CN103232508A - Industrialized gemcitabine hydrochloride synthesis method - Google Patents
Industrialized gemcitabine hydrochloride synthesis method Download PDFInfo
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- CN103232508A CN103232508A CN2012101601270A CN201210160127A CN103232508A CN 103232508 A CN103232508 A CN 103232508A CN 2012101601270 A CN2012101601270 A CN 2012101601270A CN 201210160127 A CN201210160127 A CN 201210160127A CN 103232508 A CN103232508 A CN 103232508A
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- Prior art keywords
- hydrochloride
- deoxidation
- gemcitabine hydrochloride
- product
- night
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- 229960005144 gemcitabine hydrochloride Drugs 0.000 title claims abstract description 16
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title claims description 15
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000008014 freezing Effects 0.000 claims abstract description 8
- 238000007710 freezing Methods 0.000 claims abstract description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 238000012546 transfer Methods 0.000 claims description 8
- LQICKZWUNRSEHI-BNHYGAARSA-N 4-amino-1-[(2r,3r,4s,5s)-5-[difluoro(hydroxy)methyl]-3,4-dihydroxyoxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](C(O)(F)F)O1 LQICKZWUNRSEHI-BNHYGAARSA-N 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 abstract 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 2
- FLEGKVSBDHUCTC-RTIVQEIQSA-N 2-[[(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-(2-carboxyphenyl)-4,4-difluoro-3-hydroxyoxolan-2-yl]-hydroxymethyl]benzoic acid Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@@](O)(C=2C(=CC=CC=2)C(O)=O)[C@@H](C(O)C=2C(=CC=CC=2)C(O)=O)O1 FLEGKVSBDHUCTC-RTIVQEIQSA-N 0.000 abstract 1
- 239000012046 mixed solvent Substances 0.000 abstract 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- -1 filter Substances 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 230000001399 anti-metabolic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002718 pyrimidine nucleoside Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an industrialized gemcitabine hydrochloride synthesis method, and belongs to the field of chemical product synthesis process. According to the invention, 2'-deoxy-2',2'-difluorocytidine-3',5'-dibenzoate is subjected to benzoyl protecting group removing in a methanol solution comprising ammonia water, and salt-formation is proceeded, such that 2'-deoxy-2',2'-difluorocytidine hydrochloride is formed; and crystallization and separation is carried out in an acetone-water mixed solvent, such that a gemcitabine hydrochloride pure product is obtained. According to the invention, a commonly used method for adding ammonia gas in the step 1 is changed into adding concentrated ammonia water; and a freezing crystallization overnight operation is adopted in subsequent purification process, such that process operability is increased, and reaction yield is improved. The synthesized process product has high refined rate. The purity of the product is maintained above 99.8%.
Description
Technical field
The present invention relates to a kind of synthesis technique of gemcitabine hydrochloride of suitability for industrialized production.
Background technology
Gemcitabine hydrochloride, chemistry is by name 2 '-deoxidation-2 ', 2 '-the difluoro cytidine hydrochloride, English gemcitabine hydrochloride by name, be the pyrimidine nucleoside analoys of U.S. Eli Lilly company research and development, nineteen ninety-five is at the listing of states such as Australia, Finland, trade(brand)name Gemzar.The existing approved import of China, Chinese commodity strong selecting by name.This product structure is similar with cytosine arabinoside (cytarabine), belongs to ucleosides antimetabolic antitumor drug, can infiltrate DNA and make its splitting of chain, plays cytotoxicity.Main synthesis technique is at present:
But this method is because feed ammonia, and reaction not exclusively influences quality and the productive rate of product.
Summary of the invention
In view of this, the invention provides the synthesis technique of the higher gemcitabine hydrochloride of a kind of yield.
Step 1: with 2 '-deoxidation-2 ', 2 '-difluoro cytidine-3 ', 5 '-dibenzoate, in containing the methyl alcohol of ammoniacal liquor, take off the benzoyl protecting group, salify gets 2 '-deoxidation-2 ', 2 '-the difluoro cytidine hydrochloride.
Step 2: with 2 '-deoxidation-2 ', 2 '-aqueous solution of difluoro cytidine hydrochloride drips a small amount of concentrated hydrochloric acid and transfers to pH≤0.5, stirs to add acetone down.After spending the night, freezing and crystallizing refilters and uses acetone drip washing, drying under reduced pressure.
Method with adding ammonia commonly used in the step 1 of the present invention changes the interpolation strong aqua into, originally the processing ease of opening ammonia produces suck-back, may influence product purity and have certain potential safety hazard, change the operability that has increased technology behind the ammoniacal liquor into, improve the productive rate of reaction simultaneously.
Increased the step that freezing and crystallizing spends the night in the step 2 of the present invention, this operation has increased the crystallization time of product, has improved the productive rate of reaction greatly.
Embodiment
Reagent and material that invention is adopted
1.2 '-deoxidation-2 ', 2 '-difluoro cytidine-3 ', 5 '-dibenzoate, commercially available, analytical pure
2. ethyl acetate is commercially available, analytical pure
3. acetone is commercially available, analytical pure
4 Virahols, commercially available, analytical pure
5. strong aqua: 28%, commercially available, analytical pure
6. concentrated hydrochloric acid: 37.2%, commercially available, analytical pure
Concrete synthesis technique step is as follows:
Embodiment 1:
2 '-deoxidation-2 ', 2 '-difluoro cytidine-3 ', 5 '-methyl alcohol (325ml) solution of dibenzoate (10g) is cooled to 0 ℃, add strong aqua 10ml, the stirring at room reaction is spent the night, concentrating under reduced pressure, residue oily matter water-soluble (100ml) is with ethyl acetate (100ml * 2) washing, organic layer merges back water (100ml) and extracts, combining water layer, activated carbon decolorizing filters, filtrate decompression is concentrated into dried, add Virahol (100ml) and concentrated hydrochloric acid (13ml) in the resistates, be heated to 70 ℃, room temperature standing over night behind the insulation 0.5h.Filter, filter cake is used cold isopropanol (13ml) and normal hexane (6ml) washing successively, and drying gets white solid, 2 '-deoxidation-2 ', 2 '-difluoro cytidine hydrochloride 4.2g, productive rate is 65%.
With 2 '-deoxidation-2 ', 2 '-difluoro cytidine hydrochloride (4.1g) and water (30ml) puts in the reaction flask, and 50 ℃ are heated to and are cooled to room temperature after molten, drip a small amount of concentrated hydrochloric acid and transfer to pH≤0.5, stir to add acetone (100ml) down, stir 2h.Freezing and crystallizing spends the night, and filters, and filter cake washs with cold acetone, drying under reduced pressure gets gemcitabine hydrochloride crude product 2.5g, gained crude product (2.5g) is dissolved in 55 ℃ the water (25ml), filtered while hot, filtrate transfers to pH≤0.5,0 ℃ stirring 1h with concentrated hydrochloric acid, separates out crystal, filter, filter cake with washing with acetone after drying under reduced pressure, get the pure product of gemcitabine hydrochloride (2.05g, refining rate 94.0%)
Embodiment 2:
2 '-deoxidation-2 ', 2 '-difluoro cytidine-3 ', 5 '-methyl alcohol (650ml) solution of dibenzoate (20g) is cooled to 0 ℃, add strong aqua 20ml, the stirring at room reaction is spent the night, concentrating under reduced pressure, residue oily matter water-soluble (200ml) is with ethyl acetate (200ml * 2) washing, organic layer merges back water (200ml) and extracts, combining water layer, activated carbon decolorizing filters, filtrate decompression is concentrated into dried, add Virahol (200ml) and concentrated hydrochloric acid (26ml) in the resistates, be heated to 70 ℃, room temperature standing over night behind the insulation 0.5h.Filter, filter cake is used cold isopropanol (25ml) and normal hexane (12ml) washing successively, and drying gets white solid, 2 '-deoxidation-2 ', 2 '-difluoro cytidine hydrochloride 8.1g, productive rate is 64%.
With 2 '-deoxidation-2 ', 2 '-difluoro cytidine hydrochloride (8.1g) and water (60ml) puts in the reaction flask, and 50 ℃ are heated to and are cooled to room temperature after molten, drip a small amount of concentrated hydrochloric acid and transfer to pH≤1, stir to add acetone (200ml) down, stir 2h.Freezing and crystallizing spends the night, and filters, and filter cake washs with cold acetone, drying under reduced pressure gets gemcitabine hydrochloride crude product 5.0g, gained 1 crude product (5.0g) is dissolved in 55 ℃ the water (50ml), filtered while hot, filtrate transfers to pH≤0.5,0 ℃ stirring 1h with concentrated hydrochloric acid, separates out crystal, filter, filter cake with washing with acetone after drying under reduced pressure, get the pure product of gemcitabine hydrochloride (4.05g, refining rate 96.0%).
Embodiment 3:
2 '-deoxidation-2 ', 2 '-difluoro cytidine-3 ', 5 '-methyl alcohol (1300ml) solution of dibenzoate (40g) is cooled to 0 ℃, add strong aqua 40ml, the stirring at room reaction is spent the night, concentrating under reduced pressure, residue oily matter water-soluble (400ml) is with ethyl acetate (400ml * 2) washing, organic layer merges back water (400ml) and extracts, combining water layer, activated carbon decolorizing filters, filtrate decompression is concentrated into dried, add Virahol (400ml) and concentrated hydrochloric acid (52ml) in the resistates, be heated to 70 ℃, room temperature standing over night behind the insulation 0.5h.Filter, filter cake is used cold isopropanol (50ml) and normal hexane (24ml) washing successively, and drying gets white solid, 2 '-deoxidation-2 ', 2 '-difluoro cytidine hydrochloride 16g, productive rate is 61%.
With 2 '-deoxidation-2 ', 2 '-difluoro cytidine hydrochloride (16g) and water (120ml) puts in the reaction flask, and 50 ℃ are heated to and are cooled to room temperature after molten, drip a small amount of concentrated hydrochloric acid and transfer to pH≤2, stir to add acetone (400ml) down, stir 2h.Freezing and crystallizing spends the night, and filters, and filter cake washs with cold acetone, drying under reduced pressure gets gemcitabine hydrochloride crude product 9.8g, gained 1 crude product (9.8g) is dissolved in 55 ℃ the water (100ml), filtered while hot, filtrate transfers to pH≤2,0 ℃ stirring 1h with concentrated hydrochloric acid, separates out crystal, filter, filter cake with washing with acetone after drying under reduced pressure, get the pure product of gemcitabine hydrochloride (7.9.g, refining rate 95.0%).
Prove by experiment: the synthesis technique of gemcitabine hydrochloride provided by the invention has increased the operability of technology, has improved productive rate and the synthesis technique product purification rate of reaction simultaneously, has overcome the existing great drawback of traditional synthesis process.
If the content that is not described in detail is arranged, should be those skilled in the art's technique known in this specification sheets, repeat no more herein.
Claims (3)
1. the synthesis technique of the gemcitabine hydrochloride of a suitability for industrialized production, route is as follows:
Step 1: with 2 '-deoxidation-2 ', 2 '-difluoro cytidine-3 ', 5 '-dibenzoate, in containing the methyl alcohol of ammoniacal liquor, take off the benzoyl protecting group, salify gets 2 '-deoxidation-2 ', 2 '-the difluoro cytidine hydrochloride.
Step 2: with 2 '-deoxidation-2 ', 2 '-aqueous solution of difluoro cytidine hydrochloride drips a small amount of concentrated hydrochloric acid and transfers to pH≤0.5, stirs to add acetone down.After spending the night, freezing and crystallizing refilters and uses acetone drip washing, drying under reduced pressure.
2. preparation method according to claim 1 is characterized in that in the step 1 changing the method for adding ammonia commonly used into the interpolation strong aqua, has increased the operability of technology, has improved the productive rate of reaction simultaneously.
3. preparation method according to claim 1 is characterized in that increasing in the step 2 step that freezing and crystallizing spends the night, and this operation has improved the productive rate of reaction greatly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101601270A CN103232508A (en) | 2012-05-22 | 2012-05-22 | Industrialized gemcitabine hydrochloride synthesis method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101601270A CN103232508A (en) | 2012-05-22 | 2012-05-22 | Industrialized gemcitabine hydrochloride synthesis method |
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| CN103232508A true CN103232508A (en) | 2013-08-07 |
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| CN2012101601270A Pending CN103232508A (en) | 2012-05-22 | 2012-05-22 | Industrialized gemcitabine hydrochloride synthesis method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864871A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Gemcitabine hydrochloride compound |
| CN103980333A (en) * | 2014-05-23 | 2014-08-13 | 上海鼎雅药物化学科技有限公司 | Method for purifying gemcitabine hydrochloride |
Citations (3)
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| CN1989147A (en) * | 2004-07-23 | 2007-06-27 | 韩美药品株式会社 | Method for the preparation of d-erythro-2,2-difluoro-2-deoxy-1-oxoribose derivative |
| CN101203524A (en) * | 2005-03-04 | 2008-06-18 | 达布尔医药有限公司 | Intermediate and process for preparing of beta- anomer enriched 21deoxy, 21 ,21-difluoro-d-ribofuranosyl nucleosides |
| 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 |
-
2012
- 2012-05-22 CN CN2012101601270A patent/CN103232508A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1989147A (en) * | 2004-07-23 | 2007-06-27 | 韩美药品株式会社 | Method for the preparation of d-erythro-2,2-difluoro-2-deoxy-1-oxoribose derivative |
| CN101203524A (en) * | 2005-03-04 | 2008-06-18 | 达布尔医药有限公司 | Intermediate and process for preparing of beta- anomer enriched 21deoxy, 21 ,21-difluoro-d-ribofuranosyl nucleosides |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 王英华，等，: ""盐酸吉西他滨的合成"", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864871A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Gemcitabine hydrochloride compound |
| CN103864871B (en) * | 2014-03-10 | 2016-03-02 | 洪军 | A kind of gemcitabine hydrochloride compound |
| CN103980333A (en) * | 2014-05-23 | 2014-08-13 | 上海鼎雅药物化学科技有限公司 | Method for purifying gemcitabine hydrochloride |
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Application publication date: 20130807 |