Process for the preparation of monocyclic beta-lactam compounds

Abstract

This invention proposes a method for preparing a monocyclic β-lactam compound, belonging to the field of pharmaceutical synthesis technology. The preparation method, wherein the monocyclic β-lactam compound has the structure of formula (I), includes the following steps: a) a compound having the structure shown in formula (3-11) undergoes a condensation reaction with a compound having the structure shown in formula (3-13) to obtain a compound having the structure shown in formula (I); wherein X is Cl or Me. This method has a shorter synthesis step, effectively improving synthesis efficiency and overall yield. Furthermore, it avoids the use of diphenyldiazomethane (Ph₂CN₂), completely eliminating the risk of explosion during the synthesis process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and particularly relates to a method for preparing monocyclic β-lactam compounds. Background Technology

[0002] Since the development and use of the first generation of penicillin in the 1940s, the problem of antimicrobial resistance has gradually emerged and become increasingly serious. Currently, the World Health Organization (WHO) has listed bacterial resistance as one of the greatest threats to global health and food safety. According to WHO reports, if the rise of drug-resistant bacteria is not curbed now, it is estimated that 10 million people will die from drug-resistant bacterial infections by 2050, even exceeding the 8.2 million deaths caused by cancer in 2050; it will also cause a 2-3.5% decline in global GDP by 2050, resulting in losses of up to $100 trillion. Therefore, countries in Europe and America have elevated the development of new antibiotics to a national strategy, and my country also formulated a similar five-year national action plan to curb bacterial resistance in 2016.

[0003] Monocyclic β-lactam antibiotics are one of the hottest areas in antibiotic research and development. However, to date, only aztreonam has been available for clinical use in this field, and no new or next-generation drugs have emerged since its FDA approval in 1984.

[0004]

[0005] In addition, Monobactam 1 from Pfizer International, BAL-30072 from Basilea Pharmaceuticals in Switzerland, and LYS228 from Novartis are leading players in this field, but they are still in the clinical research stage and have not yet been approved for marketing.

[0006]

[0007] The Ningxia Antibiotic New Drug R&D Innovation Team has successfully screened two compounds in the field of monocyclic lactone antibiotics: DPI-2015 (as shown in Formula Ib, WO2022027439A1; Medicinal Chemistry. 2022, vol. 18, issue 5, 574-588) and DPI-2016 (as shown in Formula Ia, WO2022011626A1; Journal of Chemistry, 2021, 6, 1174-1178), and preclinical studies have been completed.

[0008]

[0009] Existing synthetic processes, as shown in Scheme 1 (WO2022027439A1, WO2022011626A1), are generally linear processes. Specifically, starting with 3_1, intermediate 3_8a is prepared through seven steps; starting with A1, A3 is prepared through three steps. Then, 3_8a and A3 are condensed to prepare BB-1, followed by two more steps to prepare the final target compound. The main drawbacks are: firstly, the reaction steps are lengthy, resulting in low overall yields, making it difficult to meet the quantity requirements of the target compound for clinical research; secondly, the preparation of intermediate 3_6a uses diphenyldiazomethane (Ph2CN2), which poses an explosion risk when using large amounts of Ph2CN2 in the scale-up synthesis of the target compound. New synthetic processes need to be developed to avoid the use of this reagent and completely eliminate the safety risk.

[0010] Summary of the Invention

[0011] This invention proposes a method for preparing monocyclic β-lactam compounds, which is a parallel synthesis process for compounds having the structure shown in Formula Ia and compounds having the structure shown in Formula Ib. This method can effectively improve synthesis efficiency, reduce costs, and enhance the safety of the synthesis route.

[0012] This invention proposes a method for preparing a monocyclic β-lactam compound having the structure of formula (I), comprising the following steps:

[0013] a) A compound having the structure shown in formula (3_11) undergoes a condensation reaction with a compound having the structure shown in formula (3_13) to obtain a compound having the structure shown in formula (I);

[0014]

[0015] Where X is either Cl or Me.

[0016] Further, in step a), the molar ratio of the compound having the structure shown in formula (3_11) to the compound having the structure shown in formula (3_13) is 1 to 1.5:1;

[0017] In step a), the reaction temperature is 0℃; the reaction time is 5 to 24 hours.

[0018] Furthermore, the compound having the structure shown in formula (3_11) is prepared by the following steps:

[0019] b1) The compound having the structure shown in formula (3_4) is reacted with N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarbonate to give the compound having the structure shown in formula (3_5);

[0020] b2) The compound having the structure shown in formula (3_5) reacts with hydrazine hydrate to give the compound having the structure shown in formula (3_6);

[0021] b3) The compound having the structure shown in formula (3_6) reacts with a base to give the compound having the structure shown in formula (3_7);

[0022] b4) The compound having the structure shown in formula (3_7) reacts with trifluoroacetic acid to give the compound having the structure shown in formula (3_11);

[0023]

[0024] Further, in step b1), the molar ratio of the compound having the structure shown in formula (3-4) to N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarbonate is 1:1.5-2:1.5-2:1.5-2;

[0025] In step b2), the molar ratio of the compound having the structure shown in formula (3_5) to hydrazine hydrate is 1.5 to 1.6:1;

[0026] In step b3), the molar ratio of the compound having the structure shown in formula (3_6) to the base is 1:2.8 to 3.2.

[0027] Furthermore, the compound having the structure shown in formula (3_13) is prepared by the following steps:

[0028] c1) A compound having the structure shown in formula (1_4) and a compound having the structure shown in formula (1_1) undergo a condensation reaction in the presence of an amidating agent and a bicarbonate to obtain a compound having the structure shown in formula (3_12).

[0029] c2) The compound having the structure shown in formula (3_12) is deprotected to obtain the compound having the structure shown in formula (3_13);

[0030]

[0031]

[0032] In equations (1_4), (3_12), and (3_12), X represents Cl or Me.

[0033] Further, in step c1), the molar ratio of the compound having the structure shown in formula (1_4), the compound having the structure shown in formula (1_1), the amidating agent, and the bicarbonate is 1:1 to 1.2:1 to 1.5:1.8 to 2.2.

[0034] Furthermore, when X is Cl, the compound having the structure shown in formula (1_4) is the compound having the structure shown in formula (1_4A);

[0035]

[0036] When X is Me, the compound having the structure shown in formula (1_4) is the compound having the structure shown in formula (1_4B);

[0037]

[0038] Compounds having the structure shown in formula (1_4A) and compounds having the structure shown in formula (1_4B) undergo condensation reactions with compounds having the structure shown in formula (1_1), and after the Boc protecting group is removed, compounds having the structure shown in formula (3_13A) and compounds having the structure shown in formula (3_13B) are obtained, respectively.

[0039]

[0040] Furthermore, compounds having the structure shown in formula (1-4B) are prepared by the following steps:

[0041] c3) The compound having the structure shown in formula (1-4d) reacts with phenyltrimethylammonium tribromide to give the compound having the structure shown in formula (1-4e);

[0042] c4) A compound having the structure shown in formula (1-4e) reacts with thiourea to give a compound having the structure shown in formula (1-4f);

[0043] c5) The compound having the structure shown in formula (1-4f) reacts with 4-dimethylaminopyridine and ditert-butyl dicarbonate to give the compound having the structure shown in formula (1-4g);

[0044] c6) The compound having the structure shown in formula (1-4g) reacts with selenium dioxide and 2-iodobenzoic acid to give the compound having the structure shown in formula (1-4h);

[0045] c7) A compound having the structure shown in formula (1-4h) reacts with a base to give a compound having the structure shown in formula (1-4B);

[0046]

[0047] Further, in step c3), the ratio of the compound having the structure shown in formula (1-4d) to phenyltrimethylammonium tribromide is 1:1 to 1.1;

[0048] In step c4), the molar ratio of the compound having the structure shown in formula (1-4e) to thiourea is 1:1 to 1.2;

[0049] In step c5), the ratio of the compound having the structure shown in formula (1-4f), 4-dimethylaminopyridine, and ditert-butyl dicarbonate is 1:0.05 to 0.1:1 to 1.05.

[0050] Further, in step c6), the molar ratio of the compound having the structure shown in formula (1-4g), selenium dioxide, and 2-iodobenzoic acid is 1:2 to 2.4:0.5 to 0.8;

[0051] In step c7), the molar ratio of the compound having the structure shown in formula (1-4h) to the base is 1:1 to 1.6.

[0052] This invention has the following advantages:

[0053] The present invention proposes a method for preparing monocyclic β-lactam compounds, which involves a condensation reaction of a compound having the structure shown in Formula 3-13 with a compound having the structure shown in Formula 3-11 to obtain the final target compound. Specifically, an intermediate compound having the structure shown in Formula 3-11 is prepared from a compound having the structure shown in Formula 3-4 through a four-step reaction. After a condensation reaction of a compound having the structure shown in Formula 1-4 with a compound having the structure shown in Formula 1-1, the compound having the structure shown in Formula 3-13 is obtained by deprotection of the Boc protecting group.

[0054] This method features shorter synthesis steps, effectively improving synthesis efficiency and overall yield. Furthermore, it avoids the use of diphenyldiazomethane (Ph₂CN₂), completely eliminating the risk of explosion. This invention successfully transforms an existing linear synthesis process (Scheme 1) into a parallel synthesis process. Currently, this scaled-up synthesis process has been used to synthesize sufficient final target compounds, completing preclinical studies and is undergoing clinical trial application. Detailed Implementation

[0055] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Unless otherwise specified, the embodiments and features in the embodiments of the present invention can be combined with each other.

[0056] This invention provides a method for preparing a monocyclic β-lactam compound having the structure of formula (I), comprising the following steps:

[0057] a) A compound having the structure shown in formula (3_11) undergoes a condensation reaction with a compound having the structure shown in formula (3_13) to obtain a compound having the structure shown in formula (I);

[0058]

[0059] In equation (3_13), X in equation (I) can be Cl or Me.

[0060] In one embodiment of the present invention, in step a), the molar ratio of the compound having the structure shown in formula (3-11) to the compound having the structure shown in formula (3-13) is 1 to 1.5:1.

[0061] Specifically, in step a), the reaction temperature is 0°C.

[0062] Specifically, in step a), the reaction time is 5 to 24 hours; more specifically, the reaction time is 7 hours.

[0063] In one embodiment of the present invention, a compound having the structure shown in formula (3-11) is prepared by comprising the following steps:

[0064] b1) The compound having the structure shown in formula (3_4) is reacted with N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarbonate to give the compound having the structure shown in formula (3_5);

[0065] b2) The compound having the structure shown in formula (3_5) reacts with hydrazine hydrate to give the compound having the structure shown in formula (3_6);

[0066] b3) The compound having the structure shown in formula (3_6) reacts with a base to give the compound having the structure shown in formula (3_7);

[0067] b4) The compound having the structure shown in formula (3_7) reacts with trifluoroacetic acid to give the compound having the structure shown in formula (3_11);

[0068]

[0069] Steps b1)-b4) of this invention are mainly used to prepare compounds having the structure shown in formula (3_11). Specifically, the compound having the structure shown in formula (3_4) reacts with N-hydroxyphthalimide, triphenylphosphine, and diethyl azodicarbonate to obtain a compound having the structure shown in formula (3_5); the compound having the structure shown in formula (3_5) reacts with hydrazine hydrate to generate a compound having the structure shown in formula (3_6), which is further hydrolyzed to obtain a compound having the structure shown in formula (3_7); the compound having the structure shown in formula (3_7) is deprotected with acid to obtain an intermediate compound having the structure shown in formula (3_11). This process only requires column chromatography purification in the last step to obtain a compound with sufficient purity having the structure shown in formula (3_11). Simultaneously, the process avoids the use of diphenyldiazomethane (Ph2CN2), completely eliminating the risk of explosion and making scale-up synthesis for clinical studies possible.

[0070] In one embodiment of the present invention,

[0071] In step b1), the molar ratio of the compound having the structure shown in formula (3-4) to N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarbonate is 1:1.5-2:1.5-2:1.5-2;

[0072] In step b2), the molar ratio of the compound having the structure shown in formula (3_5) to hydrazine hydrate is 1.5 to 1.6:1.

[0073] Preferably, in step b2), the reaction temperature is 0°C and the reaction time is 3 to 5 hours.

[0074] In one embodiment of the present invention, in step b3), the molar ratio of the compound having the structure shown in formula (3-6) to the base is 1:2.8 to 3.2.

[0075] In one embodiment of the present invention, in step b3), the alkali includes at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0076] Preferably, in step b3), the molar ratio of the compound having the structure shown in formula (3-6) to the base is 1:3.

[0077] Preferably, in step b3), the reaction temperature is 0°C and the reaction time is 3 to 5 hours.

[0078] In one embodiment of the present invention, in step b4), the ratio of the compound having the structure shown in formula (3-7) to trifluoroacetic acid is 1 mmol: (1.5-2) mL.

[0079] Preferably, in step b4), the ratio of the compound having the structure shown in formula (3_7) to trifluoroacetic acid is 1 mmol: 1.86 mL.

[0080] Preferably, in step b4), the reaction temperature is 0°C and the reaction time is 3 to 5 hours.

[0081] It should be noted that the synthesis method of compounds having the structure shown in formula (3_4) can be found in patent WO2022027439A1 or in the literature Medicinal Chemistry.2022, vol.18, issue 5, 574-588.

[0082] In one embodiment of the present invention, a compound having the structure shown in formula (3-13) is prepared by comprising the following steps:

[0083] c1) A compound having the structure shown in formula (1_4) and a compound having the structure shown in formula (1_1) undergo a condensation reaction in the presence of an amidating agent (HATU) and a bicarbonate to obtain a compound having the structure shown in formula (3_12).

[0084] c2) The compound having the structure shown in formula (3_12) is deprotected to obtain the compound having the structure shown in formula (3_13);

[0085]

[0086] In equations (1_4), (3_12), and (3_12), X represents Cl or Me.

[0087] Steps c1)-c2) of this invention are mainly used to prepare compounds having the structure shown in formula (3-13), wherein X in the structure of formula (3-13) can be Cl or Me, thus producing structures as shown in formula (3-13A) and formula (3-13B):

[0088]

[0089] In one embodiment of the present invention, in step c1), the molar ratio of the compound having the structure shown in formula (1-4), the compound having the structure shown in formula (1-1), HATU, and bicarbonate is 1:1 to 1.2:1 to 1.5:1.8 to 2.2.

[0090] In one embodiment of the present invention, in step c1), the bicarbonate includes at least one of sodium bicarbonate or potassium bicarbonate.

[0091] In one embodiment of the present invention, in step c2), the compound having the structure shown in formula (3-12) is desterilized in formic acid. In step c2), the ratio of the compound having the structure shown in formula (3-12) to formic acid is 1 mmol:(3-4) mL; preferably, in step c2), the ratio of the compound having the structure shown in formula (3-12) to formic acid is 1 mmol:3.8 mL. The mass concentration of formic acid is 98%.

[0092] Preferably, in step c2), the reaction temperature is 10–30°C; more preferably, the reaction temperature is 20°C.

[0093] Preferably, in step c2), the reaction time is 4 to 8 hours; more preferably, the reaction time is 6.5 hours.

[0094] In this embodiment of the invention, when X is Cl, the compound having the structure shown in formula (1-4) is the compound having the structure shown in formula (1-4A); when X is Me, the compound having the structure shown in formula (1-4) is the compound having the structure shown in formula (1-4B).

[0095]

[0096] Compounds having the structure shown in formula (1_4A) and compounds having the structure shown in formula (1_4B) undergo condensation reactions with compounds having the structure shown in formula (1_1), and the Boc protecting group is removed to obtain compounds having the structure shown in formula (3_13A) and compounds having the structure shown in formula (3_13B), respectively.

[0097] In this embodiment of the invention, the compound having the structure shown in formula (3-13A) is prepared from the compound having the structure shown in formula (1-4A). The compound having the structure shown in formula (1-4A) is synthesized according to patent WO2022027439A1.

[0098] In this embodiment of the invention, the compound having the structure shown in formula (3-13B) is prepared from the compound having the structure shown in formula (1-4B).

[0099] In the prior art, the synthetic process of compounds with the structure shown in formula (1-4B) is as shown in Scheme 2 (WO2022011626A1, the old process). This method has a long reaction route and low yield. This invention optimizes the existing old process, increasing the yield of 1-4e from 65% to approximately 100%, the yield of 1-4f from 52% to approximately 81%, the yield of 1-4g from 66% to 96%, and although the yield of 1-4h is not ideal, it is still increased from 33% to approximately 49%. The obtained 1-4h is then hydrolyzed to obtain 1-4B. This method increases the overall yield of intermediate 1-4B from 7.3% [Medicinal Chemistry. 2022, vol. 18, issue 5, 574-588] to 38.1%, significantly improving the synthetic efficiency.

[0100] Traditional techniques:

[0101]

[0102] New process:

[0103]

[0104] In one embodiment of the present invention, a compound having the structure shown in formula (1-4B) is prepared by comprising the following steps:

[0105] c3) The compound having the structure shown in formula (1-4d) reacts with phenyltrimethylammonium tribromide to give the compound having the structure shown in formula (1-4e);

[0106] c4) A compound having the structure shown in formula (1-4e) reacts with thiourea to give a compound having the structure shown in formula (1-4f);

[0107] c5) The compound having the structure shown in formula (1-4f) reacts with 4-dimethylaminopyridine (DMAP) and ditert-butyl dicarbonate ((Boc)2O) to give the compound having the structure shown in formula (1-4g);

[0108] c6) The compound having the structure shown in formula (1-4g) reacts with selenium dioxide (SeO2) and 2-iodobenzoic acid (IBX) to give the compound having the structure shown in formula (1-4h);

[0109] c7) A compound having the structure shown in formula (1-4h) reacts with a base to give a compound having the structure shown in formula (1-4B);

[0110]

[0111] In one embodiment of the present invention, in step c3), the ratio of the compound having the structure shown in formula (1-4d) to phenyltrimethylammonium tribromide is 1:1 to 1.1; preferably, in step c3), the ratio of the compound having the structure shown in formula (1-4d) to phenyltrimethylammonium tribromide is 1:1.05.

[0112] It should be noted that compounds with the structure shown in formula (1-4d) as the initial reactants can be purchased directly.

[0113] In one embodiment of the present invention, in step c4), the molar ratio of the compound having the structure shown in formula (1-4e) to thiourea is 1:1 to 1.2. Preferably, in step c4), the molar ratio of the compound having the structure shown in formula (1-4e) to thiourea is 1:1.1.

[0114] Preferably, in step c4), the reaction temperature is 70–90°C; more preferably, the reaction temperature is 85°C.

[0115] Preferably, in step c4), the reaction time is 4 to 8 hours; more preferably, the reaction time is 5 hours.

[0116] In one embodiment of the present invention, in step c5), the ratio of the compound having the structure shown in formula (1-4f), 4-dimethylaminopyridine (DMAP), and ditert-butyl dicarbonate ((Boc)2O) is 1:0.05 to 0.1:1 to 1.05.

[0117] Preferably, in step c5), the ratio of the compound having the structure shown in formula (1-4f), 4-dimethylaminopyridine (DMAP), and ditert-butyl dicarbonate ((Boc)2O) is 1:0.07:1.04.

[0118] Preferably, in step c5), the reaction temperature is room temperature.

[0119] Preferably, in step c5), the reaction time is 24 hours.

[0120] In one embodiment of the present invention, in step c6), the molar ratio of the compound having the structure shown in formula (1-4g), selenium dioxide (SeO2), and 2-iodobenzoic acid (IBX) is 1:2 to 2.4:0.5 to 0.8. Preferably, in step c6), the molar ratio of the compound having the structure shown in formula (1-4g), selenium dioxide (SeO2), and 2-iodobenzoic acid (IBX) is 1:2 to 2.2:0.6.

[0121] Preferably, in step c6), the reaction temperature is 100-110°C; preferably, in step c6), the reaction temperature is 105°C.

[0122] Preferably, in step c6), the reaction time is 5 to 10 hours; preferably, in step c6), the reaction time is 6 hours.

[0123] In one embodiment of the present invention, in step c7), the molar ratio of the compound having the structure shown in formula (1-4h) to the base is 1:1 to 1.6.

[0124] Preferably, in step c7), the alkali includes at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0125] Preferably, in step c7), the molar ratio of the compound having the structure shown in formula (1-4h) to sodium hydroxide is 1:1.5.

[0126] Preferably, in step c7), the reaction temperature is 0°C and the reaction time is 5 hours.

[0127] When X is Cl, the structure shown in equation (1_4) is the same as the structure shown in equation (1_4A); wherein, the structure shown in equation (1_4A) is synthesized based on the literature (patent WO2022027439A1).

[0128] The present invention will now be described in detail with reference to the embodiments.

[0129] Example 1 Synthesis of monocyclic β-lactam compounds (Ia)

[0130]

[0131] 1. A compound having the structure shown in formula (3_11) is prepared by the following steps:

[0132] Step 1-1: Compound tert-butyl having the structure shown in formula (3_5)

[0133] Synthesis of (R)-3-(4-((S)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methoxy-3-oxopropoxy)benzimida mido)pyrrolidine-1-carboxylate(3_5)

[0134]

[0135] Compound 3_4 (20.2 g, 49.6 mmol, synthesized according to Medicinal Chemistry. 2022, vol. 18, issue 5, 574-588, or patent WO2022027439A1), N-hydroxyphthalimide (13.0 g, 79.7 mmol), and triphenylphosphine (22.2 g, 84.3 mmol) were dissolved in anhydrous THF / DMF (220 mL / 20 mL), and then a solution of diethyl azodicarbonate (16.7 mL, 84.3 mmol) was added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature, and tetrahydrofuran was removed by rotary evaporation. The concentrate was treated with diethyl ether (4 x 150 mL) to give a white solid compound 3_5 (32 g, quantitative yield, ~100%).

[0136] 1 H NMR (400MHz, DMSO-d6): δ1.41(s,9H),1.96-2.09(m,1H),2.17-2.30(m,1H),3.00-3.10(m ,1H),3.40-3.47(m,1H),3.60-3.70(m,1H),3.76(s,3H),4.34-4.47(m,1H),4.48-4.57(m ,1H),4.57-4.66(m,1H),5..26-5.37(m,1H),7.14(d,J=8.80Hz,2H),7.74(d,J=8.80Hz,2 H),7.85-7.90(m,4H),9.22(s,1H),9.52(s,1H),9.71-9.77(m,1H).LC-MSanalysis:[M+H] + =554.2.

[0137] Step 1-2: Compound tert-butyl having the structure shown in formula (3-6)

[0138] Synthesis of (R)-3-(4-((S)-2-(aminooxy)-3-methoxy-3-oxopropoxy)benzimidamido)pyrrolidine-1-carbo xylate(3_6)

[0139]

[0140] Compound 3_5 (33.6 g, 60.9 mmol) was dissolved in 140 mL of anhydrous ethanol. Then, an anhydrous ethanol solution (5 mL) of hydrazine hydrate (1.94 g, 38.8 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 4 hours, followed by stirring at room temperature for another 0.5 hours. The precipitate formed was removed by filtration, and the filter cake was washed with ethanol (2 x 8 mL). The resulting filtrate was concentrated under reduced pressure to obtain a pale yellow, foamy compound 3_6 (30.5 g), which did not require further purification and was directly used in the next reaction.

[0141] 1 H NMR (400MHz, DMSO-d6): δ1.41(s,9H),1.96-2.10(m,1H),2.17-2.30(m,1H) ,3.01-3.10(m,1H),3.40-3.47(m,1H),3.60-3.70(m,1H),3.70(s,3H),4.32 -4.35(m,1H),4.37-4.45(m,2H),4.48-4.52(m,1H),6.41(s,2H),7.14(d,J= 8.80Hz, 2H), 7.72 (d, J = 8.80Hz, 2H), 9.20 (s, 1H), 9.50 (s, 1H), 9.72 (s, 1H). LC-MS analysis:[M+H] + =424.2.

[0142] Steps 1-3: Compounds having the structure shown in formula (3_7)

[0143] Synthesis of (S)-2-(aminooxy)-3-(4-(N-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)carbamimidoyl)phe noxy)propanoic acid(3_7)

[0144]

[0145] 32 mL of 4 N NaOH was added to a mixed solution of 3_6 (33.4 g, 42.9 mmol) and THF / H₂O (120 mL / 40 mL). The mixture was stirred at 0 °C for 4 hours, followed by stirring at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure. The concentrate was washed with 120 mL of water (2 x 120 mL) with ethyl acetate. The aqueous layer was adjusted to pH 5 with 1 N HCl and filtered. The filtrate was freeze-dried to give 24.6 g of a yellow solid compound 3_7. No further purification was required, and the mixture was directly used for the next reaction.

[0146] 1H NMR (400MHz, DMSO-d6): δ1.40(s,9H),1.94-2.03(m,1H),2.14-2.22(m,1H),3.24-3.34(m,2H),3.39-3.45(m,1H),3.57-3.66 (m,1H),3.99-4.05(m,1H),4.13-4.18(m,1H),4.26-4.31(m,1H),4.41(s,2H),7.04(d,J=8.40Hz,2H),7.75(d,J=8.40Hz,2H). LC-MS analysis:[M+H] + =410.1.

[0147] Steps 1-4: Synthesis of (S)-2-(aminooxy)-3-(4-(N-((R)-pyrrolidin-3-yl)carbamimidoyl)phenoxy)propanoic acid, a compound having the structure shown in formula (3_11).

[0148]

[0149] Trifluoroacetic acid (TFA) (80 mL) was added to a solution of 3_7 (24.6 g, 42.9 mmol) in anhydrous dichloromethane (60 mL) at 0 °C. The mixture was stirred for 4 hours, followed by stirring at room temperature for another 0.5 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was added to 180 mL of water and then lyophilized. The lyophilized compound was purified by C18 reversed-phase column chromatography to obtain a white solid target compound 3_11 (10.3 g, 26%, three-step reaction).

[0150] 1 H NMR (400MHz, DMSO-d6): δ2.11-2.20(m,1H),2.27-2.37(m,1H),3.29-3.37(m,1H),3.38-3.47(m,2H),3.54-3.59(m, 1H),4.37(d,J=4.30Hz,2H),4.49-4.56(m,2H),7.16(d,J=8.88Hz,2H),7.76(d,J=8.88Hz,2H),9.28(s,1H),9.49(br s,2H),9.61(s,1H),9.71(d,J=6.4Hz,1H).LC-MS analysis:[M+H] + =310.1.

[0151] 2. A compound having the structure shown in formula (3_13A) is prepared by the following steps:

[0152] Step 2-1: The compound having the structure shown in formula (1-4A) was synthesized according to patent WO2022027439A1. Step 2-2: The compound having the structure shown in formula (3-12A) was (S)-3-(2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-iminoacetamido)-2,2-dimethyl-4-oxoazetidin-1-ylhydrogen sulfate.

[0153]

[0154] At room temperature, HA=TU (6.03 g, 15.86 mmol) and NaHCO3 (2.05 g, 24.4 mmol) were added to a 20 mL solution of DMF containing compound 1_4A (4.0 g, 12.2 mmol), followed by the addition of (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (1_1, 2.82 g, 13.4 mmol). The reaction was allowed to proceed overnight at room temperature. The mixture was then purified using a Biotage C18 reversed-phase column (240 g, 30 μm) and lyophilized to obtain a pale yellow solid compound 3_12A (4.59 g, 76%).

[0155] 1 H NMR (400MHz, DMSO-d6) δ1.29(s,3H),1.45(s,3H),1.49(s,9H),4.61(d,J=8.4Hz,1H),9.69(d,J=8.4Hz,1H),12.18(s,1H).LC-MS analysis[MH] - =497.0.

[0156] Steps 2-3: Synthesis of compound (S)-3-(2-(2-amino-5-chlorothiazol-4-yl)-2-oxoacetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate (3-13A) having the structure shown in formula (3_13A)

[0157]

[0158] Compound 3_12A (6.60 g, 11.1 mmol) was dissolved in 98% formic acid (20 mL) and stirred at 20 °C for 7.5 h. The reaction mixture was concentrated under reduced pressure to give a yellow solid, target compound 3_13A (5.80 g, quantitative yield), which was directly used for the next reaction without purification.

[0159] 1 H NMR (400MHz, DMSO-d6): δ1.26 (s, 3H), 1.43 (s, 3H), 4.37 (d, J = 8.2Hz, 1H), 9.60 (d, J = 8.2Hz, 1H). LC-MS analysis: [MH] - =397.0.

[0160] 3. A compound having the structure shown in formula (Ia) is prepared by the following steps:

[0161] (S)-2-((((Z)-1-(2-amino-5-chlorothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulf Synthesis of ooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-(4-(N-((R)-pyrrolidin-3-yl)carbamimidoyl)phenoxy)propanoic acid(Ia)

[0162]

[0163] Compound 3_11 (8.6 g, 13.2 mmol) was added in portions to a MeOH (12 mL) / DMF (12 mL) solution containing compound 3_13A (5.8 g, 11.1 mmol). The mixture was stirred at 0 °C for 30 min, then heated to room temperature and stirred for 7 h. The mixture was purified by passing it through a Biotage C18 reversed-phase column (240 g, 30 μm) and freeze-dried to give a white solid target compound Ia (2 g, 26%).

[0164] 1H NMR (400MHz, DMSO-d6): δ1.27(s,3H),1.41(s,3H),2.00-2.09(m,1H),2.17-2.26(m,1H),3.07-3.15(m,1H),3.21-3.36( m,3H),4.22-4.27(m,1H),4.36-4.44(m,2H),4.65(t,J=8.6Hz,1H),4.72(d,J=8.5Hz,1H),7.13(d,J=8.5Hz,2H),7.35(br s,2H),7.74(d,J=8.5Hz,2H),8.30(br s,3H),10.35(d,J=8.6Hz,1H).LC-MS analysis:[MH] - =687.1and[M-H+2] - =689.1. HPLC: 98.2%.

[0165] Example 2 Synthesis of monocyclic β-lactam compounds (Ib)

[0166]

[0167] 1. The preparation method of the compound having the structure shown in formula (3_11) is the same as in Example 1;

[0168] 2. A compound having the structure shown in formula (3_13B) is prepared by the following steps:

[0169] Step 2-1: Synthesis of Ethyl 4-bromo-3-oxyvalerate(1-4e), a compound having the structure shown in formula (1-4e).

[0170]

[0171] Compound 1-4d (39 g, 300 mmol) was dissolved in dichloromethane (250 mL) and phenyltrimethylammonium tribromide (118.417 g, 315 mmol) at 0 °C and reacted for 3 h. After the reaction was completed by TLC monitoring, the organic phase was diluted with dichloromethane, washed three times with water (30 mL × 3), and then washed with saturated saline water (20 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to give compound 1-4e (62.7 g, quantitative yield, ~100%).

[0172] 1H NMR (400MHz, DMSO-d6) δ1.20 (t, J = 7.1 Hz, 3H), 1.65 (d, J = 6.7 Hz, 3H), 3.84 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.88 (q, J = 6.7 Hz, 1H).

[0173] Step 2-2: Synthesis of 2-(2-amino-5-methylthiazole-4-yl)ethyl acetate (1-4f), a compound having the structure shown in formula (1-4f).

[0174]

[0175] Compound 1-4e (62.7 g, 300 mmol) was dissolved in acetonitrile (200 mL) at room temperature, and thiourea (25.08 g, 330 mmol) was added. The mixture was refluxed at 85 °C for 5 hours. After the reaction was completed as monitored by TLC, water (200 mL) was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution to obtain a solid suspension. After stirring for 5 minutes, the obtained solid was filtered, washed, and dried to give compound 1-4f (48.37 g, 81%).

[0176] 1 H NMR (400MHz, DMSO-d6) δ1.17 (t, J = 7.2 Hz, 3H), 2.12 (s, 3H), 3.39 (s, 2H), 4.05 (q, J = 7.2 Hz, 3H), 6.62 (s, 2H).

[0177] Steps 2-3: Compounds having the structure shown in formula (1-4g)

[0178] Synthesis of 2-(2-((tert-butylcarbonyl)amino)-5-methylthiazole-4-yl)-2-oxy ethylacetate(1_4g)

[0179]

[0180] Compound 1,4f (18.62 g, 100 mmol) was dissolved in dichloromethane (100 mL), and Boc₂O (22.7 g, 10⁴ mmol) and DMAP (0.85 g, 7 mmol) were added at room temperature. The reaction mixture was reacted at room temperature for 24 hours, and the reaction solution was concentrated after confirmation of complete reaction by TLC. Acetonitrile (115 mL) was added and the mixture was stirred for 12 hours. After filtration, the residue was washed with cold acetonitrile (35 mL) to give a white solid compound 1,4f (27.39 g, 96%).

[0181] 1 H NMR (400MHz, DMSO-d6) δ1.17(t,J=7.2Hz,3H),1.46(s,9H),2.24(s,3H),3.57(s,2H),4.05(q,J=7.2Hz,2H),11.23(s,1H).

[0182] Steps 2-4: Synthesis of the compound (2-(2-((tert-butylcarbonyl)amino)-5-methylthiazole-4-yl)ethyl acetate (1-4h) having the structure shown in formula (1-4h)

[0183]

[0184] Compound 1-4 g (2.85 g, = 10 mmol) was dissolved in dioxane (40 mL), and SeO2 (2.44 g, 22 mmol) was added at room temperature. The reaction mixture was then refluxed at 105 °C for 6 hours. The reaction was monitored by TLC. Before filtration, the reaction mixture was cooled to room temperature, and the filter cake was washed with ethyl acetate (10 mL × 2). The concentrated filtrate was dissolved in acetonitrile (40 mL), and 2-iodobenzoic acid (IBX, 80%) (2.1 g, 6 mmol) was added at room temperature. The reaction mixture was then further reacted at 85 °C for 3 hours. The system was cooled to room temperature, filtered, and washed with acetonitrile (10 mL × 2). The pH of the system was adjusted to 8-9 with saturated sodium bicarbonate solution, the organic phase was separated and concentrated, and purified by column chromatography to give a white solid compound 1-4 h (1.47 g, 49.2%).

[0185] 1 H NMR (400MHz, DMSO-d6): δ1.30 (t, J=7.2Hz, 3H), 1.48 (s, 9H), 2.66 (s, 3H), 4.32 (q, J=7.2Hz, 2H), 11.72 (s, 1H).

[0186] Steps 2-5: Compounds having the structure shown in formula (1-4B)

[0187] Synthesis of 2-(2-(tert-butylcarbonyl)amino)-5-methylthiazole-4-yl)-2-oxyaceticacid(1_4B)

[0188]

[0189] Compound 1_4h (1.5 g, 5 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8 mL) and ethanol (8 mL), cooled to 0 °C, and then 1 N sodium hydroxide aqueous solution (7.5 mL) was added dropwise. The reaction was carried out in an ice bath for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to remove the solvent, then cooled to 0 °C, and the pH was adjusted to 4 with 1 N hydrochloric acid. The precipitate was filtered off and dried to give white compound 1_4B (1.45 g, quantitative yield, ~100%).

[0190] 1 H NMR (400MHz, DMSO-d6): δ1.46(s,9H),2.55(s,3H),11.51(s,1H).LC-MSanalysis[MH] - m / z = 285.

[0191] As can be seen from the above, the reaction proceeds from the compound with the structure shown in formula (1_4f) to the compound with the structure shown in formula (1_4B) in five steps. The yield of the two steps can be considered as 100%, and the total yield of the compound with the structure shown in formula (1_4B) is 81% × 96% × 49% = 38.1%.

[0192] Steps 2-6: Synthesis of the compound (S)-3-(2-(2-((tert-butoxycarbonyl)amino)-5-methylthiazol-4-yl)-2-iminoacetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (3-12B) having the structure shown in formula (3_13B).

[0193]

[0194] Compound 1_4B (4 g, 14 mmol), (S)-3-(l2-azanyl)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (l1, 3.23 g, 15.4 mmol), and sodium bicarbonate (2.35 g, 28 mmol) were dissolved in anhydrous DMF (20 mL) at 0 °C, followed by the addition of HATU (6.92 mg, 18.2 mmol). The reaction mixture was stirred at room temperature for 16 hours, purified using a Biotage C18 reversed-phase column (240 g, 30 μm), and lyophilized to obtain the target compound 3_12B (4.8 g, 72%) as a pale yellow solid.

[0195] 1H NMR (400MHz, DMSO-d6): δ1.27(s,3H),1.44(s,3H),1.47(s,9H),2.63(s,3H),4.61(d,J=8.3Hz,1H),9.58(d,J=8.3Hz,1H),11.74(s,1H).LC-MS analysis[MH] - =477.1.

[0196] Steps 2-7: Compound (S)-3-(2-(2-amino-5-methylthiazol-4-yl)-2-oxoacetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate having the structure shown in formula (3_13B)

[0197]

[0198] Compound 3_12B (2.82 g, 5.9 mmol) was dissolved in 98% formic acid (12 mL) and stirred at 20 °C for 7.5 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid, target compound 3_13B (2.84 g), which was directly proceeded to the next reaction without purification.

[0199] 1 H NMR (400MHz, DMSO-d6): δ1.27(s,3H),1.44(s,3H),2.54(s,3H),4.59(d,J=8.2Hz,1H),9.68(d,J=8.2Hz,1H).LC-MS analysis[MH] - =377.1.

[0200] 3. Synthesis of the compound (S)-2-((((Z)-1-(2-amino-5-methylthiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfoox y)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-(4-(N-((R)-pyrrolidin-3-yl)carbamimidoyl)phenoxy)propanoic acid (Ib) having the structure shown in formula (Ib)

[0201]

[0202] Compound 3_11 (6.66 g, 10.2 mmol) was added in portions to a mixed solution of MeOH (7.5 mL) and DMF (7.5 mL) containing compound 3_13B (3.51 g, 7.16 mmol). The mixture was stirred at 0 °C for 30 minutes, and then stirred for 7 hours after being brought back to room temperature. The mixture was purified by passing it through a Biotage C18 reversed-phase column (240 g, 30 μm) and freeze-dried to give a white solid target compound Ib (2 g, 30%).

[0203] 1 H NMR (400MHz, DMSO-d6): δ1.25(s,3H),1.41(s,3H),1.95-2.03(m,1H),2.17(s,3H),2.2 0-2.25(m,1H),3.57-3.60(m,1H),4.04-4.07(d,J=9.58Hz,1H),4.31-4.36(m,1H),4.49 -4.53(m,1H),4.60(d,J=9.02Hz,1H),4.70-4.74(m,1H),6.90(s,1H),7.07(d,J=9.01Hz ,2H),7.75(d,J=7.89Hz,2H),9.36(s,1H),10.12(d,J=7.89Hz,1H),10.62(s,1H).LC-MS analysis[MH] - =667.1.

[0204] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a monocyclic β-lactam compound, wherein the monocyclic β-lactam compound has the structure of formula (I), comprising the following steps: c6) the compound having the structure of formula (1_4g) is reacted with selenium dioxide, 2-iodoxybenzoic acid to give the compound having the structure of formula (1_4h); wherein, The molar ratio of the compound having the structure shown in formula (1-4g), selenium dioxide, and 2-iodobenzoic acid is 1:2~2.4:0.5~0.8; c7) A compound having the structure shown in formula (1-4h) reacts with a base to give a compound having the structure shown in formula (1-4B); c1) A compound having the structure shown in formula (1_4B) and a compound having the structure shown in formula (1_1) undergo a condensation reaction in the presence of an amidating agent and a bicarbonate to obtain a compound having the structure shown in formula (3_12). c2) The compound having the structure shown in formula (3_12) is deprotected to obtain the compound having the structure shown in formula (3_13); a) A compound having the structure shown in formula (3_11) undergoes a condensation reaction with a compound having the structure shown in formula (3_13) to obtain a compound having the structure shown in formula (I); ； ； ； ； ； ； ； ； In equations (3_12), (3_13), and (I), X represents Me.

2. The preparation method according to claim 1, characterized in that, In step a), the molar ratio of the compound having the structure shown in formula (3_11) to the compound having the structure shown in formula (3_13) is 1~1.5:1; In step a), the reaction temperature is 0°C; the reaction time is 5 to 24 hours.

3. The preparation method according to claim 1, characterized in that, Compounds having the structure shown in formula (3_11) are prepared by the following steps: b1) The compound having the structure shown in formula (3_4) is reacted with N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarbonate to give the compound having the structure shown in formula (3_5); b2) The compound having the structure shown in formula (3_5) reacts with hydrazine hydrate to give the compound having the structure shown in formula (3_6); b3) The compound having the structure shown in formula (3_6) reacts with a base to give the compound having the structure shown in formula (3_7); b4) The compound having the structure shown in formula (3_7) reacts with trifluoroacetic acid to give the compound having the structure shown in formula (3_11); ； ； ； ； 。 4. The preparation method according to claim 3, characterized in that, In step b1), the molar ratio of the compound having the structure shown in formula (3-4) to N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarbonate is 1:1.5~2:1.5~2:1.5~2; In step b2), the molar ratio of the compound having the structure shown in formula (3_5) to hydrazine hydrate is 1.5~1.6:1; In step b3), the molar ratio of the compound having the structure shown in formula (3_6) to the base is 1:2.8~3.

2.

5. The preparation method according to claim 1, characterized in that, In step c1), the molar ratio of the compound having the structure shown in formula (1_4B), the compound having the structure shown in formula (1_1), the amidating agent, and the bicarbonate is 1:1~1.2:1~1.5:1.8~2.

2.

6. The method of claim 1, wherein, Compounds having the structure shown in formula (1-4g) are prepared by the following steps: c3) The compound having the structure shown in formula (1-4d) reacts with phenyltrimethylammonium tribromide to give the compound having the structure shown in formula (1-4e); c4) A compound having the structure shown in formula (1-4e) reacts with thiourea to give a compound having the structure shown in formula (1-4f); c5) The compound having the structure shown in formula (1-4f) reacts with 4-dimethylaminopyridine and ditert-butyl dicarbonate to give the compound having the structure shown in formula (1-4g); ； ； 。 7. The preparation method according to claim 6, characterized in that, In step c3), the ratio of the compound having the structure shown in formula (1-4d) to phenyltrimethylammonium tribromide is 1:1 to 1.1; In step c4), the molar ratio of the compound having the structure shown in formula (1-4e) to thiourea is 1:1 to 1.2; In step c5), the ratio of the compound having the structure shown in formula (1-4f), 4-dimethylaminopyridine, and ditert-butyl dicarbonate is 1:0.05~0.1:1~1.

05.

8. The preparation method according to claim 1, characterized in that, In step c7), the molar ratio of the compound having the structure shown in formula (1-4h) to the base is 1:1 to 1.6.

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