CN104829633A - Preparation method of high-purity biapenem - Google Patents
Preparation method of high-purity biapenem Download PDFInfo
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Abstract
The invention relates to a preparation method of high-purity biapenem, which includes the steps of: (A) carrying out a condensation reaction with a compound represented as the formula V and a compound represented as the formula VI in an acetonitrile solvent in the presence of a less amount of N,N-dimethylformamide and an organic alkali to obtain a compound represented as the formula VII; (B) carrying out a catalytic hydrogenation to the reaction product in the step (A) in a mixed solution composed of an alcohol solvent and a non-proton polarity organic solvent in the presence of a catalyst and an organic alkali to remove a carboxylic acid protective group in the compound represented as the formula VII; and (C) filtering a reaction mixed solution to obtain a filter cake, adding the filter cake in water with stirring to obtain a filtrate, mixing the filtrates, adding an organic solvent under stirring, performing precipitation crystallization, and filtering and drying a product to obtain the biapenem.
Description
Technical field:
The present invention relates to a kind of preparation method of medical compounds, particularly a kind of preparation method of biapenem with high purity.
Background technology:
Biapenem, chemistry 6-[[(4R by name, 5S, 6S)-2-carboxyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-base] sulphur]-6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazole-4-inner salt, it is a kind of 1 Beta-methyl carbapenem antibiotic, has a broad antifungal spectrum, more stable than meropenem to dehydropeptidase of kidney DHP-I, do not need to urinate cytostatics drug combination with DHP-I inhibitor or kidney, wide clinical application is in gram negative aerobic bacteria, gram positive aerobic bacteria and the microbial acute and chronic infection of anaerobism, sub-limb training south is better than to the activity of gram-negative bacteria, train southern similar to the activity of gram positive organism to sub-limb, Cosmetics Surgery is infected, gynecological infection and otorhinolaryngology infect and all have good curative effect, oneself is through multiple countries listing in the whole world.
Biapenem has multiple preparation method, and the method for bibliographical information is with formula II compound and formula III compound for raw material obtains formula IV compound through condensation, then goes protection and obtain biapenem (formula I):
Wherein, R
1for benzyl, 4-nitrobenzyl, methoxy-benzyl or dimethoxy-benzyl, X
-for Cl
-, CH
3sO
3 -or CF
3cOO
-.
Document (J.Org.Chem.1998,63,8145; Chinese patent application CN101121716A) be for raw material with formula II compound and formula III compound; in the mixed solvent of acetone and acetonitrile; obtain formula IV compound; again with excessive zinc powder for reductive agent; the protecting group of carboxylic acid is removed in phosphate buffered saline buffer; then spent ion exchange resin is purified, and last elutriant obtains biapenem through freeze-drying.This process is more complicated, is unsuitable for suitability for industrialized production; Use acetonitrile and acetone mixed solvent, not easily reclaim, cost is high; Zinc powder is excessive more, not easily processes, and easily causes environmental pollution, and cost is high.
Document (Chinese patent application CN101007816A) is with formula II compound and formula III compound for raw material, reacts in the mixed solvent of acetonitrile and tetrahydrofuran (THF), then concentrated dry, stirs precipitation formula IV compound with methylene dichloride; Again with 10% palladium charcoal for catalyzer catalytic hydrogenation removes the protecting group of IV compound carboxylic acid.The mixed solvent of condensation reaction not easily reclaims, and methylene dichloride toxicity is also larger.The de-protected yield of catalytic hydrogenation partially lower (52%), needs in process to use SODIUM PHOSPHATE, MONOBASIC adjust ph, there are inorganic salt and not easily remove the problem affecting content; The quantity of solvent used large (40 times of reactant), the generative capacity of pressure reaction still is reduced (yielding poorly of unit volume), and concentrated solvent causes energy consumption cost to raise, and the production cycle is extended, and these are all unfavorable for commercial scale production.
Document (Chinese patent application CN101805359A) adopts Raney nickel to be catalyzer; catalytic hydrogenation removes the carboxylic acid protecting group of formula IV compound; yield is higher; product purity is also higher; but use quantity of solvent larger (30 times) to cause equipment capacity lower during reaction, simultaneously because the activity of Raney nickel is higher, improper use easily causes spontaneous combustion; cause the risk of security incident higher, institute is also unsuitable for large-scale production in this way.
Document (Chinese patent application CN101768174) is to contain palladium or to contain platinic compound for catalyzer; in aprotic capital punishment organic solvent; catalytic hydrogenation is adopted to remove carboxylic acid protecting group; again reaction mixture is dissolved in the water; filter; adding organic solvent in filtrate makes product be precipitated out, and the biapenem purity obtained is more than 98%.But the price comparison of aprotic capital punishment organic solvent is high, and rear separation difficulty miscible with water, not easily reclaim; Do not use damping fluid or acid binding agent, can not neutralization reaction process produce hydrogen ion, in acid after making reaction mixture water-soluble, and biapenem less stable in an acidic solution (Journal ofPharmaceutical and Biomedical Analysis49 (2009) 937 – 944), easy open loop, produces dipolymer, impurity is increased, cause purity drop, only reach more than 98%.
In sum, exploitation one overcomes above-mentioned the deficiencies in the prior art, and process stabilization, yield are high, product purity is high (more than 99.0%), the biapenem preparation method of low cost and applicable suitability for industrialized production becomes the focus that we pay close attention to.
Summary of the invention:
The object of the present invention is to provide a kind of preparation method of new biapenem with high purity, overcome above-mentioned the deficiencies in the prior art, make it be more suitable for suitability for industrialized production.
The invention provides a kind of preparation method of biapenem with high purity, described method, step is as follows:
Step (1):
Formula V compound and formula VI compound, in acetonitrile solvent, under a small amount of DMF and organic bases exist, obtain formula VII compound through condensation reaction:
Wherein, R
2for can the carboxy protective group of catalytic hydrogenation, be preferably benzyl, nitrobenzyl or C1-C4 alkoxybenzyl, X
-for electronegative ion, be preferably Cl
-, CH
3sO
3 -or CF
3cOO
-.
The consumption of formula VI compound is 0.9 to 2 times of formula V compound molar weight, is preferably 1.0 to 1.5 times, most preferably is 1.1 to 1.3 times.
The consumption of DMF is 0.1% to 10% of acetonitrile volume, is preferably 0.5 to 5%, most preferably is 2-4%.
The organic bases adopted, non-exclusively, is selected from triethylamine, DIPEA, consumption be 0.1 to 1 times of formula V compound by weight, be preferably 0.15 to 0.5, most preferably be 0.2 to 0.35 times.
Temperature of reaction is room temperature extremely subzero 30 DEG C, and be preferably 10 DEG C to subzero 20 DEG C, most preferably be subzero 5 to-15 DEG C, the reaction times is 1 to 20 hour, is preferably 5 to 15 hours, most preferably is 7 to 9 hours.Step (2)
In the mixed solution of alcoholic solvent and aprotic polar organic solvent; under the existence of catalyzer and organic bases, catalytic hydrogenation removes the carboxylic acid protecting group of formula VII compound, then is filtered by reaction mixture; filter cake is added to the water stirring; filter, merging filtrate, under stirring; add organic solvent; crystallization, filter, drying obtains biapenem (type I compound):
Mixed solvent used during catalytic hydrogenation, wherein alcoholic solvent is one or two or more kinds mixture of the straight or branched alkyl monocarbon alcohol of C1-C10, dibasic alcohol or trivalent alcohol, be preferably methyl alcohol, ethanol, n-propyl alcohol, Virahol, one or two or more kinds mixture of propyl carbinol, consumption is 1-10 times of formula VII compound by weight, is preferably 4-8 doubly, most preferably is 5-7 doubly; Aprotic polar organic solvent is selected from one or more the mixture in following solvent: methane amide, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, 1,3-dimethyl-imidazolinone, methyl-sulphoxide, tetramethylene sulfone, consumption is 0.5 to 5 times, is preferably 1 to 3 times, most preferably is 1.5 to 2.5 times.
Organic bases used during catalytic hydrogenation can neutralize the hydrogen ion of generation, non-exclusively, elects 2,6-lutidine as, and consumption is 0.1 to 1 times of VII compound, is preferably 0.2 to 0.8 times, most preferably is 0.4 to 0.6 times.
Used catalyst during catalytic hydrogenation, non-exclusively, elect as containing palladium or containing platinic compound, be preferably palladium charcoal, palladium zeolite, platinum charcoal or platinum dioxide, consumption is 1 to 50% of formula VII compound by weight, is preferably 5 to 40%, elects 15 to 30% as most.
The pressure of catalytic hydrogenation is 0.1 to 5MPa, is preferably 1 to 3MPa; Temperature of reaction is 0 to 80 DEG C, is preferably 20 to 60 DEG C, most preferably is 30 to 45 DEG C; Reaction times is 10 minutes to 4 hours, is preferably 15 minutes to 2 hours, most preferably is 20 to 60 minutes.
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, the temperature of water is room temperature to 95 DEG C, is preferably 40 to 80 DEG C, most preferably is 50 to 65 DEG C, the consumption of water is 5 to 50 times of formula VII compound by weight, is preferably 15 to 30 times, most preferably is 20 to 25 times; Filter, merging filtrate, the organic solvent added is can be miscible with water, is infinitely selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone or butanone, and its consumption is 1 to 10 times of water weight, is preferably 2 to 8 times, most preferably is 3 to 6 times.
Preparation method of the present invention, the deficiency of the aspect such as the poor stability, the cost that overcome prior art are high, yield is lower and product purity is low, makes it be more suitable for suitability for industrialized production.The present invention has simple to operate compared with prior art, and production efficiency is high, and cost is low, and yield is higher, and product purity reaches more than 99.0%, is particularly useful for commercial scale production.
Below by way of experimental data, beneficial effect of the present invention is described:
Condensation process conditions correlation table
Hydrogenation process conditions correlation table
By above contrast, beneficial effect of the present invention be mainly reflected in following some:
1, condensation reaction adopts single solvent, recyclablely applies mechanically;
2, catalytic hydrogenation goes protection process without the need to using buffered soln and a large amount of solvent, and reaction volume is little, and production efficiency is high;
3, catalytic hydrogenation goes protection process to use organic bases to do acid binding agent, improves biapenem stability in the solution in last handling process, reduces the generation of impurity, can obtain the product that purity reaches more than 99.0%;
4, filter obtain biapenem after mother liquor can reclaim through simple distillation, dewater etc. process after reuse as crystallization solvent;
5, simple to operate, production efficiency is high, and cost is low, and the biapenem yield prepared is higher, purity is high,
Be particularly suitable for commercial scale production.
Embodiment
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
6-[[(4R, 5S, 6S)-2-[(4-nitro benzyloxy) carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-base] sulphur]-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] preparation of triazole-4-muriate (formula VII compound)
By (4R, 5R, 6S)-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's (formula V compound) 50.0g, 6-sulfydryl-6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazole-4-muriate (formula VI compound) 18.6g, N, dinethylformamide 23.7g and triethylamine 11.7g adds 400g in acetonitrile, stir, logical nitrogen protection,-10 to-15 DEG C are stirred 10 hours, filter, dry, obtain 6-[[(4R, 5S, 6S)-2-[(4-nitro benzyloxy) carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-base] sulphur]-6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazole-4-muriate (formula VII compound) 36.7g, yield 83.7%, purity 98.6%.
Embodiment 2
6-[[(4R, 5S, 6S)-2-[(4-nitro benzyloxy) carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-base] sulphur]-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] preparation of triazole-4-muriate (formula VII compound)
By (4R, 5R, 6S)-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's (formula V compound) 50.0g, 6-sulfydryl-6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazole-4-muriate (formula VI compound) 19.2g, N, dinethylformamide 23.7g and triethylamine 11.7g adds 400g in acetonitrile, stir, logical nitrogen protection,-10 to-15 DEG C are stirred 10 hours, filter, dry, obtain 6-[[(4R, 5S, 6S)-2-[(4-nitro benzyloxy) carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-base] sulphur]-6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazole-4-muriate (formula VII compound) 39.1g, yield 89.1%, purity 99.0%.
Embodiment 3
6-[[(4R, 5S, 6S)-2-[(4-nitro benzyloxy) carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-base] sulphur]-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] preparation of triazole-4-muriate (formula VII compound)
By (4R, 5R, 6S)-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's (formula V compound) 400.0g, 6-sulfydryl-6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazole-4-muriate (formula VI compound) 154.8g, N, dinethylformamide 129.6g and triethylamine 93.6g adds 3200g in acetonitrile, stir, logical nitrogen protection,-10 to-15 DEG C are stirred 8 hours, filter, dry, obtain 6-[[(4R, 5S, 6S)-2-[(4-nitro benzyloxy) carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-base] sulphur]-6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazole-4-muriate (formula VII compound) 320.3g, yield 91.2%, purity 98.9%.
Embodiment 4
The preparation of biapenem (type I compound)
Add formula VII compound 60.0g, 2,6-lutidine 30.0g, 10% palladium charcoal 12.0g, DMF 120mL and ethanol 480mL in hydriding reactor, be heated to 40 DEG C, keep hydrogen pressure 2.5MPa, insulation reaction 60 minutes.Filter, filter cake adds in the pure water of 60 DEG C, stirs, and filters, adds ethanol, be cooled to less than 10 DEG C in filtrate, stirs, and filters, dry, obtains biapenem (type I compound) 30.9g, yield 76.9%, purity 99.3%.
Embodiment 5
The preparation of biapenem (type I compound)
Add formula VII compound 60.0g, 2, the 6-lutidine 30.0g described in embodiment 1,5% platinum charcoal 12.0g, DMF 120mL and ethanol 480mL in hydriding reactor, be heated to 40 DEG C, keep hydrogen pressure 3MPa, insulation reaction 40 minutes.Filter, filter cake adds in the pure water of 60 DEG C, stirs, and filters, adds ethanol, be cooled to less than 10 DEG C in filtrate, stirs, and filters, dry, obtains biapenem (type I compound) 29.6g, yield 73.6%, purity 99.4%.
Embodiment 6
The preparation of biapenem (type I compound)
Add formula VII compound 60.0g, 2, the 6-lutidine 33.0g described in embodiment 1,5% palladium charcoal 18.0g, N-Methyl pyrrolidone 90mL and ethanol 450mL in hydriding reactor, be heated to 40 DEG C, keep hydrogen pressure 3MPa, insulation reaction 60 minutes.Filter, filter cake adds in the pure water of 60 DEG C, stirs, and filters, adds ethanol, be cooled to less than 10 DEG C in filtrate, stirs, and filters, dry, obtains biapenem (type I compound) 31.4g, yield 78.0%, purity 99.2%.
Embodiment 7
The preparation of biapenem (type I compound)
Add the formula VII compound 60.0g described in embodiment 1,2,6-lutidine 33.0g, platinum dioxide 9.0g, N-Methyl pyrrolidone 90mL and ethanol 450mL in hydriding reactor, be heated to 40 DEG C, keep hydrogen pressure 3MPa, insulation reaction 30 minutes.Filter, filter cake adds in the pure water of 60 DEG C, stirs, and filters, adds ethanol, be cooled to less than 10 DEG C in filtrate, stirs, and filters, dry, obtains biapenem (type I compound) 31.0g, yield 77.1%, purity 99.4%.
Embodiment 8
Reactions steps is identical with embodiment 1, wherein
Formula V compound is: the benzyl ester of (4R, 5R, 6S)-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
Formula VI compound is: 6-sulfydryl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-4-Cl
Reaction solvent is: the mixture of DMF and acetonitrile
Organic bases is: triethylamine
The consumption of compound VI is 0.9 times of compound V molar weight
The consumption of DMF is 0.1% of acetonitrile volume,
The organic bases consumption adopted be 0.1 times of compound V weight,
Temperature of reaction is room temperature, and the reaction times is 1 hour;
Embodiment 9
Reactions steps is identical with embodiment 1, wherein
Formula V compound is: (4R, 5R, 6S)-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl
The nitrobenzyl ester of base-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
Formula VI compound is: 6-sulfydryl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-4-CH3SO3-
Reaction solvent is: the mixture of DMF and acetonitrile
Organic bases is: DIPEA
The consumption of compound VI is 2 times of compound V molar weight
The consumption of DMF is 10% of acetonitrile volume,
The organic bases adopted, consumption be 1 times of compound V weight,
Temperature of reaction is subzero 30 DEG C, and the reaction times is 20 hours;
Embodiment 10
Reactions steps is identical with embodiment 1, wherein
Formula V compound is: (4R, 5R, 6S)-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid ethoxy benzyl ester
Formula VI compound is: 6-sulfydryl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-4-CF
3cOO
-
Reaction solvent is: the mixture of DMF and acetonitrile
Organic bases is: triethylamine
The consumption of compound VI is 1.0 times of compound V molar weight;
The consumption of DMF is 0.5% of acetonitrile volume.
The organic bases adopted, consumption be 0.15 of compound V weight;
Temperature of reaction is 10 DEG C, and the reaction times is 5 hours.
Embodiment 11
Reactions steps is identical with embodiment 1, wherein
Formula V compound is: (4R, 5R, 6S) the propoxy-benzyl ester of-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
Formula VI compound is: 6-sulfydryl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-4-Cl-
Reaction solvent is: the mixture of DMF and acetonitrile
Organic bases is: triethylamine
The consumption of compound VI is 1.5 times of compound V molar weight;
The consumption of DMF is 5% of acetonitrile volume.
The organic bases adopted, consumption be 0.5 of compound V weight;
Temperature of reaction is 10 DEG C to subzero 20 DEG C, and the reaction times is 15 hours.
Embodiment 12
Reactions steps is identical with embodiment 1, wherein
Formula V compound is: (4R, 5R, 6S) the methoxy-benzyl ester of-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
Formula VI compound is: 6-sulfydryl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-4-CH
3sO
3 -
Reaction solvent is: the mixture of DMF and acetonitrile
Organic bases is: triethylamine
The consumption of compound VI is 1.1 times of compound V molar weight;
The consumption of DMF is 2% of acetonitrile volume;
The organic bases adopted, consumption be 0.2 times of compound V weight;
Temperature of reaction is subzero 5 DEG C; Reaction times is 7 hours.
Embodiment 13
Reactions steps is identical with embodiment 1, wherein
Formula V compound is: (4R, 5R, 6S) the butoxy benzyl ester of-3-(two phenoxy group phosphonatos)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
Formula VI compound is: 6-sulfydryl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-4-CF3COO-
Reaction solvent is: the mixture of DMF and acetonitrile
Organic bases is: DIPEA
The consumption of compound VI is 1.3 times of compound V molar weight;
The consumption of DMF is 4% of acetonitrile volume;
The organic bases adopted, consumption be 0.35 times of compound V weight;
Temperature of reaction is subzero 15 DEG C; Reaction times is 9 hours.
Embodiment 14
Reactions steps is identical with embodiment 4, wherein
Reaction solvent is the mixed solvent of alcoholic solvent and aprotic polar organic solvent: wherein alcoholic solvent is selected from: methyl alcohol, and aprotic polar organic solvent is selected from methane amide
Catalyzer is: palladium charcoal
Organic bases is: 2,6-lutidine
Crystallization organic solvent is: methyl alcohol
Alcoholic solvent consumption is 0.5 times of compound VII weight,
Organic bases consumption is 0.1 times of compound VII,
Catalyst levels is 1% of compound VII weight.
The pressure of catalytic hydrogenation is 0.1MPa;
Catalytic hydrogenation temperature is 0 DEG C;
The catalytic hydrogenation time is 10 minutes.
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, and the temperature of water is room temperature to 95 DEG C, and the consumption of water is 5 times of compound VII weight, and filter, merging filtrate, the crystallization organic solvent consumption added is 1 times of water weight.
Embodiment 15
Reactions steps is identical with embodiment 4, wherein
Reaction solvent is the mixed solvent of alcoholic solvent and aprotic polar organic solvent: wherein alcoholic solvent ethanol, aprotic polar organic solvent is selected from DMF
Catalyzer is: palladium zeolite
Organic bases is: 2,6-lutidine
Crystallization organic solvent is: ethanol
Alcoholic solvent consumption is 5 times of compound VII weight,
Organic bases consumption is 1 times of compound VII,
Catalyst levels is 50% of compound VII weight.
The pressure of catalytic hydrogenation is 5MPa;
Catalytic hydrogenation temperature is 80 DEG C;
The catalytic hydrogenation time is 4 hours.
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, and the temperature of water is room temperature to 95 DEG C, and the consumption of water is 50 times of compound VII weight, and filter, merging filtrate, the consumption of organic solvent added is 10 times of water weight.
Embodiment 16
Reactions steps is identical with embodiment 4, wherein
Reaction solvent is the mixed solvent of alcoholic solvent and aprotic polar organic solvent: wherein alcoholic solvent is selected from: n-propyl alcohol, and aprotic polar organic solvent is selected from N,N-dimethylacetamide
Catalyzer is: platinum charcoal
Organic bases is: 2,6-lutidine
Crystallization organic solvent is: n-propyl alcohol
Alcoholic solvent consumption is 4 times of compound VII weight;
Aprotic polar organic solvent consumption is 1 times of compound VII weight;
Organic bases consumption used is 0.2 times of compound VII;
Catalyst levels is 5% of compound VII weight.
The pressure of catalytic hydrogenation is 1MPa;
Catalytic hydrogenation temperature is 20 DEG C;
The catalytic hydrogenation time is 15 minutes.
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, and the temperature of water is 40 to 80 DEG C, and the consumption of water is 15 times of compound VII weight, and filter, merging filtrate, the consumption of organic solvent added is 2 times of water weight.
Embodiment 17
Reactions steps is identical with embodiment 4, wherein
Reaction solvent is the mixed solvent of alcoholic solvent and aprotic polar organic solvent: wherein alcoholic solvent is selected from: Virahol, and aprotic polar organic solvent is selected from N-Methyl pyrrolidone
Catalyzer is: platinum dioxide
Organic bases is: 2,6-lutidine
Crystallization organic solvent is: Virahol
Alcoholic solvent consumption is 8 times of compound VII weight; Aprotic polar organic solvent consumption is 3 times of compound VII weight;
Organic bases consumption used is 0.8 times of compound VII;
Catalyst levels is 40% of compound VII weight.
The pressure of catalytic hydrogenation is 3MPa;
Catalytic hydrogenation temperature is 60 DEG C;
The catalytic hydrogenation time is 2 hours.
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, and the temperature of water is 40 to 80 DEG C, and the consumption of water is 30 times of compound VII weight, and filter, merging filtrate, the consumption of organic solvent added is 8 times of water weight.
Embodiment 18
Reactions steps is identical with embodiment 4, wherein
Reaction solvent is the mixed solvent of alcoholic solvent and aprotic polar organic solvent: wherein alcoholic solvent is selected from: first propyl carbinol, and aprotic polar organic solvent is selected from 1,3-dimethyl-imidazolinone
Catalyzer is: palladium charcoal
Organic bases is: 2,6-lutidine
Crystallization organic solvent is: acetone
Alcoholic solvent consumption is 5 times of compound VII weight; Aprotic polar organic solvent consumption is 1.5 times of compound VII weight;
Organic bases consumption is 0.4 times of compound VII;
Catalyst levels is 5% of compound VII weight.
Catalytic hydrogenation temperature is 30 DEG C;
The catalytic hydrogenation time is 20 minutes;
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, and the temperature of water is 50 to 65 DEG C, and the consumption of water is 20 times of compound VII weight, and filter, merging filtrate, the consumption of organic solvent added is 3 times of water weight.
Embodiment 19
Reactions steps is identical with embodiment 4, wherein
Reaction solvent is the mixed solvent of alcoholic solvent and aprotic polar organic solvent: wherein alcoholic solvent propyl carbinol, aprotic polar organic solvent is selected from methyl-sulphoxide
Catalyzer is: platinum dioxide
Organic bases is: 2,6-lutidine
Crystallization organic solvent is: butanone
Organic bases consumption is 0.5 times of compound VII;
Catalyst levels is 20% of compound VII weight.
Catalytic hydrogenation temperature is 45 DEG C;
The catalytic hydrogenation time is 60 minutes;
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, and the temperature of water is 50 to 65 DEG C, and the consumption of water is 25 times of compound VII weight, and filter, merging filtrate, the consumption of organic solvent added is 6 times of water weight.
Embodiment 20
Reactions steps is identical with embodiment 4, wherein
Reaction solvent is the mixed solvent of alcoholic solvent and aprotic polar organic solvent: wherein alcoholic solvent ethanol, and aprotic polar organic solvent is selected from tetramethylene sulfone,
Catalyzer is: palladium zeolite
Organic bases is: 2,6-lutidine
Crystallization organic solvent is: acetone
Organic bases consumption is 0.5 times of compound VII;
Catalyst levels is 20% of compound VII weight.
The pressure of catalytic hydrogenation is 2MPa;
Catalytic hydrogenation temperature is 25 DEG C;
The catalytic hydrogenation time is 1 hour.
After catalytic hydrogenation terminates, filtered by reaction mixture, filter cake is added to the water stirring, and the temperature of water is 50 to 65 DEG C, and the consumption of water is 22 times of compound VII weight, and filter, merging filtrate, the consumption of organic solvent added is 4 times of water weight.
Claims (10)
1. a preparation method for biapenem with high purity, is characterized in that, described method steps is as follows:
Step 1, compound V and formula compound VI, in acetonitrile solvent, under a small amount of DMF and organic bases exist, obtain formula VII compound through condensation reaction;
Wherein, R
2for can the carboxy protective group of catalytic hydrogenation; The X of compound VI
-for electronegative ion; The consumption of compound VI is 0.9 to 2 times of compound V molar weight, and the consumption of DMF is 0.1% to 10% of acetonitrile volume, the organic bases adopted, consumption be 0.1 to 1 times of compound V weight, temperature of reaction be room temperature to subzero 30 DEG C, the reaction times is 1 to 20 hour;
Step 2, in the mixed solution of alcoholic solvent and aprotic polar organic solvent, under the existence of catalyzer and organic bases, catalytic hydrogenation removes the carboxylic acid protecting group of compound VII, filtered by reaction mixture, filter cake is added to the water stirring again, filters, merging filtrate, under stirring, add organic solvent, crystallization, filter, drying obtains biapenem;
Wherein alcoholic solvent is the straight or branched alkyl monocarbon alcohol of C1-C10, one or two or more kinds mixture of dibasic alcohol or trivalent alcohol, aprotic polar organic solvent is selected from one or more the mixture in following solvent: methane amide, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, 1, 3-dimethyl-imidazolinone, methyl-sulphoxide, tetramethylene sulfone, consumption is 0.5 to 5 times, organic bases used can neutralize the hydrogen ion of generation, consumption is 0.1 to 1 times of compound VII, used catalyst, consumption is 1 to 50% of compound VII weight.
2. preparation method according to claim 1, is characterized in that, in step 1, and R
2be selected from benzyl, nitrobenzyl or C1-C4 alkoxybenzyl; The X of compound VI
-for electronegative ion, be selected from: Cl
-, CH
3sO
3 -or CF
3cOO
-; The consumption of compound VI is 1.0 to 1.5 times of compound V molar weight; The consumption of DMF is 0.5 to 5% of acetonitrile volume.The organic bases adopted, is selected from triethylamine, DIPEA, consumption be 0.15 to 0.5 of compound V weight; In step 1, temperature of reaction is 10 DEG C to subzero 20 DEG C, and the reaction times is 5 to 15 hours.
3. preparation method according to claim 1, is characterized in that, in step 1, the consumption of compound VI is 1.1 to 1.3 times of compound V molar weight; The consumption of DMF is the 2-4% of acetonitrile volume; The organic bases adopted, is selected from triethylamine, DIPEA, consumption be 0.2 to 0.35 times of compound V weight; Temperature of reaction is subzero 5 to-15 DEG C; Reaction times is 7 to 9 hours.
4. preparation method according to claim 1, is characterized in that, in step 2, wherein alcoholic solvent is selected from: methyl alcohol, ethanol, n-propyl alcohol, Virahol, one or two or more kinds mixture of propyl carbinol, and consumption is 4-8 times of compound VII weight; Aprotic polar organic solvent is selected from methane amide, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 1,3-dimethyl-imidazolinone, methyl-sulphoxide, tetramethylene sulfone, and consumption is compound VII weight 1 to 3 times; Organic bases used is selected from 2,6-lutidine, and consumption is 0.2 to 0.8 times of compound VII; Used catalyst, is selected from containing palladium or containing platinic compound.
5. preparation method according to claim 1, is characterized in that, in step 2,
The pressure of catalytic hydrogenation is 0.1 to 5MPa;
Catalytic hydrogenation temperature is 0 to 80 DEG C;
The catalytic hydrogenation time is 10 minutes to 4 hours.
6. preparation method according to claim 1, is characterized in that, in step 2, wherein alcoholic solvent is selected from: methyl alcohol, ethanol, n-propyl alcohol, Virahol, one or two or more kinds mixture of propyl carbinol, and consumption is 5-7 times of compound VII weight; Aprotic polar organic solvent is selected from methane amide, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 1,3-dimethyl-imidazolinone, methyl-sulphoxide, tetramethylene sulfone, and consumption is 1.5 to 2.5 times; Organic bases used is selected from 2,6-lutidine, and consumption is 0.4 to 0.6 times of compound VII; Used catalyst, is selected from palladium charcoal, palladium zeolite, platinum charcoal or platinum dioxide, and consumption is 5 to 40% of compound VII weight.
7. preparation method according to claim 1, is characterized in that, in step 2,
The pressure of catalytic hydrogenation is 1 to 3MPa;
Catalytic hydrogenation temperature is 20 to 60 DEG C;
The catalytic hydrogenation time is 15 minutes to 2 hours.
8. preparation method according to claim 1, is characterized in that, in step 2,
Catalytic hydrogenation temperature is 30 to 45 DEG C;
The catalytic hydrogenation time is 20 to 60 minutes;
After catalytic hydrogenation terminates, reaction mixture is filtered, filter cake is added to the water stirring, the temperature of water is room temperature to 95 DEG C, the consumption of water is 5 to 50 times of compound VII weight, filters, merging filtrate, the organic solvent added is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone or butanone, and its consumption is 1 to 10 times of water weight.
9. preparation method according to claim 1, it is characterized in that, in step 2, after catalytic hydrogenation terminates, reaction mixture is filtered, filter cake is added to the water stirring, and the temperature of water is 40 to 80 DEG C, and the consumption of water is 15 to 30 times of compound VII weight, filter, merging filtrate, the organic solvent added is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone or butanone, and its consumption is 2 to 8 times of water weight.
10. preparation method according to claim 1, it is characterized in that, in step 2, after catalytic hydrogenation terminates, reaction mixture is filtered, filter cake is added to the water stirring, and the temperature of water is 50 to 65 DEG C, and the consumption of water is 20 to 25 times of compound VII weight, filter, merging filtrate, the organic solvent added is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone or butanone, and its consumption is 3 to 6 times of water weight.
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