CN108191925A - The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C07H1/00—Processes for the preparation of sugar derivatives
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to formula (I) compound, the i.e. industrial manufacturing process of gemcitabine key intermediate sulfonation sugar, formula (II) compound through sodium borohydride reduction, hydroxyl protection, split to obtain final product.This method is simple for process, and yield is high, good product purity, without harsh reaction condition, is very suitable for industrial production.
Description
The application is application No. is 201610806573.2, and the applying date is September in 2016 6 days, entitled " Ji Xita
The divisional application of the Chinese patent application of the industrial manufacturing process of shore key intermediate sulfonation sugar ".
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to the industrially prepared work of gemcitabine key intermediate sulfonation sugar
Skill.
Background technology
Gemcitabine hydrochloride is cell cycle specific antimetabolitas, as antitumoral compounds, U.S. in 1996
State FDA has approved first-line drug of the gemcitabine hydrochloride of Lilly Co., Eli.'s production as treatment cancer of pancreas, ratifies within 1998
As treatment non-small cell lung cancer medicine.
Gemcitabine hydrochloride mainly acts on the tumour cell of DNA synthesis phases, i.e. S phase cells, under certain condition, can be with
Prevent progress of the G1 phases to the S phases；It has apparent cytotoxic activity to the people of various cultures and mouse tumour, in non-lethal dose,
There is good active anticancer to the kinds of tumors of mouse.
The synthesis about gemcitabine hydrochloride of document report at present is mostly the D- Erythro-2,3-octadecane-diols with hydroxyl protection ', 2 '-two
Fluoro- 1- carbonyls ribose is intermediate.For L.W.Hertel et al. first with R-2,3-O- contracting Acetone-glycerols aldehyde is raw material, is synthesized
D- Erythro-2,3-octadecane-diols '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-O- tertiary butyls dimethyl silicon substrate -1- carbonyl ribose are gone forward side by side one-step synthesis
2 '-deoxidation -2 ', 2 '-difluoro glycosides urine (J.Org.Chem., 1988,2406).The asymmetry of substrate control is utilized in the reaction
Reformatsky reacts, but selectivity is not high, needs to be further processed the reaction that can just obtain chiral purity production with column chromatography
Object, this method are not suitable for industrially mass producing.
T.S.Chou et al. improves above-mentioned route (Synthesis, 1992,565), will be asymmetric
Reformatsky reactions are directly used in reaction along the mixture of anti-product, finally handle product with crystallisation, although which avoids
Using column chromatography, but synthetic route is longer, and product gross production rate is not high, and only 25% so that increased production cost.
It is raw material, and add in trialkyl chlorine silicon in the reaction that Osamu Kitagawa, which are once attempted using iodo difluoro acetate,
The method of alkane improves the selectivity along anti-product, (Tetrahdron Lett., 1988,29,1803), Yasushi Matsumra
Et al. with (R) -2,3-O- contractings cyclohexanone-glyceraldehyde be raw material, in the reaction system add Titanocene catalyst, Jin Erti
The high selectivity (J.Flurine chem., 1992,57,203) along anti-product, but these methods all employ it is expensive
Reagent, and severe reaction conditions, are not suitable for industrial production still.
The gemcitabine hydrochloride synthetic route of EP2018005A1 and CN20121004040.8 reports is with the D- of hydroxyl protection
Erythro-2,3-octadecane-diol ', 2 '-two fluoro- 1- carbonyls ribose are starting material, and through carbonyl reduction, that hydroxyl sulfonation obtains 2- deoxidations -2,2- bis- is fluoro-
D- erythros-furan pentose -3,5- dibenzoate -1- methanesulfonates (α/β), with cytimidine be condensed after, Deprotection, into salt,
Crystallization purifies to obtain gemcitabine hydrochloride.The route carries out α and beta isomer purifying after synthesizing gemcitabine, and selectivity is not
Height, reaction yield is relatively low, and raw material availability is low, is not suitable for industrially mass producing.
Therefore, find a kind of preparation method that can ensure high-quality and high-efficiency has weight for industrially producing gemcitabine hydrochloride
Want meaning.
Invention content
It is an object of the invention to solve above-mentioned technical problem, it is desirable to provide a kind of technique is simpler, and purity is good, and yield is high
Gemcitabine hydrochloride key intermediate sulfonation sugar, i.e. the preparation process of formula (I) compound.
The preparation method of formula (I) compound provided by the invention, formula (IV) compound (α/β isomer mixture) is dissolved in
Organic solvent, cool down precipitation formula (I) compound,
Wherein, R1, R2, R3 are hydroxyl protection bases.
R1 is selected from mesyl, benzylsulphonyl or p-toluenesulfonyl, preferably mesyl；R2 is selected from formoxyl, second
Acyl group, benzoyl or to methyl benzoyl, preferably benzoyl；R2 is selected from formoxyl, acetyl group, benzoyl or to first
Base benzoyl, preferably benzoyl.
The organic solvent of dissolution type (IV) compound is selected from the alcohol of C1-C6, preferably methanol, ethyl alcohol, isopropanol or butanol, more
Preferred alcohol；The solution temperature of formula (IV) compound is 50-60 DEG C；The cooling Precipitation Temperature of formula (I) compound is 28-33 DEG C,
It is preferred that 31 DEG C.
Further specifically, formula (I) compounds process for production thereof provided by the invention includes the following steps：
A, formula (II) compound is reduced to formula (III) compound under the action of additive and reducing agent,
B, the hydroxyl protection of formula (III) compound is obtained into formula (IV) compound,
C, formula (IV) compound is dissolved in organic solvent, cool down precipitation formula (I) compound,
Wherein, R1, R2, R3 are hydroxyl protection bases.
R1 is selected from mesyl, benzylsulphonyl or p-toluenesulfonyl, preferably mesyl；R2 is selected from formoxyl, second
Acyl group, benzoyl or to methyl benzoyl, preferably benzoyl；R2 is selected from formoxyl, acetyl group, benzoyl or to first
Base benzoyl, preferably benzoyl.
Preferably, the reducing agent of step a is sodium borohydride, and additive is zinc chloride and the tert-butyl alcohol；The reaction dissolvent of step a
Selected from ethyl acetate and/or tetrahydrofuran, more preferable ethyl acetate and tetrahydrofuran volume ratio are 3:1 mixed solvent.
Preferably, in step c dissolution type (IV) compound organic solvent be selected from C1-C6 alcohol, preferred alcohol；Formula (IV)
The solution temperature of compound is 50-60 DEG C；The cooling Precipitation Temperature of formula (I) compound is 28-33 DEG C, preferably 31 DEG C.
The preparation process of the present invention mainly has the following advantages that：
1st, the go back original reagent combination of sodium borohydride/zinc chloride/tert-butyl alcohol is selected, not only reaction efficiency higher, also improves
The ratio of formula (III) compound α/β isomers realizes the effect of selective reduction.
2nd, the method for formula (IV) compound recrystallization resolution of alpha/beta isomer provided by the invention, not only with stronger pure
Change effect and split efficient, fractionation obtains that formula (I) compound purity is high, content of isomer is extremely low.
3rd, the multiple method of purifying gemcitabine hydrochloride resolution of alpha/beta isomer compared with the prior art, the present invention is with tying again
Brilliant method splits to obtain formula (I) compound to formula (IV) compound progress α/β isomers, is further reacted with cytimidine
Target product gemcitabine, αisomer content is extremely low in gained target product, without further resolving and purifying.
Specific embodiment
In order to further illustrate the technique effect of technical scheme of the present invention and its acquirement, below in conjunction with specific implementation
The present invention will be further described, but the scope of the invention is not limited to specific embodiments for example.
Embodiment 1
Ethyl acetate 45mL, tetrahydrofuran 15mL are added in into reaction bulb, add in bis- fluoro- D- erythros-furans of 2- deoxidations -2,2-
Pentose -1- ketone -3,5- dibenzoate 10g, anhydrous zinc chloride 1.8, stirring and dissolving add in tert-butyl alcohol 2g, and temperature control is less than 15 DEG C
Sodium borohydride 0.67g is added in, is reacted 1 to 1.5 hour.Reaction finishes, and adds in dilute hydrochloric acid 40mL, stirs 10 minutes, stratification,
Abandon water layer, organic layer are washed respectively with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL, mistake after anhydrous magnesium sulfate drying
Filter, concentration, obtains 2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoate 10g, α/β=3.7, yield 100%.
Embodiment 2
Ethyl acetate 45mL, tetrahydrofuran 15mL are added in into reaction bulb, add in bis- fluoro- D- erythros-furans of 2- deoxidations -2,2-
Pentose -1- ketone -3,5- diacetate esters 10g, anhydrous zinc chloride 1.8, stirring and dissolving add in tert-butyl alcohol 2g, and temperature control adds less than 15 DEG C
Enter sodium borohydride 0.67g, react 1 to 1.5 hour.Reaction finishes, and adds in dilute hydrochloric acid 40mL, stirs 10 minutes, stratification is abandoned
Water layer, organic layer are washed respectively with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL, mistake after anhydrous magnesium sulfate drying
Filter, concentration, obtains 2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- diacetate esters 10g, α/β=3.1, yield 100%.
Embodiment 3
Ethyl acetate 60mL is added in into reaction bulb, adds in bis- fluoro- D- erythros of 2- deoxidations -2,2--furan pentose -1- ketone -3,
5- dibenzoate 10g, anhydrous zinc chloride 1.8, stirring and dissolving add in tert-butyl alcohol 2g, less than 15 DEG C addition sodium borohydrides of temperature control
0.67g reacts 1 to 1.5 hour.Reaction finishes, and adds in dilute hydrochloric acid 40mL, stirs 10 minutes, stratification, and abandon water layer is organic
Layer is washed respectively with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL, is filtered after anhydrous magnesium sulfate drying, is concentrated, obtain
2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoate 10g, α/β=3.1, yield 100%.
Embodiment 4
Tetrahydrofuran 60mL is added in into reaction bulb, adds in bis- fluoro- D- erythros of 2- deoxidations -2,2--furan pentose -1- ketone -3,
5- dibenzoate 10g, anhydrous zinc chloride 1.8, stirring and dissolving add in tert-butyl alcohol 2g, less than 15 DEG C addition sodium borohydrides of temperature control
0.67g reacts 1 to 1.5 hour.Reaction finishes, and adds in dilute hydrochloric acid 40mL, stirs 10 minutes, stratification, and abandon water layer is organic
Layer is washed respectively with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL, is filtered after anhydrous magnesium sulfate drying, is concentrated, obtain
2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoate 10g, α/β=3.3, yield 100%.
Embodiment 5
By 2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoates 10g, triethylamine 5.4ml, dichloromethane
100mL mixings are cooled to 5-10 DEG C, and mesyl chloride 2.2ml is added dropwise in less than 15 DEG C in temperature control, and cryostat, room are removed after being added dropwise
Temperature is stirred to react 2h, after reaction, successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, organic phase
It is dried with anhydrous sodium sulfate, concentrates, obtain the bis- benzoic ether -1- methanesulfonates of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5-
10.8g, α/β=3.8, yield 91.8%.
Embodiment 6
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.8) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add in ethyl alcohol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 31 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry bis- benzoic ether -1- methanesulfonates 8.1g, the β isomeries of α -2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.07%, yield 81%.
Embodiment 7
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.8) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add in methanol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 28 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry bis- benzoic ether -1- methanesulfonates 7.1g, the β isomeries of α -2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.21%, yield 71%.
Embodiment 8
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.8) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add in isopropanol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 33 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry bis- benzoic ether -1- methanesulfonates 7.4g, the β isomeries of α -2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.09%, yield 74%.
Embodiment 9
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.1) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add in ethyl alcohol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 31 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry bis- benzoic ether -1- methanesulfonates 7.8g, the β isomeries of α -2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.08%, yield 78%.
Embodiment 10
By cytimidine (24.4g, 0.22mol), hexamethyldisilazane (46.2mL, 0.22mol) and ammonium sulfate (0.03g)
The mixing in 2L there-necked flasks is heated to reflux to reaction solution after clarifying, continues insulation reaction 30min.80 DEG C are cooled to hereinafter, decompression
Solvent is evaporated off, solid is precipitated.Add in Me3SiOTf (48.9g, 0.22mol), methyl phenyl ethers anisole (400ml), heating stirring make solid molten
Solution.Added in reaction solution α -2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- bis- benzoic ether -1- methanesulfonates (90.0g,
0.20mol, beta isomer content 0.07%), the mixed solution of methyl phenyl ethers anisole (200ml), 120 DEG C of reaction 3h, TLC detection reaction knots
Beam adds in ethyl acetate (500ml) dilution after being cooled to room temperature, and stirring is added dropwise 4M hydrochloric acid (300mL), is warming up to 70 DEG C of guarantors later
Warm 2h.It filters while hot, filter cake is beaten 1h then at 70 DEG C of water, filters while hot, and filter cake adds water (300mL) to suspend and with 5% bicarbonate
Sodium solution tune pH to 7, filtering, after vacuum drying Gemzart -3 ', 5 '-dibenzoate 80.6g, α
Content of isomer 0.08%, yield 85.5%.
Embodiment 11
By Gemzart -3 ', 5 '-dibenzoate (75.0g, 0.16mol, αisomer content
0.08%), sodium tert-butoxide (33.6g, 0.34mol), methanol (800ml) mixing in 2L there-necked flasks react at room temperature 2h, TLC inspections
Survey reaction terminates, 1M hydrochloric acid tune pH to 7, be concentrated under reduced pressure into it is dry, add in water (1L), removal of impurities is extracted with ethyl acetate, later acetic acid
The a small amount of water backwash of methacrylate layer, combining water layer, activated carbon decolorizing, filtering, filtrate is spin-dried for, added in residue isopropanol (1L) and
Concentrated hydrochloric acid (40ml) is heated to 70 DEG C, and room temperature is stood overnight after keeping the temperature 30min.Filtering, filter cake use cold isopropanol and just oneself successively
Alkane washs, dry, obtains gemcitabine hydrochloride 44.8g, purity 99.5%, αisomer content 0.02%, yield 93.4%.
1H NMR(DMSO-d6)δ:10.40 (s, 1H, OH-2), 9.00 (s, 1H, OH-4), 8.20 (d, J=8.29Hz,
1H, H-9), 6.32 (br, 2H, NH2), 6.31 (d, J=8.29Hz, 1H, H-8), 6.08 (t, 1H, H-5), 4.22 (m, 1H, H-
2),3.93(m,1H,H-3),3.80(dd,1H,H-4),3.66(dd,1H,H-4)；13C NMR(DMSO-d6)δ:159.56(C-
7),146.78(C-6),143.42(C-9),122.8(C-1),94.7(C-8),83.8(C-5),81.59(C-3),68.1(C-
2),58.69(C-4)；MS-ESI(m/z):264.0[M+H]+.
Claims (9)
1. a kind of preparation method of III compound of formula, which is characterized in that by II compound of formula additive and reducing agent effect
Under be reduced to III compound of formula,
Wherein, R2, R3 are hydroxyl protection bases.
2. the preparation method of III compound of formula according to claim 1, which is characterized in that additive be selected from lewis acid and
The tert-butyl alcohol.
3. the preparation method of III compound of formula according to claim 2, which is characterized in that lewis acid be selected from zinc chloride,
Aluminium chloride or iron chloride, preferably zinc chloride.
4. the preparation method of III compound of formula according to claim 1, which is characterized in that reducing agent be selected from sodium borohydride,
Sodium triacetoxy borohydride or sodium cyanoborohydride, preferably sodium borohydride.
5. the preparation method of III compound of formula according to claim 1, which is characterized in that R2 be selected from formoxyl, acetyl group,
Benzoyl or to methyl benzoyl, preferably benzoyl；R3 is selected from formoxyl, acetyl group, benzoyl or to methylbenzene
Formoxyl, preferably benzoyl.
6. the preparation method of III compound of formula according to claim 1, which is characterized in that reaction dissolvent is selected from ethyl acetate
And/or tetrahydrofuran.
7. the preparation method of III compound of formula according to claim 1, which is characterized in that reaction dissolvent is selected from ethyl acetate
It is equal to 3 with tetrahydrofuran volume ratio:1 mixed solvent.
8. the preparation method of III compound of formula according to claim 1, which is characterized in that reaction temperature is less than 15 DEG C.
9. the preparation method of III compound of formula according to claim 1, which is characterized in that lewis' acid and the tert-butyl alcohol rub
You are than selected from 1~5：1, preferably 4~5：1, more preferable 4.5~5：1.
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| 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 |
| CN109651460B (en) * | 2019-01-24 | 2020-06-26 | 江苏八巨药业有限公司 | Preparation method of 2-deoxy-2, 2-difluoro-D-erythro-pentofuranose-3, 5-dibenzoate |
| CN112574268B (en) * | 2020-11-24 | 2021-11-30 | 山东安弘制药有限公司 | Preparation method of beta-configuration gemcitabine hydrochloride intermediate |
| CN112225767A (en) * | 2020-12-10 | 2021-01-15 | 苏州华鑫医药科技有限公司 | High-selectivity synthesis method of gemcitabine intermediate |
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| CN106478747A (en) | 2017-03-08 |
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Application publication date: 20180622 |