Preparation of boronic acid intermediates useful for the preparation of compounds for treating bacterial infections

Abstract

Provided herein are methods of preparing intermediates which are useful in the preparation of compounds which are useful in treating bacterial infections.

Description

PREPARATION OF BORONIC ACID INTERMEDIATES USEFUL FOR THE PREPARATION OF COMPOUNDS FOR TREATING BACTERIAL INFECTIONSRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. provisional application No. 63 / 599,421, filed November 15, 2023, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] Sulbactam / durlobactam (XACDURO®), is a co-packaged antibacterial product that is approved for the treatment of hospital-acquired bacterial pneumonia and ventilator- associated bacterial pneumonia (HABP / VABP) caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC). Processes for the preparation of durlobactam are described in e.g., WO 2013 / 150296. Given the medical need for this drug product, more efficient and cost-effective means for preparing durlobactam are needed.SUMMARY

[0003] Provided herein are methods of using copper as a co-catalyst for the preparation of a boronic acid intermediate used in the synthesis of durlobactam. Such methods include borylation of a compound having the structural formula II:using copper as a co-catalyst for the reaction. In one aspect, the inclusion of a catalytic amount of copper significantly reduces the amount of palladium source required for the transformation.

[0004] Also provided are methods for preparing a compound having the formula III:said method comprising reacting the compound of formula I prepared by the process described above and herein, with a compound of the formula IV :to form the compound of formula III.DETAILED DESCRIPTION

[0005] In one aspect, provided is a preparing a compound having the structural formula I:said method comprising reacting a compound having the structural formula II:with a boronating agent, a palladium source, and a copper catalyst to form the compound of formula I.

[0006] In one aspect, the copper catalyst is selected from Cui, CuBr, CuCl, Cu(CO2CH3), CuBr2, CuCh, CuSO4, CuO, Cu(CO2CH3)2, Cu(CF3SO3)2, Cu(NO3)2, (NH4)2CuCl4, and copper(II) tosylate. In another aspect, the copper catalyst is CuCl2.

[0007] In one aspect, the amount of copper catalyst used in the reaction ranges from about 0.009 equivalents to about 0.1 equivalents per about 1 equivalent of the compound of formula II. In another aspect, the amount of copper catalyst used in the reaction is about 0.05 equivalents per about 1 equivalent of the compound of formula II.

[0008] In one aspect, the palladium source is selected from PdCl2, (CeHsCN PdCh, [PdCl(C3H5)]2, Pd(OCOCH3)2, Pd[(C6H5)3P]4, [(C6H5)3P]2PdCl2, (C6H5CH=CHCOCH=CHC6H5)2Pd, Pd(NO3)2, Pd(C5H7O2)2, PdCl2(C26H44FeP2), Pd(CF3COO)2, Pd(CH3CN)4(BF4)2, PdCl2(CH3CN)2, and Pd(NH3)4Cl2. In another aspect, the palladium source is PdCl2.

[0009] In one aspect, the amount of palladium source used in the reaction ranges from about 0.005 equivalents to about 0.1 equivalents per about 1 equivalent of the compound of formula II. In another aspect, the amount of palladium source used in the reaction is about 0.02 equivalents per about 1 equivalent of the compound of formula II.

[0010] In one aspect, the boronating agent is selected from B2(OH)4, CH3(CH2)3B(OH)2, C6H4[B(OH)2]2, C6H5B(OH)2, CH3B(OH)2, CH3OC6H4B(OH)2, CH3C6H4B(OH)2, NH2C6H4B(OH)2, HO2CC6H4B(OH)2, CH3O2CC6H4B(OH)2, HCOC6H4B(OH)2, CNC6H4B(OH)2, IC6H4B(OH)2, BrC6H4B(OH)2, C1C6H4B(OH)2, FC6H4B(OH)2, NCSH4B(OH)2, C3HSB(OH)2, CIOH7B(OH)2, pinacolborane, bis(pinacolato)diboron,phenylboronic acid pinacol ester, bis(neopentyl glycolato)diboron, catecholborane, and bis(catecholato)diboron. In another aspect, the boronating agent is B2(OH)4.

[0011] In one aspect, the amount of the boronating agent used in the reaction ranges from about 0.5 equivalents to about 3 equivalents per about 1 equivalent of the compound of formula II. In another aspect, the amount of the boronating agent used in the reaction is about 1.2 equivalents per about 1 equivalent of the compound of formula II.

[0012] In one aspect, the reaction of compound II with the boronating agent, a palladium source, and a copper catalyst further comprises the addition of acid to the reaction. In one aspect, the acid selected from H2SO4, HF, HC1, HBr, HI, HCIO4, HNO3, HO2C2O2H, H2SO3, H3PO4, HNO2, HCO2H, C6H5COOH, CH3COOH, H2CO3, and H2S. In another aspect, the acid is H2SO4.

[0013] In one aspect, the amount of acid used in the reaction ranges from about 0.05 equivalents to about 1.5 equivalents per about 1 equivalent of the compound of formula II. In another aspect, the amount of acid used in the reaction is about 0.3 equivalents per about 1 equivalent of the compound of formula II.

[0014] The following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure.EXEMPLIFICATION

[0015] A general procedure for preparing the compounds described herein are shown in the scheme below.

[0016] Preparation for Compound I

[0017] MeOH (465 kg, 2.0 V) was charged to a reactor with agitation (e.g., at a speed set at 100 rpm). The solvent was allowed to reflux (e.g., for at least 1 hour) and was cooled (e.g., to 20 + 5°C). CuCl2(163.4 g, 0.05% eq.) was added cold (e.g., at 0 + 5°C) followed by PdCl2(86.3 g, 0.02% eq.) and H2SO4 (72 kg, 0.30 eq.). (E)-but-2-en-l-ol (227 kg, 1.3 eq.) was added (e.g., at 10 ± 10°C) and the reaction was warmed (e.g., to 40 ± 5°C). B2(OH)4 (262 kg, 1.20 eq.) was charged in batches at elevated temperature (e.g., 40 ± 5°C) and the reaction was stirred at temperature (e.g., for at least 1 hour at 40 ± 5°C). The reaction was cooled (e.g., temperature was adjusted to 0 ± 5°C) and was stirred once cooled (e.g., for at least 30 min at 0 ± 5°C). The reaction was centrifuged and the mother liquor was transferred back to the reactor. Agitation was started (e.g., at 100 rpm) and the mixtures was cooled (e.g., to 0 ± 5°C).

[0018] H2SO4 (48 kg, 0.20 eq.) was added to the cold solution (e.g., at 0 ± 5°C and and stirred (e.g., at 0 ± 5°C for further use).

[0019] Preparation for Int-1

[0020] Dichloromethane (1175 kg, 3.0 V) was charged to a reactor with agitation (e.g., at a speed of 100 rpm). The temperature was adjusted (e.g., to 15 ± 5°C) and glyoxylic acid monohydrate (268 kg, 1.2 eq.) and trimethylamine (244 kg, 1.0 eq.) were added (e.g., at 15 ± 5°C). The reaction was stirred (e.g., for at least 4 hour at 15 ± 5°C) and AC2O (495 kg, 2.0 eq.) was slowly added (e.g., at 15 ± 5°C). The reaction was stirred (e.g., for at least 30 minutes) and (S)-(-)-tert butyl sulfonamide (295 kg, 1.0 eq.) was added (e.g., at 15 ± 5°C). The reaction was stirred (e.g., for at least 10 hours at 20 ± 5°C) and the solution was labeled as Compound III solution.

[0021] Preparation for Compound III

[0022] The Compound I solution as generated above was added to the reaction containing the Compound III solution (e.g., at 5 ± 10°C). The reaction was stirred (e.g., for 1 hour at 5 ± 10°C) and soften water (1767 kg, 6.0 V) was added to the reaction (e.g., at 10 ± 10°C), and the mixture was stirred (e.g., for at least 1 hour at 20 ± 5°C) and held (e.g., for at least 0.5 hour) before separation. The organic phase was transferred to a separate reactor and soften water (1473 kg, 5.0 V) was added (e.g., at 20 ± 5°C). The mixture was stirred (e.g., for at least 0.5 hour at 20 ± 5°C) and then held (e.g., for at least 0.5 hour) before separation. The organic phase was transferred and the aqueous phase was discarded, and the organic phase was concentrated under vacuum (e.g., with inner temperature < 40°C to 3-4 V). Soften water (1767 kg, 6.0 V) was added and the mixture was concentrated under vacuum (e.g., with inner temperature < 45°C to 7-8 V). The concentrated mixture was stirred (e.g., for at least 2 hours at 20 ± 5 °C). Soften water (1178 kg, 4.0 V) was added (e.g., at 20 ± 5°C) and the mixture was cooled (e.g., to 5 ± 5°C) and stirred (e.g., for at least 2 hours). The mixture was centrifuged and the cake was washed with soften water (589 kg, 2.0 V), and dried at undervacuum (e.g., 45 ±5°C for at least 24 hours) to afford Compound III (373 kg, 100 % purity, 66% yield in three steps). HPLC purity was is >95%. Chiral HPLC purity was > 99%.

[0023] By way of comparison, the same experiments were performed above except that in Step 1, no CuCh was added. In this case 45-180 fold more palladium was needed to drive the reaction forward.

[0024] While we have described several embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0025] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

Listing of Claims:

1. A method for preparing a compound having the structural formula I:said method comprising reacting a compound having the structural formula II:with a boronating agent, a palladium source, and a copper catalyst to form the compound of formula I.

2. The method of Claim 1, wherein the copper catalyst is selected from Cui, CuBr, CuCl, CU(CO2CH3), CuBr2, CuCl2, CuSO4, CuO, Cu(CO2CH3)2, Cu(CF3SO3)2, Cu(NO3)2, (NH4)2CUC14, and copper(II) tosylate.

3. The method of Claim 1 or 2, wherein the copper catalyst is CuCl2.

4. The method of any one of Claims 1 to 3, wherein the amount of copper catalyst used in the reaction ranges from about 0.009 equivalents to about 0.1 equivalents per about 1 equivalent of the compound of formula II.

5. The method of any one of Claims 1 to 4, wherein the amount of copper catalyst used in the reaction is about 0.05 equivalents per about 1 equivalent of the compound of formula II.

6. The method of any one of Claims 1 to 5, wherein the palladium source is selected from PdCl2, (C6H5CN)2PdCl2, [PdCl(C3H5)]2, Pd(OCOCH3)2, Pd[(C6H5)3P]4, [(C6H5)3P]2PdCl2, (C6H5CH=CHCOCH=CHC6H5)2Pd, Pd(NO3)2, Pd(C5H7O2)2, PdCl2(C26H44FeP2), Pd(CF3COO)2, Pd(CH3CN)4(BF4)2, PdCl2(CH3CN)2, and Pd(NH3)4Cl2.

7. The method of any one of Claims 1 to 6, wherein the palladium source is PdCl2.

8. The method of any one of Claims 1 to 7, wherein the amount of palladium source used in the reaction ranges from about 0.005 equivalents to about 0.1 equivalents per about 1 equivalent of the compound of formula II.

9. The method of any one of Claims 1 to 8, wherein the amount of palladium source used in the reaction is about 0.02 equivalents per about 1 equivalent of the compound of formula II.

10. The method of any one of Claims 1 to 9, wherein the boronating agent is selected from B2(OH)4, CH3(CH2)3B(OH)2, C6H4[B(OH)2]2, C6H5B(OH)2, CH3B(OH)2, CH3OC6H4B(OH)2, CH3C6H4B(OH)2, NH2C6H4B(OH)2, HO2CC6H4B(OH)2, CH3O2CC6H4B(OH)2, HCOC6H4B(OH)2, CNC6H4B(OH)2, IC6H4B(OH)2, BrC6H4B(OH)2, C1C6H4B(OH)2, FC6H4B(OH)2, NC5H4B(OH)2, C3H5B(OH)2, CIOH7B(OH)2, pinacolborane, bis(pinacolato)diboron, phenylboronic acid pinacol ester, bis(neopentyl glycolato)diboron, catecholborane, and bis(catecholato)diboron.

11. The method of any one of Claims 1 to 10, wherein the boronating agent is B2(OH)4.

12. The method of any one of Claims 1 to 11, wherein the amount of the boronating agent used in the reaction ranges from about 0.5 equivalents to about 3 equivalents per about 1 equivalent of the compound of formula II.

13. The method of any one of Claims 1 to 12, wherein the amount of the boronating agent used in the reaction is about 1.2 equivalents per about 1 equivalent of the compound of formula II.

14. The method of any one of Claims 1 to 13, further comprising the addition of acid to the reaction.

15. The method of any one of Claims 1 to 14, further comprising the addition of acid selected from H2SO4, HF, HC1, HBr, HI, HC1O4, HNO3, HO2C2O2H, H2SO3, H3PO4, HNO2, HCO2H, C6H5COOH, CH3COOH, H2CO3, and H2S.

16. The method of any one of Claims 1 to 15, further comprising the addition of H2SO4.

17. The method of any one of Claims 14 to 16, wherein the amount of acid used in the reaction ranges from about 0.05 equivalents to about 1.5 equivalents per about 1 equivalent of the compound of formula II.

18. The method of any one of Claims 14 to 17, wherein the amount of acid used in the reaction is about 0.3 equivalents per about 1 equivalent of the compound of formula II.

19. A method of preparing a compound having the structural formula III:said method comprising reacting the compound of formula I prepared by the method of any one of Claims 1 to 18, with a compound of the structural formula IV:to form the compound of formula III.

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