SIMPLE PREPARATION METHOD FOR VABORBACTAM

Abstract

A simple method is preparing Vaborbactam, in which S-3-hydroxy-6-oxohexanoic acid ester is used as the starting material to finally form the Vaborbactam (I) by carrying out the procedures of hydroxyl protection, imidization, asymmetric addition from borane or borate compounds, amino deprotection, amidation, cyclization and hydrolysis. The present invention is suitable for commercial production by virtue of the advantages: widely available and low cost raw materials; safe, simple and convenient process steps; no rigorous reaction conditions; and environment-friendly reaction courses.

Claims

1. A method for preparing Vaborbactam comprises the steps as follows: (1) reacting a compound of Formula II with a hydroxyl protecting group reagent to form a compound of Formula III; ##STR00020## in the Structural Formulas II and III, R is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl or tert-butyl; in the Structural Formula III, the protecting group (PG) is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), benzyl (Bn), methanesulfonyl (Ms), p-toluenesulfonyl (Ts), trifluoroacetyl (TFA) or acetyl (Ac); (2) reacting a compound of Formula III with an amine compound by imidization to form a compound of Formula IV; ##STR00021## in the Structural Formula IV, R.sub.3 is hydroxyl, benzoyl, phenylacetyl, 2-thiopheneacetyl or alkylsulfinyl, and the meanings of R and PG are the same as those in Formula III; (3) reacting a compound of Formula IV with a borane or borate compound to form a compound of Formula V; ##STR00022## in the Structural Formula V, n is 0, 1, 2 or 3; when n is 0, R.sub.1 and R.sub.2 are alkyl or aryl; when n is 1, 2 or 3, R.sub.1 and R.sub.2 are alkyl having 1 to 4 carbon atoms; R.sub.1 and R.sub.2 are the same or different; and the meanings of R, PG, and R.sub.3 are the same in Formula IV; (4) deprotecting a compound of Formula V to remove the protecting amino to form a compound of Formula VI; ##STR00023## in the Structural Formula VI, the meanings of R.sub.1, R.sub.2, n, R and PG are the same as those in Formula V; (5) amidating a compound of Formula VI in the presence of an amidation reagent to form a compound of Formula VII; ##STR00024## in the Structural Formula VII, the meanings of R.sub.1, R.sub.2, n, R and PG are the same as those in Formula V; (6) cyclizing and hydrolyzing a compound of Formula VII to form Vaborbactam (I).

2. The method for preparing Vaborbactam as set forth in claim 1 is characterized in that it comprises one or several conditions as listed below: a. in Step (1), reacting the compound of Formula II with a hydroxyl protecting group reagent in a Solvent A and in the presence of a base; b. in Step (2), imidizing the compound of Formula III by using an amine compound in a Solvent B under the action of a Catalyst C; c. in Step (3), reacting the compound of Formula IV with a borane or borate compound in a Solvent D in the presence of a Catalyst E and a ligand; d. in Step (4), deprotecting the compound of Formula V in a Solvent F and in the presence of a deprotection reagent; e. in Step (5), amidating the compound of Formula VI with the amidation reagent in a Solvent G under the action of the Base H; and f. in Step (6), cyclizing and hydrolyzing the compound of Formula VII in a Solvent J and in the presence of an acid.

3. The method for preparing Vaborbactam as set forth in claim 2 is characterized in that it comprises one or several conditions as listed below for carrying out Step (1) according to Item “a” therein: i. the aforesaid Solvent A is a non-alcoholic solvent, preferably ethyl acetate, butyl acetate, acetone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 2,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, or halogenated hydrocarbon solvents or benzene solvents, or any combination thereof; and the mass ratio of Solvent A to the compound of Formula II is (4˜20):1; ii. the aforesaid base is an organic base or inorganic base, and preferably, the organic base is trimethylamine, triethylamine, tri-n-butylamine, diisopropylethylamine or imidazole, while the inorganic base is potassium carbonate, sodium carbonate or calcium carbonate, or any combination thereof; and the molar ratio of the base to the compound of Formula II is (1.0˜2.0):1; iii. the aforesaid hydroxyl protecting group reagent is trimethylchlorosilane, trimethyliodosilane, tert-butyldimethylchlorosilane, tert-butyldimethyliodosilane, methanesulfonyl chloride, p-toluenesulfonyl chloride, benzyl chloride, benzyl bromide, trifluoroacetic acid or acetic anhydride; and the molar ratio of the hydroxyl protecting group reagent to the compound of Formula II is (1.0˜2.0):1; and iv. the aforesaid reaction temperature of the compound of Formula II and the hydroxyl protecting group reagent is 0-60° C., preferably, 20˜40° C.;

4. The method for preparing Vaborbactam as set forth in claim 2 is characterized in that it comprises one or several conditions as listed below for carrying out Step (2) according to Item “b” therein: i. the aforesaid Solvent B is methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 2,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, or halogenated hydrocarbon solvents or benzene solvents, or any combination thereof; and the mass ratio of Solvent B to the compound of Formula III is (1˜20):1; ii. the aforesaid Catalyst C is acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonic acid, copper sulfate, copper acetate, copper chloride, cuprous chloride or ferric chloride, or any combination thereof; and the molar ratio of Catalyst C to the compound of Formula III is (1˜3):1; iii. the aforesaid amine compound is hydroxylamine, benzamide, phenylacetamide, thiopheneacetamide or alkylsulfenamide; and the molar ratio of the amine compound to the compound of Formula III is (1.0˜2.0):1; and iv. The aforesaid imidization reaction is carried out at a temperature of −10˜100° C., preferably 0˜70° C., and more preferably 30˜50° C.

5. the method for preparing Vaborbactam as set forth in claim 2 is characterized in that it comprises one or several conditions as listed below for carrying out Step (3) according to Item “c” therein: i. the aforesaid Solvent D is methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane, methoxycyclopentane, methyl tert-butyl ether, water, or halogenated hydrocarbon solvents or benzene solvents, or any combination thereof; and the mass ratio of Solvent D to the compound of Formula IV is (2˜20):1; ii. the aforesaid Catalyst E is copper sulfate, copper chloride, cuprous chloride, palladium chloride, palladium acetate, tris(triphenylphosphine)rhodium(I) chloride, Grubb's catalyst, iridium/alumina or (1, 5-cyclooctadiene)(pyrimidine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate; and the molar quantity of Catalyst E is 1.0˜10.0% of that of the compound of Formula IV; iii. the aforesaid ligand is nitrogen ligand or phosphorus ligand, or preferably, a combination thereof; preferably, the nitrogen ligand is substituted imidazole or benzylamine, and the phosphorus ligand is triphenylphosphine or triphenylphosphine oxide; and the molar quantity of ligand is 1.0˜10.0% of that of the compound of Formula IV; iv. the aforesaid borane is dialkylborane or pinacolborane; the aforesaid borate compound is trialkyl borate or biborate; the molar ratio of the borane or borate compound to the compound of Formula IV compound is 1.0˜2.0:1; and v. the aforesaid reaction of the compound of Formula IV with the borane or borate compound is carried out at a temperature of 20˜120° C., more preferably 20˜40° C.

6. The method for preparing Vaborbactam as set forth in claim 2 is characterized in that it comprises one or several conditions as listed below for carrying out Step (4) according to Item “d” therein: i. the aforesaid Solvent F is methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 2,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, water, or halogenated hydrocarbon solvents or benzene solvents, or any combination thereof; and the mass ratio of the Solvent F to the compound of Formula V is 1˜20:1; ii. the aforesaid deprotection reagent is an acid or a base; the acid is hydrogen chloride, sulfuric acid or phosphoric acid; the hydrogen ion concentration in the acid is 3˜8 mol/L; the base is sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate or potassium carbonate; the molar ratio of the deprotection reagent to the compound of Formula V is (3˜7):1; and iii. the aforesaid deprotection is carried out at a temperature of −10˜100° C., preferably −5˜30° C.

7. The method for preparing Vaborbactam as set forth in claim 2 is characterized in that it comprises one or several conditions as listed below for carrying out Step (5) according to Item “e” therein: i. the aforesaid Solvent G is methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 2,4-dioxane, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, or halogenated hydrocarbon solvents or benzene solvents, or any combination thereof; and the mass ratio of the Solvent G to the compound of Formula VI is (4˜20):1; ii. the aforesaid amidation reagent is 2-thiopheneacetyl chloride or 2-thiopheneacetic acid; and the molar ratio of the amidation reagent to the compound of Formula VI is 1˜2.0:1; preferably, when the amidation reagent is 2-thiopheneacetic acid, a dehydrating and condensing agent is required; the dehydrating and condensing agent is dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) or 1-hydroxybenzotriazole (HOBT), or any combination thereof; and the molar ratio of the dehydrating and condensing agent to the compound of Formula VI is 1.0˜3.0:1; iii. the aforesaid Base H is an organic base or inorganic base; the organic base is trimethylamine, triethylamine, tri-n-butylamine, diisopropylethylamine, imidazole, morpholine or N-methylmorpholine; the inorganic base is potassium carbonate, sodium carbonate or calcium carbonate, or any combination thereof; the molar ratio of the Base H to the compound of Formula VI is (1.0˜3.0):1; and iv. the aforesaid amidation is carried out at a temperature of 0˜120° C., more preferably 15˜80° C.

8. The method for preparing Vaborbactam as set forth in claim 2 is characterized in that it comprises one or several conditions as listed below for carrying out Step (6) according to Item “f” therein: i. the aforesaid Solvent J is methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, or halogenated hydrocarbon solvents or benzene solvents, or any combination thereof; and the mass ratio of the Solvent J to the compound of Formula VII is (4˜20):1; ii. the aforesaid acid is hydrochloric acid, sulfuric acid, boric acid or trifluoroacetic acid, or any combination thereof; and the molar ratio of the acid to the compound of Formula VII is (5˜7):1; and iii. the aforesaid cyclization and hydrolysis are carried out at a temperature of 10˜100° C.; and the time of cyclization and hydrolysis is 1˜10 hours.

Description

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0064] The present invention is illustrated by but not limited to the following examples.

[0065] The raw materials and reagents used in the examples are all commercially available products, and the optical purity of S-3-hydroxy-6-oxohexanoic acid ester (II) is 99.6%.

[0066] Unless otherwise specified, the symbol “%” in the examples indicates a mass percentage, and the term “yield” indicates a molar yield.

[0067] A gas or liquid chromatograph is used to monitor the reaction process and product purity, and a liquid chromatograph equipped with a chiral column (ES-OVS, 150 mm×4.6 mm, Agilent) to detect the optical purity (area ratio, %), and calculate the yield as well as the value of ee.

Example 1: Preparation of S-3-trimethylsilyloxy-6-oxo-hexanoic acid tert-butyl ester (Ilk)

[0068] ##STR00010##

[0069] Under the protection of nitrogen, add 120 g of dichloromethane, 20.2 g (0.1 mol) of S-3-hydroxy-6-oxo-hexanoic acid tert-butyl ester (II.sub.1) and 12.1 g (0.12 mol) of triethylamine into a 250 ml 4-necked flask equipped with a stirrer and a thermometer. Add a solution of 13.1 g (0.12 mol) of trimethylchlorosilane and 20 g of dichloromethane dropwise and evenly across a time span of 30 minutes when the internal temperature is 15˜20° C. Then, stir to accelerate the reaction at 20˜25° C. for 3 hours. Introduce the solution into 50 g of water, and wait for separation. Extract the water layer twice with dichloromethane, 30 g each time. Combine the organic phases, and wash twice with a saturated sodium chloride solution, 20 g each time. Recover the solvents from the organic phases, to obtain 26.0 g of S-3-trimethylsilyloxy-6-oxo-hexanoic acid tert-butyl ester (III.sub.1) which has an LC purity of 99.9% and a yield of 94.9%.

Example 2: Preparation of S-3-tert-butyldimethylsiloxy-6-oxo-hexanoic acid tert-butyl ester (III.SUB.2.)

[0070] ##STR00011##

[0071] Under the protection of nitrogen, add 120 g of dichloromethane, 20.2 g (0.1 mol) of S-3-hydroxy-6-oxo-hexanoic acid tert-butyl ester (II.sub.1) and 8.2 g (0.12 mol) of imidazole into a 250 ml 4-necked flask equipped with a stirrer and a thermometer. Add a solution of 16.6 g (0.11 mol) of tert-butyldimethylchlorosilane and 30 g of dichloromethane dropwise and evenly across a time span of 30 minutes when the internal temperature is 15˜20° C. Then, stir to accelerate the reaction at 20˜25° C. for 4 hours. Introduce the solution into 50 g of water, and wait for separation. Extract the water layer twice with dichloromethane, 30 g each time. Combine the organic phases, and wash twice with a saturated sodium chloride solution, 20 g each time. Recover the solvents from the organic phases, to obtain 30.4 g of S-3-tert-butyldimethylsiloxy-6-oxo-hexanoic acid tert-butyl ester (III.sub.2) which has an LC purity of 99.9% and a yield of 96.0%.

Example 3: Preparation of S-3-trimethylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IV.SUB.1.)

[0072] ##STR00012##

[0073] Under the protection of nitrogen, add 120 g of dichloromethane, 27.4 g (0.1 mol) of S-3-trimethylsilyloxy-6-oxo-hexanoic acid tert-butyl ester (III.sub.1) as obtained in Example 1, 2.5 g (0.1 mol) of pyridine p-toluenesulfonate, 31.9 g (0.2 mol) of copper sulfate and 13.3 g (0.11 mol) of R-tert-butylsulfonamide into a 250 ml 4-necked flask equipped with a stirrer, a thermometer and a reflux apparatus. Reflux after heat to 40˜45° C., and stir at 40˜45° C. till the reaction is confirmed as completed by using the HPLC. Filter to remove any insoluble matters. Reduce the pressure and distill to recover the dichloromethane. Separate and purify the residues by using the column chromatography (PE/EA=10:1), or rectify the residues, to obtain 36.0 g of S-3-trimethylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IVA which has an LC purity of 99.9% and a yield of 95.3%.

Example 4: Preparation of S-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IV.SUB.2.)

[0074] ##STR00013##

[0075] Under the protection of nitrogen, add 120 g of dichloromethane, 31.7 g (0.1 mol) of S-3-tert-butyldimethylsiloxy-6-oxo-hexanoic acid tert-butyl ester (III.sub.2) as obtained in Example 2, 2.5 g (0.1 mol) of pyridine p-toluenesulfonate, 31.9 g (0.2 mol) of copper sulfate and 13.3 g (0.11 mol) of R-tert-butylsulfonamide into a 250 ml 4-necked flask equipped with a stirrer, a thermometer and a reflux apparatus. Reflux after heat to 40˜45° C., and stir at 40−45° C. till the reaction is confirmed as completed by using the HPLC. Filter to remove any insoluble matters. Reduce the pressure and distill to recover the dichloromethane. Separate and purify the residues by using the column chromatography (PE/EA=10:1), or rectify the residues, to obtain 36.0 g of S-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IV.sub.2), which has an LC purity of 99.9% and a yield of 95.3%.

Example 5: Preparation of (3S,6R)-3-trimethylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (V.SUB.1.)

[0076] ##STR00014##

[0077] Add 100 g of toluene, 20 g of water, 0.2 g (1.2 mmol) of copper sulfate, 0.37 g (1.2 mmol) of triphenylphosphine oxide and 0.54 g (5 mmol) of benzylamine into a 250 ml 4-necked flask equipped with a stirrer and a thermometer, and stir the solution. Add 37.7 g (0.1 mol) of S-3-trimethylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IV.sub.1) as prepared in Example 3 and 30.5 g (0.12 mol) of bis(pinacolato)diboron, and stir at the room temperature till the reaction is confirmed as completed by using the HPLC. Add 50 g of ethyl acetate into the system. Filter, then reduce the pressure and distill to concentrate. Separate and purify the residues by using the column chromatography (EA/DCM=10:90), or rectify the residues, to obtain 39.2 g of (3S,6R)-3-trimethylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (V.sub.1), which has an LC purity of 98.6% and a yield of 77.6%.

Example 6: Preparation of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (V.SUB.2.)

[0078] ##STR00015##

[0079] Add 100 g of toluene, 20 g of water, 0.2 g (1.2 mmol) of copper sulfate, 0.37 g (1.2 mmol) of triphenylphosphine oxide and 0.54 g (5 mmol) of benzylamine into a 250 ml reaction flask equipped with a stirrer and a thermometer, and stir the solution. Add 42.0 g (0.1 mol) of S-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IV.sub.2) as prepared in Example 4 and 30.5 g (0.12 mol) of bis(pinacolato)diboron, and stir at the room temperature till the reaction is confirmed as completed by using the HPLC. Add 50 g of ethyl acetate into the system. Filter, then reduce the pressure and distill to concentrate. Separate and purify the residues by using the column chromatography (EA/DCM=10:90), or rectify the residues, to obtain 44.7 g of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (V.sub.2), which has an LC purity of 98.4% and a yield of 81.6%.

Example 7: Preparation of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-amino-6-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester hydrochloride (VI)

[0080] ##STR00016##

[0081] Add 100 g of 20% methanol solution of hydrogen chloride to a 250 ml reaction flask equipped with a stirrer and a thermometer, and cool to 0° C. Add 54.8 g (0.1 mol) of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (V.sub.2) as prepared in Example 6, and then stir at 0° C. till the reaction is confirmed as completed by using the HPLC. Reduce the pressure, distill and concentrate to obtain 47.3 g of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester hydrochloride, which has an LC purity of 99.2% and a yield of 98.6%.

Example 8: Preparation of (3S,6R)-3-dimethyltert-butylsilyloxy-6-[2-(2-thiophene)acetamido]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (VII)

[0082] ##STR00017##

[0083] Add 100 g of tetrahydrofuran, 24.0 g (0.05 mol) of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester hydrochloride (VI) as prepared in Example 7, 9.6 g (0.06 mol) of 2-thiopheneacetyl chloride, and 11.1 g (0.11 mol) of triethylamine into a 250 ml reaction flask equipped with a stirrer and a thermometer, and then stir at the room temperature till the reaction is confirmed as completed by using the HPLC. Add 80 g of water and stir for 0.5 hours. Add 100 g of ethyl acetate, and transfer to a separating funnel for static separation. Wash the organic phases with water twice, 30 g each time. Combine the organic phases, and dry out with anhydrous sodium sulfate. Remove the sodium sulfate by filtering. Reduce the pressure of filtrate, and then distill to remove the solvents to form a pale yellow crude product. Recrystallize from methyl tert-butyl ether and n-hexane to obtain 21.7 g of (3S,6R)-3-dimethyltert-butylsilyloxy-6-[2-(2-thiophene)acetamido]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (VII), which is a white solid having an LC purity of 99.3% and a yield of 76.4%.

Example 9: Preparation of (3S,6R)-3-dimethyltert-butylsilyloxy-6-[2-(2-thiophene)acetamido]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (VII)

[0084] ##STR00018##

[0085] Under the protection of nitrogen, add 100 g of dichloromethane, 8.5 g (0.06 mol) of thiopheneacetic acid, 14.8 g (0.075 mol) of EDC-HCl (EDCl), and 8.1 g (0.06 mol) of 1-hydroxybenzotriazole (HOBT) into a 250 ml reaction flask equipped with a stirrer and a thermometer, and then stir after cool to 0° C. Dissolve 24.0 g (0.05 mol) of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester hydrochloride (VI) as prepared in Example 7 into 60 g of dichloromethane, and then introduce to the system together with (0.11 mol) of N-methylmorpholine. Heat to the room temperature, and stir till the reaction is confirmed as completed by using the HPLC. Add 80 g of water, and transfer to a separating funnel for static separation. Wash the organic phases with water, and dry out with anhydrous sodium sulfate. Reduce the pressure, distill and concentrate. Recrystallize from methyl tert-butyl ether and n-hexane to obtain 23.3 g of (3S,6R)-3-dimethyltert-butylsilyloxy-6-[2-(2-thiophene)acetamido]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (VII), which is a white solid having an LC purity of 99.4% and a yield of 82.1%.

Example 10: Preparation of Vaborbactam (I)

[0086] ##STR00019##

[0087] Add 80 g of 1,4-dioxane and 28.4 g (0.05 mol) of (3S,6R)-3-dimethyltert-butylsilyloxy-6-[2-(2-thiophene)acetamido]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (VII) as obtained in Example 9 into a 250 ml reaction flask equipped with a stirrer and a thermometer. After stir, add 100 ml of 3 mol/L dilute hydrochloric acid, heat the mixture to 90˜95° C., reflux and stir for 2 hours. Cool to the room temperature, add 100 g of water and 150 g of methyl tert-butyl ether, and transfer to a separating funnel for static separation. Distill and concentrate the aqueous phase under a reduced pressure. Add acetonitrile into the residues, then reduce the pressure and distill via azeotropic process for 3 times, with 80 g of acetonitrile used for each time. Dissolve the residues into a 20% 1,4-dioxane/water solution, and lyophilize to form 14.3 g of white powder. Add 200 g of ethyl acetate and 60 g of water to the white powder, stir at the room temperature for 1 hour and then wait for the formation of white sediment. Process by suction filtration, and wash the residual cake twice with ethyl acetate, 15 g each time. Finally vacuum-dry to obtain 10.5 g of product (I), which is a white solid having an LC purity of 99.6% and a yield of 71.0%.

[0088] The NMR data of the product are presented as follows:

[0089] .sup.1H NMR (CD.sub.3OD) ppm: δ 7.35 (dd, 1H), 7.05 (dd, 1H), 7.0 (dd, 1H), 4.15-4.05 (m, 1H), 3.98 (s, 2H), 2.61 (br d, 1H), 2.37 (dd, 1H), 2.24 (dd, 1H), 1.74 (br d, 1H), 1.66-1.52 (m, 2H), 1.03 (br q, 1H).

Comparative Example 1: Preparation of (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (V.SUB.2.)

[0090] Add 10 g of toluene, 2 g of water, 0.02 g (0.12 mmol) of copper sulfate, and 0.037 g (0.12 mmol) of triphenylphosphine oxide into a 250 ml reaction flask equipped with a stirrer and a thermometer, and stir the mixture. Add 4.2 g (10 mmol) of S-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IV.sub.2) as prepared in Example 4 and 3.1 g (12 mmol) of bis(pinacolato)diboron, and stir at the room temperature. Track and monitor the reaction by using the HPLC for 2 days, and find that only a little, less than 5%, of the raw material IV.sub.2 is converted. Heat to 100° C. to resume the reaction, then track and monitor by using the HPLC for another 2 days, and find that only a little portion, less than 10%, of the raw material IV.sub.2 is converted.

[0091] Comparative Example 1 shows that, in the reaction of imine addition, the presence of benzylamine is very important, the lack of benzylamine will obviously affect the reaction time and temperature, and finally almost no target product can be obtained.

Comparative Example 2: (3S,6R)-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl) amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid tert-butyl ester (V.SUB.2.)

[0092] Add 10 g of toluene, 2 g of water, 0.037 g (0.12 mmol) of triphenylphosphine oxide and 0.054 g (0.5 mmol) of benzylamine into a 250 ml reaction flask equipped with a stirrer and a thermometer, and then stir the mixture. Add 4.2 g (10 mmol) of S-3-dimethyl-tert-butylsilyloxy-6-(N—(R-1-tert-butylsulfinyl)imino)hexanoic acid tert-butyl ester (IV.sub.2) as prepared in Example 4 and 3.1 g (12 mmol) of bis(pinacolato)diboron, and stir at the room temperature. Track and monitor the reaction by using the HPLC for 2 days, and find that no target product is formed, and the raw material IV.sub.2 remains unchanged.

[0093] Comparative Example 2 shows that in the reaction of imine addition, a catalyst is indispensable, and the reaction does not occur in absence of a catalyst.