CN102372714B - Method for preparing doripenem - Google Patents
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- CN102372714B CN102372714B CN201110403234.7A CN201110403234A CN102372714B CN 102372714 B CN102372714 B CN 102372714B CN 201110403234 A CN201110403234 A CN 201110403234A CN 102372714 B CN102372714 B CN 102372714B
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Abstract
The invention relates to a method for preparing doripenem. The method comprises the following step of: reducing pyrrolidine sulfonyl carbapenem protected by a doripenem precursor into doripenem under the transferring and catalyzing actions of hydrogen. The method has the advantages of mild chemical reaction conditions, simple process, high transformation rate, high yield, product purity stabilized over 99 percent, recycling of solvents and catalysts in the entire process, great saving in the production cost, and suitability for large-scale production; and a novel thought and a novel method for a penem compound are provided.
Description
(1) technical field:
The present invention relates to organic synthesis and prepare chemical field, particularly a kind of method of preparing S-4661.
(2) background technology:
S-4661 is the new Broad spectrum antibiotics of carbapenems of being developed by Japanese Shionogi Seiyaku Kabushiki Kaisha, there is has a broad antifungal spectrum, to the stable feature of most β-lactamases, its structure is suc as formula shown in (I), be a 1 new beta-methylcarbapenem antibiotics, 2 side chains are Pyrrolidine rings that SULFAMIDE replaces.Structure activity study shows, the increase that the acidylate of S-4661 side chain amino or sulfonylation are conducive to anti-microbial activity, to the inhibition activity of gram-positive microorganism higher than meropenem, to the inhibition activity of Gram-negative bacteria higher than imipenum, also effective to imipenem-resistant bacterium, to Serine β-lactamase and dehydropeptidase of kidney stable (Chinese Journal of New Drugs the 12nd volume the 9th phase 700-703 in 2003), can be used for abdominal cavity infection, lower respiratory infection, gynecological infection, urogenital infections, bone joint infection, Skin and soft tissue infection, endocarditis, severe meningitis, the severe infections such as septicemia, last line of defense under other anti-infective invalid situation often.
Present stage, the method for preparing S-4661 mainly contains following three kinds:
1, with (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid benzhydryl ester and (2S, the reaction of 4S)-1-tertbutyloxycarbonyl-2-(N-tertbutyloxycarbonyl-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine generates pyrrolidine sulfsulopenem deprotection under the effect of Lewis acid aluminum chloride of protection and prepares S-4661 (Organic Process Research & Development 2003,7,846-850; CN1032257) (see Fig. 1), this method needs to use divinylbenzene type macroporous resin column to carry out purifying after adopting aluminum chloride deprotection, is not suitable for suitability for industrialized production, and in product, residual aluminum ion is difficult to eliminate simultaneously, and the difficulty of purifying products is very large.
2, with (2S, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-sulfamoylamino group) methyl-4-mercapto pyrrolidine and (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy reacts the pyrrolidine sulfsulopenem that generates protection and under the catalysis of palladium carbon, in the mixed solvent of tetrahydrofuran (THF) and water, carries out hydrogenolysis deprotection and prepare S-4661 (WO2010/97686) (seeing Fig. 2), this method products obtained therefrom is impure and by product is more, the a large amount of solvents of purifying products consumption, and yield is lower, from technological angle and economic benefit angle, all be not suitable for scale operation.
3, with (2S; 4S)-1-allyloxycarbonyl-2-(N-sulfamoylamino group) methyl-4-mercapto pyrrolidine and (1R; 5R; 6S)-6-[(1R)-1-hydroxyethyl] reaction of-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-allyl carboxylate generates the pyrrolidine sulfsulopenem of protection and the Virahol of 0.5eq forms complex compound; under the effect of four (triphenyl phosphorus) palladium, deprotection is prepared S-4661 (EP1595883 again; 2005) (see Fig. 3); this method catalyzer is with high costs; purifying process is loaded down with trivial details, and scale operation S-4661 is restricted.
Therefore, be to solve the difficult problem existing in prior art, suddenly wait to find one with low cost, technique is simple, yield and purity are all higher, and the practicable synthetic route of applicable large-scale production.
(3) summary of the invention:
The object of the invention is to provide a kind of method of preparing S-4661, the deficiency existing to overcome prior art.This method is reduced to S-4661 by hydrogen transference catalysis method by the pyrrolidine sulfsulopenem (structure is suc as formula II) of protection in specific damping fluid; reaction conditions is gentle; simple to operate; process stabilizing; transformation efficiency and yield are all higher; product specification meets API requirement, for large-scale production S-4661 provides a kind of new thinking and method.
Technical scheme of the present invention: a kind of method of preparing S-4661, is characterized in that concrete preparation process is as follows:
(1) to the damping fluid that adds pH=6.8～7.8 in reactor, be cooled to 0～15 ℃; The pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of damping fluid are 1g/5～15mL;
(2) in reactor, add successively metal catalyst; the pyrrolidine sulfsulopenem (structure is suc as formula II) of the main raw material protection of ether solvent dilution; drip the hydrogen carrier of ether solvent dilution, drip and finish in 0～15 ℃ of insulation 4.5～5h to reacting completely, wherein:
The pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of metal catalyst are 1g/0.5～1g,
The pyrrolidine sulfsulopenem of main raw material protection and the mol ratio of hydrogen carrier are 1: 8～15,
The amount ratio of the ether solvent of the pyrrolidine sulfsulopenem of main raw material protection and dilution main raw material is 1g/4～10mL,
The amount ratio of the pyrrolidine sulfsulopenem of main raw material protection and the ether solvent of dilute hydrogen carrier is 1g/1～5mL;
(3) step (2) reaction is finished, and reaction products therefrom is carried out to suction filtration, and filtrate extracts with ether solvent, and separatory gained water adds activated carbon decolorizing successively, and magnesium chloride is stable, wherein:
The pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of ether solvent are 1g/10～20mL,
The pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of gac are 1g/0.05～0.1g,
The pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of magnesium chloride are 1g/0.4～0.8g;
(4) water by decolouring in step (3) and after stablizing filters, and by dripping water-miscible organic solvent crystallization to filtrate, obtains S-4661 crude product; The pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of water-miscible organic solvent are 1g/100～200mL;
(5) by obtaining more than 99% S-4661 of purity by membrane sepn after step (4) gained S-4661 dissolving crude product, can directly as API, use.
In above-mentioned said step (1), the pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of damping fluid are 1g/8～12mL, and cooling temperature is 5～10 ℃.
In above-mentioned said step (2); the pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of metal catalyst are 1g/0.6～0.8g; the pyrrolidine sulfsulopenem of main raw material protection and the mol ratio of hydrogen carrier are 1: 10～12; the amount ratio of the ether solvent of the pyrrolidine sulfsulopenem of main raw material protection and dilution main raw material is 1g/6～8mL; the amount ratio of the pyrrolidine sulfsulopenem of main raw material protection and the ether solvent of dilute hydrogen carrier is 1g/2～3mL, and temperature of reaction is 5～10 ℃.
In above-mentioned said step (3); the pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of ether solvent are 1g/14～18mL; the pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of gac are 1g/0.07～0.08g, and the pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of magnesium chloride are 1g/0.5～0.7g.
In above-mentioned said step (4), the pyrrolidine sulfsulopenem of main raw material protection and the amount ratio of water-miscible organic solvent are 1g/150～180mL.
In above-mentioned said step (1), the N-methylmorpholine that damping fluid is pH=6.8～7.8 and the mixing solutions of acetic acid.
In above-mentioned said step (2), metal catalyst is palladium carbon, platinum carbon, platinum dioxide or Raney's nickel, and hydrogen carrier is formic acid, oxalic acid or oxoethanoic acid, and ether solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or Isosorbide-5-Nitrae-dioxane.
In above-mentioned said step (3), ether solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or Isosorbide-5-Nitrae-dioxane.
In above-mentioned said step (4), water-miscible organic solvent is acetonitrile, methyl alcohol or ethanol.
In above-mentioned said step (1), the N-methylmorpholine that damping fluid is pH=7.5 and the mixing solutions of acetic acid; In said step (2), metal catalyst is 10% palladium carbon, and hydrogen carrier is formic acid, and ether solvent is tetrahydrofuran (THF); In said step (3), ether solvent is methyl tertiary butyl ether; In said step (4), water-miscible organic solvent is acetonitrile.
Following table has been enumerated respectively the reaction result under the catalyst system of different pH values:
| pH | Metal catalyst | Reaction times | Transformation efficiency | Yield | Purity |
| 6.8 | 10% platinum carbon | 5h | 94.6％ | 70％ | 99.7％ |
| 7.3 | 10% palladium carbon | 4.5h | 95.8％ | 80％ | 99.8％ |
| 7.8 | Raney's nickel | 4.5h | 95.0％ | 65％ | 99.4％ |
Superiority of the present invention: 1, reaction solvent for use and catalyzer all can recovery, conservation cost greatly, for large-scale production S-4661 is established economic base; 2, hydrogen transference catalytic reduction method is used in reaction, mild condition, and process stabilizing, total recovery is stabilized in 65%～80%; Stabilization minimizing impurity by metal halide generates, and improves product purity, through simple process, target product purity is stabilized in more than 99%, is applicable to the S-4661 of large-scale production api class.
(4) accompanying drawing explanation:
Fig. 1,2,3 is respectively the chemical reaction process schema that three kinds in background technology are prepared the method for S-4661.
Fig. 4 is the related a kind of chemical reaction process schema of preparing the method for S-4661 of the present invention.
(5) embodiment:
For the interval range occurring in embodiment, be because temperature in single test is with certain the floating of there will be of reaction process, its statement is the routine statement in the synthetic field of chemical industry.
Embodiment 1:
A method of preparing S-4661, is characterized in that concrete preparation process is as follows:
To the N-methylmorpholine and the acetate buffer 20kg (5vol) that add pH=6.8 in 100L reactor, be cooled to 0 ± 2 ℃, add successively 10% platinum carbon 2kg (0.5g/g), main raw material (the 4kg of 2-methyltetrahydrofuran (4vol) dilution, 1eq) solution 17.8kg, drip oxalic acid (8eq) the solution 7.4kg of 2-methyltetrahydrofuran (1vol) dilution, drip and finish in 0 ± 2 ℃ of insulation 5h to reacting completely.Reaction is finished, suction filtration, filtrate adds gac 200g (0.05g/g) decolouring successively with methyl tertiary butyl ether 15kg (5vol*2) extracting twice, water, after magnesium chloride 1.6kg (0.4g/g) is stable, filter, by dripping methyl alcohol 316kg (100vol) crystallization to filtrate, obtain S-4661 crude product, after dissolving crude product, by membrane sepn, obtain S-4661 1.6kg, yield 70%, HPLC purity 99.7%, can directly be used as API.
Embodiment 2:
A method of preparing S-4661, is characterized in that concrete preparation process is as follows:
To the N-methylmorpholine and the acetate buffer 20kg (10vol) that add pH=7.3 in 100L reactor, be cooled to 5 ± 2 ℃, add successively 10% palladium carbon 1.2kg (0.6g/g), main raw material (the 2kg of tetrahydrofuran (THF) (8vol) dilution, 1eq) solution 16.2kg, drip formic acid (12eq) the solution 5.1kg of tetrahydrofuran (THF) (2vol) dilution, drip and finish in 5 ± 2 ℃ of insulation 4.5h to reacting completely.Reaction is finished, suction filtration, filtrate adds gac 160g (0.08g/g) decolouring successively with tetrahydrofuran (THF) 7.1kg (4vol*3) extraction three times, water, after magnesium chloride 1.2kg (0.6g/g) is stable, filter, by dripping acetonitrile 253kg (160vol) to water, obtain S-4661 crude product, after dissolving crude product, by membrane sepn, obtain S-4661 915kg, yield 80%, HPLC purity 99.8%, can directly be used as API.
Embodiment 3:
A method of preparing S-4661, is characterized in that concrete preparation process is as follows:
To the N-methylmorpholine and the acetate buffer 12kg (15vol) that add pH=7.8 in 50L reactor, be cooled to 15 ± 2 ℃, add successively Raney's nickel 0.8kg (1g/g), main raw material (the 0.8kg of methyl tertiary butyl ether (10vol) dilution, 1eq) solution 6.4kg, drip oxoethanoic acid (15eq) the solution 4.2kg of methyl tertiary butyl ether (5vol) dilution, in 15 ± 2 ℃ of insulation 4.5h to reacting completely.Reaction is finished, suction filtration, filtrate adds gac 80g (0.1g/g) decolouring successively with 2-methyltetrahydrofuran 7kg (10vol*2) extracting twice, water, after magnesium chloride 640g (0.8g/g) is stable, filter, by dripping ethanol 126kg (200vol) to filtrate, obtain S-4661 crude product, after dissolving crude product, by membrane sepn, obtain S-4661 298g, yield 65%, HPLC purity 99.4%, can directly be used as API.
As can be seen here; disclosed a kind of synthetic method of preparing S-4661 in the present invention; chemical reaction condition is gentle; technique is simple, and transformation efficiency and yield are all higher, and the purity of target product is stabilized in more than 99%; the solvent of whole technique and catalyzer be recovery all; greatly saving production cost, is the synthesis technique of feasible applicable large-scale production, for the southern compounds of preparation training provides a kind of new thinking and method.
Claims (9)
1. a method of preparing S-4661, is characterized in that concrete preparation process is as follows:
(1) to the damping fluid that adds pH=6.8～7.8 in reactor, be cooled to 0～15 ℃; The pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of damping fluid are 1g/5～15mL; Damping fluid is the N-methylmorpholine of pH=6.8～7.8 and the mixing solutions of acetic acid;
(2) in reactor, add successively metal catalyst, the pyrrolidine sulfsulopenem of the main raw material PNZ protection of ether solvent dilution, the structural formula of the pyrrolidine sulfsulopenem of main raw material PNZ protection is
drip the hydrogen carrier of ether solvent dilution, drip and finish in 0～15 ℃ of insulation 4.5～5h to reacting completely, wherein:
The pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of metal catalyst are 1g/0.5～1g,
The pyrrolidine sulfsulopenem of main raw material PNZ protection and the mol ratio of hydrogen carrier are 1:8～15,
The amount ratio of the ether solvent of the pyrrolidine sulfsulopenem of main raw material PNZ protection and dilution main raw material is 1g/4～10mL,
The amount ratio of the pyrrolidine sulfsulopenem of main raw material PNZ protection and the ether solvent of dilute hydrogen carrier is 1g/1～5mL;
Metal catalyst is palladium carbon, platinum carbon, platinum dioxide or Raney's nickel, and hydrogen carrier is formic acid, oxalic acid or oxoethanoic acid, and ether solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or Isosorbide-5-Nitrae-dioxane;
(3) step (2) reaction is finished, and reaction products therefrom is carried out to suction filtration, and filtrate extracts with ether solvent, and separatory gained water adds activated carbon decolorizing successively, and magnesium chloride is stable, wherein:
The pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of ether solvent are 1g/10～20mL,
The pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of gac are 1g/0.05～0.1g,
The pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of magnesium chloride are 1g/0.4～0.8g;
(4) water by decolouring in step (3) and after stablizing filters, and by dripping water-miscible organic solvent crystallization to filtrate, obtains S-4661 crude product; The pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of water-miscible organic solvent are 1g/100～200mL;
(5) by obtaining more than 99% S-4661 of purity by membrane sepn after step (4) gained S-4661 dissolving crude product, can directly as API, use.
2. a kind of method of preparing S-4661 according to claim 1, is characterized in that in said step (1), and the pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of damping fluid are 1g/8～12mL, and cooling temperature is 5～10 ℃.
3. a kind of method of preparing S-4661 according to claim 1, it is characterized in that in said step (2), the pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of catalyzer are 1g/0.6～0.8g, the pyrrolidine sulfsulopenem of main raw material PNZ protection and the mol ratio of hydrogen carrier are 1:10～12, the amount ratio of the ether solvent of the pyrrolidine sulfsulopenem of main raw material PNZ protection and dilution main raw material is 1g/6～8mL, the amount ratio of the pyrrolidine sulfsulopenem of main raw material PNZ protection and the ether solvent of dilute hydrogen carrier is 1g/2～3mL, temperature of reaction is 5～10 ℃.
4. a kind of method of preparing S-4661 according to claim 1; it is characterized in that in said step (3); the pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of ether solvent are 1g/14～18mL; the pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of gac are 1g/0.07～0.08g, and the pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of magnesium chloride are 1g/0.5～0.7g.
5. a kind of method of preparing S-4661 according to claim 1, is characterized in that in said step (4), and the pyrrolidine sulfsulopenem of main raw material PNZ protection and the amount ratio of water-miscible organic solvent are 1g/150～180mL.
6. a kind of method of preparing S-4661 according to claim 1, is characterized in that in said step (3), and ether solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or Isosorbide-5-Nitrae-dioxane.
7. a kind of method of preparing S-4661 according to claim 1, is characterized in that, in said step (4), water-miscible organic solvent is acetonitrile, methyl alcohol or ethanol.
8. a kind of method of preparing S-4661 according to claim 1, is characterized in that in said step (1) N-methylmorpholine that damping fluid is pH=7.5 and the mixing solutions of acetic acid; In said step (2), metal catalyst is 10% palladium carbon, and hydrogen carrier is formic acid, and ether solvent is tetrahydrofuran (THF); In said step (3), ether solvent is methyl tertiary butyl ether; In said step (4), water-miscible organic solvent is acetonitrile.
9. a kind of method of preparing S-4661 according to claim 1, is characterized in that the reaction result under the catalyst system of different pH values is different, as follows:
At pH=6.8, catalyzer is under the catalyst system of 10% platinum carbon, reacts after 5 hours, and system transformation efficiency reaches 94.6%, and separated that product purity is 99.7%, yield is 70%;
At pH=7.3, catalyzer is under the catalyst system of 10% palladium carbon, reacts after 4.5 hours, and system transformation efficiency reaches 95.8%, and separated rear product purity is 99.8%, and yield is 80%;
At pH=7.8, under the catalyst system that catalyzer is Raney's nickel, react after 4.5 hours, system transformation efficiency reaches 95.0%, and separated rear product purity is 99.4%, and yield is 65%.
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