Preparation method of monocyclic beta lactam compound

Abstract

The invention belongs to the field of pharmaceutical chemicals, and mainly relates to a preparation method of a monocyclic beta lactam compound. At present, the prior art has the problems of non-ideal reaction selectivity, high resolution difficulty, low yield and the like. According to the method, a target chiral center is constructed in advance, the problems that optical isomers are difficult to separate and the yield is low under the condition of small steric hindrance are solved, meanwhile, due to the fact that target configuration can be directionally synthesized, the atom utilization rate is increased, industrial production is facilitated, environmental pollution is reduced, and commercialization feasibility is improved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a monocyclic β-lactam compound. Background Art

[0002] β-lactam antibiotics play an important role in clinical practice due to their broad-spectrum, high potency, and high safety. As an important part of β-lactam antibiotics, monocyclic β-lactams are one of the hotspots in the field of drug research and development because their structures are simpler than those of penicillins and cephalosporins, and their chemical properties are more stable than those of other non-classical β-lactam antibiotics.

[0003] Compounds containing the azetidin-2-one partial structure in the molecular structure of monocyclic β-lactam antibiotics are important components of monocyclic β-lactam antibiotics.

[0004] The known patents and currently commonly used methods for preparing the monocyclic β-lactam ring mainly include:

[0005]

[0006] The selectivity of this method in the case of small steric hindrance is not ideal, and other optical isomers will be produced, facing the problems of difficult resolution 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. Summary of the Invention

[0008] The present invention provides a preparation method of a monocyclic β-lactam, which is prepared by a condensation reaction, an aldol condensation reaction, an oxidative removal reaction, an amide condensation reaction, a Mitsunobu cyclization reaction, and an oxidative removal reaction.

[0009] To achieve the technical objectives of the present invention, the technical solutions provided by the present invention are as follows:

[0010] The present invention provides a monocyclic β-lactam compound of formula VII, and the structural formula is as follows:

[0011]

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

[0013]

[0014] The present invention provides an intermediate compound of formula V, and the structural formula is as follows:

[0015]

[0016] The present invention provides a method for preparing a compound of formula VII, a monocyclic β-lactam compound, which is prepared by an oxidative removal reaction from a compound of formula VI.

[0017]

[0018] The reagent for the oxidative removal reaction can be CAN, DDQ or Oxone; more preferably, it is ammonium cerium nitrate (CAN).

[0019] In the oxidative removal reaction, the molar ratio range of compound VI to the oxidation reagent can be 1:(2 - 8).

[0020] The solvent for the oxidative removal reaction can be an organic solvent or an inorganic solvent; more preferably, it is an aqueous solution of acetonitrile.

[0021] The present invention provides a method for preparing a compound of formula VI, which is prepared by Mitsunobu cyclization reaction from a compound of formula V.

[0022]

[0023] The reagents for the Mitsunobu cyclization reaction can be phosphine reagents and azo reagents. The phosphine reagent can be triphenylphosphine, n-butylphosphine or cyclohexylphosphine, more preferably triphenylphosphine; the azo reagent can be diethyl azodicarboxylate, diisopropyl azodicarboxylate or dibutyl azodicarboxylate, more preferably diethyl azodicarboxylate.

[0024] In the Mitsunobu cyclization reaction, the molar ratio range of compound V, the phosphine reagent to the azo reagent can be 1:(2 - 5):(2 - 5).

[0025] The solvent for the Mitsunobu cyclization reaction can be an organic solvent or an inorganic solvent; more preferably, it is tetrahydrofuran.

[0026] The compound of formula V is prepared by an amide condensation reaction of a compound of formula IV with 2,4-dimethoxybenzylamine.

[0027]

[0028] The reagents for the amide condensation reaction can be HOBT / DCC, HOBT / EDCI, HATU, HBTU, HCTU or TCFH; more preferably, they are 1-hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC).

[0029] In the amide condensation reaction, the molar ratio range of compound IV, 2,4-dimethoxybenzylamine to the amide condensation reagent can be 1:(2 - 5):(2 - 7).

[0030] The solvent for the amide condensation reaction can be an organic solvent or an inorganic solvent; more preferably, it is acetonitrile.

[0031] The compound of formula IV is prepared by an oxidative removal reaction from the compound of formula III.

[0032]

[0033] The oxidative removing 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; more preferably, it is hydrogen peroxide / lithium hydroxide.

[0034] In the oxidative removal reaction, the molar ratio range of compound III to the oxidative removing agent can be 1:(8 - 15).

[0035] The solvent for the oxidative removal reaction can be an organic solvent or an inorganic solvent; more preferably, it is water.

[0036] The compound of formula III is prepared by an aldol condensation reaction from the compound of formula II and 2,6-difluorobenzaldehyde.

[0037]

[0038] 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-butyllithium, tert-butyllithium. The base salt combination can be TEA / magnesium chloride, DIPEA / magnesium chloride or DIPEA / cesium carbonate; more preferably, it is titanium tetrachloride or tetraisopropyl titanate.

[0039] In the aldol condensation reaction, the molar ratio range of compound II to 2,6-difluorobenzaldehyde can be 1:(0.8 - 1.5).

[0040] The solvent for the aldol condensation reaction can be an organic solvent or an inorganic solvent; more preferably, it is dichloromethane.

[0041] The compound of formula II is prepared by a condensation reaction from the compound of formula I and an oxazolidinone compound.

[0042]

[0043] The reagent for the condensation reaction can be HOBT / DCC, HOBT / EDCI, HATU, HBTU, HCTU or TCFH / NMI; more preferably, it is N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI).

[0044] In the condensation reaction, the molar ratio range of compound I, oxazolidinone compounds and the condensation reagent can be 1:(0.5 - 2):(2 - 5).

[0045] The solvent for the condensation reaction can be an organic solvent or an inorganic solvent; more preferably, it is acetonitrile.

[0046] The technical solution for preparing a monocyclic β-lactam compound provided by the present invention constructs the target chiral center in advance, solves the problems of difficult separation of optical isomers and low yield under the condition of small steric hindrance. At the same time, due to the directional synthesis of the target configuration, the atom utilization rate is improved, which is beneficial to industrial production, reduces environmental pollution, and improves commercial feasibility. Therefore, it is a route with industrialization potential. Specific Embodiments

[0047] To further understand the present invention, the following provides a detailed description of the present invention in combination with examples. It should be understood that these example descriptions are only for further detailed description of the features of the present invention, rather than a limitation on the scope of the present invention or the scope of the claims of the present invention.

[0048] Example 1:

[0049]

[0050] Under nitrogen protection, 500 mL of acetonitrile was added to the reaction flask, the internal temperature of the reaction flask was controlled at 20°C - 30°C, 61.7 g of compound I was added, 63.0 g of NMI was added, and 129.0 g of TFCH was added in batches. After addition, the mixture was stirred for 30 minutes. 50.0 g of (S)-4-phenyloxazol-2-one was added, and the temperature was raised to reflux for more than 12 hours. After the reaction was completed, most of the acetonitrile was distilled off under reduced pressure, then the temperature was lowered and 300 mL of water was added, 500 mL of a 1:1 mixture of ethyl acetate and n-heptane was added, stirred for 10 minutes and left to stand. The system was divided into three layers. The top layer was taken and concentrated under reduced pressure to 5V, 300 mL of absolute ethanol was added, and distilled under reduced pressure to 4V, and white solid would precipitate. The temperature was lowered and filtered, and dried under reduced pressure at 45°C to obtain 41.0 g of 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)

[0051] Example 2:

[0052]

[0053] Under nitrogen protection, add 600 mL of dichloromethane to the reaction flask, control the internal temperature of the reaction flask to be 0 °C to -5 °C, add 38.7 g of titanium tetrachloride, add 19.7 g of tetraisopropyl titanate, control the temperature at 0 °C to -5 °C, and dropwise add a dichloromethane solution of 66.8 g of Compound II. After addition, stir the reaction for 30 minutes. Add 55.3 g of diisopropylethylamine. Heat to reflux for more than 12 hours. Keep warm and stir for 30 min. Cool down to -30 °C to -25 °C, and dropwise add a dichloromethane solution of 45.0 g of 2,6-difluorobenzaldehyde (21 mL of dichloromethane). After the IPC reaction is completed, drop in a 150 mL dichloromethane solution of 60.0 g of acetic acid, dropwise add 500 mL of 2N sulfuric acid solution. After dropping, stir for 30 min, separate the phases, and extract the aqueous phase. Combine the organic phases, concentrate to dryness, and mix the samples. 53.0 g of Compound III is obtained through column chromatography and chiral alcohol inversion.

[0054] 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)

[0055] Example 3:

[0056]

[0057] Add 193 mL of water to Reaction Flask 1, stir and add 4.2 g of lithium hydroxide. After dissolving clearly, add 14 mL of 50% hydrogen peroxide and stir for 1 min for standby. Add 600 mL of THF and 129 mL of water to Reaction Flask 2, stir and add 33.1 g of Compound III, control the temperature at 0 °C to -5 °C, and dropwise add the solution in Reaction Flask 1. After addition, stir the reaction at 0 °C to -5 °C for 2 h, then naturally rise to room temperature and react for 15 h. After the IPC reaction is completed, cool down to 0 °C to -5 °C, slowly add anhydrous sodium sulfite, then stir for 30 min, concentrate under reduced pressure to remove THF, and extract the aqueous phase with 200 mL of ethyl acetate twice. Add 200 mL of ethyl acetate to the aqueous phase.

[0058] Adjust the pH to 2 - 3 with 3N hydrochloric acid, separate the phases, extract the aqueous phase with 50 mL of ethyl acetate once, combine the organic phases, concentrate to dryness, and steam with ethyl acetate twice to obtain 19.0 g of a white solid, with a liquid chromatography purity of 96.3% and a yield of 92.0%.

[0059] 1 HNMR (400 MHz, CDCl3) δ 2.45 - 2.55 (m, 2H) 3.15 (dd, J = 6 Hz, 2H) 3.40 (dd, J = 6 Hz, 2H) 5.10 (d, J = 2 Hz, 1H) 7.37 (s, 1H) 7.74 (t, J = 4 Hz, 1H) 11.13 (s, 1H)

[0060] Example 4:

[0061]

[0062] Control the internal temperature of the reaction flask at 0 - 10 °C, add 100 mL of acetonitrile to the reaction flask. Stir and add 11.8 g of 2,4 - dimethoxybenzylamine. After dissolving clearly, add 2.1 g of HOBT, add 5.1 g of Compound IV, add 3.5 g of DCC. After adding, stir and react for 20 min, then raise the temperature. Control the temperature at 30 °C and react for about 2 h. After the reaction is completed, filter. The filter cake is washed with acetonitrile. Combine the organic phases and concentrate. Add water and ethyl acetate to dissolve clearly. Adjust the pH to 4 with 3N hydrochloric acid. Separate the phases. The aqueous phase is extracted with ethyl acetate. Combine the organic phases and concentrate to dryness. The crude product is purified by column chromatography to obtain 5.2 g of pink foaming solid, with HPLC purity of 85.7%. Yield: 70%.

[0063] 1 HNMR (400 MHz, CDCl3) δ 2.43 (m, 1H) 2.62 (dd, J = 3 Hz, 1H) 3.15 (dd, J = 7 Hz, 2H) 3.40 (dd, J = 7 Hz, 2H) 3.81 (s, 6H) 4.40 (d, J = 2 Hz, 2H) 5.08 (d, J = 6 Hz, 1H) 6.36 (s, 1H) 6.65 (s, 2H) 7.4 (t, J = 7 Hz, 2H) 7.74 (t, J = 2 Hz, 1H) 8.87 (t, J = 3 Hz, 1H)

[0064] Example 5:

[0065]

[0066] Control the internal temperature of the reaction flask at 0 - 10 °C, add 68 mL of THF to the reaction flask, add 3.0 g of Compound V, stir and add 4.8 g of triphenylphosphine. Control the temperature and dropwise add 3.2 g of DEAD. After adding, stir and react for 1 h. After the reaction is completed, add water, add ethyl acetate, separate the phases. The organic phase is concentrated to dryness, add methyl tert - butyl ether, keep it at 0 °C for about 12 h to crystallize, filter. The filter cake is washed with methyl tert - butyl ether. Combine the organic phases and concentrate to obtain 2.5 g of crude product in the form of an oily substance, which is directly used for the next step. HPLC chromatographic purity is 92.1%, and the yield is 81%.

[0067] 1H NMR (400 MHz, CDCl3) δ 2.43 (m, 1H) 3.05 (dd, J = 4 Hz, 1H) 3.15 (dd, J = 7 Hz, 2H) 3.40 (dd, J = 7 Hz, 2H) 3.81 (s, 6H) 4.23 (d, J = 5 Hz, 1H) 4.46 (s, 2H) 6.36 (s, 1H) 6.65 (s, 2H) 7.70 (t, J = 5 Hz, 2H) 7.74 (t, J = 2 Hz, 1H)

[0068] Example 6:

[0069]

[0070] Add 10 mL of (acetonitrile / water = 5 / 1) to the reaction flask, stir and add 0.80 g of Compound VI, stir and add 4.8 g of CAN. After adding, warm up to 65 °C and stir for 2 h. After the reaction is completed, concentrate. Add a small amount of water and ethyl acetate, stir for 10 minutes. A large amount of yellow solid precipitated here is the nitrate of the compound. Filter. Add ethyl acetate and saturated sodium carbonate solution to the filter cake, stir for 10 min, separate the phases. Wash the organic phase with water, then separate the organic phase and dry it with anhydrous sodium sulfate. Filter. Concentrate the organic phase to obtain 400 mg of yellow solid. HPLC: 96.9%, optical purity RR: 97.2%, yield 74%.

[0071] 1 1H NMR (400 MHz, CDCl3) δ 2.43 (m, 1H) 3.05 (dd, J = 4 Hz, 1H) 3.15 (dd, J = 7 Hz, 2H) 3.40 (dd, J = 7 Hz, 2H) 4.6 (d, J = 2 Hz, 1H) 7.40 (t, J = 6 Hz, 2H) 7.74 (t, J = 2 Hz, 1H).

Claims

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

2. A method for preparing a compound of formula VII, a monocyclic β-lactam compound, characterized in that, Prepared by an oxidative removal reaction from a 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, dichlorodicyanobenzoquinone or Oxone.

4. A method for preparing a compound of formula VI, characterized in that, Prepared by Mitsunobu cyclization reaction from a compound of formula 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 a compound of formula I through a condensation reaction, an aldol condensation reaction, an oxidative removal reaction, and an 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. According to the preparation method described in 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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