阅读说明：本技术 阿维巴坦中间体(2s,5s)-n-保护基-5-羟基-2-甲酸哌啶的合成方法 (synthetic method of abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate ) 是由 王文宽 师军寿 颜连忠 郑长胜 杨庆坤 李卓华 于 2019-08-28 设计创作，主要内容包括：本发明公开了一种阿维巴坦中间体(2S,5S)-N-保护基-5-羟基-2-甲酸哌啶的合成方法。本发明以N-保护的-L-焦谷氨酸酯(SM)为起始原料,通过三甲基碘化亚砜增碳开环,酸作用下卤代,高选择性还原,酸催化下成内酯环,在碱作用下关哌啶环,水解共6步反应得到(2S,5S)-N-保护基-5-羟基-2-甲酸哌啶。该合成方法的反应条件温和,操作简便,杂质易于控制,收率稳定。所用试剂价格低廉,有效降低成本,对环境友好,适合工业化生产。<Image he="209" wi="700" file="DDA0002181896520000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(the invention discloses a synthesis method of an avibactam intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate. The invention takes N-protected-L-pyroglutamic acid ester (SM) as a starting material, and obtains (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate through 6 steps of reactions of recarburization and ring opening by trimethyl sulfoxide iodide, halogenation under the action of acid, high-selectivity reduction, lactone ring formation under the catalysis of acid, piperidine ring closure under the action of alkali and hydrolysis. The synthesis method has the advantages of mild reaction conditions, simple and convenient operation, easy control of impurities and stable yield. The used reagent has low price, effectively reduces the cost, is environment-friendly and is suitable for industrial production.)

1. a synthetic method of an avibactam intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate is characterized by comprising the following steps:

(1) Taking N-protected-L-pyroglutamic acid ester as a starting material, carrying out ring opening in the presence of an alkaline reagent, and increasing a carbon chain by trimethyl sulfoxide iodide to obtain a compound II;

(2) carrying out halogenation reaction on the compound II and a halogenating reagent under the action of acid to obtain a compound III;

(3) reducing the compound III by borane under the catalysis of a chiral ligand to obtain a compound IV with an S configuration;

(4) The compound IV forms a lactone ring under the catalysis of acid to obtain a compound V;

(5) The compound V is subjected to piperidine ring base under the action of alkali to obtain a compound VI;

(6) hydrolyzing the compound VI under the action of alkali to obtain (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate;

Wherein the content of the first and second substances,

The protective group R is tert-butyloxycarbonyl, benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, phenoxycarbonyl, allyloxycarbonyl or trifluoroacetyl;

R₁: any one of an alkyl group having 1 to 6 carbon atoms and an aralkyl group having 7 to 11 carbon atoms;

X: a halogen.

2. the method for synthesizing the intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate of avibactam according to claim 1,

The protective group R is tert-butyloxycarbonyl or benzyloxycarbonyl;

R₁: methyl, ethyl, tert-butyl or benzyl;

X: chlorine, bromine, iodine.

3. The method for synthesizing the (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate as an intermediate of avibactam according to claim 1, wherein the chiral ligand is (R) -2-methyl-CBS-oxazaborolidine.

4. The method for synthesizing the abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate according to claim 1, wherein the basic reagent used in the step (1) is potassium tert-butoxide, sodium tert-butoxide or sodium hydride; the reaction solvent is one or a mixture of dimethyl sulfoxide, 2-methyltetrahydrofuran and tetrahydrofuran.

5. the method for synthesizing abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-carboxylic acid piperidine as claimed in claim 1, wherein the halogenating agent used in step (2) is lithium chloride, 1, 4-dioxane solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, dimethyl sulfoxide solution of hydrogen chloride, lithium bromide, acetic acid solution of hydrogen bromide, hydrogen iodide, sodium iodide or potassium iodide; the acid is sulfuric acid, methanesulfonic acid or ethanesulfonic acid; the reaction solvent is one or more of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, 1, 4-dioxane, ethyl acetate, isopropyl acetate and acetone.

6. the method for synthesizing abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate according to claim 1, wherein the reaction solvent (3) is one or more of tetrahydrofuran, toluene, dichloromethane, ethyl acetate, 1, 4-dioxane and methyl tert-butyl ether.

7. The method for synthesizing abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-carboxylic acid piperidine as claimed in claim 1, wherein the acid used in step (4) is p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, hydrogen chloride in tetrahydrofuran solution, hydrogen chloride in toluene solution, hydrogen chloride in 1,4 dioxane solution or hydrogen chloride in ethyl acetate solution; the reaction solvent is one or more of toluene, acetonitrile, tetrahydrofuran, N-dimethyl amide, N-dimethyl acetamide, 1, 4-dioxane or ethyl acetate.

8. The method for synthesizing abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-carboxylic acid piperidine as claimed in claim 1, wherein the base used in step (5) is N, N-diisopropylethylamine, pyridine, 2-methylpyridine, 4-dimethylaminopyridine, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate; the reaction solvent is one or more mixed solvents of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, ethyl acetate or acetonitrile.

9. the method for synthesizing abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate according to claim 1, wherein the base used in step (6) is lithium hydroxide, sodium hydroxide or potassium hydroxide; the reaction solvent is one or more mixed solvents of ethyl acetate, isopropyl acetate, methanol, ethanol, 1-propanol, 1-butanol, tert-butyl methyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone and acetonitrile.

10. the method for synthesizing the abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate according to any one of claims 1 to 9,

(1) Adding potassium tert-butoxide and trimethyl sulfoxide iodide into a mixed solvent of tetrahydrofuran and dimethyl sulfoxide, cooling to-15-10 ℃, and dropwise adding a tetrahydrofuran solution of N-protected-L-pyroglutamic acid ester; carrying out heat preservation reaction, and carrying out post-treatment after the reaction to obtain a compound II;

(2) Taking tetrahydrofuran as a solvent, and adding a compound II and lithium bromide or lithium chloride under stirring; cooling to-10-0 ℃, dropwise adding a tetrahydrofuran solution of methanesulfonic acid, and reacting for 0.5-2 h under heat preservation; slowly heating to 20-35 ℃ for heat preservation reaction; after the reaction is finished, carrying out post-treatment to obtain a compound III;

(3) Dissolving (R) -2-methyl-CBS-oxazaborolidine in toluene solution in tetrahydrofuran, adding borane in tetrahydrofuran solution at-10-0 ℃, and reacting for 0.5-1.5 h under heat preservation; dripping a tetrahydrofuran solution of a compound III, and keeping the temperature of-5-0 ℃ for reaction after dripping; after the reaction is finished, carrying out post-treatment to obtain a compound IV;

(4) Dissolving a compound IV in toluene, adding p-toluenesulfonic acid, and controlling the temperature to be 60-70 ℃ for reaction; after the reaction is finished, carrying out reduced pressure concentration to obtain a compound V;

(5) Dissolving the compound V in N, N-dimethylformamide, adding cesium carbonate, and stirring for reaction; after the reaction is finished, carrying out post-treatment to obtain a compound VI;

(6) Dissolving the compound VI in tetrahydrofuran, dropwise adding a lithium hydroxide aqueous solution at room temperature, and stirring for reaction; and after the reaction is finished, carrying out post-treatment to obtain a target product.

Technical Field

the invention belongs to the field of drug synthesis, and particularly relates to a synthetic method of an avibactam intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate.

Background

Abamebactam (Avibactam, NXL-104) belongs to a diazabicyclooctanone compound and is a novel beta-lactamase inhibitor in the current market. (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate and derivatives thereof (such as (2S,5S) -N-protecting group-5-hydroxy piperidine-2-ethyl formate) are important intermediates of the compounds, and the compounds have two chiral centers on the structure, are very difficult to synthesize and can be obtained by generally complicated synthesis steps. Since the price of the compound is expensive, the cost of the drug using the compound as a raw material is increased, and a new method for preparing the compound needs to be developed.

document 1: tetrahedron letters, vol.29, no,19, pp: 2231-. The diazomethane is used in the route, so the method has high danger and harsh reaction conditions, and is not beneficial to industrial production.

Document 2: tetrahedron asymmetry 17(2006),2479 and 2486 and document 3: mol, biosyst, 2011,7,1564-1575 reports that L-hydroxyproline is used as a starting material to protect N in proline, oxidize hydroxyl into ketone, esterify carboxylic acid, increase ring with boron trifluoride diethyl etherate, remove 4-ester group of pyridine ring, reduce and hydrolyze to obtain N-benzyloxycarbonyl-5-hydroxy-2-piperidine formate. The 4-position ester group, the 5-position carbonyl group and the 4-position carbonyl group exist in the ring increasing step of the route, and the 5-position ester group brings difficulty to the purification of a sample. In the reduction step, the R and S configuration at the 5-position exists, silica gel is needed for column purification in order to remove isomer impurities, and according to the record of patent CN 104662001A, the 2-position ester group or carboxylic acid and the 5-position hydroxyl are lactonized and purified in an alcohol solvent, so that the purification problem of the step can be solved, the column purification operation is avoided, and the single configuration compound is obtained. But the total yield is less than 7 percent, the cost is high, and the method is not suitable for industrial production.

patents US20140275001, WO2010/126820 and the like disclose that N-tert-butoxycarbonyl-L-pyroglutamic acid ester is used as a starting material, a carbon chain is added by opening a ring of trimethyl sulfoxide iodide, an iridium catalyst is used for ring closure, and sodium borohydride is reduced to obtain an S-configuration compound. The synthetic route is shown below. The method uses an iridium catalyst, is expensive, requires anhydrous and anaerobic conditions for reaction, and can not effectively remove the introduced iridium. In the reduction step, the reaction temperature is-40 ℃, the requirement on equipment is high, and the energy consumption is high. Therefore, the route is still not completely industrially produced.

In conclusion, the method for synthesizing the (2S,5S) -N-protecting group-5-hydroxy-2-formic acid piperidine analogue reported in the literature has obvious defects, and the difficulty lies in the construction of the piperidine hexahydric acid. Therefore, there is a need to develop a method for industrially producing piperidine (2S,5S) -N-protecting group-5-hydroxy-2-carboxylate.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a synthetic method of an avibactam intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate. The invention takes N-protected-L-pyroglutamic acid ester (SM) as a starting material, and obtains (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate through 6 steps of reactions of recarburization and ring opening by trimethyl sulfoxide iodide, halogenation under the action of acid, high-selectivity reduction, lactone ring formation under the action of acid catalysis, piperidine ring closing under the action of alkali and hydrolysis, wherein the synthetic route is shown as follows. The reaction condition is mild, the operation is simple and convenient, the impurities are easy to control, and the yield is stable. The used reagent has low price, effectively reduces the cost, is environment-friendly and is suitable for industrial production.

wherein the content of the first and second substances,

R protecting groups are t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl, ethyloxycarbonyl, phenoxycarbonyl, allyloxycarbonyl, trifluoroacetyl and equivalents thereof known to those skilled in the art; preferred examples thereof include a tert-butoxycarbonyl group (Boc) and a benzyloxycarbonyl group (Cbz), and more preferred is a tert-butoxycarbonyl group (Boc) which is industrially inexpensive and easily detachable.

R₁: alkyl group having 1 to 6 carbon atoms (including primary, secondary and tertiary alkyl groups), aralkyl group having 7 to 11 carbon atoms, such as benzyl group,1-phenylethyl, 1-phenylpropyl, and the like. Methyl, ethyl, tert-butyl and benzyl are preferred, and ethyl is more preferred.

X: halogen is preferably chlorine, bromine or iodine, and more preferably bromine.

(2S,5S) -N-protecting group-5-hydroxy-2-carboxylic acid piperidine compounds as described in I, preferably the following compounds are listed: (2S,5S) -N-tert-butoxycarbonyl-5-hydroxy-2-carboxylic acid piperidine, (2S,5S) -N-benzyloxycarbonyl-5-hydroxy-2-carboxylic acid piperidine, (2S,5S) -methyloxycarbonyl-5-hydroxy-2-carboxylic acid piperidine, (2S,5S) -ethyloxycarbonyl-5-hydroxy-2-carboxylic acid piperidine, (2S,5S) -phenoxycarbonyl-5-hydroxy-2-carboxylic acid piperidine, (2S,5S) -allyloxycarbonyl-5-hydroxy-2-carboxylic acid piperidine and (2S,5S) -trifluoroacetyl-5-hydroxy-2-carboxylic acid piperidine.

The synthesis method of the abamectin intermediate (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate comprises the following steps:

(1) Taking N-protected-L-pyroglutamic acid ester (SM) as a starting material, opening the ring in the presence of an alkaline reagent, and increasing the carbon chain by trimethyl sulfoxide iodide to obtain a compound II;

(2) Carrying out halogenation reaction on the compound II and a halogenating reagent under the action of acid to obtain a compound III;

(3) The compound III is reduced by borane under the catalysis of chiral ligand ((R) -2-methyl-CBS-oxazaborolidine) to obtain a compound IV with an S configuration;

(4) The compound IV forms a lactone ring under the catalysis of acid to obtain a compound V;

(5) the compound V is subjected to piperidine ring base under the action of alkali to obtain a compound VI;

(6) And hydrolyzing the compound VI under the action of alkali to obtain (2S,5S) -N-protecting group-5-hydroxy-2-piperidine formate (compound I).

Further, the compound I can be subjected to esterification reaction with ethanol to obtain a derivative (2S,5S) -N-protecting group-5-hydroxy-2-piperidine-ethyl formate, and can also be used as an intermediate for synthesizing avibactam.

The alkaline reagent used in the step (1) is potassium tert-butoxide, sodium tert-butoxide or sodium hydride, preferably potassium tert-butoxide; the reaction solvent is one or a mixture of more than one of dimethyl sulfoxide, 2-methyltetrahydrofuran and tetrahydrofuran, and is preferably a mixed solvent of dimethyl sulfoxide and tetrahydrofuran; the reaction temperature is-20 to 20 ℃.

The halogenating reagent used in the step (2) is lithium chloride, 1, 4-dioxane solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, dimethyl sulfoxide solution of hydrogen chloride, lithium bromide, acetic acid solution of hydrogen bromide, hydrogen iodide, sodium iodide and potassium iodide. Reagents containing hydrogen chloride and hydrogen bromide provide both halogen and acidity. The halogenated salts are prepared by the action of an acid, such as sulfuric acid, methanesulfonic acid or ethanesulfonic acid, preferably lithium bromide by the action of methanesulfonic acid. The reaction temperature is-20 to 40 ℃. The reaction solvent is one or more of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, 1, 4-dioxane, ethyl acetate, isopropyl acetate and acetone, preferably tetrahydrofuran.

The reaction temperature of the step (3) is-25 ℃; the reaction solvent is one or more of tetrahydrofuran, toluene, dichloromethane, ethyl acetate, 1, 4-dioxane and methyl tert-butyl ether, preferably tetrahydrofuran.

the acid used in the step (4) is p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, tetrahydrofuran solution of hydrogen chloride, toluene solution of hydrogen chloride, 1,4 dioxane solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, and preferably p-toluenesulfonic acid; the reaction solvent is toluene, acetonitrile, tetrahydrofuran, N-dimethyl amide, N-dimethyl acetamide, 1, 4-dioxane and ethyl acetate. Preferably toluene; the reaction temperature is 25-70 ℃, preferably 60-70 ℃.

The base used in the step (5) is organic base or inorganic base, and the organic base is N, N-diisopropylethylamine, pyridine, 2-methylpyridine, 4-dimethylaminopyridine and triethylamine; the inorganic base is a hydroxide, carbonate or bicarbonate of an alkali metal, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, preferably cesium carbonate. The reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, ethyl acetate and acetonitrile, and preferably N, N-dimethylformamide.

The alkali used in the step (6) is lithium hydroxide, sodium hydroxide or potassium hydroxide, and preferably lithium hydroxide. The reaction solvent may be water; esters such as ethyl acetate and isopropyl acetate; alcohols such as methanol, ethanol, 1-propanol, and 1-butanol; ethers such as t-butyl methyl ether, tetrahydrofuran, and dioxane; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; one or more nitriles such as acetonitrile. Water or a solvent in which water is mixed with the above solvent is preferable, and a mixed solvent of tetrahydrofuran and water is more preferable.

Preferably, the preparation method is as follows:

(1) Adding potassium tert-butoxide and trimethyl sulfoxide iodide into a mixed solvent (volume ratio is 1: 1-1.5) of tetrahydrofuran and dimethyl sulfoxide, cooling to-15-10 ℃, and dropwise adding a tetrahydrofuran solution of N-protected-L-pyroglutamic glutamate; reacting for 1-3 hours under heat preservation, and carrying out post-treatment to obtain a compound II;

(2) taking tetrahydrofuran as a solvent, and adding a compound II and a halogenating agent lithium bromide or lithium chloride under stirring; cooling to-10-0 ℃, dropwise adding a tetrahydrofuran solution of methanesulfonic acid, and reacting for 0.5-2 h under heat preservation; slowly heating to 20-35 ℃ and reacting for 6-12 hours; carrying out post-treatment to obtain a compound III;

(3) Dissolving a toluene solution of (R) -2-methyl-CBS-oxazaborolidine in tetrahydrofuran, adding a tetrahydrofuran solution of borane at the temperature of-10-0 ℃, and reacting for 0.5-1.5 h under heat preservation; dripping a tetrahydrofuran solution of a compound III, and keeping the temperature of minus 5-0 ℃ for reaction for 1-3 h after dripping; after-treatment, compound IV is obtained;

(4) dissolving a compound IV in toluene, adding p-toluenesulfonic acid, and controlling the temperature to be 60-70 ℃ for reaction; after the reaction is finished, carrying out reduced pressure concentration to obtain a compound V;

(5) dissolving the compound V in N, N-dimethylformamide, adding cesium carbonate, and stirring for reaction; after the reaction is finished, carrying out post-treatment to obtain a compound VI;

(6) Dissolving a compound VI in tetrahydrofuran, dropwise adding a lithium hydroxide aqueous solution at room temperature, and stirring for 1-3 h; and after the reaction is finished, carrying out post-treatment to obtain a target product.

the molar ratio of the potassium tert-butoxide, the trimethyl sulfoxide iodide and the N-protected-L-pyroglutamate in the step (1) is 1-5: 1.0-1.5: 1; preferably 1.0-1.5: 1.1-1.3: 1. The post-treatment of the step (1) comprises the following steps: after the reaction is finished, adding an ammonium chloride saturated solution to quench the reaction, extracting with ethyl acetate, washing, drying and vacuum-concentrating to obtain a compound II.

The molar ratio of the methanesulfonic acid, the halogenating agent and the compound II used in the step (2) is 1-6: 1-3: 1, preferably 1-1.5: 1; the post-treatment of the step (2) comprises the following steps: and after the reaction is finished, carrying out vacuum concentration, adding an extraction organic solvent and water, separating liquid, washing an organic phase, drying, and carrying out vacuum concentration until the organic phase is dried to obtain a compound III.

The molar ratio of the chiral ligand (R) -2-methyl-CBS-oxazaborolidine, borane tetrahydrofuran and the compound III in the step (3) is 0.5-1.5: 1-3: 1; the post-treatment of the step (3) comprises the following steps: and after the reaction is finished, adjusting the pH value to 6-7, extracting with ethyl acetate, washing, drying and concentrating to obtain an oily compound IV.

The molar ratio of the compound IV in the step (4) to the p-toluenesulfonic acid is 1.5-3: 1, preferably 1.5-2: 1.

The molar ratio of the compound V in the step (5) to the cesium carbonate is 1-3: 1, preferably 1-1.5: 1. The post-treatment in the step (5) comprises the following steps: and after the reaction is finished, adding ethyl acetate and water, adjusting the pH to 6-7, washing an organic phase, drying and concentrating to obtain a compound VI.

the molar ratio of the compound VI in the step (6) to the lithium hydroxide is 1-1.5: 1; the post-treatment in the step (6) is as follows: after the reaction is finished, carrying out reduced pressure concentration, extracting with ethyl acetate, washing, drying and concentrating to obtain the compound I.

The invention has the beneficial effects that: the method adopts a mode of closing lactone ring firstly and then closing piperidine ring, and a mode of hydrolyzing to obtain piperidine main ring can smoothly obtain a target product; the chiral compound is obtained by adopting (R) -2-methyl-CBS-oxazaborolidine high position selection. The reaction condition is mild, the operation is simple and convenient, the impurities are easy to control, and the yield is stable. The used reagent has low price, effectively reduces the cost, is environment-friendly and is suitable for industrial production.

Detailed Description

The present invention will be described in further detail with reference to examples for the purpose of making the objects, aspects and advantages of the present invention clearer, but the present invention is not limited to these examples and may be variously modified.