Beta-lactamase inhibitor intermediate and preparation method thereof

Abstract

The invention relates to a preparation method of a beta-lactamase inhibitor intermediate, and provides a preparation method of a beta-lactamase inhibitor intermediate 1, the reaction is as follows: # imgabs0 #, R1 is selected from any one of Bn, Cbz, Boc and Fmoc, and R2 is C1-4 alkyl; the method comprises the following steps: step 1, under the action of Lewis acid and an organic solvent, reacting a compound shown in a formula 3 with ethyl diazoacetate to obtain a compound shown in a formula 1; as mentioned above, the preparation method of the beta-lactamase inhibitor intermediate has the advantages of high selectivity, low cost and simplification of post-treatment.

Description

Technical Field

[0001] The invention relates to a method for preparing a beta-lactamase inhibitor intermediate, and belongs to the technical field of medicine and chemistry. Background Art

[0002] β-lactamase inhibitors can inhibit most β-lactamases produced by bacteria and are often used in combination with β-lactam antibiotics to prevent the β-lactam ring in the antibiotics from being hydrolyzed, thereby protecting the antibacterial effect of β-lactam antibiotics.

[0003] The most commonly used β-lactamase inhibitors are clavulanic acid, sulbactam, tazobactam, avibactam, vaborbactam and relebactam.

[0004] The key intermediate of β-lactamase inhibitor is Formula I, and its structure is as follows:

[0005]

[0006] The existing method for further using compound 1 to prepare β-lactamase inhibitors is reported as follows:

[0007] 1) Medicinal Chemistry Research (1992), 2 (7-8), 491-6 disclosed the following route:

[0008]

[0009] The literature reported that the ratio of the isomers in the ring expansion was not disclosed. The ratio of the target product to the isomeric impurity after decarboxylation was 1.3:1. The results showed that the isomer ratio was low and the overall yield was also low.

[0010] 2) Tetrahedron: Asymmetry (2006), 17 (17), 2479-2486 The published route is as follows:

[0011]

[0012] This document adds enol impurities in addition to isomeric impurities, and the types of impurities are more numerous and difficult to remove.

[0013] The invention provides a novel preparation method of a beta-lactamase inhibitor intermediate. The preparation method of the invention has high selectivity, few impurities, simple purification, and is suitable for industrial production, so it has good market value and far-reaching practical significance. Summary of the invention

[0014] In view of the above technical background, the present invention provides a β-lactamase inhibitor intermediate and a preparation method thereof.

[0015] The first aspect of the present invention provides a method for preparing a β-lactamase inhibitor intermediate 1, the reaction is as follows:

[0016]

[0017] Wherein, R1 is selected from any one of Bn, Cbz, Boc, and Fmoc, and R2 is C 1-4 Alkyl, preferably methyl, ethyl, tert-butyl;

[0018] The following steps are included:

[0019] Step 1: Under the action of Lewis acid and an organic solvent, the compound of formula 3 is reacted with ethyl diazoacetate to obtain a compound of formula 1;

[0020] The Lewis acid is selected from one of BF3·Et2O, Me3Al, and methylaluminum bis(2,6-di-tert-butyl-4-anisole) (MAD);

[0021] The organic solvent is selected from one or more of DCM, THF and Et2O;

[0022] In step 1, the ratio of the compound of formula 3 to ethyl diazoacetate is 1:(1-2), preferably 1:(1.1-1.7);

[0023] The reaction temperature of step 1 is 0°C to -78°C, preferably -20°C to -65°C, more preferably -45°C to -65°C; the reaction time is 2 to 12 hours, preferably 2 to 8 hours;

[0024] Another preferred technical solution of the present invention adopts a staged temperature increase reaction condition, wherein the reaction temperature of step 1 is preferably between -45°C and -65°C and stirred for 2 to 8 hours, preferably 5 to 7 hours, and then heated to -35°C to -55°C and stirred for 1 to 2 hours.

[0025] The second aspect of the present invention provides a method for preparing compound 4, the reaction is as follows:

[0026]

[0027] Wherein, R1 is selected from any one of Bn, Cbz, Boc, and Fmoc, and R2 is C 1-4 Alkyl, preferably methyl, ethyl, tert-butyl;

[0028] The following steps are included:

[0029] Step 1: Under the action of Lewis acid and an organic solvent, the compound of formula 3 is reacted with ethyl diazoacetate to obtain a compound of formula 1;

[0030] Step 2: The compound of formula 1 is reacted in a reaction system of NaCl and DMF to obtain a compound of formula 4.

[0031] The Lewis acid is selected from one of BF3·Et2O, Me3Al, and methylaluminum bis(2,6-di-tert-butyl-4-anisole) (MAD);

[0032] The organic solvent is selected from one or more of DCM, THF and Et2O;

[0033] In step 1, the ratio of the compound of formula 3 to ethyl diazoacetate is 1:(1-2), preferably 1:(1.1-1.7);

[0034] The reaction temperature of step 1 is 0°C to -78°C, preferably -20°C to -65°C, more preferably -45°C to -65°C; the reaction time is 2 to 12 hours, preferably 2 to 8 hours;

[0035] Another preferred technical solution of the present invention adopts a staged temperature increase reaction condition, wherein the reaction temperature of step 1 is preferably between -45°C and -65°C and stirred for 2 to 8 hours, preferably 5 to 7 hours, and then heated to -35°C to -55°C and stirred for 1 to 2 hours.

[0036] The reaction temperature of step 2 is 110°C to 130°C, preferably 120°C to 125°C; the reaction time is 6 to 15h, preferably 8 to 12h;

[0037] The decarboxylation reaction in step 2 is preferably carried out in a reaction system of NaCl, DMF, a small amount of water, 120-125° C., and 10-12 h.

[0038] The third aspect of the present invention provides a β-lactamase inhibitor intermediate, the structural formula of which is shown in Formula 1:

[0039]

[0040] Wherein, R1 is Boc, and R2 is selected from any one of ethyl and tert-butyl;

[0041] Or R1 is Cbz, R2 is selected from any one of methyl and ethyl;

[0042] Or R1 is Fmoc, and R2 is selected from any one of methyl, ethyl, and tert-butyl;

[0043] Or R1 is Bn, and R2 is selected from any one of methyl and tert-butyl.

[0044] The fourth aspect of the present invention provides a method for preparing a β-lactamase inhibitor (eg, Avibactam, Relebactam, Zidabactam, Nacubactam, Zidebactam, WCK 5153) from the above-mentioned β-lactamase inhibitor intermediate compound of formula 1.

[0045] The fifth aspect of the present invention also provides a method for preparing a β-lactamase inhibitor (such as Avibactam, Relebactam, Zidabactam, Nacubactam, Zidebactam, WCK 5153), comprising the method for preparing a β-lactamase inhibitor intermediate 1 provided by the first aspect of the present invention.

[0046] The sixth aspect of the present invention also provides a method for preparing a β-lactamase inhibitor (e.g., Avibactam, Relebactam, Zidabactam, Nacubactam, Zidebactam, WCK 5153), comprising the second aspect of the present invention providing a method for preparing compound 4. Compound 4 can be prepared by referring to the method in the prior art WO2012172368A1 to obtain Avibactam.

[0047] As described above, the method for preparing the β-lactamase inhibitor intermediate of the present invention has the advantages of high selectivity, low cost and simplified post-treatment.

[0048] Beneficial technical effects of the present invention:

[0049] 1. High selectivity; compared with the literature Medicinal Chemistry Research (1992), 2 (7-8), 491-6, the selectivity is increased from 1.3:1 to (2-5):1.

[0050] 2. Impurities are reduced; compared with the document Tetrahedron: Asymmetry (2006), 17 (17), 2479-2486, the preparation method provided by the present invention does not contain impurities of enol interconversion.

[0051] 3. The preparation method of the β-lactamase inhibitor intermediate provided by the present invention improves selectivity while reducing impurity generation and improving yield, and is suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 This is the HPLC spectrum of Example 1.2 of the present invention after 6 hours of reaction;

[0053] Figure 2 This is the HPLC spectrum of Example 1.5 of the present invention after a reaction time of 6 hours;

[0054] Figure 3 This is the HPLC spectrum of Example 1.8 of the present invention after 6 hours of reaction;

[0055] Figure 4 This is the HPLC spectrum of Example 1.12 of the present invention after a reaction time of 2 h;

[0056] Figure 5 This is the HPLC spectrum of Example 1.12 of the present invention after a reaction time of 4 hours;

[0057] Figure 6 This is the HPLC spectrum of Example 1.12 of the present invention after 7 hours of reaction;

[0058] Figure 7 This is the HPLC spectrum of Example 2.4 of the present invention after 6 hours of reaction;

[0059] Figure 8 This is the HPLC spectrum of the reaction solution of Example 3.2 of the present invention; DETAILED DESCRIPTION

[0060] The present invention will be further described in conjunction with specific examples. It should be understood that the following detailed description of the technical solution of the present invention with examples will help to further understand the advantages and effects of the technical solution of the present invention, and the examples do not limit the protection scope of the present invention, which is determined by the claims.

[0061] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0062] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0063] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used directly without further treatment.

[0064] Specific implementation:

[0065] Example 1.1:

[0066]

[0067] At -65 ° C, compound 3A (25.73 g, 100 mmol), DCM (130 mL), ethyl diazoacetate (17.1 g, 150 mmol), BF3·Et2O (17.03 g, 120 mmol) were slowly added to a three-necked flask. The mixture was stirred at -65 ° C for 6 h, then heated to -55 ° C and stirred for 1 h. After the detection reaction was completed, the mixture was poured into a saturated NaHCO3 aqueous solution and stirred for 30 minutes, separated, extracted, dried, filtered, and concentrated to obtain a crude product, which was purified by silica gel chromatography (petroleum ether / ethyl acetate / triethylamine=20 / 1 / 0.02) to obtain: colorless oil compound 1A (23.87 g, 69.5 mmol, yield: 69.5%); Mass (m / z) = 244.1 [M + -100+1]; 1H NMR(400MHz, CDCl3):5.03(d,1 / 2·1H),4.86(d,1 / 2·1H),4.16-4.29(m,6H),3.91-3.94(m,1H),2. 94-3.01(m,1H),2.52-2.57(m,1H),1.49(s,1 / 2·9H),1.46(s,1 / 2·9H),1.32(m,3H),1.25(m,3H).

[0068] The obtained compound 2A (4.98 g, 14.5 mmol, yield: 14.5%) was obtained as a colorless oil; Mass (m / z) = 244.1 [M + -100+H]; 1 H NMR (400MHz, CDCl3): 4.95 (d, J=6.5Hz, 1 / 2·1H), 4.83 (d, 1 / 2·1H), 4.06-4.24 (m, 6H), 3.81-3.91 (m, 1H ),2.82-2.88(m,1H),2.69-2.75(m,1H),1.50(s,1 / 2·9H),1.47(s,1 / 2·9H),1.32(m,3H),1.25(m,3H).

[0069] Examples 1.1 to 1.11 Referring to the operation method of Example 1.1, the type and amount of solvent, reaction temperature, catalyst type and feeding method were changed to prepare the product compound 1A, as shown in Table 1 below.

[0070] Table 1 Experimental conditions and results of Examples 1.1 to 1.11

[0071]

[0072] Example 2.1:

[0073]

[0074] Compound 3B (15.97 g, 50 mmol) and ethyl diazoacetate (8.56 g, 75 mmol) were dissolved in DCM (80 mL), and BF3·Et2O (8.52 g, 60 mmol) was slowly added dropwise at -65°C, and the mixture was stirred at -65°C for 6 h. The reaction mass was detected to have a residual of about 3%, and the mixture was poured into saturated NaHCO3 (80 mL) and stirred for 30 minutes. Liquid separation, extraction, liquid separation, drying, filtration and concentration were performed to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate / triethylamine = 25 / 1 / 0.02) to obtain: colorless oil compound 1B (12.73 g, 31.4 mmol, yield: 62.8%); Mass (m / z) = 406.1 [M+ +H]; 1 H NMR(CDCl3,500MHz):7.42-7.30(m,5H),5.24(dd,2H),5.16-5.06(m,1 / 2·1H),5.02-4.94(m,1 / 2·1H),4.24-4.10( m,2H),4.10–3.95(m,2H),3.61(m,1H),2.98(m,1H),2.70(m,1H),1.43(s,1 / 2·9H),1.42(s,1 / 2·9H),1.32(d,3H).

[0075] The colorless oily compound 2B (3.2 g, 7.8 mmol, yield: 15.7%) was obtained; Mass (m / z) = 406.1 [M + +H]; 1 H NMR(CDCl3,500MHz):7.41-7.28(m,5H),5.23(dd,2H),5.14-5.04(m,1 / 2·1H),5.00-4.84(m,1 / 2·1H),4.22-4.08( m,2H),4.00-3.85(m,2H),3.55(m,1H),2.88(m,1H),2.60(m,1H),1.42(s,1 / 2·9H),1.41(s,1 / 2·9H),1.32(d,3H).

[0076] Examples 2.1 to 2.5 Referring to the operation method of Example 2.1, the type and amount of solvent, the type of catalyst and the method of adding materials were changed to prepare compound 1B, as shown in Table 2 below.

[0077] Table 2 Experimental conditions and results of Examples 2.1 to 2.5

[0078]

[0079] Example 3.1:

[0080]

[0081] Compound 1A (80 g, 294.9 mmol), N,N-dimethylformamide (320 mL), water (32 mL) and sodium chloride (17.2 g, 294.9 mmol) were added to the reaction flask. The reaction solution was heated to between 120 and 125 °C in an oil bath and stirred for 12 h. After the reaction, the reaction solution was poured into water (240 mL), stirred for 30 min, methyl tert-butyl ether (MTBE) (80 mL) was added, and the stratification was allowed to stand. The aqueous phase was extracted with MTBE (40 mL × 2). The organic phases were combined and concentrated to obtain 92 g of crude product, with a crude yield of more than 100%. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate / =30 / 1) to obtain: colorless oil compound 4A (55.62 g, 205 mmol, yield: 88%); Mass (m / z) = 172.3 [M + +H-100]; 1 H NMR(CDCl3,500MHz):4.63-4.82(dd,2H),4.19-4.21(q,2H),4.07-4.11(d,1H),3.64(m,1H),2.67-2.77( m,1H),2.27-2.30(dd,1H),1.95-1.99(dq,1H),1.77(m,1H),1.47-1.50(s,9H),(s,1 / 2·9H),1.27(t,3H).

[0082] Example 3.2

[0083]

[0084] Add compound 1A+2A mixture (80g, 294.9mmol, configuration ratio 2.4:1), N,N-dimethylformamide (320mL), water (32mL) and sodium chloride (17.2g, 294.9mmol) to a 1000mL three-necked flask. Heat the reaction solution to 120-125°C in an oil bath and stir for 12h. After the reaction, pour the reaction solution into water (240mL), stir for 30min, add MTBE (80mL), let stand for stratification, and extract the aqueous phase with MTBE (40mL×2). Combine the organic phases, concentrate the organic phase to obtain 97g of crude product, and the crude product yield is greater than 100%. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate / =30 / 1) to obtain: colorless oil compound 4A+4B (53.7 g, 198 mmol, yield: 85%). After testing, the ratio of 4A to 4B was 2.3:1; Mass (m / z) = 172.3 [M + +H-100].

Claims

1. A method for preparing a β-lactamase inhibitor intermediate 1, comprising the following steps: in, R1 is selected from any one of Bn, Cbz, Boc and Fmoc, and R2 is C 1-4 Alkyl, preferably methyl, ethyl, tert-butyl; The following steps are included: Step 1: Under the action of Lewis acid and organic solvent, the compound of formula 3 is reacted with ethyl diazoacetate to obtain the compound of formula 1.

2. A method for preparing compound 4, the reaction is as follows: in, R1 is selected from any one of Bn, Cbz, Boc and Fmoc, and R2 is C 1-4 Alkyl, preferably methyl, ethyl, tert-butyl; The following steps are included: Step 1: Under the action of Lewis acid and an organic solvent, the compound of formula 3 is reacted with ethyl diazoacetate to obtain a compound of formula 1; Step 2: The compound of formula 1 is reacted in a reaction system of NaCl and DMF to obtain a compound of formula 4.

3. The preparation method according to claim 1 or 2, characterized in that: The Lewis acid is selected from one of BF3.Et2O, Me3Al, and methylaluminum bis(2,6-di-tert-butyl-4-anisole) (MAD).

4. The preparation method according to claim 1 or 2, characterized in that: The organic solvent is selected from one or more of DCM, THF and Et2O.

5. The preparation method according to claim 1 or 2, characterized in that: In the step 1, the ratio of the compound of formula 3 to ethyl diazoacetate is 1:(1-2), preferably 1:(1.1-1.7).

6. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step 1 is 0°C to -78°C, preferably -20°C to -65°C, more preferably -45°C to -65°C; the reaction time is 2 to 12 hours, preferably 2 to 8 hours.

7. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step 1 adopts a staged heating reaction condition. The reaction temperature of step 1 is preferably at -45°C to -65°C and stirred for 2 to 8 hours, preferably 5 to 7 hours, and then heated to -35°C to -55°C and stirred for 1 to 2 hours.

8. A β-lactamase inhibitor intermediate, the structural formula of which is shown in Formula 1: in, R1 is Boc, R2 is selected from any one of ethyl and tert-butyl; Or R1 is Cbz, R2 is selected from any one of methyl and ethyl; Or R1 is Fmoc, and R2 is selected from any one of methyl, ethyl, and tert-butyl; Or R1 is Bn, and R2 is selected from any one of methyl and tert-butyl.

9. A method for preparing a β-lactamase inhibitor from the β-lactamase inhibitor intermediate compound of formula 1 according to claim 8, wherein the β-lactamase inhibitor is selected from avibactam, relebactam, zidabactam, nacubactam, zidebactam or WCK 5153.

10. A method for preparing a β-lactamase inhibitor, wherein the β-lactamase inhibitor is selected from Avibactam, Relebactam, Zidabactam, Nacubactam, Zidebactam, and WCK 5153), comprising the method for preparing a β-lactamase inhibitor intermediate 1 according to claim 1 or the method for preparing a compound 4 according to claim 2.

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