CN100497338C - 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method - Google Patents
4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method Download PDFInfo
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Abstract
The invention discloses a making method of 4-methyl-7-oxy-1-aza bicyclo [3. 2. 0] pimelic-2-olefin-2-carboxyl derivant, which is characterized by the following: adopting two-phase solvent as solvent to catalyze and hydrogenate; simplifying the operating method of separation and purifying; reducing the need of reacting equipment and condition; fitting for large scale of industrial manufacturing.
Description
Technical field
The present invention relates to the preparation method of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid derivative, be specifically related to reaction process, solvent and method of purification.
Background technology
Hept-2-ene"-the 2-carboxylic acid derivative has 4-methyl-7-oxygen-1-azabicyclo [3.2.0] much becomes β-beta-lactam antibiotics, has good antibacterial effect, a plurality of countries listing in the whole world such as meropenem (shown in 1a), biapenem (shown in 1b), doripenem (shown in 1c) etc.
4-methyl in the practical application of being addressed-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid derivative has as shown in the formula structure shown in (1):
R wherein
1=-OH ,-OSi (CH
3)
2C (CH
3)
3Or-OSi (CH
3)
3
1a：R
1＝-OH
1b：R
1＝-OH
1c：R
1＝-OH
(J of Antibiotics 1990,43 (5): 519 for bibliographical information; Chem Pharm Bull1996,44 (12): 2326; EP 256; 377); 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid derivative is done buffer reagent catalytic hydrogenation deprotection base with phosphoric acid salt or methylmorpholine sulfonate (MOPS) by compound shown in the following formula (2) or compounds such as (3) in the mixing solutions of water and tetrahydrofuran (THF); separate through ion-exchange chromatography then; last lyophilize or high pressure reverse osmosis membrane are removed moisture and are obtained target compound; in these structural formula of compound, R
3, R
4The expression protecting group.
In the described method of aforesaid document, methylmorpholine sulfonate (MOPS) or other phosphate buffered saline buffers have all been used, with the pH value in the conditioned reaction process, after finishing, reaction to remove buffer reagent and other impurity, all need to carry out column chromatography for separation, and need to remove redundant moisture with reverse osmosis membrane under lyophilize and the high pressure after the reaction, obtain product at last.These methods require on suitability for industrialized production than higher, are difficult to relatively realize.Therefore, 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid derivative common cost when carrying out suitability for industrialized production is higher, is necessary to find out more suitable production process route.
Summary of the invention
The objective of the invention is to, the preparation method of a kind of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid derivative is provided, in this method, pass through to change the method for reaction conditions and aftertreatment, avoid the above-mentioned shortcoming that exists in the prior art, make described compound be fit to suitability for industrialized production more.
When being studied, the character of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid derivative finds, these compounds water-soluble all relatively good, unstable under acidity or alkaline condition, solution state is preserved down for a long time or temperature is too high also easily decomposes.
Therefore, in the solution of the present invention, adopt the reaction media of two-phase solvent as catalytic hydrogenation, catalytic hydrogenation is sloughed protecting group in the two-phase solvent that compound shown in the formula (I) is formed at water with the immiscible organic solvent of water.In the described method, 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid derivative compound general formula that needs the deprotection base is as shown in the formula shown in (I):
In the formula: R
1=-OH ,-OSi (CH
3)
2C (CH
3)
3Or-OSi (CH
3)
3
R wherein
3, R
4Be protecting group, protecting group comprises:
It is characterized in that catalytic hydrogenation is sloughed protecting group in the two-phase solvent that compound shown in the formula (I) is formed at water with the immiscible organic solvent of water.
In the above-mentioned two-phase solvent wherein one be mutually and the not miscible organic solvent of water, as: ethyl acetate, methyl acetate, N-BUTYL ACETATE, isobutyl acetate, ethyl formate, methyl-formiate, methylene dichloride, trichloromethane, chloroform, 1,2-ethylene dichloride, toluene, dimethylbenzene or its mixture, institute's consumption is 10 times to 200 times of raw material, is preferably 30 times to 100 times.Another is water mutually, and institute's consumption is 5 to 80 times of raw material, preferred 10 times to 50 times.Catalyzer is 5%～10% palladium carbon, and institute's consumption is 0.2 times～2 times of raw material, preferred 0.5 times.Temperature of reaction is 0～30 ℃, preferred 20 ℃.The pressure range of catalytic hydrogenation is 0～50kg/cm in the reaction
2, preferred 2～10kg/cm
2
Behind the above-mentioned hydrogenation, isolate the water in the described two-phase solvent, to wherein adding and the miscible organic solvent of water, for example acetone, tetrahydrofuran (THF), ethanol, methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol etc., its consumption is 0.5 times to 20 times of weight of water, preferred 1 to 5 times.Make the product of aqueous phase form crystallization, through filtering, drying can obtain the product crystallization of purifying then.
The invention has the advantages that, owing to adopted two-phase solvent, and avoid having used buffer reagent, the impurity that produces in the feasible reaction is dissolved in organic phase, the impurity of aqueous phase is considerably less, thereby avoided the separation buffer agent only to need to collect reacted water and just can obtain the high product aqueous solution of purity with the operation steps of ion-exchange chromatography.Just can obtain the product crystallization behind the organic solvent of adding and water immiscible phase.Thereby the step of having avoided lyophilize or high pressure reverse osmosis membrane to dewater.This greatly simplifies processing step, is very beneficial for industrial large-scale production.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.The analytical instrument that the following example adopted is following model:
Ultimate analysis: CARLO ERBA STRUMETAZIONE ELEMENTAL ANALYIER MOD-1109
Infrared: NICOLET-670-FTIR
Nucleus magnetic resonance: INOVA-600 nuclear magnetic resonance analyser, interior mark: TMS
Embodiment 1
(4R, 5S, 6S)-3-[(3S, 5S)-and 5-(dimethyl amine acyl group)-3-tetramethyleneimine] sulphur-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid trihydrate (formula 1a)
With (4R; 5S; 6S)-3-[(3S; 5S)-and 1-(to nitro benzyloxy carbonyl acyl group)-5-(dimethyl amine acyl group)-3-tetramethyleneimine] sulphur-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (2a) 40g (0.067mol) adding ethyl acetate 2000ml and water 400ml; the palladium carbon 10g that dissolves back and 5% places 5L hydrogenation still; feed hydrogen, be forced into 5kg/cm
2, be stirred under the room temperature and react completely.Layering behind the reacting liquid filtering, water layer washs with ethyl acetate.Add acetone 1200ml then, stirred one hour under the room temperature, filter, washing with acetone, vacuum-drying gets faint yellow solid (1a) 15g (0.034mol), yield 51.2%.
Ultimate analysis: calculated value C:46.47; H:7.14; N:9.60
Measured value C:46.68; H:7.22; N:9.44
IR(KBr)crm
-1：3405.46，1750.36，1654.69
1H?NMR(D
2O)：δ?1.25(3H，d)；1.33(3H，d)；2.01(1H，m)；3.02(3H，s)；3.08(4H，m)；3.38(1H，m)；3.50(2H，m)，3.80(1H，dd)，4.08(1H，m)，4.28(2H，d)；4.83(1H，t)
Embodiment 2
The preparation of 1a
With (4R; 5S; 6S)-3-[(3S; 5S)-and 1-(to nitro benzyloxy carbonyl acyl group)-5-(dimethyl amine acyl group)-3-tetramethyleneimine] sulphur-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (formula 2a) 5g (0.0084mol) adding methylene dichloride 200ml and water 250ml; the palladium carbon 1.5g that dissolves back and 5% places 1L hydrogenation still; feed hydrogen, be forced into 2kg/cm
2, be stirred under the room temperature and react completely.Layering behind the reacting liquid filtering, water layer washs with ethyl acetate.Add tetrahydrofuran (THF) 200ml then, stirred one hour under the room temperature, filter, the tetrahydrofuran (THF) washing, vacuum-drying gets faint yellow solid (1a) 1.6g (0.0036mol), yield 43.2%.
Ultimate analysis: calculated value C:46.47; H:7.14; N:9.60
Measured value C:46.52; H:7.31; N:9.53
Embodiment 3
(4R, 5S, 6S)-3-[(3S, 5S)-and 5-(aminosulfonyl amido) methyl-3-tetramethyleneimine] sulphur-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (formula 1c)
With (4R; 5S; 6S)-3-[(3S; 5S)-1-(to nitro benzyloxy carbonyl acyl group)-5-((aminosulfonyl amido) methyl-3-tetramethyleneimine) sulphur-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 15g (0.02mol) adding ethyl acetate 2500ml and water 450ml; the palladium carbon 7.5g that dissolves back and 5% places 5L hydrogenation still; feed hydrogen, be forced into 10kg/cm
2, be stirred under the room temperature and react completely.Layering behind the reacting liquid filtering, water layer washs with ethyl acetate.Add ethanol 800ml then, stirred 1 hour under the room temperature, filter, washing with alcohol, vacuum-drying gets off-white color solid (1c) 5.1g (0.012mol), yield 60.7%.
Ultimate analysis: calculated value C:42.86; H:5.71; N:13.33
Measured value C:42.99; H:5.69; N:13.41
Embodiment 4
The preparation of formula 1c compound
With (4R; 5S; 6S)-3-[(3S; 5S)-1-(to nitro benzyloxy carbonyl acyl group)-5-((aminosulfonyl amido) methyl-3-tetramethyleneimine) sulphur-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 15g (0.02mol) adding toluene 1500ml and water 300ml; the palladium carbon 7.5g that dissolves back and 5% places 5L hydrogenation still; feed hydrogen, be forced into 2kg/cm
2, be stirred under the room temperature and react completely.Layering behind the reacting liquid filtering, water layer washs with ethyl acetate.Add methyl alcohol 800ml then, stirred 1 hour under the room temperature, filter, methanol wash, vacuum-drying gets off-white color solid (1c) 5.1g (0.012mol), yield 60.7%.
Ultimate analysis: calculated value C:42.86; H:5.71; N:13.33
Measured value C:42.99; H:5.69; N:13.41
Embodiment 5
6-[[(4R, 5S, 6S)-and 2-carboxyl-6-((R)-1-hydroxyethyl)-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-3-] sulphur]-6, the preparation of 7-dihydro-5H-piperazine azoles [1,2-a] [1,2,4] triazole-4-inner salt (formula 1b)
With 6-[[(4R, 5S, 6S)-2-formic acid is to nitrobenzyl ester-6-((R)-1-hydroxyethyl)-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-3-] sulphur]-6,7-dihydro-5H-piperazine azoles [1,2-a] [1,2,4] triazolium salt hydrochlorate (2b) 5g (0.01mol) adds ethyl acetate 300ml and water 20ml, the palladium carbon 2.5g that dissolves back and 5% places 1L hydrogenation still, feeds hydrogen, is forced into 2kg/cm
2, be stirred under the room temperature and react completely.Layering behind the reacting liquid filtering, water layer washs with ethyl acetate.Add acetone 300ml then, stirred 1 hour under the room temperature, filter, washing with acetone, vacuum-drying gets off-white color solid (1b) 2.10g (0.006mol), yield 60.0%.
Ultimate analysis: calculated value C:51.42; H:5.18; N:15.99
Measured value C:51.63; H:5.40; N:15.78
Embodiment 6
The preparation of formula 1a compound
2a4g (0.0067mol) is added ethyl acetate 150ml, methylene dichloride 100 and water 40ml, and the palladium carbon 1g that dissolves back and 5% places 1L hydrogenation still, feeds hydrogen, is forced into 5kg/cm
2, be stirred under the room temperature and react completely.Layering behind the reacting liquid filtering, water layer washs with ethyl acetate.Add acetone 40ml then, stirred one hour under the room temperature, filter, washing with acetone, vacuum-drying gets faint yellow solid (1a) 1.2g (0.0027mol), yield 40.6%.
Ultimate analysis: calculated value C:46.47; H:7.14; N:9.60
Measured value C:46.71; H:7.41; N:9.82
Claims (7)
1. method for preparing compound shown in general formula (1), the protecting group that is used to slough compound shown in general formula (I):
In the formula: R
1=-OH ,-OSi (CH
3)
2C (CH
3)
3Or-OSi (CH
3)
3
R wherein
3, R
4Be protecting group, be:
It is characterized in that, obtain product after catalytic hydrogenation is sloughed protecting group in the two-phase solvent that compound shown in the formula (I) is formed at water with the immiscible organic solvent of water,
Its formula of (1) is as follows:
(1)
Wherein, R
1=-OH ,-OSi (CH
3)
2C (CH
3)
3Or-OSi (CH
3)
3
2. method according to claim 1, wherein comprise ethyl acetate, methyl acetate, N-BUTYL ACETATE, isobutyl acetate, ethyl formate, methyl-formiate, methylene dichloride, trichloromethane, chloroform, 1,2-ethylene dichloride, toluene, dimethylbenzene or its mixture with the not miscible organic solvent of water.
3. method according to claim 1, wherein the consumption of water is 10 times to 50 times of formula (I) compound weight.
4. method according to claim 1 wherein is 30 times to 100 times of weight of formula (I) compound with the consumption of the not miscible organic solvent of water.
5. method according to claim 1, it is characterized in that also comprising the following steps: making the target product crystallization through the aqueous phase adding of reaction and the organic solvent of water immiscible phase, filtration, drying obtain finished product then, and used organic solvent is acetone, tetrahydrofuran (THF), ethanol, methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol.
6. method according to claim 5 wherein is 0.5 times to 20 times of weight of water with the consumption of the organic solvent of water immiscible phase.
7. method according to claim 5 wherein is 1 to 5 times of weight of water with the consumption of the organic solvent of water immiscible phase.
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| CN101768174B (en) * | 2009-01-07 | 2012-08-08 | 四川科伦药业股份有限公司 | Method for preparing biapenem |
| CN102212077B (en) * | 2010-04-08 | 2013-06-19 | 上海医药工业研究院 | Preparation method of biapenem |
| CN101805359B (en) * | 2010-04-10 | 2015-03-25 | 浙江华海药业股份有限公司 | Method for preparing biapenem with high purity |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
| CN102603745A (en) * | 2011-01-18 | 2012-07-25 | 深圳市海滨制药有限公司 | Preparation method of beta-methyl carbapenem compound |
| CN102617611B (en) * | 2011-01-28 | 2013-07-10 | 江苏正大天晴药业股份有限公司 | Preparation method of biapenem aseptic powder |
| CN102731505B (en) * | 2011-04-13 | 2015-09-02 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of preparation method of S-4661 |
| CN102757430B (en) * | 2011-04-29 | 2016-04-13 | 上海医药工业研究院 | A kind of preparation method of tebipenem |
| CN102372714B (en) * | 2011-12-07 | 2014-04-16 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing doripenem |
| CN103664946B (en) * | 2012-09-03 | 2015-11-25 | 凌沛学 | The Industrialized synthesis method of a kind of many Li Peinan |
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| EP0006639A1 (en) * | 1978-07-03 | 1980-01-09 | Merck & Co. Inc. | Crystalline N-formimidoyl thienamycin |
| EP0162242A1 (en) * | 1984-04-09 | 1985-11-27 | Merck & Co. Inc. | Crystalline dimethyliminothienamycin |
| EP0256377A1 (en) * | 1986-07-30 | 1988-02-24 | Sumitomo Pharmaceuticals Company, Limited | Carbapenem compound in crystalline form, and its production and use |
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2006
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0006639A1 (en) * | 1978-07-03 | 1980-01-09 | Merck & Co. Inc. | Crystalline N-formimidoyl thienamycin |
| EP0162242A1 (en) * | 1984-04-09 | 1985-11-27 | Merck & Co. Inc. | Crystalline dimethyliminothienamycin |
| EP0256377A1 (en) * | 1986-07-30 | 1988-02-24 | Sumitomo Pharmaceuticals Company, Limited | Carbapenem compound in crystalline form, and its production and use |
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Effective date of registration: 20151217 Address after: 222006 No. 8 Julong North Road, Jiangsu, Lianyungang Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |