WO2006095359A1 - Synthese du 2-desoxy-2,2-difluoro-d-ribofuranose-3,5-di(4-methyl-4-nitro-chloro)benzoate et sa conversion en chlorhydrate de gemcitabine - Google Patents

Synthese du 2-desoxy-2,2-difluoro-d-ribofuranose-3,5-di(4-methyl-4-nitro-chloro)benzoate et sa conversion en chlorhydrate de gemcitabine Download PDF

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Publication number
WO2006095359A1
WO2006095359A1 PCT/IN2005/000160 IN2005000160W WO2006095359A1 WO 2006095359 A1 WO2006095359 A1 WO 2006095359A1 IN 2005000160 W IN2005000160 W IN 2005000160W WO 2006095359 A1 WO2006095359 A1 WO 2006095359A1
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formula
product
chloride
toluene
deoxy
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PCT/IN2005/000160
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English (en)
Inventor
Ramesh Babu Potluri
Hariharakrishnan Venkata Subramanian
Ramesh Betini
Satyanarayana Gunturu
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Sms Pharmaceuticals Limited
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Publication of WO2006095359A1 publication Critical patent/WO2006095359A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

Definitions

  • the invention relates to the filed of chemistry and more particularly relates to the synthesis of 2-deoxy-2,2-di fluoro-D-ribo furanose - 3,5 di (4-me ⁇ hyl / 4-nitro/4- chloro) benzoate and its conversion to Gemcitabine, HCI thereof.
  • Furanosyl nucleosides like Cytarabine and Zalcitabine have been used for the treatment of acute mylogenous leukemia. Introducing fluorine into nucleosides has also proved to be useful procedure for modifying the biological activity of these compounds.
  • Gemcitabine a 2'-deoxy-2 ,2'-difluoro nucleoside has proved to be highly active against cancer and has been used for treating several types of tumors.
  • the product of formula V was reduced to give iactol derivative of formula Va and then mesylated to give a product of formula Vl.
  • the mesylate, of formula Vl was coupled with bissilyl acetyl cytosine to give the protected nucleoside, which was hydrolyzed, converted into hydrochloride salt and crystallized to give Gemcitabine HCI of greater than 99% purity.
  • One of the objective of the present invention is to prepare a novel derivative similar to di benzoate of fomula-V Viz diaroyl derivative of formula Vb , which can be isolated and easily purified .
  • Another objective is to convert the lactone derivative of formula Vb to lactol derivative by using a reagent, which is cheaper and easier to handle.
  • Yet another objective of the invention is to develop a methodology , which results in Gemcitabine hydrochloride of extra high purity.
  • the invention describes a new process for the manufacture of high pure Gemcitabine hydrochloride of formula I
  • R is CH 3 -CI, NO 2
  • R' is CH 3 SO 2 , C 6 H 5 SO 2 ⁇ -CH 3 -C 6 H 4 SO 2 etc
  • the product of formula - VII was reacted with an aroyl chloride like p- toluoyl chloride, p-chloro benzoyl chloride, p-nitro benzoyl chloride etc in the presence of an organic base like pyridine, picolines etc.
  • the reaction was preferably conducted in the presence of a promoter like 4-dimethyl amino pyridine.
  • the reaction was conducted more preferably at a temperature of 60 - 70° C and the progress of the reaction was followed by TLC.
  • the solvent systems tried were mixture of benzene, toluene, xylene, fluoro benzene etc and hexane, petroleum ether/ heptane, cyclohexane etc. It was preferable to use a mixture of toluene or fluoro benzene with hexane, heptane, cyclohexane etc.
  • the residue after aroylation, with the respective aroyl chloride, was dissolved in about 6 to 8 volumes of the aromatic solvent and subjected to azeotropic distillation. It was preferably concentrated completely and then the residue was again dissolved in 4 to 6 volumes of the aromatic solvent.
  • the solution was warmed to 60 - 80° C and with stirring was diluted with an equal volume of the alkane VIZ petroleum ether, hexane, heptane, cyclohexane etc.
  • the diaroyl derivative precipitated in good yield and excellent purity (>99% by HPLC).
  • the yield of the diaroyl derivative was about 25%.
  • reaction was preferably conducted at -10° to +20 0 C.
  • the progress of the reaction mixture was monitored by HPLC(Zorbax CN hexane and isopropylakcohol 92:8 at ⁇ 254).
  • the product showed up as two peaks.
  • the product obtained as described above was converted into a product of formula - Vib by reacting with aliphatic/aromatic sulphonyl chloride.
  • This reaction was conducted preferably in a solvent like dichloro methane dichloroethane, ethyiacetate etc using triethylamine or diisopropylethylamine or N- methyl morpholine as the acid scavenger.
  • the progress of the reaction was monitored by HPLC(Zorbax CN hexane: isopropyl alcohol 92:8 ⁇ 254).
  • the product showed up as two peaks.
  • the reaction mixture was worked up and the product obtained was used for coupling with bis silyl acetyl cytosine.
  • Acetyl cytosine was converted into bissilyl acetyl cytosine by treatment with hexa methyl disilazane before it was subjected to coupling with product of product of Vl b.
  • the reaction was conducted preferably in the presence of trimethyl silyltri fluoro methane sulfonate.
  • Several other reagents like SnCI 4 , ZnCI 2 etc. were also tried but the yields were not very good.
  • the coupling reaction was tried in several solvents like benzene, toluene, xylene, fluoro benzene, methylenechloride.dichloro ethane, ethylacetate, acetonitrile, etc.
  • the product obtained on coupling of bis silyl acetyl cytosine and the di aroyl derivative of formula VIb, was preferably deprotected in a solvent like methanol, ethanol, isopropanol, etc. in the presence of base like ammonia, mono methyl amine, dimethyl amine etc at a temperature of 0 - 30° C during a period of 15 - 20 hours.
  • the alcoholic solution was concentrated under reduced pressure, and dissolved in 2 to 4 volumes of water.
  • the aqueous solution was washed preferably with an organic solvent like ethyl acetate, hexane, etc.
  • the aqueous layer was diluted with 3 - 4 volumes of isopropyl alcohol and concentrated. This process was preferably repeated 2 to 4 times.
  • the residue obtained was again dissolved in 3 to 6 volumes of iso propyl alcohol.
  • the residue was more preferably dissolved in 4 to 6 ' volumes of iso propyl alcohol, warmed to 60 - 80° C and hydrochloric acid, 0.5 volume to that of the residue, was added.
  • the reaction mixture was preferably stirred at 65 - .75 0 C for 30 - 60 minutes, allowed to cool to room temperature under stirring and was stirred further for 10 to 16 hours. Then the reaction mixture was cooled to about 0 - 5 0 C and preferably stirred for 2 to 4 hours.
  • the precipitated solid was filtered, washed with acetone and dried.
  • the sample was ⁇ 95% rich in the ⁇ -anomer.
  • the yield at this step was ⁇ 15% starting the diaroyl derivative Vb.
  • the solid, obtained above, was further purified by first stirring with water.
  • the solid was taken in 1 to 2 volumes of water and stirred preferably for 1 - 3 hours at 15 - 30° C, filtered, washed with acetone and dried. Dissolving in water and precipitating with a solvet like acetonitrile or isopropyl alcohol or acetone further purified the product.
  • the solid was preferably dissolved in 3 to 6 volumes of water.
  • the solid was more preferably dissolved in 4 to 6 volumes of water, heated to about 60 - 70° C and filtered.
  • the filterate was diluted with one of the organic solvent mentioned earlier.
  • the ratio of water to that of the organic solvent was preferably 1 :8 to 12.
  • the ratio of water to organic solvent was more preferably 1 :9 to 1 1.
  • Ethyl-2,2-difluoro-3-(2,2-dimethyl dioxalan-4-yl) propionate was prepared by the methods described in the literature. The product was rich in R-isomer by about 75% and this product was used in the following reactions
  • reaction mixture wis stirred at 60 0 C to 65 0 C for about 3 hours and then cooled to 25 0 C to 30 0 C and filtered through a bed of hyflow. Then the hyflow bed was washed with 200 ml ethyl acetate.
  • the combained extract was successively washed with 300 ml each of 10%hydrochloric acid, 10% sodium bicarbonate, saturated sodiumchloride solution and finally dried over anhydrous sodium sulphate
  • the ethylacetate solution was filtered and concentrated under reduced pressure. The residue was dissolved in 150 ml toluene and transferred into a three-necked round bottom flask fitted with a stirrer, addition funnel and a thermometer socket.
  • the reaction mixture was analyzed byTLC (Mobile phase-Ethyl acetate: Pet. Ether: 2:8). It was also analyzed by HPLC in zarboax CN using hexane + isopropyl alcohol 92ml + 8ml which indicated the product as two peaks.
  • the reaction mixture was washed with 5% aqueous sodium bicarbonate solution, 325ml, saturated sodium chloride solution 325ml and separated.
  • the toluene extract was dried over anhydrous sodium sulphate, filtered and then concentrated to give 100 gms of the title product. This was used for the Verbruggen protocol.
  • Example- 4 Preparation of 2'-Deoxy-2',2'-difluoro cytidine(I)
  • a stirrer, condenser and a stopper acetyl cytosine 97.36gms, toluene 2lit, hexamethyl disilazane 169ml and trimethyl silyl chloride 5ml were charged and the reaction mixture was heated to reflux under stirring. The reaction mixture slowly attained clarity and from that point the mixture was stirred at reflux for another 3 hours.
  • the progress of the reaction was monitored by TLC (dichloromethane: methanol 9:1).
  • the reaction mixture was cooled to 20 0 C to 25 0 C and 5% aqueous hydrochloric acid, 600ml, was added dropwise in about 30minutes. After the addition, the reaction mixture was stirred for 15minutes and allowed the layers to separate.
  • the aqueous layer was washed with toluene 2000ml and the combined toluene 9 extract was washed with a saturated solution of sodium chloride, 300ml. Then the organic layer was separated and dried with anhydrous sodium sulphate.
  • the fluoro benzene solution was filtered and concentrated under reduced pressure at 50 0 C.
  • the residue was dissolved in 1.5lit methanol and cooled to about 0 0 C to 5 0 C. Ammonia gas was bubbled into the methanolic solution for about 8 hours. Then the solution was brought to about 20 0 C to 25 0 C and ammonia gas was bubbled for further 8 hours. The progress of the reaction reaction was monitored by TLC for completion. The methanolic solution was treated with carbon, 15gms and filtered. The filtrate was concentrated under reduced pressure at 45 0 C. The residue was dissolved in about 400ml Water and the aqueous solution was washed first with 100ml ethyl acetate and then with 100ml hexane .
  • the ethyl acetate and hexane extracts were separately washed with 50ml each of water and the water extracts were combined with the main aqueous solution.
  • the aqueous extract was stirred with carbon, 10gm, and filtered through a bed of hyflow.The hyflow bed was washed with water, 50ml.
  • the combined aqueous solution was then concentrated.
  • the residue was dissolved in 1500ffil isopropyl alcohol and then the solution was subjected to distillation.
  • the addition of isopropyl alcohol and distillation was repeated two more times by adding 750ml of alcohol each time.
  • isopropyl alcohol, 700ml was added to the residue and the solution was warmed to about 70 0 C.
  • Method A About 50gms of the product of about 95% rich in ⁇ -anomer was stirred with 50ml DM water at 30 0 C for about 30minutes in a 250ml three-necked round bottom flask. The solid material was filtered, washed with acetone and pressed dry to give40.0 gm of product.
  • the solid obtained above was taken in about 188 ml water in a 250 ml three- necked round bottom flask fitted with a stirrer, condenser and a stopper.
  • the slurry was heated to 70 0 C to 75 0 C in order to dissolve the solid:
  • the solution was filtered to remove any insoluble material and the filtrate was transferred into a 3 lit three- necked flask fitted with a stirrer, addition funnel and stopper.
  • the aqueous solution was stirred at 25 0 C to 30 0 C and acetone2.3 lit, was added dropwise from the addition funnel. After the completion of addition the slurry was stirred at 25 0 C to 3.0 0 C for 1 hour and the solid was filtered. It was washed'with acetone and dried at 60 0 C to give 36.0 gm of very pure product.
  • Method B About 50gms of the product of about 95% rich in ⁇ -anomer, was stirred with 50ml DM water at 30 0 C for about 30minutes in a 250ml three-necked round bottom flask. The solid material was filtered, washed with acetone and pressed dry to give gms of product
  • the solid obtained above was taken in about 190 ml of water in a 250 ml three-necked round bottom flask fitted with a stirrer, condenser and a stopper.
  • the slurry was heated to about 70 0 C to 75 0 C in order to dissolve the solid.
  • the solution was filtered to remove any insoluble material and the filtrate was transferred into a 3lit three-necked round bottom flask fitted with a stirrer, addition funnel and stopper.
  • the aqueous solution was stirred at 25 0 C to 30 0 C and 3 lit acetonitrile was added dropwise from the addition funnel. After the completion of addition the slurry was stirred at 25 0 C to 3O 0 C and the solid was filtered, washed with acetone, pressed dry and dried 60 0 C to give 36 gm of very pure product.
  • Method C About 50gms of the product about 95% rich ⁇ -anomer was stirred with 50ml DM water at 30 0 C for about 30minutes in a 250ml three-necked round bottom flask. The solid material was filtered, washed with acetone and pressed dry to give 40 gm of product.
  • the solid obtained above was later dissolved in about 188 ml water in a 250 ml three-necked round bottom flask fitted with a stirrer, condenser and a stopper.
  • the slurry was heated to about 70 0 C to 75 0 C ⁇ n order to dissolve the solid.
  • the solution was filtered to remove any insoluble material and the filtrate was transferred into a 3 lit three necked round bottom flask fitted with a stirrer, addition funnel and stopper.
  • the aqueous solution was stirred at 25 0 C to 30 0 C and isopropyl alcohol 2.3 lits was added dropwise from the addition funnel.

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Abstract

L'invention décrit la synthèse d’un dérivé non rapporté jusqu’ici, le 2-désoxy-2,2-difluoro-D-ribofuranose-3,5-di-(aroyle) répondant à la formule (Vb), où R représente CH3, Cl ou NO2. L’invention décrit également sa conversion en chlorhydrate de Gemcitabine de formule (I), un produit anti-cancéreux.
PCT/IN2005/000160 2005-03-10 2005-05-19 Synthese du 2-desoxy-2,2-difluoro-d-ribofuranose-3,5-di(4-methyl-4-nitro-chloro)benzoate et sa conversion en chlorhydrate de gemcitabine WO2006095359A1 (fr)

Applications Claiming Priority (2)

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IN240CH2005 2005-03-10
IN240/CHE/2005 2005-03-10

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WO2006095359A1 true WO2006095359A1 (fr) 2006-09-14

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1960378A1 (fr) * 2005-12-14 2008-08-27 Dong-A Pharmaceutical Co., Ltd. Procede de fabrication de 2',2'-difluoronucleoside et de son intermediaire
WO2008117955A1 (fr) * 2007-03-23 2008-10-02 Dongwoo Syntech Co., Ltd. Procédé de préparation de la 2'-désoxy-2',2'-difluorocytidine
KR100863463B1 (ko) * 2007-03-23 2008-10-16 동우신테크 주식회사 광학적으로 순수한 옥소라이보스유도체의 제조방법
ITMI20081874A1 (it) * 2008-10-23 2010-04-24 Prime Europ Therapeuticals Procedimento per la preparazione di gemcitabina cloridrato
CN102617483A (zh) * 2011-06-30 2012-08-01 江苏豪森药业股份有限公司 盐酸吉西他滨制备过程中胞嘧啶的回收处理方法
CN102617484A (zh) * 2011-06-30 2012-08-01 江苏豪森药业股份有限公司 盐酸吉西他滨制备过程中胞嘧啶的回收处理方法
CN102659884A (zh) * 2012-04-23 2012-09-12 南京臣功制药股份有限公司 盐酸吉西他滨的提纯方法
CN103980333A (zh) * 2014-05-23 2014-08-13 上海鼎雅药物化学科技有限公司 一种盐酸吉西他滨的纯化方法
CN107200757A (zh) * 2017-06-29 2017-09-26 上海泓博智源医药股份有限公司 一种桥环氟代酯及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0719788A2 (fr) * 1994-12-13 1996-07-03 Eli Lilly And Company Procédé pour la préparation de l'hydrochlorure de 1-(2'-deoxy-2',2'-difluoro-D-ribofuranosyl)-4-amino-pyrimidine-2-one

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0719788A2 (fr) * 1994-12-13 1996-07-03 Eli Lilly And Company Procédé pour la préparation de l'hydrochlorure de 1-(2'-deoxy-2',2'-difluoro-D-ribofuranosyl)-4-amino-pyrimidine-2-one

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHOU T.S. ET AL.: "Stereospecific Synthesis of 2-Deoxy-2,2-difluororibonolactone and Ist Use in the Preparation of 2-Deoxy-2,2-difluoro-beta-D-ribofuranosyl Pyrimidine Nucleosides: The Key Role of Selective Crystallization", SYNTHESIS, June 1992 (1992-06-01), pages 565 - 570, XP000572747, DOI: doi:10.1055/s-1992-26167 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1960378A4 (fr) * 2005-12-14 2011-05-25 Dong A Pharm Co Ltd Procede de fabrication de 2',2'-difluoronucleoside et de son intermediaire
EP1960378A1 (fr) * 2005-12-14 2008-08-27 Dong-A Pharmaceutical Co., Ltd. Procede de fabrication de 2',2'-difluoronucleoside et de son intermediaire
WO2008117955A1 (fr) * 2007-03-23 2008-10-02 Dongwoo Syntech Co., Ltd. Procédé de préparation de la 2'-désoxy-2',2'-difluorocytidine
KR100863463B1 (ko) * 2007-03-23 2008-10-16 동우신테크 주식회사 광학적으로 순수한 옥소라이보스유도체의 제조방법
US7994310B2 (en) 2007-03-23 2011-08-09 Dongwoo Syntech Co., Ltd. Process for preparing 2′-deoxy-2′, 2′-difluorocytidine
JP2010522158A (ja) * 2007-03-23 2010-07-01 ドンウ シンテック カンパニー リミテッド ２’−デオキシ−２’，２’−ジフルオロシチジンの製造方法
ITMI20081874A1 (it) * 2008-10-23 2010-04-24 Prime Europ Therapeuticals Procedimento per la preparazione di gemcitabina cloridrato
EP2180005A1 (fr) * 2008-10-23 2010-04-28 Prime European Therapeuticals S.p.A. in forma Abbreviata Euticals S.p.A. Procédé pour la préparation du chlorohydrate de Gemcitabine
US8299239B2 (en) 2008-10-23 2012-10-30 Prime European Therapeucials S.p.A. Process for the preparation of gemcitabine hydrochloride
CN102617483A (zh) * 2011-06-30 2012-08-01 江苏豪森药业股份有限公司 盐酸吉西他滨制备过程中胞嘧啶的回收处理方法
CN102617484A (zh) * 2011-06-30 2012-08-01 江苏豪森药业股份有限公司 盐酸吉西他滨制备过程中胞嘧啶的回收处理方法
CN102659884A (zh) * 2012-04-23 2012-09-12 南京臣功制药股份有限公司 盐酸吉西他滨的提纯方法
CN102659884B (zh) * 2012-04-23 2014-07-02 南京臣功制药股份有限公司 盐酸吉西他滨的提纯方法
CN103980333A (zh) * 2014-05-23 2014-08-13 上海鼎雅药物化学科技有限公司 一种盐酸吉西他滨的纯化方法
CN107200757A (zh) * 2017-06-29 2017-09-26 上海泓博智源医药股份有限公司 一种桥环氟代酯及其制备方法和应用

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