CN109970784A - A method for preparing carbapenem antibiotic intermediate 4-BMA - Google Patents

Abstract

The invention discloses a method for preparing a carbapenem antibiotic intermediate 4-BMA, which comprises the following steps: in the presence of a solvent and a metal, the compound of the following formula A is contacted with the compound of the following formula B to obtain the compound of the following formula C; The compound of the formula C is reacted with ozone to generate the compound of the following formula D; the compound of the formula D is subjected to alkaline hydrolysis to obtain the intermediate 4-BMA; wherein, in the compound of the formula B, X is a halogen. The preparation method of the invention has short reaction route, easy-to-obtain raw materials, high yield and is suitable for large-scale production.

Description

A method for preparing carbapenem antibiotic intermediate 4-BMA

technical field

The invention belongs to the technical field of synthesizing carbapenem antibiotic intermediates. Specifically, the invention discloses a preparation method of carbapenem antibiotic intermediate 4-BMA.

Background technique

Carbapenem antibiotics are a class of β-lactam antibiotics with broad-spectrum antibacterial activity and good chemical stability, and are often used clinically for severe infections. Carbapenem antibiotics that have been commercialized include meropenem, doripenem, biapenem, imipenem, panipenem, etc. They have significant antibacterial effects against many drug-resistant bacteria and can be very effective The ability to stabilize β-lactamase and inhibit the interference of β-lactamase has received extensive attention and in-depth research. The research on such compounds has made great progress, but it is still of great significance to develop a high-yield, easy-to-operate intermediate synthesis process.

(3R,4R)-3-[(1R)-tert-Butyldimethylsiloxyethyl]-4-[(1R)-1-methyl-1-carboxyethyl]-2-azetidinine -2-keto (abbreviated as 4-BMA) is the key intermediate for the synthesis of this type of carbapenem, and most of its synthetic methods and routes have been reported so far based on 4-acetoxyazetidinone (abbreviated as 4- AA) is raw material, constructs chiral methyl on the C-4 position of 4-AA, comprises the following methods:

(1) Asymmetric hydrogenation of terminal alkenes or terminal epoxy groups, this method generally has the disadvantages of high cost, long route, difficulty and low yield;

(2) After introducing the dimethylallylsilane group, carry out intramolecular Sakurai reaction, this method has the disadvantages of low yield and difficult production control;

(3) Reformatsky reaction in which prosthetic groups such as enolate or α-bromopropionamide with an inducing group participate. This method has the advantage of fewer steps but low yield.

In summary, in view of the problems existing in the existing technical routes, it is an urgent task to develop a synthetic 4-BMA route with high yield, easy operation and suitable for large-scale production.

Contents of the invention

In view of this, the present invention provides a method for preparing the carbapenem antibiotic intermediate 4-BMA, which has the advantages of easy operation, high yield, environmental protection and suitable for large-scale production.

In order to realize the object of the invention, the present invention adopts following technical scheme:

The present invention prepares the method for carbapenem antibiotic intermediate 4-BMA, comprises the steps:

(1) In the presence of a solvent and a metal, the compound of the following formula A is contacted with the compound of the following formula B to obtain the compound of the following formula C;

(2) reacting the compound of the formula C with ozone to generate the compound of the following formula D;

(3) the compound of formula D is subjected to alkaline hydrolysis to obtain the intermediate 4-BMA;

Wherein, X in the compound of formula B is halogen.

In the preparation method of the present invention, the temperature of the reaction described in step (1) is 10～15°C

In the present invention, the compound of formula B is an α-halogenated amide with an inducing group, which can react with the compound of formula A in the presence of an active metal and an inert solvent; in some specific embodiments Among them, in the compound structure of formula B shown in the above reaction equation, X is selected from Cl, Br or I, and the metal is selected from zinc, magnesium or indium; the solvent can be selected from tetrahydrofuran.

In some preferred embodiments, the compound of formula A and the compound of formula B can be dissolved respectively to obtain A solution and B solution; at the same time, the metal is added to the solvent to form a suspension, and then to the obtained suspension Add the B solution and the A solution in turn to react; in some specific implementations, the temperature is controlled at 15-25°C when adding the B solution, and in some specific implementations, the A solution and the B solution are prepared The solvent used for the solution may also be selected from tetrahydrofuran.

In some specific embodiments, the molar ratio of the compound of formula A to the compound of formula B added in step (1) is 1:1 to 1:3, for example, 1:1.1; the metal and The molar ratio of the compound of formula A is 1:1-5:1, for example, 2.5:1.

In the preparation method of the present invention, the compound of formula A is the key intermediate 4-AA precursor of β-lactam drugs, namely (3R,4R)-3-[(1R)-tert-butyldimethyl Siloxyethyl]-4-acetoxy-1-p-methoxyphenyl-2-azetidin-2-one.

In step (1) of the present invention, there are unreacted metals, compounds of formula B and other small molecular impurities in the reaction system after the reaction is complete. In some preferred embodiments, the reaction obtained by step (1) The liquid is subjected to impurity-removing post-treatment, specifically, the reaction liquid is suction-filtered to obtain a filtrate, and methyl tert-butyl ether is added to the filtrate to extract the product in the filtrate, which is then washed with water and saturated brine in sequence, left to stand, The organic layer was obtained by layering, and the viscous compound of formula C was directly obtained after the organic layer was concentrated, which could be directly used in the next reaction without purification.

In step (2) of the present invention, use solvent ethanol, acetonitrile, acetone, methanol or isopropanol to dissolve the compound of formula C obtained after the above concentration, and continuously feed into the above solution at -60～-20°C The ozone is reacted, more preferably at -30～-20°C, -40～-30°C; when the compound of formula C is completely reacted, the introduction of ozone is stopped. The ozone used above can be obtained by a technical method known to those skilled in the art, for example, it is produced by electrolysis of an ozone generator.

In some specific embodiments, if it is detected that the compound of formula C in the reaction system disappears completely, it is considered that the reaction step (2) is completed, and the temperature of the system is raised to -15～0°C, and an alkaline solution is added thereto and the temperature is controlled at A hydrolysis reaction is carried out at 0-10°C to obtain the carbapenem antibiotic intermediate 4-BMA; in some specific embodiments, the above-mentioned alkaline solution is selected from sodium hydroxide aqueous solution, sodium carbonate aqueous solution or bicarbonate The sodium aqueous solution, the mass percent concentration of the alkaline solution is 1-20%, for example, 5%, 10%.

In some preferred embodiments, after the alkaline hydrolysis reaction is carried out completely, use the reducing solution to remove the residual oxidant in the system, as well known to those skilled in the art, starch potassium iodide test paper can be used to detect whether the oxidizing substance exists; in some specific In the embodiment of the present invention, use starch potassium iodide test paper to detect whether oxidizing agent is completely removed to the system that removes residual oxidizing agent, if not, can continue to add reducing solution in the system until detecting that oxidizing agent is completely consumed.

In a specific embodiment, a reducing solution is added to the reaction solution until the starch potassium iodide test paper does not change color, then water is added thereto and filtered, and the water layer is obtained after standing; then the pH value of the water layer is adjusted to 2.0 to 3.0 The crude product was precipitated, and the intermediate 4-BMA was obtained after the crude product was suction filtered, washed with water and dried. The above-mentioned reducing solution can be selected from sodium sulfite aqueous solution, and its mass percent concentration can be 5-20%, preferably 15%.

In the present invention, conventional technical methods in the art can be used to detect the extent of the reaction. In some specific embodiments, the method of the present invention uses thin layer chromatography (abbreviated as TLC) in the preparation process to detect the reaction. Whether there are reactants remaining in the system, and then the degree of reaction can be known.

Adopt above-mentioned technical scheme, have following technical effect:

The invention provides a method for preparing carbapenem antibiotic intermediate 4-BMA, which uses the precursor (3R,4R)-3-[(1R)-tert-butyldimethylsilyl of 4-AA Oxyethyl]-4-acetoxy-1-p-methoxyphenyl-2-azetidin-2-one is used as the reaction raw material, without going through 4-AA, the carbapenem prepared by the inventive method The antibiotic-like intermediate 4-BMA has only three steps of reaction, the reaction route is short, the raw materials used are easily available, the yield is high, and it is suitable for large-scale production.

At the same time, the reaction liquid containing the compound of formula D obtained by ozonation in the present invention does not need post-treatment such as separation, and the target product can be obtained by alkaline hydrolysis of the system, which reduces the use of organic solvents, reduces the waste liquid treatment process, and conforms to the principles of green chemistry. idea.

Detailed ways

In order to better understand the technical solution of the present invention, the content of the present invention will be further described below in conjunction with the examples, but the content of the present invention is not limited only to the following examples.

The raw materials used in the examples are conventional raw materials in the field, and the purity specification used is chemically pure.

The compound represented by formula A used in the following examples: Jiangsu Hankuo Biological Co., Ltd., chemically pure, content 98%;

Compound represented by formula B: Jiangsu Hankuo Biological Co., Ltd., chemically pure, content 98%;

The following embodiments of the present invention adopt following detection method:

(1) TCL detection method: the developer used is a mixed solvent of petroleum ether/ethyl acetate with a volume ratio of 1:1;

(2) Purity assay method: adopt HPLC to measure the purity of product;

(3) Yield determination method: the output of actual product/theoretical product × 100%;

(4) Structural characterization method: NMR was used to characterize the structure of the product.

Example 1

(1) Add 45g of zinc powder and 350mL of THF to the reaction flask in sequence, stir to form a suspension, add 65g of trimethylchlorosilane dropwise to the suspension at room temperature, and keep warm for 1h;

110 g of the compound of formula A was dissolved in 140 mL of THF to obtain a solution of A;

110 g of the compound of formula B (where X is Br) was dissolved in 140 mL of THF to obtain a B solution;

Add the above B solution dropwise to the suspension, control the temperature between 15-25°C, complete the dropwise addition for 1 hour, and carry out the reaction under heat preservation until the compound of formula B completely disappears as monitored by TLC; then, cool the system down to 10-20°C Between 15°C, add the above-mentioned solution A dropwise, and after 1 hour, the dropwise addition is completed, and the reaction is continued until the compound of formula A as monitored by TLC disappears completely;

Suction filter the reaction liquid obtained from the above reaction, add 150 mL of methyl tert-butyl ether to the filtrate, wash with 300 mL of water and 300 mL of saturated brine, and then concentrate the organic phase to dryness. Obtain 165g formula C compound crude product;

(2) Dissolve 82.5g of the crude product of the above-mentioned compound of formula C in 415mL of ethanol to obtain an ethanol solution of the compound of formula C, continuously pass ozone into it, control the temperature of the reaction system at -30～-20°C, and monitor the compound of formula C by TLC Completely disappear, stop feeding ozone;

(3) Raise the temperature of the reaction solution obtained in the above step (2) to -15～0°C, and add 100mL of 5% sodium hydroxide aqueous solution to it, control the temperature at 0～10°C for 2～5h, until TLC Monitor the complete disappearance of compound D;

Then, in the reaction solution obtained above, drip an aqueous solution of sodium sulfite with a mass percent concentration of 15% until the starch-potassium iodide test paper does not change color; continue to add 300 mL of water therein, filter, and stand to obtain a water layer. The pH of the aqueous layer was adjusted to 2.5 with hydrochloric acid under the range of 2.5, and a white solid was precipitated; suction filtration, washing of the filter cake with water, and drying gave 48.5 g of intermediate 4-BMA.

The total yield was calculated to be 57.6%, and the prepared intermediate 4-BMA was a white powder. The purity of the intermediate 4-BMA was 98.6% as detected by HPLC.

NMR (CD ₃ OD) data are as follows:

¹ H-NMR (400MHz): δ4.23(m,1H),3.80(m,1H),3.00(dd,1H),2.58(m,1H),1.22(d,3H),1.18(d,3H ),0.88(s,9H),0.07(s,6H).

Example 2

(1) Add 45g of zinc powder and 350mL of THF to the reaction flask in sequence, stir to form a suspension, add 65g of trimethylchlorosilane dropwise to the suspension at room temperature, and keep warm for 1h;

110 g of the compound of formula A was dissolved in 140 mL of THF to obtain a solution of A;

96g of the compound of formula B (wherein X is Cl) was dissolved in 140mL of THF to obtain a B solution;

Add the above B solution dropwise to the suspension, control the temperature between 15-25°C, complete the dropwise addition for 1 hour, and carry out the reaction under heat preservation until the compound of formula B completely disappears as monitored by TLC; then, cool the system down to 10-20°C Between 15°C, add the above-mentioned solution A dropwise, and after 1 hour, the dropwise addition is completed, and the reaction is continued until the compound of formula A as monitored by TLC disappears completely;

Suction filter the reaction liquid obtained from the above reaction, add 150 mL of methyl tert-butyl ether to the filtrate, wash with 300 mL of water and 300 mL of saturated brine, and then concentrate the organic phase to dryness. Obtain 158g formula C compound crude product;

(2) Dissolve 82.5g of the crude compound of the above formula C in 415mL of acetonitrile to obtain an acetonitrile solution of the compound of formula C, continuously pass ozone into it, control the temperature of the reaction system at -30～-20°C, and monitor the compound of formula C by TLC Completely disappear, stop feeding ozone;

(3) Raise the temperature of the reaction solution obtained in the above step (2) to -15～0°C, and add 100mL of 5% sodium hydroxide aqueous solution to it, control the temperature at 0～10°C for 2～5h, until TLC Monitor the complete disappearance of compound D;

Then, in the reaction solution obtained above, drip an aqueous solution of sodium sulfite with a mass percentage concentration of 15% until the starch-potassium iodide test paper does not change color; after adding 300 mL of water to it, filter, and the filtrate is washed twice with ethyl acetate, and left to separate The aqueous layer was obtained; the pH of the aqueous layer was adjusted to 2.5 with hydrochloric acid at a temperature range of 10-20° C., and a white solid was precipitated; suction filtration, the filter cake was washed with water and dried to obtain 49.7 g of intermediate 4-BMA.

The total yield was calculated to be 59.0%; the purity of the intermediate 4-BMA was 98.5% as detected by HPLC.

The nuclear magnetic data of the intermediate 4-BMA prepared in Example 2 is consistent with the nuclear magnetic data of the intermediate 4-BMA prepared in Example 1.

Example 3

(1) Add 48g of indium powder and 350mL THF to the reaction flask in sequence, stir to form a suspension, add 65g of trimethylchlorosilane dropwise to the above suspension at room temperature, and keep warm for 1h;

110 g of the compound of formula A was dissolved in 140 mL of THF to obtain a solution of A;

96g of the compound of formula B (wherein X is Cl) was dissolved in 140mL of THF to obtain a B solution;

Add the above B solution dropwise to the suspension, control the temperature between 15-25°C, complete the dropwise addition for 1 hour, and carry out the reaction under heat preservation until the compound of formula B completely disappears as monitored by TLC; then, cool the system down to 10-20°C Between 15°C, add the above-mentioned solution A dropwise, and after 1 hour, the dropwise addition is completed, and the reaction is continued until the compound of formula A as monitored by TLC disappears completely;

Suction filter the reaction liquid obtained from the above reaction, add 150 mL of methyl tert-butyl ether to the filtrate, wash with 300 mL of water and 300 mL of saturated brine, and then concentrate the organic phase to dryness. Obtain 147g crude product of formula C compound;

(2) Dissolve 82.5 g of the crude compound of the above formula C in 415 mL of acetone to obtain an acetone solution of the compound of formula C, continuously pass ozone into it, control the temperature of the reaction system at -40 to -30 ° C, and monitor the compound of formula C by TLC Completely disappear, stop feeding ozone;

(3) Raise the temperature of the reaction solution obtained in the above step (2) to -15～0°C, and add 50 mL of 10% aqueous sodium hydroxide solution to it, and control the temperature to react at 0～10°C for 2～5h to TLC Monitor compound D for complete disappearance;

Then, in the reaction solution obtained above, drip an aqueous solution of sodium sulfite with a mass percentage concentration of 15% until the starch-potassium iodide test paper does not change color; after adding 300 mL of water to it, filter, and the filtrate is washed twice with ethyl acetate, and left to separate The aqueous layer was obtained; the pH of the aqueous layer was adjusted to 2.5 with hydrochloric acid at a temperature range of 10-20° C., and a white solid was precipitated; the filter cake was filtered with suction, washed with water and dried to obtain 43 g of intermediate 4-BMA.

The total yield was calculated to be 51%; the purity of the intermediate 4-BMA was 97.1% as detected by HPLC.

The nuclear magnetic data of the intermediate 4-BMA prepared in Example 3 is consistent with the nuclear magnetic data of the intermediate 4-BMA prepared in Example 1.

Example 4

(1) 18g magnesium powder and 350mL THF were successively added to the reaction flask, stirred to form a suspension, 65g of trimethylchlorosilane was added dropwise to the above-mentioned suspension at room temperature, and incubated for 1h;

110 g of the compound of formula A was dissolved in 140 mL of THF to obtain a solution of A;

110 g of the compound of formula B (where X is Br) was dissolved in 140 mL of THF to obtain a B solution;

Add the above B solution dropwise to the suspension, control the temperature between 15-25°C, complete the dropwise addition for 1 hour, and carry out the reaction under heat preservation until the compound of formula B completely disappears as monitored by TLC; then, cool the system down to 10-20°C Between 15°C, add the above-mentioned solution A dropwise, and after 1 hour, the dropwise addition is completed, and the reaction is continued until the compound of formula A as monitored by TLC disappears completely;

Suction filter the reaction liquid obtained from the above reaction, add 150 mL of methyl tert-butyl ether to the filtrate, wash with 300 mL of water and 300 mL of saturated brine, and then concentrate the organic phase to dryness. Obtain 166.5g crude product of formula C compound;

(2) Dissolve 82.5 g of the crude compound of the above formula C in 415 mL of acetone to obtain an acetone solution of the compound of formula C, continuously pass ozone into it, control the temperature of the reaction system at -40 to -30 ° C, and monitor the compound of formula C by TLC Completely disappear, stop feeding ozone;

(3) Raise the temperature of the reaction solution obtained in the above step (2) to -15~0°C, and add 50mL of 10% sodium hydroxide aqueous solution to it, and react at 0~10°C for 2~5h under temperature control, until TLC Monitor the complete disappearance of compound D;

Then, in the reaction solution obtained above, drip an aqueous solution of sodium sulfite with a mass percentage concentration of 15% until the starch-potassium iodide test paper does not change color; after adding 300 mL of water to it, filter, and the filtrate is washed twice with ethyl acetate, and left to separate The aqueous layer was obtained; the pH of the aqueous layer was adjusted to 2.5 with hydrochloric acid at a temperature range of 10-20° C., and then a white solid was precipitated; suction filtered, the filter cake was washed with water and dried to obtain 41.1 g of intermediate 4-BMA.

The total yield was calculated to be 48.8%, and the purity of the intermediate 4-BMA was 96.4% as detected by HPLC.

The nuclear magnetic data of the intermediate 4-BMA prepared in Example 4 is consistent with the nuclear magnetic data of the intermediate 4-BMA prepared in Example 1.

Claims (10)

1. a kind of method for preparing carbapenem antibiotic intermediate 4-BMA, described method includes following steps:

(1) it in the presence of solvent and metal, such as Formula A EMI and such as following formula B compound haptoreaction, obtains such as following formula Cization Close object；

(2) the formula C compound and ozone reaction are generated into such as following formula D compound；

(3) the formula D compound described in obtains the intermediate 4-BMA through basic hydrolysis；

Wherein, X is halogen in the formula B compound.

2. the method according to claim 1, wherein the temperature of reaction described in step (1) is 10~15 DEG C.

3. according to the method described in claim 2, it is characterized in that, in step (1), the formula A compound and the formula B The molar ratio of compound is 1:1~1:3；The metal and the formula A compound mole ratio are 1:1~5:1.

4. according to the method described in claim 3, it is characterized in that, X is selected from Cl, Br in the structure of the formula B compound Or I.

5. method according to claim 1-4, which is characterized in that metal described in step (1) is selected from zinc, magnesium Or indium, the solvent are selected from tetrahydrofuran；

The formula A compound is dissolved using tetrahydrofuran, obtains solution A；The formula B compound is used into tetrahydrofuran Dissolution, obtains B solution；

The metal is added into the solvent, forms suspension, then sequentially adds the B into the suspension Solution, the solution A carry out the reaction.

6. according to the method described in claim 5, it is characterized in that, will be obtained after the progress completely of reaction described in step (1) Reaction solution filtered to obtain filtrate, remove and obtain the formula C compound after the impurity in the filtrate；

Preferably, methyl tertiary butyl ether(MTBE) is added in the filtrate of Xiang Suoshu, then it is successively used to water and saturated common salt water washing, it is quiet It sets, be layered and obtain organic layer, the formula C compound will be obtained after organic layer concentration.

7. method according to claim 1-6, which is characterized in that the temperature of reaction described in step (2) be- 60~-20 DEG C, preferably -30~-20 DEG C.

8. the method according to the description of claim 7 is characterized in that in step (2), after the formula C compound is dissolved, It is passed through ozone thereto and carries out the reaction；

Wherein, the solvent for dissolving the formula C compound is selected from ethyl alcohol, acetonitrile, acetone, methanol or isopropanol.

9. according to the method described in claim 8, it is characterized in that, after formula C compound fully reacting described in step (2), Step (2) obtained reaction solution is warming up to -15~0 DEG C and alkaline solution is added thereto and controls temperature at 0~10 DEG C It is hydrolyzed；

Wherein, the alkaline solution is selected from sodium hydrate aqueous solution, aqueous sodium carbonate or sodium bicarbonate aqueous solution, described The mass percent concentration of alkaline solution is 1~20%.

10. according to the method described in claim 9, it is characterized in that, reaction described in step (3) carry out completely after, will be anti- Reaction solution after answering completely is cleaned, is dried to obtain the intermediate 4-BMA；

Preferably, it is non-discolouring to starch-kalium iodide test paper that reducing solution is added into the reaction solution after fully reacting；Again to it In plus water after be filtered, water layer is obtained after standing；Then the pH value of the water layer is adjusted to crude product is precipitated after 2.5~3.0, institute It states crude product and obtains the intermediate 4-BMA after suction filtration, washing, drying.