Preparation method for monocyclic β-lactam compound

Abstract

The present invention relates to the field of pharmaceutical chemicals, and mainly relates to a preparation method for a monocyclic β-lactam compound. At present, the reaction selectivity in the prior art is not ideal, and there are problems such as high resolution difficulty and low yield. In the present invention, for constructing a target chiral center in advance, the problems that an optical isomer is difficult to separate and has low yield under the condition of small steric hindrance are solved, and because a target configuration can be directionally synthesized, the atom utilization rate is increased and industrial production is facilitated, thereby reducing environmental pollution and improving the commercial feasibility.

Description

Preparation method of monocyclic β-lactam compound

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on January 16, 2024, with application number 202410057557.2 and invention name “Method for preparing monocyclic β-lactam compounds”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a method for preparing a monocyclic beta-lactam compound. Background Art

[0003] The discovery and use of antibiotics is one of the greatest medical achievements of the 20th century. β-lactam antibiotics, with their broad spectrum, potent efficacy, and high safety, hold a crucial position in clinical practice. As a key component of the β-lactam antibiotic class, monocyclic β-lactams are a key focus of pharmaceutical research, as their structure is simpler than penicillins and cephalosporins, and their chemical properties are more stable than those of other non-classical β-lactam antibiotics.

[0004] The molecular structure of monocyclic β-lactam antibiotics contains a compound with a partial structure of azetidine-2-one, which is an important component of monocyclic β-lactam antibiotics.

[0005] The methods for preparing monocyclic β-lactam mother rings in known patents and currently commonly used methods are mainly:

[0006] The method has unsatisfactory selectivity under low steric hindrance conditions and produces other optical isomers, resulting in problems of difficulty in separation and low yield.

[0007] Therefore, considering the important uses of monocyclic β-lactam antibiotics, it is necessary to develop a process route with high yield, high atom economy and suitable for industrial production.

[0008] Summary of the Invention

[0009] The invention provides a method for preparing a monocyclic beta-lactam. The method comprises the following steps: condensation reaction, aldol condensation reaction, oxidation removal reaction, amide condensation reaction, Mitsunobu cyclization reaction and oxidation removal reaction.

[0010] In order to achieve the technical purpose of the present invention, the technical solution provided by the present invention is:

[0011] The present invention provides a monocyclic β-lactam compound of formula VII, the structural formula of which is as follows:

[0012] The present invention provides an intermediate compound of formula VI, the structural formula of which is as follows:

[0013] The present invention provides an intermediate compound of formula V, the structural formula of which is as follows:

[0014] The present invention provides a method for preparing a monocyclic β-lactam compound of formula VII, which is prepared by oxidative removal reaction of a compound of formula VI.

[0015] The reagent for the oxidative removal reaction can be CAN, DDQ or Oxone; preferably, it is cerium ammonium nitrate (CAN).

[0016] The molar ratio of compound VI to the oxidizing agent in the oxidation removal reaction can be in the range of 1:(2-8).

[0017] The solvent for the oxidative removal reaction can be an organic solvent or an inorganic solvent; preferably, it is an aqueous solution of acetonitrile.

[0018] The present invention provides a method for preparing a compound of formula VI, which is prepared by subjecting a compound of formula V to a Mitsunobu cyclization reaction.

[0019] The reagents for the Mitsunobu cyclization reaction can be phosphine reagents and azo reagents. The phosphine reagent can be triphenylphosphine, n-butylphosphine or cyclohexylphosphine, preferably triphenylphosphine; the azo reagent can be diethyl azodicarboxylate, diisopropyl azodicarboxylate or dibutyl azodicarboxylate, preferably diethyl azodicarboxylate.

[0020] The molar ratio of compound V, phosphine reagent and azo reagent in the Mitsunobu cyclization reaction can be in the range of 1:(2-5):(2-5).

[0021] The solvent for the Mitsunobu cyclization reaction can be an organic solvent or an inorganic solvent; preferably, tetrahydrofuran.

[0022] The compound of formula V is prepared by reacting the compound of formula IV with 2,4-dimethoxybenzylamine via an amide condensation reaction.

[0023] The reagents for the amide condensation reaction can be HOBT / DCC, HOBT / EDCI, HATU, HBTU, HCTU or TCFH; preferably, they are 1-hydroxybenzotriazole (HOBT) and dicyclohexanecarbodiimide (DCC).

[0024] In the amide condensation reaction, the molar ratio of compound IV, 2,4-dimethoxybenzylamine and amide condensation reagent can be in the range of 1:(2-5):(2-7).

[0025] The solvent for the amide condensation reaction can be an organic solvent or an inorganic solvent; preferably acetonitrile.

[0026] The compound of formula IV is prepared by oxidation removal reaction of the compound of formula III.

[0027] The oxidative removal agent for the oxidative removal reaction can be hydrogen peroxide / lithium hydroxide, hydrogen peroxide / sodium hydroxide, hydrogen peroxide / potassium hydroxide, hydrogen peroxide / cesium hydroxide, hydrogen peroxide / potassium carbonate or hydrogen peroxide / cesium carbonate; preferably, hydrogen peroxide / lithium hydroxide.

[0028] The molar ratio of compound III to the oxidative removal agent in the oxidative removal reaction can be in the range of 1:(8-15).

[0029] The solvent for the oxidative removal reaction can be an organic solvent or an inorganic solvent; preferably water.

[0030] The compound of formula III is prepared by reacting the compound of formula II with 2,6-difluorobenzaldehyde via aldol condensation reaction.

[0031] The aldol condensation reaction is carried out in the presence of a base or a salt or a combination thereof. The base can be sodium hydroxide, potassium hydroxide, cesium hydroxide, etc. The salt can be titanium tetrachloride, tetraisopropyl titanate, n-butyl lithium, tert-butyl lithium. The alkali salt combination can be TEA / magnesium chloride, DIPEA / magnesium chloride or DIPEA / cesium carbonate; preferably, titanium tetrachloride or tetraisopropyl titanate.

[0032] The molar ratio of compound II to 2,6-difluorobenzaldehyde in the aldol condensation reaction can be in the range of 1:(0.8-1.5).

[0033] The solvent for the aldol condensation reaction can be an organic solvent or an inorganic solvent; preferably, dichloromethane.

[0034] The compound of formula II is prepared by condensing the compound of formula I with an oxazolidinone compound.

[0035] The reagents for the condensation reaction can be HOBT / DCC, HOBT / EDCI, HATU, HBTU, HCTU or TCFH / NMI; preferably, N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (TCFH) and N-methylimidazole (NMI).

[0036] In the condensation reaction, the molar ratio of compound I, oxazolidinone compound and condensation reagent can be in the range of 1:(0.5-2):(2-5).

[0037] The solvent for the condensation reaction can be an organic solvent or an inorganic solvent; preferably acetonitrile.

[0038] The present invention provides a technical solution for preparing a monocyclic β-lactam compound. By pre-constructing the target chiral center, the invention solves the problems of difficult separation and low yield of optical isomers under low steric hindrance. Furthermore, since the target configuration can be synthesized in a targeted manner, atom utilization is improved, facilitating industrial production, reducing environmental pollution, and enhancing commercial feasibility. Therefore, this method is a feasible route for industrialization. DETAILED DESCRIPTION

[0039] In order to further understand the present invention, the present invention is described in detail below with reference to the embodiments. It should be understood that these embodiments are only for further illustrating the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0040] Example 1:

[0041] Under nitrogen protection, 500mL of acetonitrile was added to the reaction flask, and the internal temperature of the reaction flask was controlled at 20℃~30℃. 61.7g of compound I was added, 63.0g of NMI was added, and 129.0g of TFCH was added in batches. After the addition was completed, the reaction was stirred for 30 minutes. 50.0g of (S)-4-phenyloxazol-2-one was added and the temperature was refluxed for more than 12 hours. After the reaction was completed, most of the acetonitrile was evaporated under reduced pressure, and then 300mL of water was added under reduced pressure. 500mL of ethyl acetate and n-heptane were added in a 1:1 ratio. The mixture was stirred for 10 minutes and allowed to stand. The system separated into three layers. The top layer was concentrated under reduced pressure to 5V, 300mL of anhydrous ethanol was added, and the mixture was distilled under reduced pressure to 4V. A white solid precipitated. The mixture was cooled and filtered, and dried under reduced pressure at 45℃ to obtain 41.0g of a white solid. HPLC chromatographic purity: 96.3%, yield: 55%. 1 HNMR(400MHz, CDCl3)δ2.10(d,J=7.5Hz,2H)2.53(m,1H)3.40(m,4H)4.75(dd,J=3Hz,1H)4.5(dd,J=3Hz,1H)5.47(dd,J=5Hz 1H)7.27(t,J=6Hz,1H)7.32(t,J=7Hz,2H)7.36(t,J=4Hz,2H)

[0042] Example 2:

[0043] Under nitrogen, add 600 mL of dichloromethane to the reaction flask, maintaining the internal temperature between 0°C and -5°C. Add 38.7 g of titanium tetrachloride and 19.7 g of tetraisopropyl titanate, maintaining the temperature between 0°C and -5°C. Add a solution of 66.8 g of Compound II in dichloromethane dropwise. Stir and react for 30 minutes. Add 55.3 g of diisopropylethylamine. Reflux for >12 hours. Maintain the temperature and stir for 30 minutes. Cool to -30°C to -25°C, and add a solution of 45.0 g of 2,6-difluorobenzaldehyde in dichloromethane (21 mL of dichloromethane) dropwise. After the IPC reaction is complete, add a solution of 60.0 g of acetic acid in 150 mL of dichloromethane dropwise. Add 500 mL of 2N sulfuric acid dropwise. Stir for 30 minutes. Separate the phases and extract the aqueous phase. Combine the organic phases, concentrate, and mix. Column chromatography and chiral alcohol inversion gave 53.0 g of compound III.

[0044] The NMR results are as follows 1 HNMR (400MHz, CDCl3) δ2.43 (m, 1H) 2.62 (dd, J = 3Hz, 1H) 3.15 (dd, J = 6Hz, 2H) 3.40 (dd, J=6Hz,2H)4.75(dd,J=3Hz,1H)4.5(dd,J=3Hz,1H)5.08(d,J=2Hz,1H)5.47(dd,J=5Hz 1H)7.27~7.40(m,7H)7.74(t,J=4Hz,1H)

[0045] Example 3:

[0046] To reaction flask 1, add 193 mL of water and stir to add 4.2 g of lithium hydroxide. Once dissolved, add 14 mL of 50% hydrogen peroxide and stir for 1 minute. To reaction flask 2, add 600 mL of THF and 129 mL of water. Add 33.1 g of compound III with stirring. Control the temperature at 0°C to -5°C and add the solution in reaction flask 1 dropwise. After the addition, stir at 0°C to -5°C for 2 hours, then naturally warm to room temperature and react for 15 hours. After the IPC reaction is complete, cool to 0°C to -5°C and slowly add anhydrous sodium sulfite. Stir for 30 minutes and concentrate under reduced pressure to remove THF. Extract the aqueous phase twice with 200 mL of ethyl acetate, and then add 200 mL of ethyl acetate to the aqueous phase.

[0047] The pH was adjusted to 2-3 with 3N hydrochloric acid, the phases were separated, the aqueous phase was extracted once with 50 mL of ethyl acetate, the combined organic phases were concentrated to dryness and distilled twice with ethyl acetate to obtain 19.0 g of a white solid with a liquid chromatography purity of 96.3% and a yield of 92.0%.

[0048] 1HNMR (400MHz, CDCl3) δ2.45~2.55(m,2H)3.15(dd,J=6Hz,2H)3.40(dd,J=6Hz,2H)5.10(d,J=2Hz,1H)7.37(s,1H)7.74(t,J=4Hz,1H)11.13(s,1H)

[0049] Example 4:

[0050] Control the temperature in the reaction flask to 0-10°C and add 100 mL of acetonitrile to the reaction flask. Stir and add 11.8 g of 2,4-dimethoxybenzylamine. Once dissolved, add 2.1 g of HOBT, 5.1 g of compound IV, and 3.5 g of DCC. Stir and react for 20 minutes after addition, then raise the temperature. Control the temperature at 30°C and react for approximately 2 hours. After completion, filter the mixture, rinse the filter cake with acetonitrile, combine the organic phases, concentrate, add water and ethyl acetate to dissolve the mixture, adjust the pH to 4 with 3N hydrochloric acid, separate the phases, extract the aqueous phase with ethyl acetate, combine the concentrated organic phases, and dry the mixture. Column chromatography yields 5.2 g of a pink, foamy solid with an HPLC purity of 85.7%. Yield: 70%.

[0051] 1 HNMR (400MHz, CDCl3) δ2.43 (m, 1H) 2.62 (dd, J = 3Hz, 1H) 3.15 (dd, J = 7Hz, 2H) 3.40 (dd, J = 7Hz, 2H) 3.81 (s, 6H) 4.40 (d,J=2Hz,2H)5.08(d,J=6Hz,1H)6.36(s,1H)6.65(s,2H)7.4(t,J=7Hz,2H)7.74(t,J=2Hz,1H)8.87(t,J=3Hz,1H)

[0052] Example 5:

[0053] Control the temperature in the reaction flask to 0-10°C, add 68mL of THF, add 3.0g of compound V, and stir to add 4.8g of triphenylphosphine. Add 3.2g of DEAD dropwise at this temperature, and stir for 1h. After the reaction, add water and ethyl acetate. The phases are separated, and the organic phase is concentrated to dryness. MTBE is added, and the mixture is crystallized at 0°C for approximately 12h. Filter, rinse the filter cake with MTBE, and combine the organic phases and concentrate to obtain 2.5g of a crude oil, which is used directly in the next step. HPLC purity is 92.1%, and the yield is 81%.

[0054] 1HNMR (400MHz, CDCl3) δ2.43 (m, 1H) 3.05 (dd, J = 4Hz, 1H) 3.15 (dd, J = 7Hz, 2H) 3.40 (dd, J = 7Hz, 2H) 3.8 1(s,6H)4.23(d,J=5Hz,1H)4.46(s,2H)6.36(s,1H)6.65(s,2H)7.70(t,J=5Hz,2H)7.74(t,J=2Hz,1H)

[0055] Example 6:

[0056] To the reaction flask, 10 mL of (acetonitrile / water = 5 / 1) was added, followed by the addition of 0.80 g of compound VI and 4.8 g of CAN. After addition, the temperature was raised to 65°C and stirred for 2 h. After completion of the reaction, the mixture was concentrated, and a small amount of water and ethyl acetate was added. The mixture was stirred for 10 minutes. A large amount of yellow solid, representing the nitrate salt of the compound, precipitated. The mixture was filtered, and the filter cake was added with ethyl acetate and saturated sodium carbonate solution. The mixture was stirred for 10 min. The phases were separated, and the organic phase was washed with water. The separated organic phase was then dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated to yield 400 mg of a yellow solid. HPLC: 96.9%, optical purity RR: 97.2%, yield 74%.

[0057] 1 HNMR(400MHz, CDCl3)δ2.43(m,1H)3.05(dd,J=4Hz,1H)3.15(dd,J=7Hz,2H)3.40(dd,J=7Hz,2H)4.6(d,J=2Hz,1H)7.40(t,J=6Hz,2H)7.74(t,J=2Hz,1H)

Claims

1. A monocyclic β-lactam compound, a compound of formula VII and its intermediate compound, with the structural formula:

2. A method for preparing a compound of formula VII, a monocyclic β-lactam compound, characterized in that, Prepared by the oxidative removal reaction of the compound of formula VI, 3. The preparation method according to claim 2, characterized in that, The reagent for the oxidative removal reaction is ammonium cerium nitrate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or Oxone.

4. A method for preparing a compound of formula VI, characterized in that, Prepared by Mitsunobu cyclization reaction of Compound V, 5. The preparation method according to claim 4, characterized in that, The reagent for the Mitsunobu cyclization reaction is a phosphine reagent and an azo reagent.

6. The preparation method according to claim 5, wherein, The phosphine reagent is triphenylphosphine, n-butylphosphine or cyclohexylphosphine; the azo reagent is diethyl azodicarboxylate, diisopropyl azodicarboxylate or dibutyl azodicarboxylate.

7. The preparation method according to claim 4, characterized in that, The compound of formula V is prepared from the compound of formula I through condensation reaction, aldol condensation reaction, oxidative removal reaction, and amide condensation reaction.

8. The preparation method according to claim 7, characterized in that, The reagent for the condensation reaction is HOBT / DCC, HOBT / EDCI, HATU, HBTU, HCTU or TCFH / NMI.

9. The preparation method according to claim 7, characterized in that, The aldol condensation reaction is carried out in the presence of a base, a salt or a combination thereof.

10. The preparation method according to claim 7, characterized in that, The reagent for the oxidative removal reaction is hydrogen peroxide / lithium hydroxide, hydrogen peroxide / sodium hydroxide, hydrogen peroxide / potassium hydroxide, hydrogen peroxide / cesium hydroxide, hydrogen peroxide / potassium carbonate or hydrogen peroxide / cesium carbonate.

11. The preparation method according to claim 7, characterized in that, The reagent for the amide condensation reaction is HOBT / DCC, HOBT / EDCI, HATU, HBTU, HCTU or TCFH.

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