CN111909177A - Tazobactam intermediate, preparation method thereof and method for preparing tazobactam by using intermediate - Google Patents
Tazobactam intermediate, preparation method thereof and method for preparing tazobactam by using intermediate Download PDFInfo
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- CN111909177A CN111909177A CN202010832032.3A CN202010832032A CN111909177A CN 111909177 A CN111909177 A CN 111909177A CN 202010832032 A CN202010832032 A CN 202010832032A CN 111909177 A CN111909177 A CN 111909177A
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- 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 relates to the field of pharmaceutical chemicals, and discloses a plurality of tazobactam intermediates and a preparation method thereof, specifically: 1-amino-1H-1, 2,3 triazole is prepared from glyoxal and hydrazine through glyoxal dihydrazone, and then the triazole reacts with (2S,3S) -3-methyl-3-chloromethyl-7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-formic acid ester to prepare an intermediate V; the intermediate V is subjected to oxidation reaction to prepare an intermediate VI, the intermediate VI is subjected to diazotization reaction to prepare an intermediate VII, and the intermediate VII is subjected to deprotection reaction to prepare tazobactam. The intermediate obtained by the invention has good purity and high yield; the yield of the finally prepared tazobactam finished product is up to more than 90 percent, and the purity is up to more than 99.0 percent; the preparation method of the intermediate is simple and convenient to operate, mature and reliable, short in reaction route, easy to obtain raw materials and suitable for large-scale industrial production; the preparation method of the tazobactam finished product has the advantages of mild reaction conditions, simple process, low cost, high yield, high purity, environmental friendliness, good economic benefit and suitability for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical production, and in particular relates to a tazobactam intermediate, a preparation method thereof and a method for preparing tazobactam by using the intermediate.
Background
Tazobactam (Tazobactam) is a novel beta-lactamase inhibitor of the penicillanesone class developed by the pharmaceutical company of Japanese Roc, and is mainly used for preparing a compound preparation with piperacillin to treat various bacterial infections. The chemical name is as follows: (2S,3S,5R) -3-methyl-7-oxo-3- (1H-1,2, 3-triazolylmethyl) -4-thioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4, 4-dioxide. The structural formula is as follows:
at the present stage, the synthetic route of tazobactam is mainly divided into two types, one type is cyclization after azide, and the other type is direct side chain triazole ring grafting. The detailed description is as follows:
the first type forms a ring after passing through azide:
(1) in the prior art, the synthetic route is to synthesize tazobactam through the steps of ring opening, chloromethylation, azidation, oxidation and the like. The reaction route is as follows:
the synthetic route has higher requirements on equipment, needs acetylene with high risk as a raw material, has poor stability in the process of azide and has potential safety hazard.
(2) Chinese patent publication No. CN103044448A discloses a method for preparing tazobactam by reacting azide with propiolic acid, which comprises the following steps:
in the synthetic route, although acetylene with high risk is not used as a raw material, an azide intermediate is still required.
(3) US4898939 discloses a process for the direct addition of a pendant triazazole ring, the reaction scheme of which is as follows:
the synthesis route uses the heavy metal salt of triazole, and has great pollution to the environment.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a tazobactam intermediate and a preparation method thereof, wherein the obtained intermediate has good purity and high yield; the preparation method has the advantages of simple operation, maturity, reliability, short reaction route, easily obtained raw materials and suitability for large-scale industrial production;
the second purpose of the invention is to provide tazobactam prepared by the intermediate and a preparation method thereof, wherein the yield of the tazobactam finished product is up to more than 90%, and the purity is up to more than 99.0%; the preparation method has the advantages of mild reaction conditions, simple process, low cost, high yield, high purity, environmental friendliness and good economic benefit, and is suitable for industrial production.
In order to achieve the above purpose, the solution adopted by the invention is as follows:
a method for synthesizing tazobactam, which prepares finished tazobactam from an intermediate VII; in particular, intermediate VII can be prepared from intermediate VI; intermediate VI can be prepared from intermediate V; the intermediate III can be prepared from glyoxal and hydrazine as starting raw materials through the intermediate II, the intermediate IV is prepared, and the intermediate V is prepared.
Or directly preparing an intermediate III from glyoxal and hydrazine serving as starting raw materials through an intermediate II, then preparing an intermediate IV, and then preparing an intermediate V; preparing an intermediate VI from the intermediate V, preparing an intermediate VII from the intermediate VI, and preparing the finished product tazobactam from the intermediate VII.
The preparation method of tazobactam comprises the following steps:
carrying out deprotection reaction on (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-4, 4-dioxide-1-azabicyclo [3.2.0] heptane-2-formic acid ester (VII) to prepare tazobactam (I); the reaction formula is as follows:
the specific operation steps are as follows: dissolving (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazole-1-yl) methyl ] -7-oxo-4-sulfo-4, 4-dioxide-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester (VII) in a reaction solvent, and reacting for a certain time at a controlled temperature; and after the reaction is finished, adding a sodium carbonate aqueous solution to extract a water layer, separating out the water layer, filtering, and drying to obtain a tazobactam product.
Wherein, the deprotection reaction time is as follows: 1-6 hours; preferably 2-4 hours.
Wherein the deprotection reaction temperature is 20-80 ℃; preferably from 40 ℃ to 60 ℃.
Wherein, the reaction solvent used in the deprotection reaction for preparing tazobactam is one of m-methyl phenol, p-methyl phenol and methoxybenzene; preferably m-methylphenol.
Wherein, when the tazobactam is prepared by deprotection reaction, the volume ratio of the intermediate hepta (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazole-1-yl) methyl ] -7-oxo-4-sulfo-4, 4-dioxide-1-azabicyclo [3.2.0] heptane-2-formic acid certain ester (VII) to the reaction solvent is 1 (3-30); preferably 1 (5-15).
Further, the intermediate, hepta (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-4, 4-dioxido-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, was prepared by the following method:
(2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-4, 4-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester (VI) is diazotized to remove amino group to obtain the (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-4, 4-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester (VII); the reaction formula is as follows:
wherein, the R group shown in the structural formula can be benzhydryl, benzyl and p-nitrobenzyl; preferably benzhydryl.
The preparation method comprises the following specific operation steps: dissolving the intermediate VI in a reaction solvent, uniformly stirring, reacting for a certain time at a controlled temperature, then slowly adding a diazotization reagent, stirring for reaction, discharging gas, and directly filtering after the reaction is finished to obtain an intermediate VII.
Wherein the reaction solvent for preparing the intermediate VII is a mixed solvent and can be any one of water/methanol, water/ethanol, water/methanol/dichloromethane and water/ethanol/dichloromethane systems; preferably the reaction solvent is water/methanol.
Wherein the reaction solvent for preparing the intermediate VII is a water/methanol mixed solvent, and the volume ratio of water to methanol is 1 (1-5); preferably 1 (1-2).
Wherein the reaction temperature for preparing the intermediate VII is as follows: -20 ℃ to 20 ℃; preferably-10 ℃ to 10 ℃.
Wherein the reaction time for preparing the intermediate VII is 1-5 hours; preferably 2-3 hours.
Wherein, the diazotization reagent for preparing the intermediate VII can be sodium nitrite and potassium nitrite; preferably sodium nitrite.
Wherein, when preparing the intermediate VII, the molar ratio of the intermediate VI to the diazotization reagent is 1 (1-3); more preferably 1 (1-1.5).
Further, intermediate VI: certain (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-4, 4-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester (VI) is prepared by the following method:
the intermediate compound is prepared from the following five: (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester (V) is oxidized to prepare (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-4, 4-dioxide-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester (VI); the reaction formula is as follows:
wherein, the R group shown in the structural formula can be benzhydryl, benzyl and p-nitrobenzyl; preferably benzhydryl.
The preparation method comprises the following specific operation steps: dissolving the intermediate V in a reaction solvent, uniformly stirring, controlling the temperature to react for a certain time, then slowly adding an oxidant in multiple batches, stirring to react, filtering, and then removing the solvent under reduced pressure to obtain an intermediate VI.
Wherein, the reaction solvent for preparing the intermediate VI is ethyl acetate, dichloromethane and trichloromethane; preferably dichloromethane.
Wherein the reaction time for preparing the intermediate VI is as follows: 1-5 hours; preferably 2-4 hours.
Wherein the reaction temperature for preparing the intermediate VI is as follows: 0 ℃ to 40 ℃; preferably from 10 ℃ to 20 ℃.
Wherein, the oxidant used for preparing the intermediate VI is potassium permanganate and sodium permanganate; potassium permanganate is preferred.
Wherein, when preparing the intermediate VI, the molar ratio of the intermediate V to the oxidant is 1 (1.0-8.0), preferably: 1:(2.0-4.0).
Further, intermediate five: certain (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester (V) is prepared by the following method:
using glyoxal and hydrazine as starting materials to prepare 1-amino-1H-1, 2,3 triazole (III) through glyoxal dihydrazone (II), stirring the obtained compound III in a reaction solvent uniformly, controlling the temperature for a period of time, then adding (2S,3S) -3-methyl-3-chloromethyl-7-oxo-4-sulfo-1-azabicyclo [3.2.0] heptane-2-formic acid ester (IV) for stirring reaction, controlling the HPLC until the raw material (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-sulfo-1-azabicyclo [3.2.0] heptane-2-formic acid diphenylmethyl ester (V) disappears, cooling to about 0 ℃ after the reaction is completed, stirring, crystallizing for a period of time, filtering, drying under reduced pressure to obtain an intermediate pentakis (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-formic acid ester (V); the reaction formula is as follows:
wherein R shown in the structural formula can be benzhydryl, benzyl and p-nitrobenzyl; preferably benzhydryl.
Wherein, when preparing the intermediate V, the reaction time of the compound III and the compound IV is as follows: 3-8 hours; preferably 4-6 hours.
Wherein, when preparing the intermediate V, the reaction temperature of the compound III and the compound IV is as follows: 20 ℃ to 70 ℃; preferably from 30 ℃ to 50 ℃.
Wherein, when preparing the intermediate V, the molar ratio of the compound IV to the compound III is 1 (1.0-2.0), and preferably: 1:(1.0-1.1).
Wherein, when the intermediate V is prepared, the reaction solvent of the compound III and the compound IV is one of acetonitrile, toluene and xylene; toluene is preferred.
Wherein, when the intermediate V is prepared, the crystallization time of the compound III and the compound IV is as follows: 4-10 hours; preferably 5-7 hours.
The invention has the beneficial effects that:
1. the invention provides a plurality of intermediates for preparing tazobactam and a preparation method thereof, and specifically comprises the following steps: the intermediate penta ((2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid certain ester), the intermediate hexa ((2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-4, 4-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid certain ester) and the intermediate hepta ((2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazole-1-yl) methyl ] -7-oxo-4-sulfo-4, 4-dioxide-1-azabicyclo [3.2.0] heptane-2-formic acid, the preparation method of the intermediate is simple and convenient to operate, mature and reliable, the reaction route is short, the raw materials are easy to obtain, and the intermediate is suitable for large-scale industrial production; and the obtained intermediate has good purity and high yield.
2. The invention provides a new tazobactam preparation method, which is prepared by the reaction of the newly prepared intermediate, has short whole reaction route, lower raw material cost and simple operation, and is suitable for large-scale industrial production; the final product yield of tazobactam is up to more than 90%, and the purity is up to more than 99.0%.
3. In the process of preparing the tazobactam finished product from the intermediate hepta, the invention avoids the use of heavy metal triazazole salt with serious pollution and avoids the condition that a six-membered ring byproduct is easy to appear when cyclization is carried out after azidation. Effectively reduces the pollution discharge pressure and the production cost, is environment-friendly and has better economic benefit.
4. The method for preparing tazobactam has the advantages of mild reaction conditions, simple process, low cost, high yield and high purity, and is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The present invention will be described in further detail with reference to the following examples.
It should be noted that: in the following examples, the HPLC detection instrument may be Shimadzu LC-20A manufactured by Shimadzu corporation, Japan, for example. The calculation method of the chemical purity adopts an area normalization method; the molar yield is calculated as: (moles of product/moles of main raw material). times.100%. The instrument used for mass spectrometric detection was a liquid chromatography mass spectrometer model API 5500 available from AB SCIES, usa. The apparatus used for NMR measurement was an AM 400MHZ NMR spectrometer available from BRUKER. The reagents used in the present invention are commercially available.
Example 1: preparation of glyoxal dihydrazone (II):
2000ml of dichloromethane and 576g (18.000mol) of hydrazine are added into a reaction flask, stirred evenly, cooled to about 0 ℃, and 348g (6.000mol) of glyoxal dissolved in 500ml of dichloromethane is added dropwise, which takes about 1-2 hours. After the dropwise addition, the temperature is slowly raised to 15-20 ℃ and the stirring reaction is continued for 2 hours, the obtained reaction solution is decompressed and desolventized to remove dichloromethane and excessive hydrazine, 492.32g (5.718mol) of oily matter is obtained, the purity is 99.1 percent, and the yield is 95.3 percent.
Example 2: preparation of 1-amino-1H-1, 2,3 triazole (III):
492.32g (5.718mol) of intermediate II and 4000ml of dichloromethane are added into a reaction bottle, the mixture is stirred uniformly, the temperature is controlled to be 20-30 ℃, 994.25g (11.436mol) of manganese dioxide is added in batches, the time is about 1 hour, and the stirring reaction is continued for 1 hour after the addition is finished. Filtration and desolventization under reduced pressure of the filtrate gave 428.39g (5.095mol) of high purity intermediate III as an oil with a purity of 99.3% and a yield of 89.1%.
It should be noted that: the intermediate of the invention, namely the tetra (2S,3S) -3-methyl-3-chloromethyl-7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-carboxylic acid (IV), is a common intermediate in the synthesis of tazobactam, and the synthesis method can refer to the documents of EP0331146 and the like.
Example 3: preparation of (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester (V):
200g (2.379mol) of the intermediate III prepared in example 2 and 3500ml of toluene are added into a reaction bottle and stirred evenly, the temperature is controlled to be between 30 and 40 ℃, 956.14g (2.379mol) of the intermediate III is added, the mixture is stirred for reaction, and the HPLC control is carried out until the raw material (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-formic acid diphenylmethyl ester (V) disappears, which takes about 5 hours. After the reaction is completed, the temperature is reduced to about 0 ℃, the mixture is stirred and crystallized for 5 hours, filtered and dried under reduced pressure at 50 ℃ to obtain 1046.36g (2.153mol) of intermediate V, and the yield is 90.5%.
The detection data of the product obtained by nuclear magnetic resonance and mass spectrometry are as follows:
1H-NMR(400MHz，CDCl3)：＝7.75(s，2H)，7.36-7.38(m，10H)，6.55(s，1H)，4.38(s，1H)，4.24(s，1H)，4.14(d，1H)，3.89(d，1H)，3.27(m，1H)，3.02(m，1H)，2.01(s，2H)，1.43(s，3H)；
13C-NMR(75MHz，CDCl3)：＝168.2，164.9，140.2，140.2，128.2，128.2，128.2，128.2，129.2，129.2，129.2，129.2，126.2，126.2，123.4，123.0，77.9，72.9，62.5，58.3，48.2，46.8，19.3ppm。
example 4: preparation of (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester (V):
219.8g (2.617mol) of the intermediate III prepared in example 2 and 3500ml of toluene are added into a reaction flask and stirred uniformly, the temperature is controlled to be between 30 and 40 ℃, 956.14g (2.379mol) of the intermediate III is added, the mixture is stirred for reaction, and the HPLC control is carried out until the raw material (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-methyl benzoate (V) disappears, which takes about 5 hours. After the reaction is completed, the temperature is reduced to about 0 ℃, the mixture is stirred and crystallized for 5 hours, filtered and dried under reduced pressure at 50 ℃ to obtain 1054.62g (2.170mol) of intermediate V with the yield of 91.2 percent.
The detection data of the product obtained by nuclear magnetic resonance and mass spectrometry are as follows:
1H-NMR(400MHz，CDCl3)：＝7.75(s，2H)，7.36-7.38(m，10H)，6.55(s，1H)，4.38(s，1H)，4.24(s，1H)，4.14(d，1H)，3.89(d，1H)，3.27(m，1H)，3.02(m，1H)，2.01(s，2H)，1.43(s，3H)；
13C-NMR(75MHz，CDCl3)：＝168.2，164.9，140.2，140.2，128.2，128.2，128.2，128.2，129.2，129.2，129.2，129.2，126.2，126.2，123.4，123.0，77.9，72.9，62.5，58.3，48.2，46.8，19.3ppm。
example 5: (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-4, 4-dioxido-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester (VI):
486.00g (1.000mol) of the intermediate V prepared in example 3 and 3000ml of dichloromethane are added into a reaction bottle and stirred uniformly, the temperature is controlled to be 10-20 ℃, 316.00g (2.000mol) of potassium permanganate is added in multiple batches, the time is about 1 hour, after the addition is finished, the reaction is continuously stirred at 10-20 ℃ for 3 hours, filtration is carried out, insoluble solids are removed, the solvent is removed under reduced pressure, and the intermediate VI 459.47g (0.887mol) of oily matter is obtained, and the yield is 88.7%.
The detection data of the product obtained by nuclear magnetic resonance and mass spectrometry are as follows:
1H-NMR(400MHz，CDCl3)：＝7.75(s，1H)，7.38(s，1H)，7.36-7.38(m，10H)，6.53(s，1H)，4.70(t，1H)，4.40(s，1H)，4.09-4.34(d，2H)，3.46(m，1H)，3.21(m，1H)，2.00(s，2H)，1.48(s，3H)；
13C-NMR(75MHz，CDCl3)：＝171.5，168.2，140.2，140.2，129.2，129.2，129.2，129.2，128.2，128.2，128.2，128.2，126.2，126.2，123.4，123.0，80.9，77.9，72.3，66.2，52.1，24.9，10.6ppm。
example 6: (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-4, 4-dioxido-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester (VI):
486.00g (1.000mol) of the intermediate V prepared in example 4 and 3000ml of dichloromethane are added into a reaction bottle and stirred uniformly, the temperature is controlled to be 10-20 ℃, 474.00g (3.000mol) of potassium permanganate is added in multiple batches, the time is about 1 hour, after the addition is finished, the temperature is controlled to be 10-20 ℃, stirring reaction is continued for 3 hours, filtration is carried out, insoluble solid is removed, the solvent is removed under reduced pressure, and the intermediate VI 461.54g (0.891mol) of oily matter is obtained, and the yield is 89.1%.
The detection data of the product obtained by nuclear magnetic resonance and mass spectrometry are as follows:
1H-NMR(400MHz，CDCl3)：＝7.75(s，1H)，7.38(s，1H)，7.36-7.38(m，10H)，6.53(s，1H)，4.70(t，1H)，4.40(s，1H)，4.09-4.34(d，2H)，3.46(m，1H)，3.21(m，1H)，2.00(s，2H)，1.48(s，3H)；
13C-NMR(75MHz，CDCl3)：＝171.5，168.2，140.2，140.2，129.2，129.2，129.2，129.2，128.2，128.2，128.2，128.2，126.2，126.2，123.4，123.0，80.9，77.9，72.3，66.2，52.1，24.9，10.6ppm。
example 7: preparation of (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-4, 4-dioxido-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester (VII):
430g (0.830mol) of the intermediate VI prepared in the example 5, 500ml of water and 1000ml of methanol are added into a reaction bottle, the mixture is stirred uniformly, the temperature is controlled to be about 0 ℃, 57.27g (0.830mol) of sodium nitrite is slowly added, the stirring reaction is carried out for 3 hours after the addition is finished, gas is discharged, and the mixture is directly filtered after the reaction is finished, so that the intermediate VII361.07g (0.774mol) is obtained, the yield is 93.3 percent, and the purity is 98.3 percent.
The detection data of the product obtained by mass spectrometry are as follows: HR-MS (ESI): c23H22N4O5S, molecular weight: 466.51, [ M + H ]]+Measurement values: 467.38.
example 8: preparation of (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazol-1-yl) methyl ] -7-oxo-4-thioxo-4, 4-dioxido-1-azabicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester (VII):
430g (0.830mol) of the intermediate VI prepared in the example 6, 500ml of water and 2000ml of methanol are added into a reaction bottle, the mixture is stirred uniformly, the temperature is controlled to be about 0 ℃, 57.27g (0.830mol) of sodium nitrite is slowly added, after the addition is finished, the stirring reaction is carried out for 3 hours, gas is discharged, and after the reaction is finished, the direct filtration is carried out, so that the intermediate VII358.92g (0.769mol) is obtained, the yield is 92.7%, and the purity is 98.4%.
The detection data of the product obtained by mass spectrometry are as follows: HR-MS (ESI): c23H22N4O5S, molecular weight: 466.51, [ M + H ]]+Measurement values: 467.62.
example 9: preparation of tazobactam:
300g (0.643mol) of the intermediate VII prepared in example 7 and 2000g of m-methylphenol are added into a reaction bottle, evenly stirred, reacted for 2 hours at the temperature of about 50 ℃, and cooled to 30 ℃; adding 5% sodium carbonate aqueous solution 500ml for 3 times, extracting, and mixing the obtained water layers; adding 200ml of ethyl acetate for 3 times, extracting impurities, adjusting the pH of a water layer to about 3-5 by using 1% dilute hydrochloric acid, separating out a product in the water layer, filtering, and drying to obtain 180.78g (0.602mol) of tazobactam product, wherein the yield is 93.6%, the purity is 99.81%, and the maximum single impurity content is 0.058%.
Detection of products obtained by mass spectrometryThe measured data are as follows: HR-MS (ESI): c10H12N4O5S, molecular weight: 300.29, [ M + H ]]+Measurement values: 301.41.
example 10: preparation of tazobactam:
300g (0.643mol) of the intermediate VII prepared in example 8 and 2000g of m-methylphenol are added into a reaction bottle, evenly stirred, reacted for 4 hours at the temperature of about 50 ℃, and cooled to 30 ℃; adding 5% sodium carbonate aqueous solution 500ml for 3 times, extracting, and mixing the obtained water layers; adding 200ml of ethyl acetate every time for 3 times, extracting impurities, adjusting the pH of a water layer to about 3-5 by using 1% dilute hydrochloric acid, separating out a product in the water layer, filtering and drying to obtain 181.68g (0.605mol) of tazobactam product, wherein the yield is 94.1%, the purity is 99.79% and the maximum single impurity is 0.063%.
The detection data of the product obtained by mass spectrometry are as follows: HR-MS (ESI): c10H12N4O5S, molecular weight: 300.29, [ M + H ]]+Measurement values: 301.23.
the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (19)
1. Tazobactam intermediate (2S,3S) -3-methyl-3- [ (1H-1,2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-4, 4-dioxide-1-azabicyclo [3.2.0] heptane-2-carboxylic acid certain ester shown as formula VII, characterized by the following formula:
wherein R is benzhydryl, benzyl or p-nitrobenzyl.
2. Tazobactam intermediate (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazol-1-yl) methyl ] -7-oxo-4-thio-4, 4-dioxido-1-azabicyclo [3.2.0] heptane-2-carboxylic acid certain ester shown in formula VI, characterized by the following formula:
wherein R is benzhydryl, benzyl or p-nitrobenzyl.
3. The tazobactam intermediate (2S,3S) -3-methyl-3- [ (3-amino-2, 3-dihydro-1H-1, 2, 3-triazole-1-yl) methyl ] -7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ester shown as the formula V is characterized by being shown as the following formula:
wherein R is benzhydryl, benzyl or p-nitrobenzyl.
4. A preparation method of a tazobactam intermediate shown in a formula VII is characterized by comprising the following steps:
diazotizing the intermediate shown in the formula VI to prepare a tazobactam intermediate shown in the formula VII; the reaction formula is as follows:
5. the preparation method of tazobactam intermediate represented by the formula VII, which is claimed in claim 4, is characterized by comprising the following steps: dissolving the intermediate shown in the formula VI in a reaction solvent, and reacting for a certain time at controlled temperature; then adding a diazotization reagent, and purifying to obtain the tazobactam intermediate shown in the formula VII.
6. The process for preparing tazobactam intermediate represented by formula VII as claimed in claim 5, wherein the diazotizing agent is sodium nitrite or potassium nitrite.
7. The preparation method of the tazobactam intermediate shown in the formula VII is characterized in that the molar ratio of the compound shown in the formula VI to the diazotization reagent is 1 (1-3).
8. A preparation method of a tazobactam intermediate shown in a formula VI is characterized by comprising the following steps: carrying out oxidation reaction on the intermediate shown in the formula V to obtain a tazobactam intermediate shown in a formula VI; the reaction formula is as follows:
9. the preparation method of the tazobactam intermediate shown in the formula VI according to claim 8, which comprises the following specific steps: dissolving the intermediate shown in the formula V in a reaction solvent, and controlling the temperature to react for a certain time; then adding an oxidant, and purifying to obtain the tazobactam intermediate shown in the formula VI.
10. The method for preparing tazobactam intermediate represented by formula VI as claimed in claim 9, wherein the oxidizing agent is potassium permanganate or sodium permanganate.
11. The method for preparing tazobactam shown in formula VI according to claim 9, wherein the molar ratio of the intermediate shown in formula V to the oxidant is 1 (1.0-8.0).
12. A preparation method of a tazobactam intermediate shown in a formula V is characterized by comprising the following steps:
using glyoxal and hydrazine as starting materials to prepare 1-amino-1H-1, 2,3 triazole as a compound shown in a formula III through glyoxal dihydrazone as shown in a formula II, controlling the temperature of the compound shown in the formula III in a reaction solvent for a certain time, and reacting the compound with (2S,3S) -3-methyl-3-chloromethyl-7-oxo-4-thio-1-azabicyclo [3.2.0] heptane-2-formic acid as a compound shown in a formula IV to prepare a tazobactam intermediate as shown in a formula V; the reaction formula is as follows:
13. the method for preparing tazobactam of formula V as claimed in claim 12, wherein the reaction solvent is one of acetonitrile, toluene and xylene.
14. The method for preparing tazobactam of formula V according to claim 12, wherein the molar ratio of the intermediate of formula IV to the compound of formula III is 1 (1.0-2.0).
15. The preparation method of tazobactam is characterized by comprising the following steps:
carrying out deprotection reaction on the intermediate shown in the formula VII to obtain tazobactam shown in the formula I; the reaction formula is as follows:
16. the tazobactam preparation method according to claim 15, comprising the following specific steps: dissolving an intermediate shown as a formula VII in a reaction solvent, and controlling the temperature to react for a certain time; purifying to obtain the tazobactam product.
17. The method for preparing tazobactam according to claim 16, wherein the reaction solvent is one of m-methylphenol, p-methylphenol and methoxybenzene.
18. The method for preparing tazobactam according to claim 16, wherein the volume ratio of the intermediate represented by the formula VII to the reaction solvent is 1 (3-30).
19. Tazobactam prepared by the preparation method of any one of claims 15 to 18.
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| CN113861122A (en) * | 2021-11-17 | 2021-12-31 | 上海皓元医药股份有限公司 | Synthesis method for preparing 1H-1,2, 3-triazole by continuous flow |
| CN113861122B (en) * | 2021-11-17 | 2024-04-26 | 上海皓元医药股份有限公司 | Synthesis method for preparing 1H-1,2, 3-triazole by continuous flow |
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| CN1136809A (en) * | 1994-09-01 | 1996-11-27 | 大鹏药品工业株式会社 | Process for producing 1-amino-1,2,3-triazole |
| CN101434610A (en) * | 2008-12-19 | 2009-05-20 | 齐鲁天和惠世制药有限公司 | Penam iodide, preparation and use thereof |
| CN108164550A (en) * | 2018-01-23 | 2018-06-15 | 常州红太阳药业有限公司 | A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application |
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| CN1136809A (en) * | 1994-09-01 | 1996-11-27 | 大鹏药品工业株式会社 | Process for producing 1-amino-1,2,3-triazole |
| CN101434610A (en) * | 2008-12-19 | 2009-05-20 | 齐鲁天和惠世制药有限公司 | Penam iodide, preparation and use thereof |
| CN108164550A (en) * | 2018-01-23 | 2018-06-15 | 常州红太阳药业有限公司 | A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113861122A (en) * | 2021-11-17 | 2021-12-31 | 上海皓元医药股份有限公司 | Synthesis method for preparing 1H-1,2, 3-triazole by continuous flow |
| CN113861122B (en) * | 2021-11-17 | 2024-04-26 | 上海皓元医药股份有限公司 | Synthesis method for preparing 1H-1,2, 3-triazole by continuous flow |
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