CN103012527A - Novel synthesis process for industrial production of gemcitabine - Google Patents
Novel synthesis process for industrial production of gemcitabine Download PDFInfo
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- CN103012527A CN103012527A CN2012105810701A CN201210581070A CN103012527A CN 103012527 A CN103012527 A CN 103012527A CN 2012105810701 A CN2012105810701 A CN 2012105810701A CN 201210581070 A CN201210581070 A CN 201210581070A CN 103012527 A CN103012527 A CN 103012527A
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- gemcitabine
- deoxidation
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Abstract
The invention discloses a novel synthesis process for an industrial production of gemcitabine. The synthesis process for the industrial production of gemcitabine hydrochloride comprises the following steps: by using 2,3-oxo-isopentylidene-D-glyceraldehyde as a raw material, implementing an addition reaction, a ring-opening reaction and a cyclization reaction; and protecting a hydroxy group by acyl chloride to prepare an intermediate product. By protecting the base in one step, the step is reduced, the yield is improved and the cost is saved; and the synthesis process is specifically suitable for an overnight production.
Description
The invention provides a kind of gemcitabine preparation method, a kind of synthesis technique of suitability for industrialized production gemcitabine of novelty is provided.
Background technology
Gemcitabine hydrochloride is known marketed drug.Its chemical name is 2-deoxidation-2, and 2-hydrochloric acid difluoro Deoxyribose cytidine (β-isomer), English name are gemcitabinehydrochloride.Its structure is similar with cytosine arabinoside.Be a kind of Difluoronucleosides class metabolic antagonist anticarcinogen that destroys cellular replication, Main Function is in the DNA tumour cell of synthesis phase, and namely S phase cell, can stop the progress of G1 phase to the S phase under certain condition; It has obvious cytotoxic activity to people and the mouse tumour of various cultivations, it is the water-soluble analogues of cytosine deoxyriboside, a kind of surrogate of substrate material of inhibition to ribonucleotide reductase, this kind of enzyme is at DNA in the synthetic and repair process, is vital to the generation of needed deoxynucleotide.Produce at present gemcitabine hydrochloride and mainly contain two kinds of techniques:
(1)
(2)
But in the above-mentioned known technique (one), because its intermediate is gone up benzoyl in two steps, complex process; cost is high; in addition two benzoyl protecting groups are also unstable very easily decomposes under alkaline condition, affects quality product and yield, is the major defect of above-mentioned technique.
In the technique (two), because its intermediate is gone up hydroxyl protecting group in two steps, complex process, cost is high, affects quality product and yield, is the major defect of above-mentioned technique.
Summary of the invention:
The object of the invention is to, provide a kind of energy to synthesize a kind of more stable and simple hydroxyl protection thing of technique intermediate, be applicable to the synthesis technique of suitability for industrialized production gemcitabine.
Technical scheme of the present invention is as follows:
A kind of synthesis technique of suitability for industrialized production gemcitabine of novelty, the following general formula of its processing step, explaining, but therefore limited range is not like this.
A kind of synthesis technique of suitability for industrialized production gemcitabine of novelty is characterized in that being realized by the following step:
(1) 3,5-acyl group-2-deoxidation-2, the preparation of 2-two fluoro-D-furan pentoses-1-ketone (2):
Under rare gas element, 2-deoxidation-2.2-two fluoro-D-furan pentoses-1-ketone (1) is dissolved in the organic solvent, add acyl chlorides reaction under the condition that organic solvent, catalyzer and alkali exist and generate target compound 2.
(2) 3,5-acyl group-2-deoxidation-2, the preparation of 2-two fluoro-D-RIBOSEs (3):
Compound 2 is dissolved in the organic solvent, obtains compound 3 at the reductive agent of adding below-5 ℃
(3) 3,5-acyl group-2-deoxidation-2, the preparation of 2-two fluoro-D-RIBOSE-1-sulphonate (4):
Compound 3 is joined in the organic solvent that contains alkali, and the lower acyl chlorides that adds below-8 ℃ obtains compound 4.
(4) 3', 5'-acyl group-2'-deoxidation-2', the preparation of 2'-difluoro cytidine (5):
Cytosine(Cyt), salt reflux to the reaction solution clarification, are continued to keep reaction 0.5h, be cooled to below 100 ℃, removal of solvent under reduced pressure is separated out solid; Add organic solvent in the solid and make dissolution of solid, then add compound 4, obtain target compound 5 after the reaction.
(5) 2'-deoxidation-2', the preparation of 2'-difluoro cytidine (6):
Compound 5 is dissolved in the organic solvent, adds alkali, obtain target compound 6 in reaction below 65 ℃.
The described catalyzer of step (1) is 4-dimethylaminopyridine.
Step (1) acyl chlorides is chloroacetyl chloride, tertiary butyl acyl chlorides, Acetyl Chloride 98Min..
The described reductive agent of step (2) is red aluminium.
Organic solvent described in the step (1) to (5) is ethyl acetate, methyl tertiary butyl ether, methylene dichloride, toluene or anhydrous methanol.
The described salt of step (4) is hexamethyldisilane ammonium, ammonium sulfate.
Alkali described in step (1), (3) is pyridine, triethylamine, and the alkali described in the step (50) is yellow soda ash.
The present invention's beneficial effect compared with prior art is:
1, the synthesis technique of this industrial production of gemcitabine hydrochloride adopts 2,3-oxygen-isopentylidene-D-Glycerose is raw material, through addition, and open loop, cyclization is again with the intermediate of acyl chlorides protection hydroxyl system.Because the upper protecting group of a step that adopts has reduced step, has improved productive rate, has saved cost.Be specially adapted to overnightization production.
2, can only adopt this reductive agent of red aluminium could realize the object of the invention in the step (2), the contriver selects multiple reductive agent, and discovery can only could realize with red aluminium.
Embodiment
Embodiment 1
(1) 3,5-chloracetyl-2-deoxidation-2, the preparation of 2-two fluoro-D-furan pentoses-1-ketone (2):
In nitrogen protection and under stirring successively with 2-deoxidation-2.2-two fluoro-D-furan pentoses-1-ketone (30.0g; 0.178mol), ethyl acetate (50mL), chloroacetyl chloride (22.2g; 0.196mol), 4-dimethylaminopyridine (0.22g, 1.79mmol), pyridine (28.3g, 0.357mol) join in the flask; add sherwood oil (150mL) behind 50 ~ 55 ℃ of lower reaction 6h; be cooled to 0 ℃, filter, filtrate decompression is concentrated; obtain yellow oil 2(44.8g, 78.4%).
(2) 3,5-chloracetyl-2-deoxidation-2, the preparation of 2-two fluoro-D-RIBOSEs (3):
In nitrogen protection and under stirring successively with 3; 5-chloracetyl-2-deoxidation-2; 2-two fluoro-D-furan pentoses-1-ketone (30.0g; 93.4mmol), methyl tertiary butyl ether (120mL) joins in the flask, slowly drips red aluminium (40mL, 138.0mmol) under-5 ℃; keep and add trifluoroethanol (8mL) after this temperature continues to stir 15min; stir and moments later to add 20% sodium tartrate solution (120mL), continue stirring reaction 2h, stopped reaction is removed water layer static a moment.Organic layer saturated common salt water washing three times, anhydrous magnesium sulfate drying gets yellow oil 3(28.8g, 95.3%).
(3) 3,5-chloracetyl-2-deoxidation-2, the preparation of 2-two fluoro-D-RIBOSE-1-p-methyl benzenesulfonic acid ester (4):
In nitrogen protection and under stirring successively with 3; 5-chloracetyl-2-deoxidation-2; 2-two fluoro-D-RIBOSE (20.0g; 61.9mmol), methylene dichloride (90mL), triethylamine (15mL) join in the flask; under-8 ℃, slowly drip p-methyl benzene sulfonic chloride (10mL), keep this temperature and continue to add the saturated common salt water washing three times, anhydrous magnesium sulfate drying behind the stirring 15min; get yellow oil 4(28.0g, 95.0%).
(4) 3', 5'-dichloro-acetyl-2'-deoxidation-2', the preparation of 2'-difluoro cytidine (5):
Under agitation successively cytosine(Cyt) (22.5g, 0.174mol), hexamethyldisilane ammonium (112mL), ammonium sulfate (28mg) are joined in the flask, reflux is to the reaction solution clarification, continue to keep reaction 0.5h, be cooled to below 100 ℃, removal of solvent under reduced pressure is separated out solid.Add toluene (30mL) in solid, trimethylsilyl triflate (5.65g, 25.4mol) is heated to 85 ℃ and makes dissolution of solid.Add 3,5-chloracetyl-2-deoxidation-2 in the reaction solution, 2-two fluoro-D-RIBOSE-1-p-methyl benzenesulfonic acid ester (12.1g; 25.4mmol), 85 ℃ of lower reaction 7 ~ 14h(HPLC detection reaction), after finishing, reaction adds ethyl acetate (200mL) dilution; be cooled to again below 50 ℃; slowly add 60mL distilled water, stir 40min, filter; filtrate is used saturated common salt water washing three times; anhydrous magnesium sulfate drying, removal of solvent under reduced pressure get yellow oil 5(8.3g, 78.8.0%).
(5) 2'-deoxidation-2', the preparation of 2'-difluoro cytidine (6):
Under agitation successively with 3'; 5'-dichloro-acetyl-2'-deoxidation-2'; 2'-difluoro cytidine (8.0g, 19.2mmol), anhydrous methanol (28mL), anhydrous sodium carbonate (4.0g, 38.0mmol), trifluoroethanol (10.0mL) join in the flask; stopped reaction behind 65 ℃ of lower continuation stirring reaction 3.5h; suction filtration, filtrate adds ethyl acetate (150mL), organic layer saturated common salt water washing three times; the anhydrous magnesium sulfate drying removal of solvent under reduced pressure gets yellow oil 6(4.2g, 82.7%).
1H?NMR(DMSO-d6)δ:10.01(S,1H,OH-3’)，8.90(s,1H,OH-5’)，8.15(d,J＝8.29Hz,1H,H-6)，6.42(br,2H,NH
2)，6.25(d,J＝8.29Hz,1H,H-5)，6.06(t,1H，H-1’)，4.18(m,1H,H-3’)，3.89(m,1H,H-4’)，3.78(dd,1H,H-5’)，3.62(dd,1H,H-5’)。
13C?NMR(DMSO-d6)δ：159.6(C-4)，147.0(C-2)，143.3(C-6)，122.8(C-2’)，94.7(C-5)，83.8(C-1’)，81.5(C-4’)，68.1(C-3’)，58.7(C-5’)。HR-ESI-MS,calcd.for?C
9H
11F
2N
3O
4([M+H]
+)263.2。
Claims (7)
1. the synthesis technique of the suitability for industrialized production gemcitabine of a novelty is characterized in that being realized by the following step:
(1) 3,5-acyl group-2-deoxidation-2, the preparation of 2-two fluoro-D-furan pentoses-1-ketone (2):
Under rare gas element, 2-deoxidation-2.2-two fluoro-D-furan pentoses-1-ketone (1) is dissolved in the organic solvent, add acyl chlorides reaction under the condition that organic solvent, catalyzer and alkali exist and generate target compound 2;
(2) 3,5-acyl group-2-deoxidation-2,2-two fluoro-D-RIBOSEs (
3) preparation:
With compound
2Be dissolved in the organic solvent, obtain compound at the reductive agent of adding below-5 ℃
3
(3) 3,5-acyl group-2-deoxidation-2,2-two fluoro-D-RIBOSE-1-sulphonate (
4) preparation:
With compound
3Join in the organic solvent that contains alkali, the lower acyl chlorides that adds below-8 ℃ obtains compound
4
(4) 3', 5'-acyl group-2'-deoxidation-2', the 2'-difluoro cytidine (
5) preparation:
Cytosine(Cyt), salt reflux to the reaction solution clarification, are continued to keep reaction 0.5 h, be cooled to below 100 ℃, removal of solvent under reduced pressure is separated out solid; Add organic solvent in the solid and make dissolution of solid, then add compound
4,Obtain target compound after the reaction
5
(5) 2'-deoxidation-2', the 2'-difluoro cytidine (
6) preparation:
With compound
5Be dissolved in the organic solvent, add alkali, obtain target compound in reaction below 65 ℃
6
2. the synthesis technique of the suitability for industrialized production gemcitabine of a kind of novelty according to claim 1 is characterized in that the described catalyzer of step (1) is 4-dimethylaminopyridine.
3. the synthesis technique of the suitability for industrialized production gemcitabine of a kind of novelty according to claim 2 is characterized in that step (1) acyl chlorides is chloroacetyl chloride, tertiary butyl acyl chlorides, Acetyl Chloride 98Min..
4. the synthesis technique of the suitability for industrialized production gemcitabine of a kind of novelty according to claim 1 is characterized in that the described reductive agent of step (2) is red aluminium.
5. the synthesis technique of the suitability for industrialized production gemcitabine of a kind of novelty according to claim 1 is characterized in that the organic solvent described in the step (1) to (5) is ethyl acetate, methyl tertiary butyl ether, methylene dichloride, toluene or anhydrous methanol.
6. the synthesis technique of the suitability for industrialized production gemcitabine of a kind of novelty according to claim 1 is characterized in that the described salt of step (4) is hexamethyldisilane ammonium, ammonium sulfate.
7. the synthesis technique of the suitability for industrialized production gemcitabine of a kind of novelty according to claim 1 is characterized in that the alkali described in step (1), (3) is pyridine, triethylamine, and the alkali described in the step (50) is yellow soda ash.
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| CN2012105810701A CN103012527A (en) | 2012-12-26 | 2012-12-26 | Novel synthesis process for industrial production of gemcitabine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066307A (en) * | 2019-05-22 | 2019-07-30 | 蚌埠学院 | A kind of method that immobilized base catalysis takes off riboacetyl |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153601A (en) * | 2011-02-26 | 2011-08-17 | 湖南欧亚生物有限公司 | Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity |
| CN102617677A (en) * | 2012-02-22 | 2012-08-01 | 江苏豪森药业股份有限公司 | Method for preparing 2-deoxidized-2, 2-hydrochloric acid difluoro deoxycytidine |
| CN102617678A (en) * | 2012-02-22 | 2012-08-01 | 江苏豪森药业股份有限公司 | Method for preparing gemcitabine hydrochloride |
| EP2508528A1 (en) * | 2011-04-07 | 2012-10-10 | Pharmaessentia Corp. | Stereoselective synthesis of beta-nucleosides |
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2012
- 2012-12-26 CN CN2012105810701A patent/CN103012527A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153601A (en) * | 2011-02-26 | 2011-08-17 | 湖南欧亚生物有限公司 | Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity |
| EP2508528A1 (en) * | 2011-04-07 | 2012-10-10 | Pharmaessentia Corp. | Stereoselective synthesis of beta-nucleosides |
| CN102617677A (en) * | 2012-02-22 | 2012-08-01 | 江苏豪森药业股份有限公司 | Method for preparing 2-deoxidized-2, 2-hydrochloric acid difluoro deoxycytidine |
| CN102617678A (en) * | 2012-02-22 | 2012-08-01 | 江苏豪森药业股份有限公司 | Method for preparing gemcitabine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 杨宝海，等.: ""抗癌药盐酸吉西他滨的合成工艺研究"", 《精细与专用化学品》, vol. 20, no. 2, 29 February 2012 (2012-02-29), pages 17 - 19 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066307A (en) * | 2019-05-22 | 2019-07-30 | 蚌埠学院 | A kind of method that immobilized base catalysis takes off riboacetyl |
| CN110066307B (en) * | 2019-05-22 | 2022-08-23 | 蚌埠学院 | Method for removing ribose acetyl by immobilized base catalysis |
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Application publication date: 20130403 |