CN106478747B - The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar - Google Patents

The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar Download PDF

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CN106478747B
CN106478747B CN201610806573.2A CN201610806573A CN106478747B CN 106478747 B CN106478747 B CN 106478747B CN 201610806573 A CN201610806573 A CN 201610806573A CN 106478747 B CN106478747 B CN 106478747B
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CN106478747A (en
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张庆捷
陈之峰
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Lianyungang Hengyun Pharmaceutical Co. Ltd.
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Abstract

The present invention relates to formula(I)The preparation method of compound, the i.e. sulfonation of gemcitabine key intermediate sugar, formula(Ⅱ)Compound through sodium borohydride reduction, hydroxyl protection, split to obtain final product.This method technique is simple, and yield is high, good product purity, without the reaction condition of harshness, is very suitable for industrial production.

Description

The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar
Technical field
The present invention relates to pharmaceutical synthesis field, and in particular to the industrially prepared work of gemcitabine key intermediate sulfonation sugar Skill.
Background technology
Gemcitabine hydrochloride is cell cycle specific antimetabolitas, and it is as antitumoral compounds, U.S. in 1996 State FDA have approved first-line drug of the gemcitabine hydrochloride of Lilly Co., Eli.'s production as treatment cancer of pancreas, ratify 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;Its people and mouse tumour to various cultures has obvious cytotoxic activity, in non-lethal dose, There is good active anticancer to the kinds of tumors of mouse.
The synthesis on 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.L.W.Hertel et al. is raw material first with R-2,3-O- contracting Acetone-glycerols aldehyde, synthesis D- Erythro-2,3-octadecane-diols '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-O- tertiary butyls dimethyl silicon substrate -1- carbonyl ribose go forward side by side one-step synthesis 2 '-deoxidation -2 ', 2 '-difluoro glycosides urine (J.Org.Chem., 1988,2406).The reaction make use of the asymmetry that substrate controls Reformatsky reacts, but selectivity is not high, it is necessary to further handle the reaction production that can just obtain chiral purity with column chromatography Thing, this method are not suitable for industrially mass producing.
T.S.Chou et al. is improved above-mentioned route (Synthesis, 1992,565), by asymmetry Reformatsky reactions are directly used in reaction along the mixture of anti-product, finally handle product with crystallisation, although the method avoids Use column chromatography, but synthetic route is longer, product gross production rate is not high, and only 25% so that production cost improves.
It is raw material that Osamu Kitagawa, which are once attempted using iodo difluoro acetate, and adds trialkyl chlorine silicon in the reaction 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 for raw material, in 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 initiation 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 industrial production gemcitabine hydrochloride Want meaning.
The content of the invention
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 technology 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 precipitation formula (I) compound,
Wherein, R1, R2, R3 are hydroxyl protecting groups.
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 C1-C6 alcohol, preferably methanol, ethanol, 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 comprises the following steps:
A, formula (II) compound is reduced to formula (III) compound in the presence 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 precipitation formula (I) compound,
Wherein, R1, R2, R3 are hydroxyl protecting groups.
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, step a reducing agent is sodium borohydride, and additive is zinc chloride and the tert-butyl alcohol;Step a reaction dissolvent Selected from ethyl acetate and/or tetrahydrofuran, more preferably ethyl acetate and tetrahydrofuran volume ratio is 3:1 mixed solvent.
Preferably, the organic solvent of dissolution type (IV) compound is selected from C1-C6 alcohol, preferred alcohol in step c;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 technology of the present invention mainly has the following advantages that:
1st, combined from the go back original reagent of sodium borohydride/zinc chloride/tert-butyl alcohol, not only reaction efficiency is higher, also improves The ratio of formula (III) compound α/β isomers, realize the effect of selective reduction.
2nd, the method for formula (IV) compound provided by the invention recrystallization resolution of alpha/beta isomer, not only have stronger pure Change effect and split efficiency high, it is extremely low that fractionation obtains formula (I) compound purity height, content of isomer.
3rd, the method that gemcitabine hydrochloride resolution of alpha/beta isomer is repeatedly purified compared to 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.
Embodiment
In order to further illustrate the technique effect of technical scheme and its acquirement, below in conjunction with specific implementation The present invention will be further described for example, but the scope of the present invention is not limited to embodiment.
Embodiment 1
Ethyl acetate 45mL, tetrahydrofuran 15mL are added into reaction bulb, add 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 tert-butyl alcohol 2g, and temperature control is less than 15 DEG C Sodium borohydride 0.67g is added, is reacted 1 to 1.5 hour.Reaction finishes, and adds watery hydrochloric acid 40mL, stirs 10 minutes, stratification, Abandon water layer, organic layer are washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, mistake after anhydrous magnesium sulfate is dried 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 into reaction bulb, add 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 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 watery hydrochloric acid 40mL, stirs 10 minutes, stratification, abandons Water layer, organic layer are washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, mistake after anhydrous magnesium sulfate is dried 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 into reaction bulb, adds 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 tert-butyl alcohol 2g, less than 15 DEG C addition sodium borohydrides of temperature control 0.67g, react 1 to 1.5 hour.Reaction finishes, and adds watery hydrochloric acid 40mL, stirs 10 minutes, stratification, and abandon water layer is organic Layer is washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, and anhydrous magnesium sulfate filters after drying, and is concentrated, is obtained 2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoate 10g, α/β=3.1, yield 100%.
Embodiment 4
Tetrahydrofuran 60mL is added into reaction bulb, adds 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 tert-butyl alcohol 2g, less than 15 DEG C addition sodium borohydrides of temperature control 0.67g, react 1 to 1.5 hour.Reaction finishes, and adds watery hydrochloric acid 40mL, stirs 10 minutes, stratification, and abandon water layer is organic Layer is washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, and anhydrous magnesium sulfate filters after drying, and is concentrated, is obtained 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 is mixed, and is cooled to 5-10 DEG C, 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 Warm stirring reaction 2h, after reaction terminates, successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, organic phase With anhydrous sodium sulfate drying, concentration, the double benzoic ether -1- methanesulfonates of 2- deoxidations -2,2- difluoro-D-ribofuranose -3,5- are obtained 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 ethanol 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 double benzoic ether -1- methanesulfonates 8.1g, the β isomeries of α -2- deoxidations -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 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 double benzoic ether -1- methanesulfonates 7.1g, the β isomeries of α -2- deoxidations -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 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 double benzoic ether -1- methanesulfonates 7.4g, the β isomeries of α -2- deoxidations -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 ethanol 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 double benzoic ether -1- methanesulfonates 7.8g, the β isomeries of α -2- deoxidations -2,2- difluoro-D-ribofuranoses -3,5- Body content 0.08%, yield 78%.
Embodiment 10
By cytimidine (24.4g, 0.22mol), HMDS (46.2mL, 0.22mol) and ammonium sulfate (0.03g) Mixed in 2L there-necked flasks, be heated to reflux to reaction solution after clarifying, continue insulation reaction 30min.Less than 80 DEG C are cooled to, decompression Solvent is evaporated off, separates out solid.Add Me3SiOTf (48.9g, 0.22mol), methyl phenyl ethers anisole (400ml), heating stirring make solid molten Solution.Added in reaction solution the double benzoic ether -1- methanesulfonates of α -2- deoxidations -2,2- difluoro-D-ribofuranoses -3,5- (90.0g, 0.20mol, beta isomer content 0.07%), the mixed solution of methyl phenyl ethers anisole (200ml), 120 DEG C reaction 3h, TLC detection reaction knot Beam, ethyl acetate (500ml) dilution is added after being cooled to room temperature, stirring, 4M hydrochloric acid (300mL) is added dropwise, is warming up to 70 DEG C of guarantors afterwards Warm 2h.Filter 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 adjust 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) mix in 2L there-necked flasks, react at room temperature 2h, TLC inspections Survey reaction terminate, 1M hydrochloric acid adjust pH to 7, be concentrated under reduced pressure into it is dry, add water (1L), removal of impurities is extracted with ethyl acetate, afterwards 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), 70 DEG C are heated to, room temperature is stood overnight after being incubated 30min.Filtering, filter cake use cold isopropanol and just oneself successively Alkane washs, and dries, 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 (10)

1. a kind of preparation method of formula (I) compound, it is characterised in that formula (IV) compound is dissolved in organic solvent, is heated to 50-60 DEG C of dissolved clarification, 28-33 DEG C of precipitation formula (I) compound is cooled to,
Wherein, R1, R2, R3 are hydroxyl protecting groups, and wherein organic solvent is selected from C1-C6 alcohol.
2. preparation method according to claim 1, it is characterised in that organic solvent is selected from methanol, ethanol, isopropanol or fourth Alcohol.
3. preparation method according to claim 1, it is characterised in that organic solvent is selected from ethanol.
4. preparation method according to claim 1, it is characterised in that the cooling Precipitation Temperature of formula (I) compound is 31 DEG C.
5. preparation method according to claim 1, it is characterised in that R1 is selected from mesyl, benzylsulphonyl or to first Benzenesulfonyl;R2 is selected from formoxyl, acetyl group, benzoyl or to methyl benzoyl;R3 is selected from formoxyl, acetyl group, benzene Formoxyl or to methyl benzoyl.
6. preparation method according to claim 1, it is characterised in that R1 is selected from mesyl;R2 is selected from benzoyl;R3 Selected from benzoyl.
7. according to the preparation method described in claim 1-6 any one, it is characterised in that formula (IV) compound is with following Mode is made:
A, formula (II) compound is reduced to formula (III) compound in the presence of additive and reducing agent,
B, formula (III) compound progress hydroxyl protection is obtained into formula (IV) compound,
8. preparation method according to claim 7, it is characterised in that step a reducing agent is sodium borohydride, and additive is Zinc chloride and the tert-butyl alcohol.
9. preparation method according to claim 7, it is characterised in that step a reaction dissolvent be selected from ethyl acetate and/or Tetrahydrofuran.
10. preparation method according to claim 7, it is characterised in that step a reaction dissolvent is ethyl acetate and tetrahydrochysene Furans volume ratio is equal to 3:1 mixed solvent.
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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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EP1940859A1 (en) * 2005-10-28 2008-07-09 Arch Pharmalabs Limited An improved process for preparation of gemcitabine hydrochloride
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