CN100395246C - Method for producing folic acid antagonist and its intermediate - Google Patents
Method for producing folic acid antagonist and its intermediate Download PDFInfo
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- CN100395246C CN100395246C CNB200510078426XA CN200510078426A CN100395246C CN 100395246 C CN100395246 C CN 100395246C CN B200510078426X A CNB200510078426X A CN B200510078426XA CN 200510078426 A CN200510078426 A CN 200510078426A CN 100395246 C CN100395246 C CN 100395246C
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Abstract
The present invention relates to a method for producing an anti-folacin agent of N-(4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo [2, 3-d] pyrimidine-5-radical) ethyl] benzoyl-L-dibenzyl glutamate, and an intermediate body for the anti-folacin agent as N-(4-[2-(2-amidol (3H)-oxygen-7H-pyrrolo [2 3-d]pyrimidine-5-radical) ethyl]benzoyl-L-dibenzyl glutamate dibenzyl ester, and pharmaceutical salt for the intermediate body.
Description
Technical field
The present invention relates to synthetic organic chemistry, particularly the present invention relates to prepare the method that is used for synthetic valuable antifol and intermediate thereof.
Background technology
The following formula I compound is used for the treatment of cancer in U.S. Pat as antifol
4,996,206, US 5,028,608, US 5,034, open in 493, the also existing many pieces of patent reports of its preparation method are as CN 1055182, CN 1271338, CN 1087910, US 5,254,687, US 6,013,828, in the method for numerous preparation I compounds, at last all be that the two ethyl esters with formula I compound make with sodium hydroxide hydrolysis, influence the purity of finished product owing to the acid amides in the possible hydrolyzing type I of the sodium hydroxide compound.
Summary of the invention
Point out in order to overcome the deficiencies in the prior art; the object of the present invention is to provide antifol N-; (4-[2-; (2-amino-4; (3H)-oxygen-7H-pyrrolo-[2; 3-d] pyrimidine-5-yl) ethyl] benzoyl-L-L-glutamic acid and intermediate N thereof; (4-[2-; (2-amino-4; (3H)-oxygen-7H-pyrrolo-[2; 3-d] pyrimidine-5-yl) ethyl] benzoyl-L-L-glutamic acid dibenzyl ester and can do medicinal salt the preparation method; the compound that particularly a kind of preparation is represented with following formula I or its can be made the method for medicinal salt
Wherein, indicate
*The configuration of carbon atom be the S type,
This method comprises that there is catalytic hydrogenation in the compound that following formula is represented at metal catalyst,
R, R among its Chinese style II
1Be hydrogen or halogen or C
1～C
4Alkyl.
In above-mentioned method, wherein R, R
1Be H, described metal catalyst is a palladium.
Another object of the present invention is to also to provide compound that a kind of preparation represents with Formula Il or its can make the method for medicinal salt
R, R among its Chinese style II
1Be hydrogen or halogen or C
1～C
4Alkyl,
This method comprises the compound that Formula Il I is represented
With the compound condensation that following formula I V represents, R, R among its Chinese style IV
1Be hydrogen or halogen or C
1～C
4Alkyl,
Or the compound cyclization that following formula V is represented, the R among the formula V, R
1Be hydrogen or halogen or C
1～C
4Alkyl.
In other words, it is raw material that the present invention adopts the Formula Il compound, makes formula I compound through catalytic hydrogenation, and its product purity height need not recrystallization.
The preparation of formula II compound, the present invention adopts Formula Il I compound and L-L-glutamic acid two
Benzyl ester condensation or the cyclization of following formula V compound made.
Embodiment
Embodiment 1
N-(4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl-L-L-glutamic acid dibenzyl ester
With 4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] phenylformic acid 10 restrains (33.6mmol) and the 100ml dimethyl formamide drops in the 250ml three-necked bottle, stir, be chilled to 5 ℃, add N-methylmorpholine 10ml (91mmol), 2-chloro-4,6-dimethoxy-triazine 7.5 grams (42.7mmol), in 5～10 ℃ of stirrings 1 hour, add L-L-glutamic acid dibenzyl ester tosilate 20 grams (40.2mmol), stirred 2 hours in 25 ℃, pour in the 500ml separating funnel, add methylene dichloride 100ml, water 100ml shakes up, and divides and gets organic layer, the water layer dichloromethane extraction, merge organic layer, remove organic solvent under reduced pressure, add ethyl acetate 50ml and stir to the greatest extent, filter, use ethyl acetate successively, washing, oven dry, get off-white color solid 15 grams, yield 73.5%.
1HNMR(400MHz?DMSO?d
6) δ 10.98(brs，1H) 10.09(brs，1H)
8.62(d，1H) 7.77(d，2H) 7.33(m，10H) 7.29(d，2H)
6.30(s，1H) 5.95(s，2H) 5.15(s，2H) 5.12(s，2H)
4.54(m，1H) 2.99(m，2H) 2.88(m，2H) 2.51(m，2H)
2.17(m，1H) 2.07(m，1H)
Embodiment 2
N-(4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl-L-L-glutamic acid dibenzyl ester
With N-{[3-(2.6-diamino-4 (3H)-oxygen pyrimidine-5-yl)-4-nitro] butyl } benzoyl-L-L-glutamic acid dibenzyl ester 10 restrains (15.2mmol), 2N sodium hydroxide 50ml (100mmol) drops in the 100ml reaction flask, stirring at room 2 hours, reaction solution is added drop-wise in the 100ml 4N sulfuric acid in 0 ℃, drip and finish, stirred 2 hours in 0 ℃, extract with methylene dichloride 60ml * 2, merge, water 60ml washes, anhydrous magnesium sulfate drying, filter, the filtrate decompression evaporate to dryness adds ethyl acetate 30ml and stirs, filter, ethyl acetate is washed, and dries to such an extent that white solid 7 restrains yield 75.9%.
Embodiment 3
N-(4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl-L-L-glutamic acid
In the 500ml reaction flask, drop into N-(4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo-[2; 3-d] pyrimidine-5-yl) ethyl] benzoyl-L-L-glutamic acid dibenzyl ester 5 gram (8.2mmol), methyl alcohol 100ml; tetrahydrofuran (THF) 200ml; stirring made dissolving, adds 10%Pd/C 1 gram, in room temperature normal pressure hydrogenation 3 hours; filter; the 50ml tetrahydrofuran (THF) is washed, and removes solvent under reduced pressure, gets title compound.
Embodiment 4
N-(4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl-L-disodium glutamate salt
With the N-of embodiment 2 gained (4-[2-(2-amino-4 (3H)-oxygen-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl-L-L-glutamic acid is dissolved in 16.5ml 1N sodium hydroxide and the 10ml water, filters, freeze-drying gets white solid 3.8 grams.
1HNMR(400MHz，D
2O) 7.58(d，2H) 7.14(d，2H)
6.28(s，1H)?4.23(m，1H) 2.83(m，4H) 2.20(m，2H)
2.08(m，1H)?1.92(m，1H)
Claims (2)
1. one kind prepares the compound represented with following formula I or it can make the method for medicinal salt,
Wherein, the configuration that indicates the carbon atom of * is the S type,
This method comprises that there is catalytic hydrogenation in the compound that following formula is represented at Pd/C,
R, R among its Chinese style II
1Be hydrogen or halogen or C
1～C
4Alkyl.
2. one kind prepares the compound represented with Formula Il or it can make the method for medicinal salt
R, R among its Chinese style II
1Be hydrogen or halogen or C
1～C
4Alkyl,
This method comprises the compound that Formula Il I is represented
With the compound condensation that following formula I V represents, R, R among its Chinese style IV
1Be hydrogen or halogen or C
1～C
4Alkyl,
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510078426XA CN100395246C (en) | 2005-06-15 | 2005-06-15 | Method for producing folic acid antagonist and its intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510078426XA CN100395246C (en) | 2005-06-15 | 2005-06-15 | Method for producing folic acid antagonist and its intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1880316A CN1880316A (en) | 2006-12-20 |
| CN100395246C true CN100395246C (en) | 2008-06-18 |
Family
ID=37518698
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510078426XA Active CN100395246C (en) | 2005-06-15 | 2005-06-15 | Method for producing folic acid antagonist and its intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100395246C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100379729C (en) * | 2006-04-06 | 2008-04-09 | 海南天源康泽医药科技有限公司 | Nitro compounds and their application in preparation of pemetrexed |
| CN104672241B (en) * | 2015-01-29 | 2018-04-24 | 王磊 | Pyrrolo- [2,3-d] pyrimidines and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0905128A1 (en) * | 1997-09-26 | 1999-03-31 | Eli Lilly And Company | Processes and intermediates useful to make antifolates |
| EP1105396A1 (en) * | 1998-08-21 | 2001-06-13 | The Trustees of Princeton University | Process for the preparation of pyrrolo[2,3-d]pyrimidines |
| CN1778797A (en) * | 2004-11-25 | 2006-05-31 | 重庆医药工业研究院有限责任公司 | Production of N-(pyrrolo[2,3-d] pyrimidine-5-) acyl glusate derivative and intermediate |
-
2005
- 2005-06-15 CN CNB200510078426XA patent/CN100395246C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0905128A1 (en) * | 1997-09-26 | 1999-03-31 | Eli Lilly And Company | Processes and intermediates useful to make antifolates |
| EP1105396A1 (en) * | 1998-08-21 | 2001-06-13 | The Trustees of Princeton University | Process for the preparation of pyrrolo[2,3-d]pyrimidines |
| CN1778797A (en) * | 2004-11-25 | 2006-05-31 | 重庆医药工业研究院有限责任公司 | Production of N-(pyrrolo[2,3-d] pyrimidine-5-) acyl glusate derivative and intermediate |
Non-Patent Citations (2)
| Title |
|---|
| A New and Efficient SynthesisofPyrrolo[2,3-d]pyrimidineAnticancer Agents: Alimta(LY231514,MTA), Homo-Alimta,TNP-351, and SomeAryl5-SubstitutedPyrrolo[2,3-d]pyrimidines. Taylor, Edward C., Liu, Bin.Journal of Organic Chemistry,Vol.68 No.26. 2003 |
| A New and Efficient SynthesisofPyrrolo[2,3-d]pyrimidineAnticancer Agents: Alimta(LY231514,MTA), Homo-Alimta,TNP-351, and SomeAryl5-SubstitutedPyrrolo[2,3-d]pyrimidines. Taylor, Edward C., Liu, Bin.Journal of Organic Chemistry,Vol.68 No.26. 2003 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1880316A (en) | 2006-12-20 |
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Address after: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |