.pdf

Tegafur, a prodrug of 5-fluorouracil (5-FUra), was discovered in 1967. The compound features high lipophilicity and water solubility compared to 5-FUra. Tegafur is used as a racemate since no significant difference in antitumor activity of enantiomers was observed.

The prodrug is gradually converted to 5-FUra by metabolism in the liver. Hence, a rapid breakdown of the released 5-FUra in the gastrointestinal tract is avoided.(6) In injectable form, tegafur provoked serious side effects, such as nausea, vomiting, or central nervous system disturbances.

The first generation of oral formulation of tegafur , UFT) is a combination of tegafur and uracil in a fixed molar ratio of 1:4, respectively. The uracil slows the metabolism of 5-FUra and reduces production of 2-fluoro-α-alanine as the toxic metabolite. UFT was approved in 50 countries worldwide excluding the USA.

S-1 is the next generation of oral formulation of tegafur.(7) It is a combination of tegafur, gimeracil, and oteracil in a fixed molar ratio of 1:0.4:1, respectively.

Gimeracil inhibits the enzyme responsible for the degradation of 5-FUra. Oteracil prevents the activation of 5-FUra in the gastrointestinal tract, thus minimizing the gastrointestinal toxicity of 5-FUra. S-1 is well-tolerated, but its safety can be influenced by schedule and dose, similar to any other cytotoxic agent. Since common side effects of S-1 can be managed with antidiarrheal and antiemetic medications, the drug can be administered in outpatient settings. S-1 was approved in Japan, China, Taiwan, Korea, and Singapore for the treatment of patients with gastric cancer.

In 2010, the Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMA), recommended the use of S-1 for the treatment of adults with advanced gastric cancer when given in a combination with cisplatin. Currently, S-1 has not been approved by the FDA in the United States.

There is a great interest in further examination of S-1 as an anticancer chemotherapeutic. Currently, 23 clinical trials with S-1 has been registered in National Institutes of Health (NIH). Combinations of S-1 and other anticancer agents have been employed in a majority of these trials.

5-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (Tegafur)

δ_H 1.89–2.10 (m, 3H), 2.38–2.45 (m, 1H), 3.97–4.01 (q-like m, 1H), 4.20–4.24 (dq-like m), 5.97–5.98 (m, 1H), 7.41 (d, ³J_HF 6.1), 9.21 (bs, 1H, NH).

δ_C 23.82, 32.90, 70.26, 87.58, 123.63 (d, ²J_CF 33.89), 140.33 (d, ¹J_CF 237.20) 148.66, 156.9 (d, ²J_CF 26.81).

HRMS m/z calcd for C₈H₁₀N₂O₃F [M – H]⁺ 201.0670, found 201.0669.

Elemental analysis. Found C%, 46.42; H%, 4.45; N%, 13.35. Calcd for 3(C₈H₉N₂O₃F)·H₂O: C%, 46.61; H%, 4.73; N%, 13.59.

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
CN85108855A *	Nov 6, 1985	Sep 24, 1986	Central Chemical Research Institute	Preparation of 1- (2-tetrahydrofuryl) -5-fluorouracil
GB1168391A *				Title not available
JPS5452085A *				Title not available
JPS5455581A *				Title not available
JPS5459288A *				Title not available
JPS52118479A *				Title not available
JPS54103880A *				Title not available
US4256885 *	Dec 10, 1976	Mar 17, 1981	Mitsui Toatsu Kagaku Kabushiki Kaisha	Process for the preparation of 1- (2-tetrahydrofuryl) -5-fluorouracil
US5075446 *	Oct 12, 1990	Dec 24, 1991	Korea Advanced Institute Of Science & Technology	Synthesis of tetrahydro-2-furylated pyrimidine derivatives

NON-PATENT CITATIONS

Reference
1	*	KAZUO KIGASAWA, et al .: ” Studies on the Synthesis of Chemotherapeutics. Synthetic of 1- (2-Tetrahydrofuryl) -5-fluorouracil [Ftorafur] (Studies on the Syntheses of Heterocyclic Compound. Part 703) “, “J. HETEROCCLIC CHEM ., Vol. 14, 31 May 1977 (1977-05-31), pages 473 – 475

References

El Sayed, YM; Sadée, W (1983). “Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes”. Cancer Research. 43 (9): 4039–44. PMID 6409396.
2
Sweetman, S, ed. (14 November 2011). “Martindale: The Complete Drug Reference”. Pharmaceutical Press. Retrieved 12 February 2014.
3
Ishikawa, T (14 May 2008). “Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma.” (PDF). World Journal of Gastroenterology : WJG. 14 (18): 2797–2801. doi:10.3748/wjg.14.2797. PMC 2710718 . PMID 18473401.
4
Caudle, KE; Thorn, CF; Klein, TE; Swen, JJ; McLeod, HL; Diasio, RB; Schwab, M (December 2013). “Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing.”. Clinical pharmacology and therapeutics. 94 (6): 640–5. doi:10.1038/clpt.2013.172. PMC 3831181 . PMID 23988873.
5
Amstutz, U; Froehlich, TK; Largiadèr, CR (September 2011). “Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity.”. Pharmacogenomics. 12 (9): 1321–36. doi:10.2217/pgs.11.72. PMID 21919607.
6
Nakayama, T; Noguchi, S (January 2010). “Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan.” (PDF). The Oncologist. 15 (1): 26–36. doi:10.1634/theoncologist.2009-0255. PMC 3227888 . PMID 20080863.
7

Matt P, van Zwieten-Boot B, Calvo Rojas G, Ter Hofstede H, Garcia-Carbonero R, Camarero J, Abadie E, Pignatti F (October 2011). “The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP).” (PDF). The Oncologist. 16 (10): 1451–1457. doi:10.1634/theoncologist.2011-0224. PMC 3228070 . PMID 21963999.

(1) Hirose, Takashi; Oncology Reports 2010, V24(2), P529-536
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(3) Tahara, Makoto; Cancer Science 2011, V102(2), P419-424
(4) Chu, Quincy Siu-Chung; Clinical Cancer Research 2004, V10(15), P4913-4921
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Hillers, Solomon; Puti Sinteza i Izyskaniya Protivoopukholevykh Preparatov 1970, VNo. 3, P109-12
Grishko, V. A.; Trudy Kazakhskogo Nauchno-Issledovatel’skogo Instituta Onkologii i Radiologii 1977, V12, P110-14
Ootsu, Koichiro; Takeda Kenkyushoho 1978, V37(3-4), P267-77
“Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US)
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Germane, S.; Eksperimental’naya i Klinicheskaya Farmakoterapiya 1970, (1), P85-92
JP 56046814 A 1981

AIST: Integrated Spectral Database System of Organic Compounds. (Data were obtained from the National Institute of Advanced Industrial Science and Technology (Japan))
ACD-A: Sigma-Aldrich (Spectral data were obtained from Advanced Chemistry Development, Inc.)
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Tegafur
Clinical data


AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: D
Routes of administration	Oral
ATC code	L01BC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)
Pharmacokinetic data
Biological half-life	3.9-11 hours
Identifiers
IUPAC name [show]
Synonyms	5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione
CAS Number	17902-23-7
PubChem CID	288216
ChemSpider	254191
UNII	1548R74NSZ
KEGG	D01244
ChEMBL	CHEMBL20883
ECHA InfoCard	100.038.027
Chemical and physical data
Formula	C₈H₉FN₂O₃
Molar mass	200.16 g/mol
3D model (Jmol)	Interactive image
SMILES [hide] FC=1C(=O)NC(=O)N(C=1)[C@@H]2OCCC2