CN101033209B - Method of preparing pharmaceutical intermediate of (2S,4R)-4-hydroxy-N,N-dimethyl-2-pyrrolidineformamide - Google Patents
Method of preparing pharmaceutical intermediate of (2S,4R)-4-hydroxy-N,N-dimethyl-2-pyrrolidineformamide Download PDFInfo
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- CN101033209B CN101033209B CN200610024535.8A CN200610024535A CN101033209B CN 101033209 B CN101033209 B CN 101033209B CN 200610024535 A CN200610024535 A CN 200610024535A CN 101033209 B CN101033209 B CN 101033209B
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Abstract
This invention provides a method for preparing a medicine intermediate(2S, 4R)-4-hydroxyl-N, N-dimethyl-2-pentazane formamide, which takes (2S, 4R)-4-hydroxyl-2-pentazane formate(4-hydroxide-L-proline ester) as the raw material to be reacted with dimethylamine to get (2S, 4R)-4-hydroxyl-N, N-dimethyl-2-pentazane formamide, in which, two step reactions of amido protection and taking off protection are left out, the circuit is short and operation is simple and venomous or costly activation agent is not used here.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of preparation method of pharmaceutical intermediate, especially a kind of synthetic drugs intermediate (2S, 4R)-4-hydroxy-n, the method for N-dimethyl-2-pyrrolidine formamide.
Background technology
(2S, 4R)-4-hydroxy-n, N-dimethyl-2-pyrrolidine formamide is the important pharmaceutical intermediate of a class, can be for some drugs, as synthesizing of meropenem.
Current bibliographical information its conventionally by (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester.Have another name called CHP after aminoterminal is protected, under activator exists, react with dimethylamine hydrochloride, then slough protecting group and obtain target product.For example following two kinds of methods are exactly current synthetic drugs intermediate (2S, 4R)-4-hydroxy-n, the method that N-dimethyl-2-pyrrolidine formamide pharmaceutical intermediate is relatively commonly used.
A, CHP are after Boc-protection; with Vinyl chloroformate, activating carboxy acid becomes Acibenzolar; be reacted into acid amides with dimethylamine; then slough Boc-protecting group; obtain pharmaceutical intermediate (2S; 4R)-4-hydroxy-n, N-dimethyl-2-pyrrolidine formyl amine hydrochlorate (referring to IN 183459,2000).
Its reaction formula is as follows:
This method need to increase amido protecting and deprotection two-step reaction, and route is long, complex operation; With Vinyl chloroformate (ClCO
2et) as activator, anhydrous condition requires harsh, and by product is many, and yield is lower, and this reagent toxicity is large, is unsuitable for the requirement of industrial batch production, and also large on the impact of environment.
B, CHP are after Boc-protection; with the special reagent of card (BOP reagent; structural formula See Figure) be reacted into acid amides for activator and dimethylamine; then slough Boc-protecting group; obtain pharmaceutical intermediate (2S; 4R)-4-hydroxy-n, N-dimethyl-2-pyrrolidine formyl amine hydrochlorate (referring to US Patent No. 0114683A1,2003).
Its reaction formula is as follows:
The structural formula that blocks special reagent (BOP reagent) is as follows:
This method also needs to increase protection and deprotection two-step reaction, and route is long, complex operation; To block special reagent as activator, expensive, make synthetic drugs intermediate (2S, 4R)-4-hydroxy-n, the cost of N-dimethyl-2-pyrrolidine formamide increases, and is unsuitable for industrial mass manufacture.
In sum, above-mentioned two kinds of synthetic drugs intermediate (2S, 4R)-4-hydroxy-n, in N-dimethyl-2-pyrrolidine formamide technique, the main technical problem existing is described above, or complex operation, or reaction reagent harm environment and human health, or process costs costliness etc., are all unsuitable for industrial production.
Summary of the invention
The object of this invention is to provide a kind of synthetic drugs intermediate (2S, 4R)-4-hydroxy-n, the method for N-dimethyl-2-pyrrolidine formamide.This method is saved increases amido protecting and deprotection two-step reaction, and route is brief, easy and simple to handle; Avoid using poisonous or expensive activator, reduce costs and environmental friendliness.Thereby this method can overcome the defect in prior art, can provide again the processing condition that are more conducive to industrial mass manufacture.
As the synthetic drugs intermediate (2S that realizes the object of the invention, 4R)-4-hydroxy-n, the method of N-dimethyl-2-pyrrolidine formamide, be taking (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) as raw material, react with dimethylamine, obtain pharmaceutical intermediate (2S, 4R)-4-hydroxy-n, N-dimethyl-2-pyrrolidine formamide (II), its reaction formula is as follows:
R=C in formula
1-C
6alkyl, C
3-C
5thiazolinyl, C
5-C
7cycloalkyl and H, low molecular weight alkyl, NO
2, X replace aryl or benzyl.
Raw material, reagent that method of the present invention is used are cheap and easy to get, and cost is low, easy and simple to handle, regioselectivity is good, and the product purity obtaining is high, can not purified next step reaction of direct input, save and increase amido protecting and deprotection two-step reaction, route is brief, easy and simple to handle; Avoid using poisonous or expensive activator, reduce costs and environmental friendliness.Thereby this method can overcome the defect in prior art, can provide again and more be conducive to industrial processing condition.
Embodiment
Synthetic (the 2S of a kind of pharmaceutical intermediate, 4R)-4-hydroxy-n, the method of N-dimethyl-2-pyrrolidine formamide, be taking (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) as raw material, react with dimethylamine, obtain pharmaceutical intermediate (2S, 4R)-4-hydroxy-n, N-dimethyl-2-pyrrolidine formamide (II), its reaction formula is as follows:
R=C in formula
1-C
6alkyl, C
3-C
5thiazolinyl, C
5-C
7cycloalkyl and H, low molecular weight alkyl, NO
2, X replace aryl or benzyl.
The different mol ratio of reacting with dimethylamine by attempting (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class in the method for the invention,, and react under different solvents, temperature, pressure, through a large amount of practices, grope to obtain feasible reaction conditions, be applicable to industrial production.
Method of the present invention can comprise following concrete steps:
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) is added in solvent, under 20 DEG C-100 DEG C, 1atm-20atm pressure, react with dimethylamine, to reacting completely.Reclaim solvent and residue dimethylamine, get final product to obtain pharmaceutical intermediate 4-hydroxy-n, N-dimethyl-2-pyrrolidine formamide (II) through recrystallization.
In the method for the invention, the solvent of employing is selected one or more mixed solvent of tetrahydrofuran (THF), DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO), methyl alcohol, ethanol, propyl alcohol, isopropanol solvent.But be not limited to this, as long as the solvent of selecting can be to the pharmaceutical intermediate 4-hydroxy-n of gained, it is unfavorable that N-dimethyl-2-pyrrolidine formamide (II) produces, and this is accomplished than being easier to for a person skilled in the art.
In the methods of the invention, between (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class and dimethylamine, feed ratio is mol ratio 1: 1.2-1: 50, and preferred scheme is 1: 3-1: 30.And the control of how both feed ratio more being optimized, this is accomplished than being easier to for a person skilled in the art.
In the method for the invention, the control of temperature of reaction is generally at 20 DEG C-100 DEG C, and preferred scheme is 60 DEG C-100 DEG C.And the control of how temperature of reaction more being optimized, this is accomplished than being easier to for a person skilled in the art.
In the method for the invention, the control of reaction pressure is generally at 1atm-20atm, and preferred scheme is 1atm-5atm.And the control of how reaction pressure more being optimized, this is accomplished than being easier to for a person skilled in the art.
In the method for the invention, the selection in reaction times is generally 0.5-30h, wherein how to grasp the optimization time of reaction, to those skilled in the art, as long as screening by experiment is just easy to realize.
Further illustrate by the following examples the present invention, but should be understood that these embodiment are exemplary, the present invention does not limit to this.
Embodiment mono-
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid methyl esters 20g is dissolved in DMF, and 155g reacts with dimethylamine, under 100 DEG C, 20atm pressure, reacts 2h to raw material complete reaction.Evaporate to dryness reclaims solvent and residue dimethylamine, obtains crude product, obtains product (17g, 80%), mp142-143 DEG C with Virahol recrystallization.
1HNMR(CDCl
3)δ：1.79(1H，m)，2.08(1H，m)，2.81(1H，m)，2.94(3H，s)，3.02(3H，s)，3.25(1H，m)，3.28-4.08(1H，s)，4.10(1H，t)，4.38(1H，m)。
13CNMR(CDCl
3)δ：35.71，36.42，39.75，55.30，56.57，72.39，173.56。ESI-MS(m/z)：159(M+1)。
Embodiment bis-
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ethyl ester 30g is dissolved in DMSO, and 25g reacts with dimethylamine, under 60 DEG C, 1atm pressure, reacts 30h to raw material complete reaction.Evaporate to dryness reclaims solvent and residue dimethylamine, obtains crude product, obtains product (22g, 75%) with Virahol recrystallization, and fusing point and spectroscopic data are the same.
Embodiment tri-
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid isopropyl ester 20g is dissolved in tetrahydrofuran (THF), adds dimethylamine 156g, under 20 DEG C, 5atm pressure, react 20h to raw material complete reaction.Evaporate to dryness reclaims solvent and residue dimethylamine, obtains crude product, obtains product (12g, 66%) with Virahol recrystallization.
Embodiment tetra-
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid tert-butyl ester 20g is dissolved in methyl alcohol, adds dimethylamine 240g, under 80 DEG C, 10atm pressure, react 15h to raw material complete reaction.Evaporate to dryness reclaims solvent and residue dimethylamine, obtains crude product, obtains product (17g, 58%) with Virahol recrystallization.
Embodiment five
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid allyl ester 30g is mixed with 118 grams of dimethylamine, under 70 DEG C, 3atm pressure, react 10h to raw material complete reaction.Reclaim residue dimethylamine, obtain crude product, obtain product (18g, 65%) with Virahol recrystallization.
Embodiment six
(2S, 4S)-4-oxyproline cyclohexyl ester 20g is dissolved in Virahol, adds dimethylamine 5g, under 50 DEG C, 4atm pressure, react 20h to raw material complete reaction.Evaporate to dryness reclaims solvent and residue dimethylamine, obtains crude product, obtains product (11g, 72%) with Virahol recrystallization.
Embodiment seven
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid phenyl ester 20g is dissolved in propyl alcohol, adds dimethylamine 87g, under 100 DEG C, 3atm pressure, react 10h to raw material complete reaction.Evaporate to dryness reclaims solvent and residue dimethylamine, obtains crude product, obtains product (10g, 68%) with Virahol recrystallization.
Embodiment eight
(2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid benzyl ester 20g is dissolved in ethanol, under 90 DEG C, 3atm pressure, reacts 8h to raw material complete reaction with dimethylamine 163g.Evaporate to dryness reclaims solvent and residue dimethylamine, obtains crude product, obtains product (7g, 50%) with Virahol recrystallization.
More than show and described ultimate principle of the present invention and 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 in above-described embodiment and specification sheets, describes just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, 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 (7)
1. pharmaceutical intermediate (2S, 4R)-4-hydroxy-n, the preparation method of N-dimethyl-2-pyrrolidine formamide, is characterized in that, is with (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) is raw material, react with dimethylamine, obtain pharmaceutical intermediate (2S, 4R)-4-hydroxy-n, N-dimethyl-2-pyrrolidine formamide (II), its reaction formula is as follows:
In formula, R is C
1-C
6alkyl, C
3-C
5thiazolinyl, C
5-C
7cycloalkyl and aryl or benzyl, described reaction is at tetrahydrofuran (THF) or N, in one or more mixed solvent of dinethylformamide or methyl alcohol or ethanol or propyl alcohol or Virahol, carry out, under 20 DEG C-100 DEG C of temperature of reaction, pressure 1atm-20atm condition, react 0.5-30h and obtain (2S, 4R)-4-hydroxy-n, N-dimethyl-2-pyrrolidine formamide (II).
2. preparation method according to claim 1, is characterized in that, described (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) and dimethylamine are with mol ratio 1: 1.2-1: 50.
3. preparation method according to claim 2, is characterized in that, described (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) and dimethylamine are with mol ratio 1: 3-1: 30.
4. preparation method according to claim 2, is characterized in that, described (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) and dimethylamine are with mol ratio 1: 3-1: 15.
5. preparation method according to claim 1, is characterized in that, 60 DEG C-100 DEG C of described temperature of reaction.
6. preparation method according to claim 1, is characterized in that, described pressure 1atm-5atm.
7. preparation method according to claim 1 and 2, it is characterized in that described (2S, 4R)-4-hydroxyl-2-pyrrolidinecarboxylic acid ester class (I) is 1 with the mol ratio of dimethylamine: 3-1: 30, and 60 DEG C-100 DEG C of temperature of reaction, pressure 1atm-5atm.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1121068A (en) * | 1994-01-27 | 1996-04-24 | 三菱化学株式会社 | Prolineamide derivatives |
| CN1404479A (en) * | 2000-01-25 | 2003-03-19 | 圣诺菲-合成实验室公司 | 1, 3-dihydro-2H-indol-2-one derivatives, process for their preparation and pharmaceutical compositions containing them |
| WO2005026114A1 (en) * | 2003-09-17 | 2005-03-24 | Pfizer Inc. | Hiv protease inhibitors, compositions containing the same and their pharmaceutical uses |
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2006
- 2006-03-09 CN CN200610024535.8A patent/CN101033209B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1121068A (en) * | 1994-01-27 | 1996-04-24 | 三菱化学株式会社 | Prolineamide derivatives |
| CN1404479A (en) * | 2000-01-25 | 2003-03-19 | 圣诺菲-合成实验室公司 | 1, 3-dihydro-2H-indol-2-one derivatives, process for their preparation and pharmaceutical compositions containing them |
| WO2005026114A1 (en) * | 2003-09-17 | 2005-03-24 | Pfizer Inc. | Hiv protease inhibitors, compositions containing the same and their pharmaceutical uses |
Non-Patent Citations (4)
| Title |
|---|
| SAMUEL NATELSON.Derivatives of the Lactam of a-Guanidinoglutaric Acid (N-Amidinopyroglutamic Acid,ApGlu) for peptide Formation.MICROCHEMICAL JOURNAL37.1988,37132-140. * |
| SAMUELNATELSON.DerivativesoftheLactamofa-GuanidinoglutaricAcid(N-AmidinopyroglutamicAcid ApGlu) for peptide Formation.MICROCHEMICAL JOURNAL37.1988 |
| 王蓓等.D-脯氨酰胺的不对称合成研究.化工进展24 8.2005,24(8),897-900页. |
| 王蓓等.D-脯氨酰胺的不对称合成研究.化工进展24 8.2005,24(8),897-900页. * |
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Effective date of registration: 20170905 Address after: 101300 Beijing city Shunyi District Niulanshan town cattle Huinan a Street No. 6 Co-patentee after: Shanghai Institute of pharmaceutical industry Patentee after: Sinopharm Group Industry Co Ltd Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |