Preparation method of fabobactam

Abstract

The invention relates to a brand-new synthesis method of fabobactam, and belongs to the field of medicine synthesis. The synthesis method comprises the following four steps: preparing chiral borate Q4 from an intermediate Q3 and bis (pinacol) diborate in the presence of catalysts of metal copper salt and alkyl phosphine fluoroborate; then under the acidic condition, hydrolysis deprotection cyclization is performed to generate a key intermediate II # imgabs0 #, and then the key intermediate II # imgabs0 # reacts with thiophene-2-acetyl chloride in the presence of alkali to obtain an intermediate III; and finally, carrying out hydrolysis reaction under an acid condition to obtain the fabobactam I. The method has the advantages of mild conditions of synthesis steps, high selectivity, less side reaction and strong operational feasibility.

Description

Technical Field

[0001] The invention relates to a new synthesis method of vaborbactam, and belongs to the technical field of drug synthesis and organic synthesis. Technical Background

[0002] Vaborbactam (I, Vaborbactam) is a new type of non-β-lactam β-lactamase inhibitor based on cyclic boronic acid pharmacophore developed by Rempex Pharmaceuticals. As a broad-spectrum inhibitor of class A and class C β-lactamases, it has very high clinical value. Structurally, Vaborbactam has a unique chiral aminoboronic acid lactone ring intermediate II. The efficient preparation of intermediate II will contribute to the development of Vaborbactam products.

[0003]

[0004] At present, there are two main synthetic routes of faborbactam reported in the literature:

[0005] Route 1:

[0006]

[0007] Patent document US20170057979A1 reports that starting from the chiral enol ester raw material S1, a key intermediate S4 is produced through multiple transformations, boric acid lactone is hydrolyzed and reacted with (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol to obtain S5, and n-butyl lithium and dichloromethane are reacted at low temperature to extend a carbon chain, and then three steps of transformation are performed to prepare the target product I. The reaction involves expensive catalysts, ultra-low temperature reactions, active reagent butyl lithium, etc., and the conditions are harsh. Among them, the multi-step purification adopts the column chromatography method, which is not conducive to large-scale production.

[0008] Route 2:

[0009]

[0010] The route adopted in patent CN111039965A starts from chiral hydroxyaldol ester raw material Q1, uses chiral tert-butyl salt sulfonamide as chiral auxiliary, produces Schiff base, and then asymmetric catalytic addition with pinacol biboric acid ester to obtain key intermediate Q4, and then hydrolyzes to remove tert-butyl sulfinyl group, and condenses with thiopheneacetic acid to produce intermediate Q5, and then transforms to generate faborbactam I. The starting raw materials of this route are difficult to obtain, the material cost is too high, the preparation conditions of intermediate Q5 are harsh, resulting in excessive removal of protective groups, increasing the difficulty of purifying the intermediate, and there are many defects such as complex process flow, which are not conducive to industrial production. Summary of the invention

[0011] In order to overcome the above technical defects, the present invention provides a method for preparing a borobactam intermediate cyclic borate compound. The present invention prepares the cyclic borate compound II, eliminating the defects of the above two routes, such as harsh reaction conditions and a large waste of solvent column chromatography. The multi-step intermediates in the route of the present invention are purified by a vacuum distillation method, and the preparation is more economical, reasonable, low-cost, less polluting, and highly efficient, overcoming many defects of the existing synthesis method. At the same time, the reagents used in the present invention are very easy to obtain in large quantities through commercial channels.

[0012] The present invention provides a faborbactam intermediate, the chemical structure of which is as follows:

[0013]

[0014] The present invention further provides a method for preparing faborbactam, which is expressed by the following chemical reaction equation:

[0015]

[0016] Where: R = t-BuMe 2 Si、Me 3 Si, Et 3 Si, i-Pr 3 Si、Ph 2 MeSi.

[0017] In the first step, the intermediate Q3 is reacted with pinacol diborate in the presence of a catalyst metal copper salt and an alkylphosphine fluoroborate to obtain a chiral borate ester Q4.

[0018] Furthermore, in the above technical solution, the metal copper salt is selected from copper sulfate or copper acetate; the alkyl phosphine fluoroborate is selected from tricyclohexyl phosphine fluoroborate and tri-tert-butyl phosphine fluoroborate.

[0019] Furthermore, in the above technical solution, the intermediate Q3 is prepared by using tert-butyl acetoacetate as a raw material, extending the carbon chain, followed by asymmetric catalytic reduction of the carbonyl group, and using a chiral auxiliary agent tert-butylsulfenamide to form a Schiff base to obtain the intermediate Q3.

[0020]

[0021] Where: R = t-BuMe 2 Si、Me 3 Si, Et 3 Si, i-Pr 3 Si、Ph 2 MeSi.

[0022] Furthermore, in the above technical solution, the molar ratio of the intermediate Q3, pinacol borate, metal copper salt, benzylamine and alkylphosphine fluoroborate is 1.0:1-1.2:0.02-0.05:0.02-0.05:0.01-0.012.

[0023] In the second step, the intermediate Q4 is hydrolyzed, deprotected and cyclized under acidic conditions to generate the key intermediate II.

[0024] Furthermore, in the above technical solution, the acid is selected from hydrochloric acid or hydrogen chloride solution.

[0025] Furthermore, in the above technical solution, the molar ratio of the intermediate Q4 to the acid is 1:2.0-4.0.

[0026] Furthermore, in the above technical solution, the intermediate II product can be directly precipitated from the reaction system, which greatly simplifies the purification operation.

[0027] Step 3: Intermediate II reacts with thiophene-2-acetyl chloride in the presence of a base to obtain intermediate III.

[0028] Furthermore, in the above technical solution, the base is selected from triethylamine, pyridine, and N-methylmorpholine.

[0029] Furthermore, in the above technical solution, the molar ratio of the intermediate II, thiophene-2-acetyl chloride and the base is 1.0:1.5-2.5:1.5-3.

[0030] Step 4: The intermediate III is hydrolyzed under acid conditions to obtain faborbactam I.

[0031] Furthermore, in the above technical solution, the acid is selected from at least one of boric acid, sulfuric acid, hydrochloric acid and acetic acid.

[0032] Furthermore, in the above technical solution, the molar ratio of the intermediate III to the acid is 1:1.5-3.0.

[0033] Beneficial effects of the invention:

[0034] 1. The intermediate structure II of this compound has not been reported in the literature and can be used as a new intermediate of borobactam. The subsequent synthesis steps are simple and easy.

[0035] 2. The synthesis process of the present invention has mild conditions, high selectivity, fewer side reactions and strong operational feasibility.

[0036] 3. The intermediate Q3 obtained by the method of the present invention is cheap and easy to obtain, and has a cost advantage over the intermediate Q3 of route 2. DETAILED DESCRIPTION

[0037] Example 1

[0038]

[0039] Under nitrogen protection, 71 g (0.196 mmol) of intermediate IV, 29.7 g (0.245 mol) of R-tert-butylsulfenamide, and 14.2 g of Molecular sieves, PPTS 4.2g (0.016m mol) and 1.4L dioxane were slowly heated to 80°C and kept under weak reflux for 16h. TLC confirmed the completion of the reaction, and the mixture was cooled to room temperature and filtered through a celite pad. The filtrate was evaporated to dryness and 200mL of petroleum ether was added. The mixture was washed twice with 50mL of saturated ammonium chloride. The organic phase was dried and concentrated to obtain a crude product, which was recrystallized to obtain 41g (0.098mol) of intermediate Q3. 1 H NMR (400 MHz, CDCl 3 ):8.09(dd,J=6.4,2.0Hz,1H),4.18(d,J=4.9Hz,1H),2.67-2.54(m,2H),2.43(dd,J=6.1,2.3Hz,1H),2.34(dd,J=14 .9,6.6Hz,1H),1.93-1.71(m,2H),1.44(s,9H),1.31(s,6H),1.19(s,8H),0.87(d,J=2.1Hz,9H),0.09-0.04(m,6H).

[0040] Example 2

[0041] Under nitrogen protection, 71 g (0.196 mmol) of intermediate IV, 28.5 g (0.235 mol) of R-tert-butylsulfenamide, and 7.1 g Molecular sieves, 7.1g magnesium sulfate, 3.2g (0.017mmol) p-toluenesulfonic acid monohydrate and 1.0L dioxane, slowly heated to 80°C, and kept warm for 12h under weak reflux. TLC confirmed the completion of the reaction, cooled to room temperature, filtered through a diatomaceous earth pad, and the filtrate was evaporated to dryness, 200mL petroleum ether was added, and washed twice with 50mL saturated ammonium chloride. The organic phase was dried and concentrated to obtain a crude product, which was recrystallized to obtain 36g of intermediate Q3.

[0042] Example 3

[0043]

[0044] Under nitrogen protection, weigh 0.57g (3.57mmol) of anhydrous copper sulfate and 0.32g (0.86mmol) of tricyclohexylphosphine-tetrafluoroborate into a three-necked flask, then add 60mL of pure water, and then add 0.385g (3.57mmol) of benzylamine to activate for 15 minutes. Dissolve 30g (71.5mmol) of intermediate Q3 in 300mL of n-heptane, add to the reaction system, add 21.8g (85.8mmol) of double pinacol diboron in batches, cool in a water bath, control 20-30℃ to react for 3 hours, and TLC confirms that the reaction is complete. Filter with diatomaceous earth pad, wash the filtrate twice with 50mL of saturated ammonium chloride, dry with anhydrous sodium sulfate, and concentrate to obtain 34g of crude intermediate Q4, which is directly used in the next step. 1 H NMR (400 MHz, CDCl 3 ):4.07-3.99(m,1H),3.16-3.05(m,1H),3.00-2.88(m,1H),2.35-2.23(m,2H),1. 36(s,9H),1.19-1.15(m,19H),1.12(s,8H),0.80(s,9H),-0.01(d,J=7.3Hz,6H).

[0045] Example 4

[0046] Weigh 0.57g (3.57mmol) of anhydrous copper sulfate and 0.32g (0.86mmol) of tricyclohexylphosphine-tetrafluoroborate into a three-necked flask, then add 60mL of pure water, replace with nitrogen three times, add 0.385g (3.57mmol) of benzylamine, activate for 15 minutes, dissolve 30g (71.5mmol) of intermediate Q3 in 300mL of toluene, add to the reaction system, add 21.8g (85.8mmol) of bis-pinacol diboron in batches, cool in a water bath, control the reaction at about 25°C for 3 hours, and confirm the completion of the reaction by TLC. Filter through a diatomaceous earth pad, wash the filtrate twice with 50mL of saturated ammonium chloride, dry over anhydrous sodium sulfate, and concentrate to obtain 31.2g of crude intermediate Q4, which is directly used in the next step.

[0047] Example 5

[0048]

[0049] The intermediate Q4 was dissolved in 200 mL of petroleum ether, and 20 mL of 4 M HCl / dioxane solution was added twice. The reaction was confirmed to be complete by LC-MS control. The system was cooled to 0-5°C in an ice bath, stirred for more than 1 hour, filtered under nitrogen protection, and then rinsed with MTBE. The product II was obtained by reducing the pressure to constant weight to obtain 6.8 g (25.7 mmol). 1 H NMR (400 MHz, DMSO-d 6):8.67(s,1H),7.77(s,3H),4.29(dd,J=7.7,3.3Hz,1H),2.79-2.60(m,1H),2.46(dd,J=9.9,5.3Hz,1 H),2.51-2.29(m,2H),2.03(s,1H),1.84(d,J=11.8Hz,1H),1.68-1.60(m,1H),1.45(d,J=5.2Hz,9H).

[0050] Example 6

[0051]

[0052] Suspend 20g (75.5mmol) of intermediate II in 200mL of dichloromethane, cool to 5°C in an ice bath, add 18.1g (112.7mmol) of thiopheneacetyl chloride, stir for 15 minutes, then add 30g (297mmol) of N-methylmorpholine, stir for 15 minutes, naturally warm to room temperature and stir for 2-3h, LC-MS confirms the completion of the reaction. Add 60mL of 10% citric acid aqueous solution in an ice bath, separate the liquids, extract the aqueous phase with 100mL*3 of ethyl acetate, dry the organic phase, concentrate to obtain a crude product, and recrystallize from ethyl acetate / petroleum ether to obtain 18.6g (52.7mmol) of product III. 1 H NMR (400 MHz, CDCl 3 ):7.19-7.08(m,1H),6.93-6.79(m,3H),4.17-4.09(m,1H),3.99-3.86(m,2H),3.80(s,1H),3.37(d,J=11.9Hz ,1H),2.81(m,1H),2.74(m,2H),1.45(s,9H),1.37(m,4H),1.18(m,2H),1.16-1.05(m,1H),0.84-0.71(m,1H).

[0053] Example 7

[0054]

[0055] 15g (42.5mmol) of intermediate III, 2.5g (40.4mmol) of boric acid, 45mL of dioxane and 15mL of 1M sulfuric acid mixture were added to the reaction flask in sequence and heated and stirred at 75°C for 7 hours. The reaction solution was cooled to 0°C. The pH was adjusted to 4.5-5.0 using 2M NaOH solution, and the aqueous layer was extracted with methyl tert-butyl ether and concentrated to dryness to obtain an oily substance, which was re-dissolved in water and filtered. The aqueous phase was adjusted to pH = 2.0 with dilute sulfuric acid, and stirred at room temperature for 2-3 hours to precipitate solids. Filter, wash the filter cake with ice water, and vacuum dry to obtain 8.8g (29.6mmol) of off-white product I, 1 H NMR (400MHz, CD 3 OD):7.34-7.38(dd,1H),7.04-7.08(m,1H),6.97-7.04(m,1H),4.06-4.14(m,1H),3.97(s,2H),2.58-2.67 (m,1H),2.33-2.41(dd,1H),2.21-2.33(td,1H),1.69-1.80(m,1H),1.47-1.69(m,2H),0.97-1.11(q,1H).

[0056] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A faborbactam intermediate, characterized in that: The chemical structure is as follows:

2. A method for preparing vaborbactam, characterized in that: The chemical reaction equation is expressed as follows: Among them: R = t-BuMe2Si, Me3Si, Et3Si, i-Pr3Si, Ph2MeSi.

3. The method for preparing vaborbactam according to claim 2, characterized in that: The steps include: In the first step, the intermediate Q3 is reacted with pinacol diborate in the presence of a catalyst metal copper salt and an alkylphosphine fluoroborate to obtain a chiral borate ester Q4; Step 2: Intermediate Q4 is hydrolyzed, deprotected and cyclized under acidic conditions to generate key intermediate II; Step 3: Intermediate II reacts with thiophene-2-acetyl chloride in the presence of a base to obtain intermediate III; Step 4: The intermediate III is hydrolyzed under acid conditions to obtain faborbactam I.

4. The method for preparing vaborbactam according to claim 3, characterized in that: In the first step, the metal copper salt is selected from copper sulfate or copper acetate; the alkyl phosphine fluoroborate is selected from tricyclohexyl phosphine fluoroborate and tri-tert-butyl phosphine fluoroborate.

5. The method for preparing vaborbactam according to claim 3, characterized in that: In the first step, the molar ratio of the intermediate Q3, pinacol diboron, copper metal salt, benzylamine and alkylphosphine fluoroborate is 1.0:1-1.2:0.02-0.05:0.02-0.05:0.01-0.

012.

6. The method for preparing vaborbactam according to claim 3, characterized in that: In the second step, the acid is selected from hydrochloric acid or hydrogen chloride solution; the molar ratio of the intermediate Q4 to the acid is 1:2.0-4.

0.

7. The method for preparing vaborbactam according to claim 3, characterized in that: In the third step, the base is selected from triethylamine, pyridine, and N-methylmorpholine.

8. The method for preparing vaborbactam according to claim 3, characterized in that: In the third step, the molar ratio of the intermediate II, thiophene-2-acetyl chloride and the base is 1.0:1.5-2.5:1.5-3.

9. The method for preparing vaborbactam according to claim 3, characterized in that: In the fourth step, the acid is selected from at least one of boric acid, sulfuric acid, hydrochloric acid and acetic acid.

10. The method for preparing vaborbactam according to claim 3, characterized in that: In the fourth step, the molar ratio of the intermediate III to the acid is 1:1.5-3.0.

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