WO2016097989A1 - Procédé de préparation de chlorhydrate de gemcitabine - Google Patents

Procédé de préparation de chlorhydrate de gemcitabine Download PDF

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WO2016097989A1
WO2016097989A1 PCT/IB2015/059620 IB2015059620W WO2016097989A1 WO 2016097989 A1 WO2016097989 A1 WO 2016097989A1 IB 2015059620 W IB2015059620 W IB 2015059620W WO 2016097989 A1 WO2016097989 A1 WO 2016097989A1
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process defined
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amine
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Khashayar Karimian
Ahmad YARI
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Khashayar Karimian
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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
    • 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

Definitions

  • the present invention relates to an improved as well as an industrially viable process for the preparation of 2'-deoxy-2',2'-difluorocytidine and its pharmaceutical acceptable acid salts thereof in high purity and acceptable yield by using a simple and inexpensive process.
  • 2'-deoxynucleosides and their analogues are useful antiviral agents. These compounds exhibit superior activity in the treatment of various cancers.
  • 2'-deoxy-2',2'-difluorocytidine of formula II which is generically known as gemcitabine and chemically described as 4-amino-1 -(2- deoxy-2,2-difluoro-p-D-ribofuranosyl)pyrimidin-2(1 H)-on, belongs to a group of chemotherapy drugs known as antimetabolites.
  • Gemcitabine is a pyrimidine which has a cytosine nucleobase at the C position of the ribofuranose and stereochemical ly oriented to ⁇ -direction and has been shown to be effective for the treatment of many types of cancers including: non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer.
  • Gemcitabine is represented by the following structure:
  • Process for preparing 2'-deoxy-2',2'-difluorocytidi involves reacting of an activated ribofuranose having a reactive leaving group at the anomeric centre, as shown in the reaction scheme 1 , with a silylated nucleobase such as cytosine and its derivatives wherein the leaving group at the anomeric carbon is replaced with the nucleobase.
  • a silylated nucleobase such as cytosine and its derivatives wherein the leaving group at the anomeric carbon is replaced with the nucleobase.
  • R [ and R 2 Benzoyl, phenylbenzoyl, TBDPhS, TBDMS, cinnamoyl, trityl, phenylcarbamoyl or naphtoyl.
  • R [ and R 2 are the same or different.
  • an a-anomer enriched carbohydrate is preferably used in SN2 coupling reaction to decrease the amount of undesired a-anomer nucleoside product.
  • the critical and cumbersome step in the preparation of the aforesaid nucleoside is the step of N-glycoside bond formation wherein the leaving group of the carbohydrate is replaced with the protected nucleobase.
  • the process for preparing 2'-deoxynucleosides is typically non-stereoselective and a mixture of alpha and beta anomer is obtained.
  • the ribofuranosyl derivative of 3,5-bis(t-butyldimethyl silyloxy)-1 -methanesulfonyloxy-2'-deoxy-2',2'-difluororibose is prepared in five steps and thereafter the reaction followed by condensing the abovementioned carbohydrate with silylated N-acetylcytosine in the precense of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as Lewis acid and reaction initiator. After the reaction is complete, the product composed of about 4: 1 ⁇ / ⁇ anomeric ratio.
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • U.S. Pat. Nos. 4,965,374 and 5.223.608 teaches a process for the preparation of gemcitabine which discloses utilizing a new ribofuranosyl in which C3 and C5 are both protected by benzoyl protecting groups.
  • the process comprises reacting 2'- deoxy-2',2'-difluoro-D-erythro-pentofuranose-3,5-dibenzo ate-1 -methanesulfonate with bis-(trimethylsilyl)-N-acetylcytosine in the precense of trimethylsilyl triflate as reaction initiator.
  • the difluoronucleoside is obtained as the dibenzoate ester and the product is as a mixture of beta and alpha anomers with about 1 :1 anomeric ratio.
  • a and p-2-deoxy-2,2-difluorocytidine are obtaind in about 1 :1 anomeric ratio with the yield of 47% (both isomers).
  • the patent describes isolating the ⁇ -2- deoxy-2,2-difluorocytidine by dissolving 1 :1 anomeric mixture of -2-deoxy-2,2- difluorocytidine in hot water, raising the pH to 7-9, cooling to a temperature of about -10-30°C and finally collecting the precipitated p-2'-deoxy-2',2'- difluorocytidine free base.
  • the p-2'-deoxy-2',2'-difluorocytidine is then converted to its hydrochloride salt by dissolving the free base in hot isopropanol, followed by addition of concentrated HCI.
  • U.S. Pat. 5,521 ,297 utilizes a new ribofuranosyl intermediate wherein 3-hydroxy group in the carbohydrate is protected by different carbamoyl derivatives to produce difluoronucleoside.
  • the patent claims using 3-hydroxy carbamoyl group on the difluororibose intermediate enhances formation of the desired beta anomer nucleoside derivative by favoring attack by the silylated nucleobase from the opposite side and as a result, beta-anomer nucleoside derivative is preferably formed.
  • 3-carbamoyl-5-benzoyl-2'-deoxy-2',2'- difluororibose-1 -alpha-mesylate is reacted with silylated cytosine in xylene in the presence of trimethylsilyl triflate.
  • the product is composed of about 60:40 ⁇ / ⁇ anomeric mixture with in situ HPLC purity of 59%.
  • haloribofuranosyl derivative intermediates for preparing difluoronucleosides.
  • U.S. Pat. No. 8,193,339 B2 describes a process for preparing gemcitabine wherein 4,4-difluoro-5-iodo-2- (trityloxymethyl)tetrahydrofuran-3-yl-benzoate is reacted with silylated cytosine in the presence of silver carbonate in acetonitrile.
  • the protected difluoro nucleoside product is composed of both beta and alpha anomers with about 5.6:1 ⁇ / ⁇ anomeric ratio with quantitative yield.
  • U.S. Pat. 7,799,907 also teaches the production of gemcitabine. Specifically, 1 -a- bromo-2'-deoxy-2',2'-difluoro -D-ribofuranosyl-5-benzoyl-3-(4-phenyl)benzoate is reacted with at least 15 molar equivalents of silyl-protected cytosine in a mixture of octane and diphenylether at the elevated temperature of about 140-150°C. The process involves continuous removal of released trimethylsilyl bromide by unremitting addition of diphenylether/heptane mixture to avoid the anomerization of furanosyl bromide.
  • the ⁇ / ⁇ anomeric ratio rages from 4.9:1 to 14:1 depending on the nucleobase/furanosyl molar ratio, which varies from 15 to 41 molar equivalents.
  • the pure p-2'-deoxy-2',2'-difluorocytidine is obtained in an overall yield of 72.6% which makes the process industrially attractive, but it still suffers from the large quantity of the solvents used in the process which need then to be recovered from in relatively pure form while the solvents are immiscible with water and have close boiling point .
  • 2'-deoxy-2',2'-difluoro-D-erythro-pentofuranose- 3,5-dib enzoate-1 -a-methanesulfonate is reacted with an excess amount of nucleobase derivative in a molar ratio ranging from about 10 molar equivalents to 12.6 molar equivalents to produce a mixture of a and ⁇ anomers in a ⁇ / ⁇ anomeric ratio of ranging from 3:1 to 58.4:1 depending on the nature of the catalyst used.
  • the catalysts of the process selected from the group comprising potassium, barium, cesium and trialkyl salts of trifluoromethanesulfonic acid, nanofluorobutanesulfonic acid etc.
  • Ribofuranosyl derivatives of imidates as leaving group at the anomeric centre have been reported for preparing difluoro nucleosides.
  • U.S. Pat. 8,168,766 rreports a process for producing 2'-deoxy-2',2'-difluoro nusleosides wherein the carbohydrate derivatives is activated by various imidates such as, ⁇ , ⁇ -dicyclohexylcarbamimidate, N,N-dicyclohexyl-N-mesyl-carbamimidate, 1 ,1 ,3,3-tetramethyl-isouronium triflate and 1 ,1 ,3,3-tetramethyl-isouronium chloride at the 1 -position of the ribofuranosyl derivatives.
  • the process comprises reacting the abovementioned imidate-activated carbohydrate with about 20-30 molar equivalents of the silylated cytosine to form a mixture of beta and alpha anomers.
  • U.S. Pat. 8,168,76 does give any details on beta and alpha anomeric ratio as well as removal of O-protecting group.
  • the novelty of the process in using an activated carbohydrate does not afford sufficient justification for its applicability to industrial scale production of gemcitabine.
  • the process uses expensive, hazardous and corrosive reagents such as oxalyl chloride, triflic anhydride and TMSOTf, which makes the invention difficult to apply for large scale production.
  • Eur. Pat. No. 1 ,853,616 B1 discloses a new ribofuranosyl derivative wherein the carbohydrate is activated by trichloroacetimidate as reactive leaving group at the 1 -position.
  • difluoronucleosides are known.
  • U.S. Pat. No. 5,633,367 reports a process for producing 2'-deoxy-2',2'-difluorocytidine which involves reacting N 4 -3',5'-tri(O-toluoyl)-2'-ketocytidine with diethylaminosulfur trifluoride (DAST) and pyridine.
  • DAST diethylaminosulfur trifluoride
  • nucleobases of cytosine (or its derivatives) is reacted with a silyl protecting group shuch as hexamethyldisilazane (HMDS) in the presence of catalytical amount of ammonium sulfate in small portion of an inert organic solvent sush as toluene at a temperature of about 1 10-130 °C to produce the silylated nucleobase of formula (IX).
  • HMDS hexamethyldisilazane
  • glycosylation reaction is conducted by the slow addition of a-methanesulfunate ribofuranosyl derivative solution of formula (X) to the silylated nucleobase mixture to obtaine the blocked 2'-deoxy- 2',2'-difluoronusleosides (XI) in about 5: 1 ⁇ / ⁇ anomeric ratio at the same temperature as mentioned above.
  • the reaction mixture is cooled to the ambient temperature and then a dilute solution of HCI was added thereto followed by filtration of the precipitate which contains hydrochloride salt of a and p-2'-deoxy-3',5'-dibenoate-2',2'-difluoronusleoside of formula (XII).
  • the precipitate is taken in a polar and preferably protic organic solvent and heated to reflux followed by the addition of an alkyl amine and then cooled to room temperature and filtered to produce the pure p-2'-deoxy-3',5'-dibenoate- 2',2'-difluoronusleoside of formula (XIII).
  • pure gemcitabine hydrochloride (I) is obtained with acceptable yield and high purity.
  • Another object of the present invention is to provide an efficient, convenient, cost effective and industrially feasible process for obtaining, in greater than 99.8% purity, nucleoside of the formula I.
  • the process comprises protecting of cytosine and its derivatives with a silyl protecting group ant optionally in the presence of a catalyst in an inert non- nucleophilic organic solvent to obtain a silyl protected nucleobase of the following structure:
  • the bases set forth above are commonly known to organic chemists, and no discussion of their synthesis is necessary. However, the primary amino group, present on some of these bases should be protected before the nucleobase is coupled with the carbohydrate.
  • the common amino-protecting groups include trimethylsilyl, t-buthyldimethylsilyl, benzyloxycarbonyl, formyl, acetyl and the like may be used according to the procedures known in the standard textbooks.
  • R 1 is selected from the group consisting and not limited to benzoyl, nitrobenzyl, chloroacetyl, phenylbenzoyl, t-butyldiphenyl silyl, phenoxy acetyl, isobutyryl, ethoxy carbonyl, benzyloxy carbonyl, mesyl, trimethylsilyl, isopropyl dimethylsilyl, methyldiisopropyl silyl, triisopropyl silyl, t-butyldimethyl silyl, cinnamoyl, trityl, phenylcarbamoyl, phenoxycarbonyl, or naphtoyl, preferably, benzoyl.
  • X is selected from the group comprising alkylsulfonyl, arylsulfonyl, substituted alkylsulfonyl, substituted arylsulfonyl, preferably, methanesulfonyl.
  • R 2 is independentaly silyl protecting group and selected from the group consisting of C1-C7 trialkylsilyl, preferably, trimethylsilyl and R 3 is H or acyl group to give the cytidine compound of formula (VI) which is composed of both alpha and beta anomers of the following structure:
  • R 1 , R 2 and R 3 are the same as defined above.
  • R 1 is the same as defined above.
  • R 1 is the same as defined hereinbefore.
  • the inventive method is characterized by limitation of the anomerization of the compound of formula (V), which can be converted to compound II in acceptable yield and in high purity. It is believed that the released trimethylsilylmethanesulfonate, which is produced during the glycosylation, anomerizes the ribifuranosyl compound and thus results in a mixure of anomers. Utilizing an excess amount of the nucleobase of formula (IV) results in high streoselectivity as well as increased ⁇ / ⁇ anomeric ratio.
  • nomer-enriched' used herein means an anomer having a specific anomer content of greater
  • anomerization means that substantially pure anomer is epimerized at the Crposition of a ribofuranose.
  • the process for producing a compound of Formula (II) can be used to produce various nucleosides such as, D-ribofuranosyl difluoronucleosides and derivatives, D-ribofuranosyl fluoronucleosides and derivatives, uridine and analogues, thymidine and analogues, cytidine and analouges or pharmaceutically acceptable salts thereof.
  • various nucleosides such as, D-ribofuranosyl difluoronucleosides and derivatives, D-ribofuranosyl fluoronucleosides and derivatives, uridine and analogues, thymidine and analogues, cytidine and analouges or pharmaceutically acceptable salts thereof.
  • the streoselective glycolysation is carried out as shown in entire schematic representation:
  • cytosine is treated with hexamethyldisilazane (HMDS) in the presence of a catalytic amount of (NH 4 ) 2 SO 4 in a small portion of an inert solvent.
  • HMDS hexamethyldisilazane
  • the nucleobase protection reaction can be conducted at a temperature between 1 10 to 130°C and more preferably at 125°C.
  • the nucleobase/(NH 4 ) 2 SO 4 molar ratio is selected ranging from 15 to 30 molar equivalents and more preferably 20 molar equivalents.
  • the HMDS/nucleobase molar ratio is selected ranging from 1 to 1 .2 molar equivalents and more preferably 1 .02 molar equivalents.
  • a preferred coupling procedure for preparing a compound of formula (XI) is comprised of reacting a compound of formula (IX) with a compound of formula (X) in an inert solvent at a temperature of about 1 10 to 130°C and more preferably at 125°C.
  • Suitable inert organic solvents that can be employed are those which are water-immiscible. Therefore, apart from their non-participation in the essential reaction, such solvents form a two-phase system with water.
  • Such a solvent offers advantage in not only effecting an efficient conversion but also helps in isolation of the product by simple evaporation or through work up by addition of water.
  • Suitable inert water-immiscible organic solvents that can be employed include halogenated e.g. chlorinated hydrocarbons, e.g. dichloromethane, chloroform, tetrachloroethylene and 1 ,2-dichloroethane; esters e.g. (Ci -4 ) alkyl esters e.g. ethyl acetate; ethers e.g. diisopropylether; aromatic hydrocarbons e.g. toluene, xylenes etc. aromatic hydrocarbons are preferred and amongst these toluene and xyelene are preferred and more preferably the suitable solvent for use is toluene.
  • halogenated e.g. chlorinated hydrocarbons, e.g. dichloromethane, chloroform, tetrachloroethylene and 1 ,2-dichloroethane
  • esters e.g. (Ci -4 ) alky
  • the compound of formula (X) was dissolved in toluene and was slowly added to the protected nucleobase mixture within 6 hours.
  • the compound of formula (X) was dissolved in 6 w/v (nucleobase) of the solvent.
  • the nucleobase/ribofuranosyl molar ratio is selected ranging from 10 to 20 molar equivalents and more preferably 15 molar equivalents.
  • the compound of formula (XI) is obtained in a ⁇ / ⁇ anomeric ratio of greater than 1 :1 and preferably greater than 3:1 and more preferably of about 5:1 ⁇ / ⁇ anomeric ratio.
  • the removal of silyl protecting group is achieved by using dilute halo acid, such as hydrochloric acid, followed by filtration of the precipitant to give a hydrodhoride salt of a compound of formula (XII) in about 5: 1 ⁇ / ⁇ anomeric ratio.
  • the volume of the water used to precipitate the compound of formula (XII) ranges from about 3 to 4.5 w/v to the nucleobase and preferably is about 4 w/v.
  • the HCI/nucleobase molar ratio used in this invention ranges from 1 .1 to 1 .5 molar equivalents and preferably 1 .3 molar equivalents.
  • the removal of the silyl protecting group can be conducted at a temperature of 10 to 40°C and preferably at ambient temperature by the slow addition of water.
  • the process for preparing a compound of formula (XIII) is comprised of dissolving a compound of formula (XII) in a polar and preferably protic solvent at reflux temperature followed by the addition of an alkyl amine to selectively isolate the title compound.
  • the solvent used herein to isolate the title compound is selected from the group comprising alcohols, ketones, esters, amides and nitriles.
  • the solvent is selected from the group comprising ethanol, isopropanol, methanol, ethyl acetate, acetone and more preferably methanol.
  • the alkyl amine is selected from the group comprising C5-C12 hetrocyclic amines and amines having the general formula R 4 R 5 R 6 N wherein R 4, R 5 and R 6 can be the same or different and are selected from the group comprising hydrogen, a CrC 6 alkyl group and a C6-C9 aryl group, with the proviso that the each of R 4, R 5 and R 6 are not hydrogen.
  • suitable hetrocyclic amines include pyridine and piperidine.
  • Non- limiting examples of other amines suitable include t-butylamine, trimethyl amine, triethyl amine, methyl amine, ethyl amine, pripyl amine, butyl amine, diethyl amine, dimethyl amine and aniline.
  • the most prefers amine for use in the present invention is triethyl amine.
  • Deprotection of the hydroxyl protecting groups of the cytidine compound of formula (XIII) is achived with aqueous ammonia in the presence of a Ci -4 alcohol at reflux temperature to give the p-2'-deoxy-2',2'-difluorocutidine of the formula (II).
  • the suitable alcohol for use herein is methanol.
  • gemcitabine base solution was acidified utilizing concentrated halo acid, such as hydrochloric acid, to give gemcitabine hydrochloride.
  • the resulting solution was acidified to pH 3 with concentrated HCI and then the precipitate was stirred at room temperature for 12 hours and thereafter the white precipitate was filtered and washed with 2 ml of methanol and dried to yield 1 .4 g of pure gemcitabine hydrochloride (85% yield) with the purity of greater than 99.8%.
  • the product was characterized by comparison of its melting point, UV, IR spectra and HPLC graph/s with those previously reported for gemcitabine hydrochloride.

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Abstract

La présente invention concerne un procédé amélioré ainsi qu'industriellement viable, pour la préparation de 2'-désoxy-2',2'-difluorocytidine et ses sels d'acide pharmaceutiquement acceptables de celle-ci à une pureté élevée et un rendement acceptable en utilisant un procédé simple et économique. Le procédé met en œuvre la réaction d'un 2'-désoxy-2',2'-difluoroglucide enrichi en anomère alpha avec des dérivés de nucléobase silylés par l'intermédiaire du déplacement SN2 d'un groupe sulfonyloxy anomère dans un solvant inerte pour produire le 2',2'-difluoro -2'-désoxycytidine-3',5'-dibenzoate dans un rapport d'anomère β/α d'environ 5:1, et un procédé d'isolement sélectif de β-2',2'-difluoro-2'-désoxycytidine-3',5'-dibenzoate à partir du mélange d'anomères β/α 5:1. Le β-2',2'-difluoro-2'-désoxycytidine-3',5'-dibenzoate pur est ensuite converti en nucléoside correspondant au moyen d'hydroxyde d'ammonium dans un solvant polaire et, de préférence, protique pour obtenir la β-2'-désoxy-2',2'-difluorocytidine, qui est ensuite convertie en chlorhydrate de gemcitabine qui est efficace contre le cancer du poumon non à petites cellules, le cancer pancréatique, le cancer de la vessie et le cancer du sein. La présente invention concerne un procédé amélioré et commode pour préparer des nucléosides antinéoplasiques, plus particulièrement, un procédé de préparation de chlorhydrate de gemcitabine, représenté par la formule I ci-dessous, qui présente une bonne activité antitumorale. (I)
PCT/IB2015/059620 2014-12-16 2015-12-15 Procédé de préparation de chlorhydrate de gemcitabine WO2016097989A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031651A (zh) * 2021-11-26 2022-02-11 江苏科本药业有限公司 一种α构型的芳酰基溴代糖的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7799907B2 (en) * 2004-12-30 2010-09-21 Hanmi Pharm. Co., Ltd Method for the preparation of 2′-deoxy-2′,2′-difluorocytidine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7799907B2 (en) * 2004-12-30 2010-09-21 Hanmi Pharm. Co., Ltd Method for the preparation of 2′-deoxy-2′,2′-difluorocytidine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031651A (zh) * 2021-11-26 2022-02-11 江苏科本药业有限公司 一种α构型的芳酰基溴代糖的制备方法

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