CN101356165A - Process for preparing gemcitabine and associated intermediates - Google Patents

Process for preparing gemcitabine and associated intermediates Download PDF

Info

Publication number
CN101356165A
CN101356165A CNA2006800471287A CN200680047128A CN101356165A CN 101356165 A CN101356165 A CN 101356165A CN A2006800471287 A CNA2006800471287 A CN A2006800471287A CN 200680047128 A CN200680047128 A CN 200680047128A CN 101356165 A CN101356165 A CN 101356165A
Authority
CN
China
Prior art keywords
general formula
chloro
erythro
mixture
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2006800471287A
Other languages
Chinese (zh)
Inventor
V·纳达卡
E·克罗普弗
S·萨伊德
D·蒙特维利斯基
O·阿拉德
J·卡斯皮
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wavelength Pharmaceuticals Ltd
Original Assignee
Chemagis Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chemagis Ltd filed Critical Chemagis Ltd
Publication of CN101356165A publication Critical patent/CN101356165A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Provided is a process for preparing gemcitabine and intermediates useful in the production of gemcitabine. Exemplary intermediates include mixtures of D-erythro and D-threo diastereomers of ethyl 3-(N-carbamoyloxy)-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)propionates, from which a preferred isomer can be separated, e.g., by selective crystallization, in accordance with the invention. Also provided are novel alkyl (D-erythro)-3-hydroxy-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)propionate intermediates, and novel ribo lactones, which can be used for producing gemcitabine.

Description

The preparation method of gemcitabine and relevant intermediate
Background technology
Gemcitabine HCl is (by Eli Lilly with trade mark
Figure A20068004712800091
Sell) be nucleoside analog, it shows antitumour activity and belongs to the big class of the chemotherapeutics that is called metabolic antagonist.Gemcitabine produces DNA and RNA by the synthetic prevention cell that hinders nucleic acid, thereby stops the growth of cancer cells and cause their death.
Gemcitabine is the synthesis of glycoside analogue of cytosine(Cyt), its chemically be described as 4-amino-1-(2-deoxidation-2,2-two fluoro-β-D-ribofuranosyl)-pyrimidine-2 (1H)-ketone or 2 '-deoxidation-2 ', 2 '-difluoro cytidine (beta isomer).Gemcitabine HCl has following structure:
Figure A20068004712800092
The gemcitabine hydrochloride
1
Figure A20068004712800093
Hydrochloride as sterile form in bottle provides, only be used for intravenously and use, it comprises 200mg or 1g have mannitol (200mg or 1g respectively) and sodium acetate (distinguishing 12.5mg or 62.5mg) as the preparation of aseptic freeze-dried powder gemcitabine HCl (as free alkali).Can add hydrochloric acid and/or sodium hydroxide and be used for the adjusting of pH value.
U.S. Patent number 4,808,614 (" ' 614 patents ") have been described the synthesis preparation method of gemcitabine, and this method has been carried out explanation generally in flow process 1.
Flow process 1
Figure A20068004712800101
In the presence of activated zinc, make D-Glycerose ketal 2 and bromo difluoro acetate ethyl ester (BrCF 2COOEt) react, and obtain to be 2 of 3-R and 3-S isomer mixture, 2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl)-ethyl propionate 3.3-R and 3-S isomer proportion are about 3: 1.This 3-R isomer has for preparing the needed stereochemical structure of required erythro (3-R) ribose structure, and can be by chromatography and 3-S isomer separation.
By with acidic ion exchange resin for example Dowex 50W-X12 handle product cyclisation with gained, and produce 2-deoxidation-2,2-two fluoro-D-are red-valeric acid-gamma lactone 4.Protect the hydroxyl of this lactone and obtain shielded lactone 3 with t-butyldimethylsilyl (TBDMS) protecting group; 5-pair-(t-butyldimethylsilyloxy base)-2-deoxidation-2; 2-two fluoro-1-oxo ribose 5; and this product reduction is obtained 3; 5-pair-(t-butyldimethylsilyl)-2-deoxidation-2,2-difluoro ribose 6.
By introducing leavings group, for example the 1-position of this carbohydrate is activated and obtained 3 by the methanesulfonyloxy group (methanesulfonates) that compound 6 and methane sulfonyl chloride reaction are formed, 5-pair-(t-butyldimethylsilyloxy base)-1-methanesulfonyloxy group-2-deoxidation-2,2-difluoro ribose 7.By making compound 7 at initiator for example in the presence of the trifluoromethane sulfonyloxy trimethyl silane (trimethylsilyl triflate) and N, O-is two-and 8 reactions of (trimethyl silyl)-cytosine(Cyt) are coupled to basic ring on this carbohydrate.Remove and the chromatogram purification of protecting group provide the gemcitabine free alkali.
U.S. Patent number 4,526,988 have described wherein following similar approach of carrying out cyclisation: with gentle tart ion exchange resin with 3-dioxolanyl-2,2-two fluoro-3-hydroxyl-alkyl propionates hydrolysis.Same J.Org.Chem.53 referring to people such as Hertel, 2406 (1998).
U.S. Patent number 4,965,374 (" ' 374 patents ") have been described the intermediate 3 by following general formula, and the lactone of 5-dibenzoyl ribose protection (ribo protected) prepares the method for gemcitabine:
Wherein required erythro isomer can be emanated out from the mixture of erythro and threo isomer by crystal form.The method of describing in ' 374 patents has carried out summarizing generally in flow process 2.
Flow process 2
Figure A20068004712800121
The mixture of α and β anomer
With the following 3-hydroxy esterification of benzoyl protecting group with compound 3: tertiary amine or catalyzer for example 4-dimethylaminopyridine or 4-pyrrolidyl pyridine in the presence of with Benzoyl chloride, benzoyl bromide, benzoyl cyanide, benzoyl azide etc. (for example; PhCOX, wherein X=Cl, Br, CN or N 3) reaction, and obtain 2,2-two fluoro-3-benzoyloxy-3-(2,2-dimethyl dioxolane-4-yl)-ethyl propionate 9.
Selectivity is removed 9 different alkylidene protecting group, for example passes through to use for example vitriol oil in ethanol of strong acid, and produces ethyl-2,2-two fluoro-3-benzoyloxys-4,5-dihydroxy-acid ester 9A.This product is cyclized into lactone 10 and is transformed into dibenzoate and is produced as the lactone 2-deoxidation-2 of erythro and threo isomer mixture, 2-difluoro penta furanose-1-glycosides-3,5-dibenzoate 11.Should ' 374 patents have described by from this mixture, emanate at least a portion of erythro isomer of selective precipitation.Equally referring to people such as Chou, Synthesis, 565-570, (1992).
Then compound 11 reduction are obtained 2-deoxidation-2; the α of 2-difluoro penta furanose-dibenzoate 12 and the mixture of β anomer; with methane sulfonyl chloride this mixture activation is obtained methanesulfonates; 2-deoxidation-2; 2-two fluoro-D-ribofuranosyls-3; the end group heterogeneous mixture of 5-two-O-benzoyl-1-O-β-methane sulfonate 13; and and N; two (trimethyl silyl)-cytosine(Cyt) 8 couplings of O-and obtain nucleosides 14 as the silyl protection of dibenzoate, it is α-and the mixture of beta-anomer-(about 1: 1 α/β anomer ratio).Ester and silyl protecting group remove the mixture that beta-anomer-(gemcitabine) and alpha-anomer (about 1: 1 α/β anomer ratio) are provided.' 374 patents have been described following selectivity segregation beta-anomer-(gemcitabine): the salt that forms the anomer mixture, for example hydrochloride or hydrobromate, and selective precipitation and obtain into 2 of salt '-deoxidation-2 ', 2 '-difluoro cytidine (α/beta ratio 1: 4).' 374 patents have also been described the beta-anomer-that in micro alkaline solution selective precipitation is free alkali form.A kind of like this method comprises: in hot sour water (the pH value is adjusted to 2.5-5.0) 1: 1 α/β anomer mixture of dissolving and, in case this mixture is gone up dissolving substantially, just increase the pH value to 7.0-9.0 and allow the cooling of this solution, and produce crystal, by this crystal of isolated by filtration.
U.S. Patent number 5,521,294 (" ' 294 patents ") relate to 1-alkyl sulphonyl-2,2-two fluoro-3-formamyl ribose intermediates and by its deutero-nucleosides.This compound especially can be used for preparing 2 '-deoxidation-2 ', 2 '-two fluoro-β-cytidines and other beta-anomer-nucleosides.The instruction of ' 294 patents especially uses 3-hydroxyl amino formyl radical to improve the formation of required β anomer nucleoside derivates on difluoro ribose intermediate.On difluoro ribose intermediate, use the method for 3-hydroxyl amino formyl radical to comprise lactone 11 (with two-step reaction) conversion to form dibenzoyl methanesulfonates 13; then go protection in the 3-position and obtain 5-one benzoyl methanesulfonates intermediate 15, it and various isocyanate reaction and obtain the compound of general formula 16.Following step is as the described coupling of previous patent and goes protection.Method and intermediate 15 and 16 illustrate in the flow process 3 below generally:
Flow process 3
Figure A20068004712800141
The anomer separating mixture of alkyl sulfonic ester intermediate has also been described.U.S. Patent number 5,256,797 and 4,526,988 have described 2-deoxidation-2, the separation method of the anomer of 2-two fluoro-D-ribofuranosyl-1-alkyl sulfonic esters, U.S. Patent number 5,256,798 have described the method for the ribofunanosyl sulfonates that obtains to be rich in alpha-anomer.
Other intermediate that can be used to prepare gemcitabine is disclosed.For example; U.S. Patent number 5; 480; 992 have described 2; the anomer mixture of 2-difluoro ribosyl trinitride and corresponding amine intermediate, this intermediate can be for example by making 2-deoxidation-2,2-two fluoro-D-ribofuranosyls-3; 5-two-O-benzoyl-1-O-β-methane sulfonate and trinitride nucleophilic reagent for example Lithium Azide react and prepare, to obtain this trinitride.The reduction of this trinitride produces corresponding amine, and this amine can be converted into nucleosides synthetically.Also referring to U.S. Patent number 5,541,345 and 5,594,155.
Other known intermediate for example comprises, tritylation (tritylated) intermediate (U.S. Patent number 5,559,222), 2-deoxidation-2,2-two fluoro-β-D-ribose-pyranopentose (U.S. Patent number 5,602,262), 2-replaces-3,3-difluoro furans intermediate (U.S. Patent number 5,633,367) and α, α-two fluoro-beta-hydroxy mercaptan ester (U.S. Patent number 5,756,775 and 5,912,366).
There is the intrinsic problem relevant, especially prepare and the separating isomerism body, and tend on commercial size, produce the method for bad productive rate for needs with the preparation of gemcitabine.Therefore, still need the improved preparation method of gemcitabine and intermediate thereof, this method is convenient to prepare gemcitabine, especially prepares on commercial size.The invention provides such method and intermediate, this will be apparent from the description of the invention that provides at this.
Summary of the invention
The invention provides the preparation method of gemcitabine, the compound that this method preferably includes following general formula transforms
Become gemcitabine, and randomly this gemcitabine is transformed salify.Preferably, X is O or S, and R is selected from unsaturated and saturated C 1-C 8Alkyl, the aryl that does not replace and replace, unsaturated and saturated C 1-C 8Alkyl sulphonyl and the aryl sulfonyl that does not replace and replace.
Can use any suitable method that the compound of general formula 10A is changed into gemcitabine, comprise, one or more methods of for example describing among the PCT/US2006/033431, this patent application requires in the Application No. 60/712 of submission on August 29th, 2005,217 right of priority, these methods are hereby incorporated by.Preferably; the present invention includes the 5-hydroxyl of the compound of protection general formula 10A; with the lactone carbonyl reduction with produce 3-carbamyl-5-hydroxyl-protection-2-deoxidation-2; 2-two fluoro-D-ribofuranoses; with the cytosine(Cyt) coupling of shielded N-1-protection with produce-3 of N-1-protection '-carbamyl-5 '-hydroxyl-protection-2 '-deoxidation-2; 2-two fluoro-cytidines; remove 3 '-formamyl, N-1 protecting group and 5 '-hydroxyl protecting group and produce gemcitabine; and randomly this gemcitabine is transformed salify, wherein X, Alk and R such as this paper limit.
Any suitable protecting group can be used to protect the 5-hydroxyl.Preferably, protecting group is an ester, for example benzoyl.The compound of general formula 10A can obtain by any suitable method, and preferably obtains with the compound for preparing general formula 10A by the compound cyclisation with following general formula:
Figure A20068004712800161
Wherein X and R such as this paper limit, and Alk is C 1-6Alkyl.In one embodiment, the compound of following acquisition general formula 10A: with the mixture separation of the D-erythro and the D-threo isomer of D-erythro isomer and following general formula:
Figure A20068004712800162
And this D-erythro isomer cyclisation is obtained the compound of general formula 10A, wherein X, Alk and R such as this paper limit.The mixture of this type of D-erythro and D-threo isomer is preferably as follows acquisition: the compound that makes following general formula
Figure A20068004712800163
With the reaction of the compound of general formula R-N=C=X, and be produced as the corresponding carbamate of the mixture of D-erythro and D-threo isomer, wherein X, Alk and R such as this paper limit.
In another embodiment, the compound of following acquisition general formula 10A: the compound that makes following general formula:
Produce the compound of following general formula with the compound reaction of general formula R-N=C=X:
Figure A20068004712800171
And cyclisation and produce the compound of general formula 10A, wherein X, Alk and R such as this paper limit.
The present invention further provides the intermediate that can be used for preparing gemcitabine, this intermediate can comprise the 3-(N-carbamoyloxy)-2 of general formula 9B, the D-erythro of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate and the mixture of D-threo form (3R and 3S) diastereomer:
Figure A20068004712800172
Wherein X is O or S, and R is selected from unsaturated and saturated C 1-C 8Alkyl, the phenyl that does not replace and replace, unsaturated and saturated C 1-C 8Alkyl sulphonyl and the benzenesulfonyl that does not replace and replace.
The present invention also provides the preparation method of the compound of general formula 9B, this method preferably includes and makes 2 of general formula 3 for example, 2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl) isocyanic ester of the mixture of the D-erythro of ethyl propionate and D-threo form diastereomer and general formula R NCX or lsothiocyanates reaction, wherein X and R such as this paper limit.
According to the present invention, can be by about at least 95.3% productive rate, the intermediate of preferred about at least 97.4% productive rate segregation general formula 9B.
Intermediate of the present invention can also comprise general formula 9C's (3R)-3-(N-carbamoyloxy)-2, the D-erythro diastereomer of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate:
Figure A20068004712800181
Wherein X and R such as this paper limit.
The present invention further provides D-erythro diastereomer (3R)-3-(N-carbamoyloxy)-2 of the general formula 9C that optionally emanates, the purification process of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.This purification process of the present invention can followingly carry out: with the D-erythro and the dissolving of D-threo form (3R and 3S) diastereomer of the compound of general formula 9C, be preferably dissolved in the non-polar solvent, this solution is cooled to approximately-20 ℃ to about 10 ℃ temperature, and collects this D-erythro isomer that is crystalline form.
Purification process of the present invention can provide by high purity, about at least 96.5% purity for example, and more preferably about at least 98.5% purity provides the intermediate of general formula 9C.
The present invention also provides by parent material, (D-erythro)-3-hydroxyl-2 of the compound general formula 3C of preferred formula 9C, the method for 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.
Figure A20068004712800182
There is the compound and uncle or secondary amine reaction that makes general formula 9C down in dried solvent in the Lewis acid that this method is preferably included in catalytic amount.After reaction is finished, can pass through the filtering separation by product, and obtain by product as filtrate.Can under reduced pressure remove and desolvate, can should precipitate by oil from organic solvent to produce oil.
The present invention also provides ribose lactone (ribo lactones) 3-(N-carbamoyloxy)-2-deoxidation-2 of general formula 10A, and 2-two fluoro-D-are red-preparation method of penta furanose-1-glycosides:
Figure A20068004712800191
Wherein X and R such as this paper limit.In one embodiment, this method is included in the component distillation that the D-erythro isomer of backflow general formula 9C in the acidiferous solvent mixture (for example, the mixture of acetonitrile, water and trifluoroacetic acid) then carries out water.
According to the present invention, gemcitabine can obtain by the lactone of general formula 10A, for example below flow process 6 describe, and as this paper describes in further detail.
Embodiment
According to the present invention, can realize 3-(N-carbamoyloxy)-2-deoxidation-2, the preparation of 2-two fluoro-D-erythro-penta furanoses-1-glycosides intermediate with high yield and high purity.Intermediate of the present invention especially can be used for preparing gemcitabine.
This intermediate can comprise the 3-(N-carbamoyloxy)-2 of general formula 9B, the erythro and threo form (3R and the 3S) mixture of isomers of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate, and wherein R is selected from unsaturated and saturated C 1-C 8Alkyl, the aryl that does not replace and replace, unsaturated and saturated C 1-C 8Alkyl sulphonyl and the aryl sulfonyl that does not replace and replace, X are O or S:
Figure A20068004712800192
In a preferred embodiment, the invention provides the intermediates preparation that can be used for synthesizing gemcitabine, this method comprises:
A) provide 2 of general formula 3, the D-erythro and the mixture of D-threo form diastereomer in toluene of 2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate;
B) randomly, adopt the component distillation of water to heat this mixture with dry toluene; With
C) in the presence of alkali, make 2 of this general formula 3,2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl) the D-erythro of ethyl propionate and D-threo form diastereomer mixture in toluene and isocyanic ester or the lsothiocyanates reaction of general formula R NCX, wherein X and R such as this paper limit, to obtain D-erythro and D-threo form 3-(N-carbamoyloxy)-2, the mixture of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.
According to an aspect of the present invention, use dean stark trap (Dean-Starktrap) to carry out the component distillation of water to come dry toluene in about 2 hours by heated mixt under refluxing.
According to the present invention; isocyanic ester that is used to react or lsothiocyanates can comprise, for example 2-chloro ethyl isothiocyanate; 5-chloro-2-aminomethyl phenyl lsothiocyanates; 2-chloro-4-nitrophenyl lsothiocyanates; 2-chloro-phenyl-lsothiocyanates; 3-chloro-phenyl-lsothiocyanates; 4-chloro-phenyl-lsothiocyanates; 3-acetylphenyl lsothiocyanates; 4-acetylphenyl lsothiocyanates; 2-(chloro methyl) phenyl isocyanate; 2-chloro-5-methyl-phenyl isocyanate; 2-chloro-6-aminomethyl phenyl isocyanic ester; 3-chloro-2-aminomethyl phenyl isocyanic ester; 3-chloro-4-aminomethyl phenyl isocyanic ester; 4-(chloro methyl)-phenyl isocyanate; 4-chloro-2-aminomethyl phenyl isocyanic ester; 5-chloro-2-aminomethyl phenyl isocyanic ester; 2-chloro-4-nitrophenyl isocyanic ester; 2-chloro-5-nitrophenyl isocyanic ester; 4-chloro-2-nitrophenyl isocyanic ester; 4-chloro-3-nitrophenyl isocyanic ester; 2-chloro-2-nitrophenyl isocyanic ester; 2-chloro-phenyl-isocyanic ester; 3-chloro-phenyl-isocyanic ester; 4-chloro-phenyl-isocyanic ester; 3-acetylbenzene based isocyanate; phenyl isocyanate; N-benzenesulfonyl isocyanic ester; ptoluene-sulfonyl isocyanic ester or adjacent tolylsulfonyl based isocyanate.
Preferably, isocyanic ester is 4-nitrophenyl isocyanic ester, 4-chloro-phenyl-isocyanic ester, 3-acetylbenzene based isocyanate or phenyl isocyanate.
Alkali preferably is selected from the organic bases of triethylamine, one or more lutidine, morpholine, diisopropylethylamine, pyridine, 2-(dimethylamino)-pyridine, 4-(dimethylamino) pyridine etc. and their binding substances.In a preferred embodiment, alkali is 4-(dimethylamino)-pyridine.
According to an embodiment preferred of the present invention, the 3-of general formula 9B (N-carbamoyloxy)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) preparation method of the isomer of ethyl propionate comprises provides 2 of compound 3, the erythro of 2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate and threo form (3R and 3S) in toluene mixture and this mixture is refluxed.
Preferably, this mixture comprises at least approximately 1ml toluene, more preferably about about 10ml toluene of 5ml-/gram 2,2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.When this mixture sufficiently dry, allow cooling and add alkali, then add isocyanic ester or lsothiocyanates.Preferably this mixture heating up is kept allowing to react the enough time of finishing to the temperature that is fit to.
In case reaction is finished, and reaction mixture is separated with the crystalline residue of by product and follows separating layer and dry organic layer on sal epsom with acidic solution and water washing subsequently.Usually obtain also preferably to carry out crystallization by evaporating solvent for the solid product.
According to another embodiment preferred of the present invention, with about at least 95.3%, preferred about at least 97.4% high yield obtains the 3-(N-carbamoyloxy)-2 of general formula 9B, the D-erythro and the D-threo isomer of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.
The present invention also provides general formula 9C's (3R)-3-(N-carbamoyloxy)-2, the D-erythro diastereomer of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate:
Figure A20068004712800211
The present invention also provides by the 3-(N-carbamoyloxy)-2 of selective crystallization from general formula 9B, the method for separating the D-erythro isomer in the D-erythro of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate and the D-threo isomer mixture.Preferably, this method comprises:
A) choose wantonly at high temperature, with D-erythro and the D-threo form 3-(N-carbamoyloxy)-2 of general formula 9B, the crude mixture of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate is dissolved in the organic solvent;
B) allow this solution enough to be cooled to approximately-20 ℃ to about 10 ℃ temperature, a whole night for example is to produce crystal; With
C) collect this crystal by filtering, with this crystal of organic solvent washing and dry, randomly at high temperature dry.
The 3-(N-carbamoyloxy)-2 of preparation general formula 9C, the illustrative methods of the D-erythro isomer of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate is described in the flow process 4 below:
Flow process 4
Figure A20068004712800221
In the method that flow process 4 is described, the preferably unsaturated or saturated C of R 1-C 8Alkyl, the aryl that does not replace or replace, unsaturated or saturated C 1-C 8Alkyl sulphonyl or the aryl sulfonyl that does not replace or replace.
Can be used for the solvent that is fit to of the compound crystal of general formula 9C is comprised that organic solvent for example, methylene dichloride, chloroform, ethyl acetate, acetate 1-propyl ester, acetate 2-propyl ester, butylacetate, tert.-butyl acetate, o-Xylol, m-xylene, orthodichlorobenzene, toluene etc., or their mixture.The preferred solvent that is used for the compound crystal of general formula 9C is a toluene.
The suitable organic solvent of crystalline that is obtained be can be used to wash and toluene, pentane, hexane, heptane, octane, sherwood oil, hexanaphthene or their mixture for example comprised.Be used to wash the crystalline preferred solvent that is obtained and comprise toluene and toluene/hexane mixtures, for example 1: 1 of toluene and hexane (v/v) mixture.
According to the present invention, can be about at least 96.5%, D-erythro diastereomer (3R)-3-(N-carbamoyloxy)-2 of segregation general formula 9C in preferred about at least 98.5% the purity range, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.
The present invention also provides (D-the erythro)-3-hydroxyl-2 that is prepared general formula 3C by parent material, the method for 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate:
Figure A20068004712800231
This parent material is preferably selected from general formula 9C's (3R)-3-(N-carbamoyloxy)-2, the D-erythro diastereomer of 2-two fluoro-3-(2,2-dimethyl-dioxolane-4-yl) ethyl propionate.Exemplary parent material can comprise following: (D-erythro)-3-of general formula 9E (4-nitre phenyl amino formyl radical)-3-(2; 2-dimethyl dioxolane-4-yl) ethyl propionate; (D-erythro)-3-of general formula 9F (4-chloro-phenyl-formamyl)-2; 2-two fluoro-3-(2; 2-dimethyl dioxolane-4-yl) ethyl propionate; (D-erythro)-3-of general formula 9G (3-acetylphenyl formamyl)-2; 2-two fluoro-3-(2; 2-dimethyl dioxolane-4-yl) (D-erythro)-3-(phenylcarbamoyl)-2 of ethyl propionate and general formula 9H; 2-two fluoro-3-(2; 2-dimethyl-dioxolane-4-yl) ethyl propionate; (D-erythro)-3-of preferred formula 9E (4-chloro-phenyl-carbamoyloxy)-2; 2-two fluoro-3-(2,2-dimethyl-dioxolane-4-yl) ethyl propionate.In one embodiment, this method comprises:
A) adopt the component distillation of water to add hot toluene and for example lewis acidic mixture of catalyzer with dry toluene;
B) 3-(N-carbamoyloxy)-2 of interpolation general formula 9C, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) the D-erythro isomer of ethyl propionate and this mixture that refluxes;
C) add alkali, preferred uncle or secondary amine, and keep this backflow and finish until reaction;
D) be that the crystalline by product obtains filtrate by filtering separation;
E) wash filtrate and evaporating solvent, vapourisation under reduced pressure randomly, and obtain oil; With
F) this oil is dissolved in the organic solvent and cooling, and produces the crystal of required product.
The catalyzer that is fit to for example can comprise venus crystals, tin protochloride, stannous oxalate, aluminium alkoxide etc. or their combination.Preferred catalyzer is a venus crystals.
The alkali that is fit to for example can comprise organic bases, and primary and secondary amine is n-propyl amine, n-Butyl Amine 99, normal hexyl Amine, dipropyl amine, dibutylamine, dicyclohexyl amine, morpholine, piperidines, lupetidine etc. for example, or their combination.Preferred organic bases is a morpholine.
The solvent that is fit to that is used to dissolve the oil that is obtained for example can comprise methylene dichloride, chloroform, ethyl acetate, acetate 1-propyl ester, acetate 2-propyl ester, butylacetate, tert.-butyl acetate, diethyl ether, diisopropyl ether, t-butyl methyl ether or their mixture.The preferred solvent that is used to dissolve this oil is a t-butyl methyl ether.
The present invention also provides (3R)-3-of general formula 9C (N-carbamoyloxy)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) the D-erythro diastereomer cyclisation of ethyl propionate to be obtaining 3-(N-carbamoyloxy)-2-deoxidation-2 of general formula 10A, and 2-two fluoro-D-are red-method of penta furanose-1-glycosides:
Figure A20068004712800241
Wherein X is O or S, the preferably unsaturated or saturated C of R 1-C 8Alkyl or the phenyl that does not replace or replace.This method preferably includes:
A) provide (3R)-3-(carbamoyloxy)-2 of general formula 9C, the D-erythro diastereomer of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate in containing sour solvent mixture solution and heat time enough and finish basically to allow reaction;
B) reduce this liquor capacity by distillation;
C) add toluene and make this mixture drying by component distillation; With
D) further distillate solvent mixture, and obtain to be the solid product.
This contains the mixture that sour solvent mixture preferably includes acetonitrile, water and trifluoroacetic acid.Exemplary acetonitrile: water: the trifluoroacetic acid ratio can comprise 30: 0.64: 0.14v/v/v, 40: 1.0: 0.21v/v/v and 30: 1.5: 0.15v/v/v.
Can use component distillation that Dean-Rodney Stark couch water distributing can device carries out water with for example by under refluxing, coming dry toluene in the about 5.5-7 of heated mixt hour.
According to the present invention, can be by high yield, for example by about at least 95.5%, preferred about at least 98.4% productive rate obtains 3-(N-carbamoyloxy)-2-deoxidation-2 of general formula 10A, and 2-two fluoro-D-are red-penta furanose-1-glycosides.
3-(carbamoyloxy)-2-deoxidation-2 of preparation general formula 10A, 2-two fluoro-D-are red-and the illustrative methods of penta furanose-1-glycosides describes in the flow process 5 below:
Flow process 5
Figure A20068004712800251
In the method for describing in flow process 5, R is preferably selected from unsaturated and saturated C 1-C 8Alkyl, the aryl that does not replace and replace, unsaturated and saturated C 1-C 8Alkyl sulphonyl and the aryl sulfonyl that does not replace and replace.
According to following flow process 6, can by comprise the still less method of step than the method for describing in ' 294 patents, for example obtain gemcitabine by the lactone of general formula 10A by further carrying out following steps:
A) make the reaction of lactone 10A and acyl chlorides or acylbromide to obtain the 3-formamyl lactone intermediate of general formula 17, wherein X is O or S, and R is selected from unsaturated and saturated C 1-C 8Alkyl, the phenyl that does not replace and replace;
B) in organic solvent, reduce the 3-formamyl lactone intermediate of this general formula 17 to obtain the lactonaphthol intermediate, this intermediate and methane sulfonyl chloride are reacted and the sulfonate intermediate of acquisition general formula 16A with the reductive agent that is fit to;
C) use catalyzer in organic solvent, preferably at ambient temperature, with compound 16A and two (trimethyl silyl)-N-acetylcytosine couplings, and obtain 3,5-two protections-N-1-trimethyl silyl ethanoyl-2 '-deoxidation-2 ', 2 '-α of difluoro cytidine and the mixture of β anomer;
D) precipitate this 3,5-two protection-N-1-trimethyl silyl ethanoyl-2 '-deoxidation-2 ', 2 '-beta isomer of difluoro cytidine, therefore by these two kinds of isomer of filtering separation; With
E) remove protecting group by hydrolysis, and obtain gemcitabine.
Therefore, according to the present invention, use 3-(carbamoyloxy)-2-deoxidation-2 of parent material general formula 10A, the 2-two fluoro-D-erythro-penta furanose-methods of 1-glycosides are better than obtaining the ordinary method (for example method of describing in the flow process 2 and 3) of gemcitabine, because the invention provides the still less method of synthesis step, and in addition, obtain erythro isomer 10A with high purity and productive rate.
Flow process 6
Figure A20068004712800261
In the method that flow process 6 is described, X is O or S, the preferably unsaturated or saturated C of R 1-C 8Alkyl, or the phenyl that does not replace or replace.
The reduction of lactone 10A (describing as flow process 6) can use any suitable reductive agent to carry out, for example lithium aluminum hydride, diisobutylaluminium hydride and sodium hydride two-(2-methoxy ethoxy)-aluminium etc., or their combination.This reduction (for example shown in the flow process 6 like that) preferably uses lithium aluminum hydride to carry out, and especially for scale operation, this is because its lower molecular weight and higher reducing power (4 available H atoms of each molecule).Can also use diisobutylaluminium hydride to reduce that (for example U.S. Patent number 4,808,614 and people's such as Chou Synthesis, 565-570 (1992) instruction like that), but in view of its molecular weight and it only have 1 fact that can be used for reductive H atom, diisobutylaluminium hydride is more not preferred.
Can carry out this coupled reaction (that for example describes in the flow process 6 is such) in any suitable solvent, this solvent for example can comprise that one or more are selected from acetonitrile, methylene dichloride, chloroform, 1, the organic solvent of 2-ethylene dichloride, toluene and dimethylbenzene.In one embodiment, coupled reaction is carried out in the 2-ethylene dichloride 1.Randomly, can be by using for example trimethylsilyl triflate (Me of suitable catalytic reagent 3SiOTf) promote this coupled reaction.
The removing of protecting group (for example describe in the flow process 6 like that) can be undertaken by using any suitable condition, and this condition for example can comprise, basic hydrolysis, for example, 20% ammonia in the methyl alcohol.
Embodiment
Though following examples have illustrated practice of the present invention with embodiments more of the present invention, these embodiment should not be construed the restriction scope of the invention.By considering specification sheets and embodiment, it will be appreciated by one of skill in the art that other embodiment.
Embodiment 1
This embodiment illustrates the preparation of (D-erythro)-3-(4-nitrophenyl carbamoyloxy)-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9E).
Use dean stark trap reflux 3-(hydroxyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane (dioxalane)-4-yl) ethyl propionates (2.6: 1 mixtures of D-erythro and D-threo form) (5.5g) solution in toluene (50ml) 2 hours with dry this mixture.Under nitrogen, this solution is cooled to envrionment temperature, adds 4-(dimethylamino) pyridine (0.05g) and 4-nitrophenyl isocyanic ester (3.8g) then.Heated this mixture 6 hours down at 80-90 ℃, be cooled to envrionment temperature, and collect yellow crystals 1,3-two (4-nitrophenyl) urea by filtering.Water, 1N HCl and water (each 50ml) wash this filtrate and at MgSO 4Last dry. under reduced pressure obtain solid (D-erythro, D-threo form)-3-(4-nitrophenyl-formamyl)-2,2-two fluoro-3-(2,2-dimethyl-dioxolane-4-yl) ethyl propionate, output: 7.2g (96%) except that desolvating.Under heating, this crude product is dissolved in the toluene (15ml) and 5 ℃ of this solution of cooling a whole nights down.Collect crystal by filtering, produce (D-erythro)-3-(4-nitrophenyl-formamyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9E) with the normal hexane washing and 50 ℃ of down dry a whole nights; Output: 2.1g (28%); [α] D 25-17.5 ° (c1, acetonitrile); Mp.126-128 ℃.The HPLC test shows 96.5% purity, contains 1.3% (D-threo form)-isomer.
1H?NMR(CDCl 3)：δ＝1.36(t，3H，CH 2 CH 3 )，1.35，1.39[d，6H，C(CH 3) 2]，4.09(m，2H，CH 2)，4.34(m，2H， CH 2 CH 3?and?1H，H-4)，5.60(m，1H，H-3)，7.65(d，2H arom)，7.88(s，1H，NHCO)，8.21(d，2H arom).
13C?NMR(CDCl 3)：δ＝13.8(CH 2 CH 3)，24.9，26.1[C( CH 3) 2]，63.7( CH 2CH 3)，65.6(C-5)，72.0(C-3，J C-F＝22.0，26.0Hz)，72.2(C-4)，110.4[ C(CH 3) 2]，112.7(C-2，J C-F＝252，252Hz)，118.3，125.2，143.42，143.46(C arom)，151.2(O CONHAr)，162.1(C-1，J C-F＝31，31Hz).ESI(negative)/MS：m/z＝417.1[M-H +].
Embodiment 2
This embodiment illustrates (D-erythro)-3-(4-chloro-phenyl-carbamoyloxy)-2, the preparation of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9F).
Adopt dean stark trap reflux 3-(hydroxyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane (dioxalane)-4-yl) ethyl propionates (2.85: 1 mixtures of D-erythro and D-threo form) (3) (60.0g) solution in toluene (300ml) 2 hours with dry this mixture.Under nitrogen, this mixture is cooled to envrionment temperature, adds 4-(dimethyl-amino) pyridine (0.50g) and 4-chloro-phenyl-isocyanic ester (35.0g) then.Heat this reaction mixture 6 hours down at 80-90 ℃, collect 1 by heat filtering then, the crystal of 3-two (4-chloro-phenyl-) urea.Water, 1N HCl and once more water (each 50ml) wash this filtrate, and at MgSO 4Last dry and use activated carbon treatment.Under reduced pressure produce 77.8g solid (D-erythro, D-threo form)-3-(4-chloro-phenyl-carbamoyloxy)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (productive rate 97.4%) except that desolvating.Under heating, this crude product is dissolved in (100ml) in the toluene, and filters this solution.This filtrate is cooled to 5 ℃ of a whole nights.Collect clear crystal by filtering, produce 37.7g (D-erythro)-3-(4-chloro-phenyl-carbamoyloxy)-2 with the washing of toluene-normal hexane (1: 1) mixture and 50 ℃ of down dry a whole nights, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9F), productive rate is 47.2%, has 98.5% the purity (0.09%D-threo isomer) by HPLC mensuration; [α] D 25-10.2 ° (c1.0, acetonitrile); Mp 120-122 ℃.
1H?NMR(CDCl 3)：δ＝1.33(t，3H，CH 2 CH 3 )，1.33，1.37[d，6H，C(CH 3) 2]，4.07(m，2H，CH 2)，4.32(m，2H， CH 2 CH 3?and?1H，H-4)，5.56(m，1H，H-3)，7.27(m，2H arom?and?1H，NHCO)，7.37(d，2H arom).
13C?NMR(CDCl 3)：δ＝13.8(CH 2 CH 3)，25.0，26.0[C( CH 3) 2]，63.6( CH 2CH 3)，65.6(C-5)，71.6(C-3，J C-F＝22.0，26.0Hz)，72.3(C-4)，110.3[ C(CH 3) 2]，112.8(C-2，J C-F＝256，256Hz)，120.1，129.2，135.8(C arom)，151.4(O CONHAr)，162.2(C-1，J C-F＝31，31Hz).
19F NMR shows and mainly has a kind of fluorine-containing product.APCI (bearing)/MS:m/z=406.2[M-H +].
Embodiment 3
This embodiment illustrates (D-erythro)-3-(3-acetylphenyl carbamoyloxy)-2, the preparation of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9G).
Adopt dean stark trap reflux 3-(hydroxyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane (dioxalane)-4-yl) ethyl propionate (D-erythro, 2.6: 1 mixtures of D-threo form) (3) (5.0g) solution in toluene (50ml) 2 hours with dry this mixture.Under nitrogen, this mixture is cooled to envrionment temperature, adds 4-(dimethyl-amino) pyridine (0.025g) and 3-acetylbenzene based isocyanate (3.05g) then.Heat this reaction mixture 6 hours down at 80-90 ℃, be cooled to envrionment temperature, and collect 1 by heat filtering, the crystal of 3-two (3-acetylphenyl) urea.Water, 1N HCl and once more water (each 50ml) wash this filtrate, and at MgSO 4Last dry.Under reduced pressure produce (D-erythro, D-the threo form)-3-(3-acetylphenyl formamyl)-2 of 6.3g for oil, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (productive rate 96.5%) except that desolvating.Under heating, this crude product is dissolved in the toluene (7ml) and 5 ℃ of this solution of cooling a whole nights down.Collect crystal by filtering, with pre-cooled toluene-normal hexane (1: 1, v/v) mixture washs and produces 2.0g (D-erythro)-3-(3-acetylphenyl carbamoyloxy)-2 50 ℃ of down dry a whole nights, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9G), productive rate 30.6%; [α] D 25-14.5 ° (c1, acetonitrile); Mp 92-93 ℃ .APCI (bearing)/MS:m/z=414.2[M-H +].
1H?NMR(CDCl 3)：δ＝1.34(t，3H，CH 2 CH 3 )，1.34，1.38[d，6H，C(CH 3) 2]，2.62[s，3H，C(O)CH 3]，4.03，4.12(2m，2H，CH 2)，4.33(m，2H， CH 2 CH 3?and?1H，H-4)，5.60(m，1H，H-3)，7.44(t)，7.69(d)，7.84(d)，8.00(s)(4H arom)，8.05(s，1H，NHCO).
13C-NMR(CDCl 3)：δ＝13.8(CH 2 CH 3)，25.0，26.0[C( CH 3) 2]，26.7[C(O) CH 3]，63.5( CH 2CH 3)，65.6(C-5)，71.4(C-3，J? C-F＝20.0，22.0Hz)，72.3(C-4)，110.2[ C(CH 3) 2]，112.9(C-2，J C-F＝250，250Hz)，118.3，123.3，123.9，129.5，137.8，138.2(C arom)，151.6(O CONHAr)，162.2(C-1，J C-F＝30，30Hz)，198.4[ C(O)CH 3].
19F NMR shows and mainly has a kind of fluorine-containing product.
Embodiment 4
This embodiment illustrates (D-erythro)-3-(phenyl amino methanoyl)-2, the preparation of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9H).
Adopt dean stark trap reflux 3-(hydroxyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane (dioxalane)-4-yl) ethyl propionate (D-erythro, 2.6: 1 mixtures of D-threo form) (3) (10.0g) solution in toluene (100ml) 2 hours with dry this mixture.Under nitrogen, this mixture is cooled to envrionment temperature, adds 4-(dimethyl-amino) pyridine (0.1g) and phenyl isocyanate (4.59g) then.Heated this reaction mixture 6 hours down at 80 ℃, be cooled to envrionment temperature, and collect 1, the crystal of 3-diphenyl urea by filtering.Water, 1N HCl and once more water (each 50ml) wash this filtrate, and at MgSO 4Last dry, and use activated carbon treatment.Under reduced pressure produce thick (D-erythro, D-the threo form)-3-(phenyl amino methanoyl)-2 of 11.2g for oil, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (productive rate 95.3%) except that desolvating.Under heating, this crude product is dissolved in the toluene (7ml) and at-20 ℃ of these solution of cooling 5 days down.Collect crystal by filtering, with pre-cooled toluene-normal hexane (1: 1, v/v) solution washing of mixture and produce 3.0g (D-erythro)-3-(phenyl amino methanoyl)-2 50 ℃ of down dry a whole nights, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (9H), productive rate 25.5%; Mp 75-77 ℃.
1H?NMR(CDCl 3)：δ＝1.33(t，3H，CH 2 CH 3 )，1.34，1.38[d，6H，C(CH 3) 2]，4.08(m，2H，CH 2)，4.35(m，2H， CH 2 CH 3?and?1H，H-4)，5.58(m，1H，H-3)，7.09(t)，7.31(t)，7.41(d)(5H arom)，7.40(s，1H，NHCO).
13C?NMR(CDCl 3)：δ＝13.9(CH 2 CH 3)，25.1，26.1[C( CH 3) 2]，63.5( CH 2CH 3)，65.7(C-5)，71.5(C-3，J C-F＝22.0，25.0Hz)，72.4(C-4)，110.2[ C(CH 3) 2]，112.9(C-2，J C-F＝248，248Hz)，118.8，124.2，129.2，137.2(C arom)，151.4(O CONHPh)，162.2(C-1，J C-F＝31，31Hz).
19F NMR shows and mainly has a kind of fluorine-containing product.ESI (bearing)/MS:m/z=372.1[M-H +].
Embodiment 5
This embodiment illustrates (D-erythro)-3-(hydroxyl)-2, the preparation of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate (3B).
The mixture 2.5 hours that adopts dean stark trap reflux toluene (120ml) and venus crystals monohydrate (0.17g) is with this mixture of drying.With (D-erythro)-3-(4-chloro-phenyl-carbamoyloxy)-2,2-two fluoro-3-(2,2-dimethyl-dioxolane-4-yl) ethyl propionate (9E) (10.0g) adds in this mixture under 80 ℃.This reaction mixture of reflux and during 3 hours, dropwise add morpholine (2.8ml) then.Continue to reflux 3 hours, and this mixture is cooled to envrionment temperature and keeps a whole night down at 5 ℃.Collect 1 by filtering, the crystal of 1-diethoxy 3-(4-chloro-phenyl-) urea is also used toluene wash.(3 * 30ml) wash this filtrate and at MgSO to water 4Last dry.Remove under reduced pressure and desolvate dry and acquisition oil.This oil is dissolved in t-butyl methyl ether (15ml) and keeps this solution 5 ℃ of following a whole nights.By filtering the by product 1 of collecting additional content, 1-diethoxy 3-(4-chloro-phenyl-) urea, from this filtrate, produce 6.0g and be oily (D-erythro)-3-(hydroxyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) propionic ester (3B) (97.6%) except that desolvating dry.GC analyzes the purity that shows compound: 81.7%.
1H?NMR(CDCl 3)：δ＝1.36(t，3H，CH 2 CH 3 )，1.34，1.39[d，6H，C( CH 3 ) 2]，3.57(bs，1H)，4.04-4.40(series?of?m，6H).
13C-NMR(CDCl 3)：δ＝13.8(CH 2 CH 3)25.0，26.0[C( CH 3) 2]，63.1( CH 2CH 3)，65.8(C-5)，71.7(C-3，J C-F＝20.0，22.0Hz)，73.5(C-4)，109.8[ C(CH 3) 2]，114.1(C-2，J? C-F＝250，250Hz)，163.3(C-1，J? C-F＝30，30Hz).
Embodiment 6
This embodiment illustrates 3-(4-nitrophenyl carbamoyloxy)-2-deoxidation-2, and 2-two fluoro-D-are red-preparation of penta furanose-1-glycosides (10B).
With (D-erythro)-3-(4-nitrophenyl carbamoyloxy)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) propionic ester (9E) (1.4g), the mixture reflux of acetonitrile (30ml), trifluoroacetic acid (0.14ml) and water (0.64ml) 5.5 hours.Concentrate this reaction mixture then and substitute acetonitrile with toluene.Reach 95-100 ℃ by this reaction mixture of azeotropic distillation drying that uses Dean-Rodney Stark water separator until the crucible temperature.Evaporating solvent and obtain 1.05g solid 3-(4-nitrophenyl carbamoyloxy)-2-deoxidation-2 in a vacuum, 2-two fluoro-D-are red-penta furanose-1-glycosides (10B), productive rate 95.5%.From ethyl acetate the crude product recrystallization is produced clear crystal; [α] D 25+ 22.8 ° (c1, acetonitrile), mp.155-156.5 ℃.
1H?NMR(DMSO-d 6)：δ＝3.87(m，2H)，4.89(m，1H)，5.59(s，1H)，5.70(m，1H)7.74，7.77(d，2H arom)，8.24，8.27(d，2H arom)，10.97(s，1H，NHCO). 13C?NMR(DMSO-d 6)：δ＝59.6(C-5 )，69.3(C-3，J? C-F＝21.8，25.8Hz)，81.6(C-4，J C-F＝7.0Hz)，112.2(C-2，J C-F＝252，252Hz)，118.3，125.1，142.4，144.6(C arom)，151.4(O CONHAr)，163.6(C-1，J C-F＝31，31Hz).
Embodiment 7
This embodiment illustrates 3-(4-chloro-phenyl-carbamoyloxy)-2-deoxidation-2, and 2-two fluoro-D-are red-preparation of penta furanose-1-glycosides (10C).
With (D-erythro)-3-(4-chloro-phenyl-carbamoyloxy)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) propionic ester (9F) (4.0g), the mixture reflux of acetonitrile (40ml), trifluoroacetic acid (0.21ml) and water (1.0ml) 7 hours.Concentrate this reaction mixture then and substitute acetonitrile with toluene.Reach 95-100 ℃ by this reaction mixture of azeotropic distillation drying that uses Dean-Rodney Stark water separator until the crucible temperature.Evaporating solvent and obtain 3.1g solid 3-(4-chloro-phenyl-carbamoyloxy)-2-deoxidation-2 in a vacuum, 2-two fluoro-D-are red-penta furanose-1-glycosides (10C), productive rate 98.4%.From toluene the crude product recrystallization is produced clear crystal; [α] D 25+ 33.4 ° (c1, acetonitrile), mp 129-131 ℃.
1H?NMR(DMSO-d 6)：δ＝3.86(s，2H)，4.89(m，1H)，5.57(s，1H)，5.68(m，1H)7.38，7.41(d，2H arom)，7.55，7.57(d，2H arom)，10.42(s，1H，NHCO). 13C?NMR(DMSO-d 6)：δ＝59.6(C-5 )，68.9(C-3，J C-F＝21.8，25.8Hz)，81.6(C-4，J C-F＝7.0Hz)，112.3(C-2，J C-F＝251，251Hz)，120.2，127.2，128.9，137.3(C arom)，151.5(O CONHAr)，163.8(C-1，J C-F＝31，31Hz).
Embodiment 8
This embodiment illustrates 3-(phenyl amino methanoyl)-2-deoxidation-2, and 2-two fluoro-D-are red-preparation of penta furanose-1-glycosides (10D).
With (D-erythro)-3-(phenyl amino methanoyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) propionic ester (9H) (2.9g), the mixture reflux of acetonitrile (30ml), trifluoroacetic acid (0.015ml) and water (1.5ml) 5.5 hours.Concentrate this reaction mixture then and substitute acetonitrile with toluene.Reach 95-100 ℃ by this reaction mixture of azeotropic distillation drying that uses Dean-Rodney Stark water separator until the crucible temperature.Evaporating solvent and obtain 2.2g solid 3-(phenyl amino methanoyl)-2-deoxidation-2 in a vacuum, 2-two fluoro-D-are red-penta furanose-1-glycosides (10D), productive rate 98.2%.From toluene the crude product recrystallization is produced clear crystal; [α] D 25+ 36.1 ° (c1, acetonitrile), mp 119-121 ℃.
1H?NMR(DMSO-d 6)：δ＝3.82(s，2H)，4.86(m，1H)，5.54(s，1H)，5.65(m，1H)7.06(t，1H? arom)，7.33(t，2H arom)，7.51(d，2H arom)，10.24(s，1H，NHCO). 13C?NMR(DMSO-d 6)：δ＝59.6(C-5 )，68.7(C-3，J? C-F＝21.8，25.8Hz)，81.6(C-4，J C-F＝7.0Hz)，112.3(C-2，J C-F＝251，251Hz)，118.6，123.3，128.9，138.2(C arom)，151.5(O CONHAr)，163.8(C-1，J C-F＝31，31Hz).

Claims (32)

1. the compound that has general formula 10A:
Figure A2006800471280002C1
Wherein X is O or S, and R is unsaturated or saturated C 1-C 8Alkyl, the aryl that does not replace or replace, unsaturated or saturated C 1-C 8Alkyl sulphonyl or the aryl sulfonyl that does not replace or replace.
2. the preparation method of the compound of claim 1, this method comprises:
A) provide (3R)-3-N-(carbamoyloxy)-2 of general formula 9C, the D-erythro diastereomer of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate in containing sour solvent mixture solution and heat time enough and finish basically to allow reaction;
B) reduce this liquor capacity by distillation;
C) add toluene and make this mixture drying by component distillation; With
D) further distillate solvent mixture, to obtain solid.
3. the method for claim 2, wherein this contains the mixture that sour solvent mixture is acetonitrile, water and trifluoroacetic acid.
4. the method for claim 3, wherein this acetonitrile: water: the trifluoroacetic acid ratio is selected from 30: 0.64: 0.14 v/v/v, 40: 1.0: 0.21 v/v/v and 30: 1.5: 0.15 v/v/v.
5. the method for claim 2, wherein the component distillation of water carried out about 5.5-7 hour under refluxing.
6. the method for claim 2 wherein obtains to have 3-(N-carbamoyloxy)-2-deoxidation-2 of general formula 10A with about at least 98.4% productive rate, and 2-two fluoro-D-are red-penta furanose-1-glycosides.
7. the preparation method of the compound of the general formula 10A of claim 1 comprises the compound cyclisation with following general formula:
Figure A2006800471280003C1
Wherein X is O or S, and Alk is C 1-6Alkyl, R are unsaturated or saturated C 1-C 8Alkyl, the aryl that does not replace or replace, unsaturated or saturated C 1-C 8Alkyl sulphonyl or the aryl sulfonyl that does not replace or replace.
8. the method for claim 7 comprises: with the compound separation of D-erythro isomer and following general formula:
Figure A2006800471280003C2
With the compound that this D-erythro isomer cyclisation is obtained general formula 10A, wherein defined in X, Alk and R such as the claim 7.
9. the method for claim 8 comprises:
Make the compound of following general formula:
Figure A2006800471280003C3
With the compound reaction of general formula R-N=C=X, to prepare the compound of following general formula:
Figure A2006800471280004C1
Separate the D-erythro isomer and this D-erythro isomer cyclisation is produced the compound of general formula 10A, wherein defined in X, Alk and R such as the claim 8.
10. the method for claim 9 comprises: the compound that makes following general formula:
With the reaction of the compound of general formula R-N=C=X, and cyclisation is with the compound of preparation general formula 10A,
Wherein defined in X, Alk and R such as the claim 9.
11. the compound of following general formula:
Figure A2006800471280004C3
Wherein X is O or S, and R is unsaturated or saturated C 1-C 8Alkyl, the aryl that does not replace or replace, unsaturated or saturated C 1-C 8Alkyl sulphonyl or the aryl sulfonyl that does not replace or replace.
12. the method for claim 9 comprises:
A) 2 of preparation general formula 3, the D-erythro and the mixture of D-threo form diastereomer in toluene of 2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate;
B) randomly, adopt the component distillation of water to heat this mixture with dry toluene;
C) in the presence of alkali, make 2 of this general formula 3,2-two fluoro-3-hydroxyl-3-(2,2-dimethyl dioxolane-4-yl) the D-erythro of ethyl propionate and D-threo form diastereomer mixture in toluene and isocyanic ester or the lsothiocyanates reaction of general formula R NCX, wherein defined in X and R such as the claim 9, to obtain D-erythro and D-threo form 3-(N-carbamoyloxy)-2, the mixture of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.
13. the method for claim 12, wherein this isocyanic ester or lsothiocyanates are 2-chloro ethyl isothiocyanates; 5-chloro-2-aminomethyl phenyl lsothiocyanates; 2-chloro-4-nitrophenyl lsothiocyanates; 2-chloro-phenyl-lsothiocyanates; 3-chloro-phenyl-lsothiocyanates; 4-chloro-phenyl-lsothiocyanates; 3-acetylphenyl lsothiocyanates; 4-acetylphenyl lsothiocyanates; 2-(chloro methyl) phenyl isocyanate; 2-chloro-5-methyl-phenyl isocyanate; 2-chloro-6-aminomethyl phenyl isocyanic ester; 3-chloro-2-aminomethyl phenyl isocyanic ester; 3-chloro-4-aminomethyl phenyl isocyanic ester; 4-(chloro methyl)-phenyl isocyanate; 4-chloro-2-aminomethyl phenyl isocyanic ester; 5-chloro-2-aminomethyl phenyl isocyanic ester; 2-chloro-4-nitrophenyl isocyanic ester; 2-chloro-5-nitrophenyl isocyanic ester; 4-chloro-2-nitrophenyl isocyanic ester; 4-chloro-3-nitrophenyl isocyanic ester; 2-chloro-2-nitrophenyl isocyanic ester; 2-chloro-phenyl-isocyanic ester; 3-chloro-phenyl-isocyanic ester; 4-chloro-phenyl-isocyanic ester; 3-acetylbenzene based isocyanate; phenyl isocyanate; N-benzenesulfonyl isocyanic ester; ptoluene-sulfonyl isocyanic ester or adjacent tolylsulfonyl based isocyanate.
14. the method for claim 13, wherein this isocyanic ester or lsothiocyanates are 4-nitrophenyl isocyanic ester, 4-chloro-phenyl-isocyanic ester, 3-acetylbenzene based isocyanate or phenyl isocyanate.
15. the method for claim 12, wherein this alkali is selected from triethylamine, one or more lutidine, morpholine, diisopropylethylamine, pyridine, 2-(dimethylamino)-pyridine, 4-(dimethylamino) pyridine and their combination.
16. the method for claim 15, wherein this alkali is 4-(dimethylamino)-pyridine.
17. the method for claim 12 wherein obtains D-erythro and D-threo form 3-(N-aryl-amino-carbonyl)-2, the crude mixture of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate with about at least 97.4% thick productive rate.
18. the compound of following general formula:
Figure A2006800471280006C1
Wherein X is O or S, and R is unsaturated or saturated C 1-C 8Alkyl, the aryl that does not replace or replace, unsaturated or saturated C 1-C 8Alkyl sulphonyl or the aryl sulfonyl that does not replace or replace.
19. the 3-of general formula 9C (N-carbamoyloxy)-2, the preparation method of the D-erythro diastereomer of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate, this method comprises:
A) choose wantonly at high temperature, with D-erythro and the D-threo form 3-(N-carbamoyloxy)-2 of general formula 9B, the mixture of 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate is dissolved in the organic solvent;
B) make this solution fully be cooled to approximately-20 ℃, to produce crystal to about 10 ℃ temperature; With
C) collect this crystal by filtering, with this crystal of organic solvent washing and dry, randomly at high temperature dry.
20. the method for claim 19, wherein this recrystallisation solvent is methylene dichloride, chloroform, ethyl acetate, acetate 1-propyl ester, acetate 2-propyl ester, butylacetate, tert.-butyl acetate, o-Xylol, m-xylene, orthodichlorobenzene, toluene or their mixture.
21. the method for claim 20, wherein this recrystallisation solvent is a toluene.
22. the method for claim 19, wherein being used to wash the crystalline organic solvent that is obtained is toluene, pentane, hexane, heptane, octane, sherwood oil, hexanaphthene or their mixture.
23. the method for claim 22 wherein is used to wash this crystalline organic solvent the mixture that is toluene or toluene and hexane.
24. the method for claim 19 is wherein with about at least 98.5% purity D-erythro diastereomer (the 3R)-3-(carbamoyloxy)-2 that emanates out, 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate.
25. the parent material by general formula 9C prepares (D-the erythro)-3-hydroxyl-2 with general formula 3C, the method for 2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate,
Figure A2006800471280007C1
This method comprises:
A) adopt the component distillation of water to add hot toluene and mixture of catalysts with dry toluene;
B) add 3-(N-carbamoyloxy)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) the D-erythro isomer of ethyl propionate, it is general formula 9E (D-erythro)-3-(4-nitre phenyl amino formyl radical)-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate, (D-erythro)-3-of general formula 9F (4-chloro-phenyl-formamyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) ethyl propionate, (D-erythro)-3-of general formula 9G (3-acetylphenyl formamyl)-2,2-two fluoro-3-(2,2-dimethyl dioxolane-4-yl) (D-erythro)-3-(phenyl amino formyl radical)-2 of ethyl propionate or general formula 9H, 2-two fluoro-3-(2,2-dimethyl-dioxolane-4-yl) ethyl propionate, and this mixture is refluxed;
C) interpolation is selected from the alkali of one or more primary and secondary amine, and keeps this backflow and finish basically until reaction;
D) crystal by the filtering separation by product;
E) wash filtrate and evaporating solvent, vapourisation under reduced pressure randomly, and obtain oil; With
F) this oil is dissolved in the organic solvent and cooling, throws aside the formed by product crystal and the product of emanating out.
26. the method for claim 25, wherein said catalyzer are venus crystals, tin protochloride, stannous oxalate, aluminium alkoxide or their combination.
27. the method for claim 26, wherein catalyzer is a venus crystals.
28. the method for claim 25, wherein alkali is selected from n-Butyl Amine 99, normal hexyl Amine, dipropyl amine, dibutylamine, dicyclohexyl amine, morpholine, piperidines, lupetidine and their combination.
29. the method for claim 28, wherein this alkali is morpholine.
30. the method for claim 25, the solvent that wherein is used to dissolve the oil that is obtained is methylene dichloride, chloroform, ethyl acetate, acetate 1-propyl ester, acetate 2-propyl ester, butylacetate, tert.-butyl acetate, diethyl ether, diisopropyl ether, t-butyl methyl ether or their mixture.
31. the method for claim 30, wherein solvent is a t-butyl methyl ether.
32. the method for claim 2 also comprises:
A) make the reaction of lactone 10A and acyl chlorides or acylbromide to obtain the 3-formamyl lactone intermediate of general formula 17, wherein X is O or S, and R is unsaturated or saturated C 1-C 8Alkyl, or the phenyl that does not replace or replace;
B) in organic solvent, reduce the 3-formamyl lactone intermediate of this general formula 17 to obtain the lactonaphthol intermediate with reductive agent;
C) in the presence of alkali, make the reaction of this lactonaphthol intermediate and methane sulfonyl chloride and the sulfonate intermediate of acquisition general formula 16A;
D) in the presence of catalyzer in organic solvent with compound 16A and two (trimethyl silyl)-N-acetylcytosine couplings, and obtain 3,5-two protections-N-1-trimethyl silyl ethanoyl-2 '-deoxidation-2 ', 2 '-α of difluoro cytidine and the mixture of β anomer;
E) precipitate this 3,5-two protection-N-1-trimethyl silyl ethanoyl-2 '-deoxidation-2 ', 2 '-beta isomer of difluoro cytidine, and separate this isomer; With
F) remove protecting group and obtain gemcitabine.
CNA2006800471287A 2005-12-13 2006-12-12 Process for preparing gemcitabine and associated intermediates Pending CN101356165A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US74968905P 2005-12-13 2005-12-13
US60/749,689 2005-12-13

Publications (1)

Publication Number Publication Date
CN101356165A true CN101356165A (en) 2009-01-28

Family

ID=38163614

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2006800471287A Pending CN101356165A (en) 2005-12-13 2006-12-12 Process for preparing gemcitabine and associated intermediates

Country Status (3)

Country Link
KR (1) KR20080094890A (en)
CN (1) CN101356165A (en)
WO (1) WO2007070804A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109651459A (en) * 2019-01-24 2019-04-19 江苏八巨药业有限公司 A kind of preparation method of gemcitabine intermediate methylsulfonyl ester
CN111393546A (en) * 2020-03-31 2020-07-10 浙江康特生物科技有限公司 Preparation of chelate resin and application of chelate resin in removing cobalt ions in kit purified water

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223608A (en) * 1987-08-28 1993-06-29 Eli Lilly And Company Process for and intermediates of 2',2'-difluoronucleosides
US5521294A (en) * 1995-01-18 1996-05-28 Eli Lilly And Company 2,2-difluoro-3-carbamoyl ribose sulfonate compounds and process for the preparation of beta nucleosides

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109651459A (en) * 2019-01-24 2019-04-19 江苏八巨药业有限公司 A kind of preparation method of gemcitabine intermediate methylsulfonyl ester
CN109651459B (en) * 2019-01-24 2020-09-08 江苏八巨药业有限公司 Preparation method of gemcitabine intermediate methanesulfonyl ester
CN111393546A (en) * 2020-03-31 2020-07-10 浙江康特生物科技有限公司 Preparation of chelate resin and application of chelate resin in removing cobalt ions in kit purified water

Also Published As

Publication number Publication date
KR20080094890A (en) 2008-10-27
WO2007070804A2 (en) 2007-06-21
WO2007070804A3 (en) 2008-01-03

Similar Documents

Publication Publication Date Title
KR860001283B1 (en) Method of preparing difluoro antivirals and intermediate therefor
EP2277878B1 (en) Process for production of ethynylthymidine compound using 5-methyluridine as starting raw material
EP3638685A1 (en) Synthesis of 3'-deoxyadenosine-5'-0-[phenyl(benzyloxy-l-alaninyl)]phosphate (nuc-7738)
CN101296934A (en) Process for preparing gemcitabine and associated intermediates
US20080262215A1 (en) Gemcitabine production process
JP5114556B2 (en) A novel highly stereoselective synthetic process and intermediate for gemcitabine
EP3684780A1 (en) Floxuridine synthesis
CN101883570B (en) Synthesis of beta-nucleosides
US20090221811A1 (en) Process for preparing gemcitabine and associated intermediates
CN101356165A (en) Process for preparing gemcitabine and associated intermediates
US20070249823A1 (en) Process for preparing gemcitabine and associated intermediates
KR101259648B1 (en) A manufacturing process of 2′,2′-difluoronucloside and intermediate
JP5349342B2 (en) Method for producing 2'-deoxy-2 ', 2'-difluorocytidine
JP2634013B2 (en) 3'-O-propargyl-trifluorothymidine derivative, method for producing the same, and anticancer agent containing the same as an active ingredient
KR20080090950A (en) Process for preparing gemcitabine and associated intermediates
WO2003080604A1 (en) Dihydroisoxazolyl substituted tetrahydrofuran coompounds as intermediates in the preparation of 2-(purin-9-yl) - tetrahydrofuran derivatives
EP1574515A2 (en) Production method of 2-deoxy-L-ribose compound
WO2010029574A2 (en) An improved process for the preparation of gemcitabine and its intermediates using novel protecting groups and ion exchange resins
KR20100039837A (en) Process for preparing of 2'-deoxy-2'2'-difluorocytidine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20090128