CN114031629A - Method for synthesizing tazobactam intermediate - Google Patents
Method for synthesizing tazobactam intermediate Download PDFInfo
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- CN114031629A CN114031629A CN202111507724.1A CN202111507724A CN114031629A CN 114031629 A CN114031629 A CN 114031629A CN 202111507724 A CN202111507724 A CN 202111507724A CN 114031629 A CN114031629 A CN 114031629A
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- tazobactam
- triazole
- reaction
- synthesizing
- triethylchlorosilane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
Abstract
The invention discloses a method for synthesizing a tazobactam intermediate. The method takes acetonitrile as a solvent, and uses (2S,5R) -3, 3-dimethyl-7-oxygen-4-thia-1-azabicyclo [3.2.0] as]Adding heptane-2-carboxylic acid diphenylmethyl ester-4-oxide, 1H-1,2, 3-triazole, triethylchlorosilane and potassium carbonate into a reaction vessel, and carrying out heating reflux reaction by a one-pot method to generate an azolbatan intermediate. The method adopts a one-pot method for synthesis, and the synthesis reaction of the tazobactam intermediate is carried out while preparing 2- (triethylsilyl) -1,2, 3-triazole, so that the production steps are simplified; acetonitrile is used as a reaction solvent, so that the conversion rate is improved, and the harm to the environment is reduced; the obtained 2- (triethylsilyl) -1,2, 3-triazole has larger steric hindrance than 2- (trimethylsilyl) -1,2, 3-triazole by using triethylchlorosilane, and has good selectivity and high yield.
Description
Technical Field
The invention relates to a method for synthesizing a tazobactam intermediate- (2S,3S,5R) -3-methyl-7-oxo-3- (1H-1,2, 3-triazole-1-ylmethyl) -4-thia-1-azabicyclo [3.2.0] heptane-2-diphenylmethyl carboxylate, belonging to the technical field of medicines.
Background
Tazobactam is a beta-lactamase inhibitor, and when used together with piperacillin sodium, tazobactam sodium produces obvious synergistic effect and is widely used for treating serious systemic and local infection, abdominal cavity infection, lower respiratory tract infection, soft tissue infection, septicemia and the like. At present, the main synthetic route of tazobactam is shown in a scheme 1, the total number of the tazobactam is 11, the yield of the first 4 steps is 65%, and the total yield is less than 20%. Route 2 takes 2- (trimethylsilyl) -1,2, 3-triazole as a key material, and the total yield is 25-30 percent by 8 steps. Compared with the route 1, the route 2 has fewer reaction steps and high yield, is suitable for industrial production and has wide application prospect. At present, 2- (trimethylsilyl) -1,2, 3-triazole needs to be prepared and separated firstly and then used for tazobactam synthesis.
2- (trimethylsilyl) -1,2, 3-triazole and 2- (triethylsilyl) -1,2, 3-triazole are important materials for synthesizing novel beta-lactamase inhibitor tazobactam. The 2- (triethylsilyl) -1,2, 3-triazole has larger steric hindrance than 2- (trimethylsilyl) -1,2, 3-triazole and good selectivity in the tazobactam synthesis process, so the 2- (triethylsilyl) -1,2, 3-triazole has wider application prospect.
2- (triethylsilyl) -1,2, 3-triazole, molecular formula: c8H17N3Si, molecular weight: 183.3, the structural formula is shown below.
Disclosure of Invention
The invention provides a method for synthesizing a tazobactam intermediate. The method adopts a one-pot method for synthesis, and the synthetic reaction of a tazobactam intermediate (compound 4) is carried out while preparing 2- (triethylsilyl) -1,2, 3-triazole, so that the production steps are simplified; acetonitrile is used as a reaction solvent, so that the conversion rate is improved, and the harm to the environment is reduced; the obtained 2- (triethylsilyl) -1,2, 3-triazole has larger steric hindrance than 2- (trimethylsilyl) -1,2, 3-triazole by using triethylchlorosilane, and has good selectivity and high yield.
The technical scheme of the invention is as follows: a method for synthesizing a tazobactam intermediate is characterized in that acetonitrile is used as a solvent, and (2S,5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester-4-oxide (compound 1), 1H-1,2, 3-triazole, triethylchlorosilane and potassium carbonate are added into a reaction vessel, and a one-pot heating reflux reaction is carried out to generate the tazobactam intermediate (compound 4).
The reaction equation is as follows:
the method specifically comprises the following steps:
(1) putting 1H-1,2, 3-triazole, (2S,5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester-4-oxide (compound 1) and acetonitrile into a reaction kettle;
(2) cooling to below 10 ℃, and slowly dripping triethylchlorosilane while stirring;
(3) slowly adding potassium carbonate after the dropwise addition of the triethylchlorosilane is finished;
(4) stirring and refluxing (90-100 ℃) for reaction, and filtering after the reaction is finished to obtain a reaction feed liquid of tazobactam intermediate- (2S,3S,5R) -3-methyl-7-oxo-3- (1H-1,2, 3-triazole-1-ylmethyl) -4-thia-1-azabicyclo [3.2.0] heptane-2-diphenylmethyl carboxylate.
The reaction liquid can be directly added with potassium permanganate and concentrated sulfuric acid for further carrying out double oxidation reaction to obtain tazobactam diphenylmethyl ester.
Furthermore, the molar ratio of the compound 1 to the 1H-1,2, 3-triazole is 1 (1.3-2.0).
Furthermore, the molar ratio of the 1H-1,2, 3-triazole to the triethylchlorosilane is 1 (1.2-1.5).
Furthermore, the mass ratio of the 1H-1,2, 3-triazole to the acetonitrile is 1 (9-12).
Furthermore, in the step (3), the mass ratio of the potassium carbonate to the 1H-1,2, 3-triazole is (1.5-2.0): 1.
Further, in the step (4), stirring and refluxing are carried out for 4-6 hours.
The invention has the technical effects that:
1. the one-pot reaction is carried out, the synthetic reaction (thioredoxin ring-opening rearrangement) of the tazobactam intermediate (compound 4) is carried out while the 2- (triethylsilyl) -1,2, 3-triazole is prepared, and the production steps are simplified;
2. acetonitrile is used as a reaction solvent, so that the conversion rate is improved, and the harm to the environment is reduced;
3. the obtained 2- (triethylsilyl) -1,2, 3-triazole has larger steric hindrance than 2- (trimethylsilyl) -1,2, 3-triazole by using triethylchlorosilane, has good selectivity, and can improve the total yield of tazobactam by more than 10%.
Detailed Description
The synthesis provided by the present invention is further illustrated by the following specific examples.
Example 1:
(1) putting 20g of 1H-1,2, 3-triazole, 60g of (2S,5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester-4-oxide and 240g of acetonitrile into a reaction kettle, starting stirring, and cooling to 5 ℃;
(2) slowly dripping 60g of triethylchlorosilane;
(3) after the dropwise addition of triethylchlorosilane, 30g of potassium carbonate was slowly added;
(4) stirring and refluxing for 4h at the temperature of 90-100 ℃, and filtering to obtain tazobactam intermediate feed liquid;
(5) adding 40g of potassium permanganate into the obtained feed liquid, dropwise adding 30g of concentrated sulfuric acid at 15 ℃, keeping the temperature for reaction for 2 hours after the dropwise adding is finished, adding 5g of sodium bicarbonate and 100g of purified water washing material into an organic layer after the reaction is finished, distilling the obtained organic phase to 152g under reduced pressure, carrying out suction filtration and drying to obtain 59.6g of tazobactam diphenylmethyl ester with the purity of 99.8% and the yield of 81.7%.
(6) Putting the tazobactam diphenylmethyl ester and 420g of m-cresol into a reaction kettle, reacting for 2h at 60 ℃, adding 15g of sodium bicarbonate and 100g of water after the reaction is finished, extracting for layering, dropwise adding 35g of AR hydrochloric acid into a water layer at 10 ℃, keeping the temperature for 1h after the dropwise adding is finished, and performing suction filtration to obtain 33.8g of crude tazobactam; putting the crude tazobactam and 500g of 95% ethanol into a reaction kettle, stirring for 2h at 25 ℃, carrying out suction filtration and drying to obtain 29.6g of tazobactam, wherein the quality meets the requirements of pharmacopoeia (CP/EP/USP), and the yield is 77.2%.
By adopting the method of the embodiment 1, the total yield of tazobactam reaches 41% (according to the route 2 in the background art, the reaction yield of the first 4 steps of tazobactam is 65%), and the yield is obviously improved compared with the yield of 20-30% of tazobactam reported in the literature.
Example 2
(1) Putting 20g of 1H-1,2, 3-triazole, 70g of (2S,5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester-4-oxide and 180g of acetonitrile into a reaction kettle, starting stirring and cooling to 5 ℃;
(2) slowly dripping 50g of triethylchlorosilane;
(3) after the dropwise addition of the triethylchlorosilane, 40g of potassium carbonate was slowly added;
(4) stirring and refluxing for 6h at 90 ℃, and filtering to obtain tazobactam intermediate feed liquid.
(5) Adding 48g of potassium permanganate into the obtained feed liquid, dropwise adding 35g of concentrated sulfuric acid at 15 ℃, preserving the temperature for 2h after dropwise adding, adding 5g of sodium bicarbonate and 100g of purified water washing materials into an organic layer after the reaction is finished, distilling the obtained organic phase to 165g under reduced pressure, carrying out suction filtration and drying to obtain 68.6g of tazobactam diphenylmethyl ester, wherein the purity is 99.9%, and the yield is 80.6%.
Example 3
(1) Putting 20g of 1H-1,2, 3-triazole, 60g of (2S,5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester-4-oxide and 220g of acetonitrile into a reaction kettle, starting stirring and cooling to 5 ℃;
(2) slowly dripping 55g of triethylchlorosilane;
(3) after the dropwise addition of triethylchlorosilane, 35g of potassium carbonate was slowly added;
(4) stirring and refluxing for 5h at 95 ℃, and filtering to obtain tazobactam intermediate feed liquid.
(5) Adding 40g of potassium permanganate into the obtained feed liquid, dropwise adding 30g of concentrated sulfuric acid at 15 ℃, preserving the temperature for 2h after dropwise adding, adding 5g of sodium bicarbonate and 100g of purified water washing material into an organic layer after the reaction is finished, distilling the obtained organic phase to 149g under reduced pressure, carrying out suction filtration and drying to obtain 59.1g of tazobactam diphenylmethyl ester, wherein the purity is 99.8%, and the yield is 80.9%.
Example 4
(1) Putting 20g of 1H-1,2, 3-triazole, 65g of (2S,5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester-4-oxide and 200g of acetonitrile into a reaction kettle, starting stirring and cooling to 5 ℃;
(2) slowly dripping 52g of triethylchlorosilane;
(3) after the dropwise addition of triethylchlorosilane, 32g of potassium carbonate was slowly added;
(4) stirring and refluxing for 5h at 95 ℃, and filtering to obtain tazobactam intermediate feed liquid.
(5) Adding 44g of potassium permanganate into the obtained feed liquid, dropwise adding 32g of concentrated sulfuric acid at 15 ℃, preserving the temperature for 2h after the dropwise adding, adding 5g of sodium bicarbonate and 100g of purified water washing material into an organic layer after the reaction is finished, distilling the obtained organic phase to 158g under reduced pressure, carrying out suction filtration and drying to obtain 63.5g of tazobactam diphenylmethyl ester, wherein the purity is 99.8%, and the yield is 80.3%.
Claims (10)
1. A method for synthesizing tazobactam intermediate is characterized in that in an organic solvent, a compound 1, 1H-1,2, 3-triazole, triethylchlorosilane and inorganic base are added into a reaction vessel, and a one-pot heating reflux reaction is carried out to generate a tazobactam intermediate compound 4;
2. the process for the synthesis of tazobactam intermediate as claimed in claim 1, wherein the organic solvent is acetonitrile.
3. The process for the synthesis of tazobactam intermediate as claimed in claim 1, wherein the inorganic base is potassium carbonate.
4. A process for the synthesis of tazobactam intermediates as claimed in any one of claims 1 to 3, comprising the steps of:
(1) putting 1H-1,2, 3-triazole, a compound 1 and acetonitrile into a reaction kettle;
(2) cooling to below 10 ℃, and slowly dripping triethylchlorosilane while stirring;
(3) slowly adding potassium carbonate after the dropwise addition of the triethylchlorosilane is finished;
(4) stirring and refluxing at 90-100 ℃, and filtering after the reaction is finished to obtain a reaction feed liquid of the tazobactam intermediate compound 4.
5. The method for synthesizing the tazobactam intermediate as claimed in claim 4, wherein the reaction solution of the tazobactam intermediate compound 4 is directly added with potassium permanganate and concentrated sulfuric acid to further carry out a double oxidation reaction to obtain tazobactam diphenylmethyl ester.
6. The method for synthesizing the tazobactam intermediate as claimed in claim 4, wherein the molar ratio of the compound 1 to the 1H-1,2, 3-triazole is 1 (1.3-2.0).
7. The method for synthesizing the tazobactam intermediate, according to claim 4, wherein the molar ratio of the 1H-1,2, 3-triazole to the triethylchlorosilane is 1 (1.2-1.5).
8. The method for synthesizing the tazobactam intermediate as claimed in claim 4, wherein the mass ratio of the 1H-1,2, 3-triazole to the acetonitrile is 1 (9-12).
9. The method for synthesizing the tazobactam intermediate as claimed in claim 4, wherein in the step (3), the mass ratio of the potassium carbonate to the 1H-1,2, 3-triazole is (1.5-2.0): 1.
10. The method for synthesizing tazobactam intermediate as claimed in claim 4, wherein in the step (4), the reaction is performed under stirring and refluxing for 4-6 h.
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