CN102153601A - Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity - Google Patents
Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity Download PDFInfo
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Abstract
The invention discloses a method for synthesizing an important intermediate 2-deoxy-2, 2-difluorofuran ribose compound of gemcitabine hydrochloride and a method for synthesizing the gemcitabine hydrochloride by using the compound as a raw material under the catalysis of cytosine. The method has good stereo selectivity, a mild reaction condition, easily obtained raw materials, low pollution and high yield, and is suitable for industrialized production.
Description
Technical field
The preparation gemcitabine hydrochloride that the present invention relates to a kind of novel highly selective with and important intermediate 2-deoxidation-2, the synthetic method of 2-difluoro ribofuranose compound.
Background technology
Gemcitabine hydrochloride (Gemcitabine Hydrochloride), chemistry 2 '-deoxidation-2 by name, 2-difluoro cytidine hydrochloride (beta isomer) is the pyrimidine nucleoside analoys of Lilly Co., Eli.'s research and development, nineteen ninety-five, commodity were called Gemzar in the listing of states such as Australia, Finland.The existing approved import of China, Chinese commodity strong selecting by name.Its structure is similar with cytosine arabinoside (Cytarabine), belongs to the antitumor class medicine of ucleosides antimetabolic, is applicable to non-small cell carcinoma, carcinoma of the pancreas, bladder cancer, mammary cancer and other solid tumors.
The preparation route of gemcitabine hydrochloride mainly contains following several:
Route one [Hertel L W etal, J.Org.Chem, 1988,53 (11) 2406-2409]
Used the silicagel column separation in this method sepn process, and in synthetic, all do not related to the steric configuration of compound, also do not explained and explanation for the steric configuration of final product with each later step of DIBAL-H reduction.
Route two [T.S.Chou etal, Synthesis, 1992,6,565-570]
Though this method has been synthesized steric configuration for the first time and has been occupied the α-2-deoxidation-2.2-difluoro ribofuranose-3 of dominant position, 5-benzyloxy methanesulfonates, and be that raw material has synthesized β-gemcitabine with this compound, but this method is at synthetic α-2-deoxidation-2.2-difluoro ribofuranose-3, adopted-78 ℃ low-temp reaction during 5-benzyloxy methanesulfonates, and yield is not high, therefore is difficult to be applicable to suitability for industrialized production.
Route three [Lee Jaeheon etal WO2006/011713]
This method has been used a large amount of irritating Hydrogen bromides, and is not only big to operator's actual bodily harm, and causes very big environmental pollution.
Route four [Yongxiang Xu etal, US20100179341]
Though the steric configuration selectivity of this method product is good, in ring closure reaction, used the fuming liquid trifluoroacetic acid of strong and stimulating, and trivial operations, be unfavorable for industrialization; Reduction reaction adopts lithium aluminum hydride to make reductive agent simultaneously, and this is a danger close for industrial production.
Summary of the invention
Technical problem solved by the invention is to provide a kind of method for preparing gemcitabine hydrochloride and its intermediate of highly selective, to solve the shortcoming in the above-mentioned background technology.
Technical problem solved by the invention realizes by the following technical solutions:
A kind of method for preparing gemcitabine hydrochloride and its intermediate of highly selective provides following technical proposals.
One aspect of the present invention provides a kind of intermediate of gemcitabine hydrochloride, i.e. 2-deoxidation-2, and the preparation method of 2-difluoro ribofuranose compound, specific as follows:
2 3 4?
5 6 7?
8?
G in the formula
1, G
2Can represent by following structure respectively:
R wherein
1Expression hydrogen, C1-C3 low carbon chain alkyl as methyl, ethyl or propyl group, are preferably hydrogen, methyl or ethyl; R
2Expression hydrogen, C1-C4 low carbon chain alkyl, phenyl or substituted-phenyl; G wherein
1, G
2In have a R at least
2Be phenyl or substituted-phenyl.
Its synthetic schemes, preferred steps is as follows:
Zinc powder and ethylene dibromide join in the exsiccant tetrahydrofuran (THF), stir down, are warming up to 40 ℃, add trimethylchlorosilane.
Stirring reaction is 30 minutes under this temperature, is warming up to 60 ℃ then, drips the tetrahydrofuran solution that is dissolved with D-glyceraldehyde acetonide (compound 2) and monobromo ethyl difluoro, carries out back flow reaction.
Reaction is cooled to room temperature after finishing, and with reaction solution impouring hydrochloric acid, in the mixing solutions of ether and frozen water, organic layer is washed successively, the saturated sodium bicarbonate aqueous solution washing, and drying, reaction solution concentrates, and the resistates underpressure distillation obtains compound 3.
3 pairs of phenyl Benzoyl chlorides of compound and triethylamine join in the methylene dichloride, back flow reaction, and after reacting completely, in the impouring dilute hydrochloric acid, organic layer washing, drying is concentrated into driedly, obtains compound 4.
Compound 4 joins in the mixing solutions of wet chemical, tetrahydrofuran (THF) and methyl alcohol, room temperature reaction, and after reaction finished, concentration of reaction solution had solid to separate out to certain volume, filtered, and filter cake washs with isopropyl ether, and drying obtains compound 5.
Compound 5 joins in the mixing solutions of acetonitrile and concentrated hydrochloric acid, back flow reaction, and reaction is cooled to room temperature after finishing, and reaction solution is concentrated into dried, adds ethyl acetate to resistates, filters insolubles, and filtrate is concentrated into dried, obtains compound 6.
Compound 6 does not need further processing, can be directly used in next step; Compound 6, Benzoyl chloride and pyridine join stirring reaction in the ethyl acetate, and reaction finishes afterreaction liquid and is poured in the dilute hydrochloric acid, and organic layer is washed successively, saturated sodium bicarbonate aqueous solution and saturated common salt washing, drying is concentrated into driedly, and the resistates recrystallization can obtain compound 7.
Compound 7 joins stirring reaction in the toluene solution that Red-Al is two (2-methoxyethoxy) sodium aluminates of dihydro, after reaction finishes, reaction solution is poured in the aqueous solution of Seignette salt, organic layer is washed with saturated common salt, anhydrous sodium sulfate drying, be concentrated into driedly, obtain compound 8, can be directly used in the next step.
The mol ratio of wherein said monobromo ethyl difluoro, zinc powder and compound 2 is preferably 1.00:1.00:1.10-1.00:1.00:1.30; Compound 3, the mol ratio of methyl benzoyl chloride and triethylamine is preferably 1.00:1.10:1.40-1.00-1.30:1.60; Compound 4 is preferably 1.00:3.50-1.00:4.00 with the mol ratio of salt of wormwood; Compound 5 is preferably 1.00:1.20-1.00:1.30 with the mol ratio of hydrochloric acid; The mol ratio of compound 6, Benzoyl chloride and pyridine is preferably 1.00:1.40:1.90-1.00:1.60:2.10; Compound 7 is preferably 1.00:1.50-1.00:2.00 with the mol ratio of Red-Al.
The present invention also provides one with compound 8, i.e. intermediate product 2-deoxidation-2, and 2-difluoro ribofuranose is the preparation method of the gemcitabine hydrochloride of starting raw material, concrete reaction formula is as follows:
10 1
G wherein
3Expression C1-C4 low carbon chain alkylsulfonyl, benzenesulfonyl, substituted benzene alkylsulfonyl, preferred methylsulfonyl, benzenesulfonyl, to Methyl benzenesulfonyl base and p-nitrophenyl alkylsulfonyl.
In its synthetic schemes, preferred steps is as follows:
The mixing solutions of compound 8, p-methyl benzene sulfonic chloride, DMAP, triethylamine and methylene dichloride, stirring reaction is after reaction finishes, use dilute hydrochloric acid successively, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, drying, be concentrated into do after, the resistates recrystallization obtains compound 9.
Cytosine(Cyt), hexamethyldisilazane, ammonium sulfate back flow reaction, cooling is concentrated into dried, resistates adds in the toluene, is warming up to 100 ℃, drips the toluene solution of compound 9, dropwise, continue back flow reaction, after reaction finishes, be chilled to 60 ℃, add methyl alcohol and hydrochloric acid soln, solid is separated out, filter, filter cake salt acid elution is used ethyl alcohol recrystallization then, remove α configuration product, obtain the beta comfiguration product.
The beta comfiguration product that obtains is dissolved in the mixing solutions of methyl alcohol and ammoniacal liquor, and the stirring at room reaction is after reaction finishes, reaction solution is concentrated into dried, and resistates adds in the entry, uses ethyl acetate extraction, water layer is concentrated into dried, obtains gemcitabine, gemcitabine be dissolved in the Virahol and acetone mixed solvent in, be cooled to 0 ℃, add concentrated hydrochloric acid, to PH=1-2,, static placement 3 hours, solid is separated out, filter, filter cake obtains purity with cold washing with acetone〉99% gemcitabine hydrochloride.
The mol ratio of wherein said compound 8, Tosyl chloride and triethylamine is preferably 1.00:1.05:1.20-1.00:1.20:1.40; The mol ratio of compound 9 and cytosine(Cyt) is preferably 1.00:1.50-1.00:2.50.
Beneficial effect:The present invention compared with prior art it is advantageous that:
1. ring closure reaction promptly synthetic compound 6 time, by two-step reaction, uses salt of wormwood and hydrochloric acid as reagent by compound 4, has avoided adopting the trifluoroacetic acid of strong and stimulating, and has reduced cost, has reduced the corrosion for reactor;
2. reduction reaction when promptly preparing compound 8, has adopted Red-Al as going back original reagent, and the reaction conditions gentleness is simple to operate, be convenient to suitability for industrialized production, and stereoselectivity is better;
3. preparation compound 9 time, replace volatile liquid methyl SULPHURYL CHLORIDE with the solid Tosyl chloride, simple to operate, injure little for operator;
4. when preparing the gemcitabine hydrochloride, adopt the mixed solvent of Virahol and acetone, yield improves.
Embodiment
For technique means, creation characteristic that the present invention is realized, reach purpose and effect is easy to understand, below in conjunction with specific embodiment, further set forth the present invention.
A kind of method for preparing gemcitabine hydrochloride and its intermediate of highly selective, flow process is:
2 3 4?
?
5 6 7?
10 1
Wherein compound (3) is synthetic:
Add 250 milliliters of tetrahydrofuran (THF)s in the reaction flask, 130 gram zinc powders (1.98mol), 5.1 the milliliter ethylene dibromide stirs, and is warming up to 40 ℃, add 7.6 milliliters of trimethylchlorosilanes, under this temperature, continue to stir 30 minutes, and rose to 60 ℃ then, slowly drip and be dissolved with 308 gram D-glyceraldehyde acetonides (compound 2) (2.36mol) and 400 milliliters of tetrahydrofuran solutions of monobromo ethyl difluoro 255 milliliters (1.98mol), temperature rising reflux reaction 2 hours then is cooled to room temperature; In the hydrochloric acid mixed solution of reaction solution impouring 3000 gram ice, 800 milliliters of ether and 2500 milliliters of 1M, stirred 30 minutes, this mixed solution layering, water layer extracts with 900 milliliters of X3 of ether, combined ether layer, with saturated aqueous common salt, saturated sodium bicarbonate aqueous solution washing, use anhydrous sodium sulfate drying at last successively; Filter, filtrate is concentrated into dried, and the resistates underpressure distillation is collected 132-135 ℃ (10mmHg), obtains colourless liquid 282 grams, and promptly compound 3, and molar yield 56.01%(calculates with the monobromo ethyl difluoro).
Wherein
1HNMR (300MHz, CDCl
3): δ (ppm) 1.35-1.49 (m, 9H), 2.19 (s, 1H), 2.95(s, 1H), 3.95-4.48 (m, 5H).
Synthesizing of compound 4:
Add 500 milliliters of methylene dichloride, 50 in the reaction flask and digest compound 3(196mmol), 51.1 grams are to phenyl Benzoyl chloride (235mmol) and 42 milliliters of triethylamines (301mmol), stirring at room reaction 8 hours, in 300 milliliters of 1M hydrochloric acid of reaction solution impouring, stirred 15 minutes, layering, water layer add 200 milliliters of dichloromethane extractions again, merge organic layer, anhydrous sodium sulfate drying is used in water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing at last successively; Filter, filtrate is concentrated into dried, obtains 83.7 gram yellow liquids, and promptly compound 4, and yield 98%(calculates with compound 3).
1HNMR(300MHz,CDCl
3):δ(ppm)?1.25-1.78（m,9H）,4.10-4.22(m,2H),
4.28-4.33(m,2H),4.56-4.60(m,2H),5.80(b,1H),5.96(b,1H),7.42-7.55（m,3H）,7.63-7.73(m,4H),8.15-8.18（m,2H）。
Synthesizing of compound 5:
3000 milliliters of mixed solvents (volume ratio is 1:1:1) that add entry, methyl alcohol and tetrahydrofuran (THF) in the reaction flask, add 86.8 and digest compound 4(200mmol) and Anhydrous potassium carbonate 110.4 grams (800mmol), stirring at room reaction 1 hour, reaction solution is concentrated into about 800 milliliters, leaves standstill half an hour, filters, filter cake washs with isopropyl ether, drying gets white solid 80.1 grams, and yield 90%(calculates with compound 4).
Synthesizing of compound 6:
Add 44.4 in the reaction flask and digest compound 5(100mmol) and 250 milliliters of acetonitriles, stir down, add 110 milliliters of concentrated hydrochloric acids, back flow reaction 8 hours, after reaction finishes, reaction solution is concentrated into dried, adds 300 milliliters of ethyl acetate in the resistates, stirs 30 minutes, filter, filtrate is concentrated into dried, obtains the spumescence solid, and promptly compound 6.Compound 6 need not be further purified, and can directly carry out next step reaction.
Synthesizing of compound 7:
Add 350 milliliters of ethyl acetate, 34.7 gram crude product compound 6(100mmol in the reaction flask) and 158 gram pyridines (200mmol), stir down, add Benzoyl chloride 21.1 grams (150mmol), stirring at room reaction 8 hours in 250 milliliters of 1M hydrochloric acid of reaction solution impouring, was stirred 15 minutes, water layer is used 200 milliliters of ethyl acetate extractions again, merge organic layer, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively, anhydrous sodium sulfate drying; Filter, filtrate is concentrated into dried, obtains yellow solid, with ether and sherwood oil mixed solvent recrystallization, obtains 35.1 gram white solids, and promptly compound 7, and yield 75%(calculates with compound 5, and two steps merged yield).
1HNMR(300MHz,CDCl
3):δ(ppm)4.69-4.77（m,2H）,5.00-5.04(m,1H),
5.74-5.80(m,1H),7.42-7.70(m,10H),8.00-8.04(m,2H),8.11-8.15(m,2H)。
Synthesizing of compound 8:
Add 23.4 in the reaction flask and digest compound 7(50mmol) and 200 milliliters of toluene, nitrogen protection is stirred time, be cooled to-20 ℃, the toluene of the Red-Al of dropping 70% is molten, and 21 milliliters (75.6mmol) dropwises, slowly return to stirring at room reaction 2 hours, to stir 30 minutes in the aqueous solution of 300 milliliters of saturated Seignette salts of reaction solution impouring, water layer extracts with 200 milliliters of toluene, merges organic layer, use the saturated common salt water washing, anhydrous sodium sulfate drying; Filter, filtrate is concentrated into dried, obtains 21.2 crude products that digest compound 8, and yield 90% can directly carry out next step reaction.
Synthesizing of compound 9:
Add 21.2 in the reaction flask and digest compound 8(45mmol) and 200 milliliters of methylene dichloride, stir and add triethylamine 5.5 grams (54.5mmol) and 0.28 gram DMAP down, be cooled to 0 ℃, add 9.4 gram Tosyl chlorides (49.5mmol) in batches, reinforced finishing, returned to room temperature reaction 3 hours, in 100 milliliters of 1M hydrochloric acid of reaction solution impouring, stirred 15 minutes, water layer is with 100 milliliters of dichloromethane extractions, merge organic layer, water, saturated sodium bicarbonate aqueous solution and saturated common salt solution washing successively, anhydrous sodium sulfate drying; Filter, filtrate is concentrated into dried, and resistates obtains light yellow solid 37.5 grams, yield 98% with methylene dichloride and ether mixed solvent recrystallization.
1HNMR(300MHz,CDCl
3):δ(ppm)?4.22-4.26（m,2H）,4.48-4.51(m,2H),
4.80-4.85(m,1H),4.89-4.94(m,1H),7.32-8.09(m,20H)。
Synthesizing of compound 10:
Add 55 gram cytosine(Cyt)s (50mmol) in the reaction flask, 150 milliliters of hexamethyldisilazanes and 0.2 gram ammonium sulfate, temperature rising reflux is to solids disappeared, continue reaction 1 hour, whole solvents are removed in underpressure distillation, and resistates adds in 300 milliliters of toluene, be warming up to 100 ℃, dropping is dissolved with the compound 9(25mmol of 14.9 grams), dropwise, continued back flow reaction 8 hours, be cooled to 60 ℃, add 350 ml methanol in the reaction solution, continue to stir 0 milliliter of 2N hydrochloric acid of Dropwise 35 20 minutes, there is solid to separate out, continue to stir 30 minutes, be cooled to room temperature, filter, filter cake 100 milliliters of washings of 2N hydrochloric acid, remove excessive cytosine(Cyt), filter cake dehydrated alcohol recrystallization is then removed the product of α configuration, obtain off-white color 7.0 and digest compound 10(α: β=1:40), yield 54%.
Synthesizing of compound 1:
Digesting compound 10 with 7.0 adds in the mixing solutions of 150 ml methanol and 2.5 ammoniacal liquor, the stirring at room reaction is spent the night, reaction solution is concentrated into dried, add the dissolving of 80 ml waters to resistates, with 100x2 milliliter ethyl acetate extraction, discard organic layer, water layer is concentrated into dried, obtain 3.2 gram gemcitabines, yield 90%; 3.2 gram gemcitabines are joined in the mixed solvent of 50 milliliters Virahol and acetone, be cooled to 0 ℃, stir and add 12N hydrochloric acid adjusting PH=1-2 down, left standstill under this temperature 3 hours, and filtered, filter cake is with icing washing with acetone, drying obtains the pure product of 3.5 gram gemcitabine hydrochlorides, yield 95.9%, purity 99.5%, fusing point 288-290 ℃.
In the present embodiment: the total recovery of product is 15.23%, calculates with the monobromo ethyl difluoro.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof
Claims (2)
1. the method for preparing gemcitabine hydrochloride and its intermediate of a highly selective provides a kind of intermediate of gemcitabine hydrochloride on the one hand, i.e. 2-deoxidation-2, and the preparation method of 2-difluoro ribofuranose compound, specific as follows:
2 3 4?
5 6 7?
8?
G in the formula
1, G
2Can represent by following structure respectively:
R wherein
1Expression hydrogen, C1-C3 low carbon chain alkyl as methyl, ethyl or propyl group, are preferably hydrogen, methyl or ethyl; R
2Expression hydrogen, C1-C4 low carbon chain alkyl, phenyl or substituted-phenyl; G wherein
1, G
2In have a R at least
2Be phenyl or substituted-phenyl, it is characterized in that the concrete steps of its making are:
Zinc powder and ethylene dibromide join in the exsiccant tetrahydrofuran (THF), stir down, are warming up to 40 ℃, add trimethylchlorosilane;
Stirring reaction is 30 minutes under this temperature, is warming up to 60 ℃ then, drips the tetrahydrofuran solution that is dissolved with D-glyceraldehyde acetonide (compound 2) and monobromo ethyl difluoro, carries out back flow reaction;
Reaction is cooled to room temperature after finishing, and with reaction solution impouring hydrochloric acid, in the mixing solutions of ether and frozen water, organic layer is washed successively, the saturated sodium bicarbonate aqueous solution washing, and drying, reaction solution concentrates, and the resistates underpressure distillation obtains compound 3;
3 pairs of phenyl Benzoyl chlorides of compound and triethylamine join in the methylene dichloride, back flow reaction, and after reacting completely, in the impouring dilute hydrochloric acid, organic layer washing, drying is concentrated into driedly, obtains compound 4;
Compound 4 joins in the mixing solutions of wet chemical, tetrahydrofuran (THF) and methyl alcohol, room temperature reaction, and after reaction finished, concentration of reaction solution had solid to separate out to certain volume, filtered, and filter cake washs with isopropyl ether, and drying obtains compound 5;
Compound 5 joins in the mixing solutions of acetonitrile and concentrated hydrochloric acid, back flow reaction, and reaction is cooled to room temperature after finishing, and reaction solution is concentrated into dried, adds ethyl acetate to resistates, filters insolubles, and filtrate is concentrated into dried, obtains compound 6;
Compound 6 does not need further processing, can be directly used in next step; Compound 6, Benzoyl chloride and pyridine join stirring reaction in the ethyl acetate, and reaction finishes afterreaction liquid and is poured in the dilute hydrochloric acid, and organic layer is washed successively, saturated sodium bicarbonate aqueous solution and saturated common salt washing, drying is concentrated into driedly, and the resistates recrystallization can obtain compound 7;
Compound 7 joins stirring reaction in the toluene solution that Red-Al is two (2-methoxyethoxy) sodium aluminates of dihydro, after reaction finishes, reaction solution is poured in the aqueous solution of Seignette salt, organic layer is washed with saturated common salt, anhydrous sodium sulfate drying, be concentrated into driedly, obtain compound 8, can be directly used in the next step.
2. the method for preparing gemcitabine hydrochloride and its intermediate of a kind of highly selective according to claim 1, also provide one with compound 8, be intermediate product 2-deoxidation-2,2-difluoro ribofuranose is the preparation method of the gemcitabine hydrochloride of starting raw material, and concrete reaction formula is as follows:
10 1?
G wherein
3Expression C1-C4 low carbon chain alkylsulfonyl, benzenesulfonyl, substituted benzene alkylsulfonyl, preferred methylsulfonyl, benzenesulfonyl, to Methyl benzenesulfonyl base and p-nitrophenyl alkylsulfonyl is characterized in that in its synthetic schemes, concrete steps are as follows:
The mixing solutions of compound 8, p-methyl benzene sulfonic chloride, DMAP, triethylamine and methylene dichloride, stirring reaction is after reaction finishes, use dilute hydrochloric acid successively, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, drying, be concentrated into do after, the resistates recrystallization obtains compound 9;
Cytosine(Cyt), hexamethyldisilazane, ammonium sulfate back flow reaction, cooling is concentrated into dried, resistates adds in the toluene, is warming up to 100 ℃, drips the toluene solution of compound 9, dropwise, continue back flow reaction, after reaction finishes, be chilled to 60 ℃, add methyl alcohol and hydrochloric acid soln, solid is separated out, filter, filter cake salt acid elution is used ethyl alcohol recrystallization then, remove α configuration product, obtain the beta comfiguration product;
The beta comfiguration product that obtains is dissolved in the mixing solutions of methyl alcohol and ammoniacal liquor, and the stirring at room reaction is after reaction finishes, reaction solution is concentrated into dried, and resistates adds in the entry, uses ethyl acetate extraction, water layer is concentrated into dried, obtains gemcitabine, gemcitabine be dissolved in the Virahol and acetone mixed solvent in, be cooled to 0 ℃, add concentrated hydrochloric acid, to PH=1-2,, static placement 3 hours, solid is separated out, filter, filter cake obtains purity with cold washing with acetone〉99% gemcitabine hydrochloride.
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| CN103232508A (en) * | 2012-05-22 | 2013-08-07 | 湖北一半天制药有限公司 | Industrialized gemcitabine hydrochloride synthesis method |
| CN104004031A (en) * | 2014-05-22 | 2014-08-27 | 北京瑞博奥生物科技有限公司 | Preparation method of 2-deoxidation-D-ribose |
| CN108484563A (en) * | 2018-04-28 | 2018-09-04 | 江苏八巨药业有限公司 | A kind of preparation method of gemcitabine intermediate |
| 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 |
| CN113603669A (en) * | 2021-08-06 | 2021-11-05 | 江苏八巨药业有限公司 | Preparation method of gemcitabine key intermediate |
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| CN103232508A (en) * | 2012-05-22 | 2013-08-07 | 湖北一半天制药有限公司 | Industrialized gemcitabine hydrochloride synthesis method |
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| CN104004031B (en) * | 2014-05-22 | 2016-08-24 | 北京瑞博奥生物科技有限公司 | A kind of preparation method of DRI |
| CN108484563A (en) * | 2018-04-28 | 2018-09-04 | 江苏八巨药业有限公司 | A kind of preparation method of gemcitabine intermediate |
| 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 |
| CN113603669A (en) * | 2021-08-06 | 2021-11-05 | 江苏八巨药业有限公司 | Preparation method of gemcitabine key intermediate |
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Application publication date: 20110817 |