Preparation method of N-substituent-3-hydroxy azetidine compound

Abstract

The invention relates to a preparation method of an N-substituted-3-hydroxy azetidine compound, and belongs to the field of medical intermediates. According to the invention, cheap and easily available N-substituted-3-hydroxy azetidine or 3-hydroxy azetidine is used as a raw material, and in the presence of a metal catalyst, hydrogenation (transfer hydrogenation) deprotection and reductive amination one-pot reaction are carried out on the raw material and various aldehydes to obtain the target N-substituted-3-hydroxy azetidine compound. The method overcomes the defects that in the prior art, when the target N-substituent-3-hydroxy azetidine compound is prepared, the steps are tedious (6-7 steps are needed for reaction to obtain the product), dangerous reagents (LiAlH4 and the like) are used, the preparation reaction conditions are harsh (no water, no oxygen and high temperature), the yield is low and the like, and provides beneficial reference for industrial amplification.

Description

Technical Field

[0001] The present invention relates to a method for preparing an N-substituted-3-hydroxyazetidine compound, belonging to the technical field of pharmaceutical intermediates. Specifically, N-protected-3-hydroxyazetidine or 3-hydroxyazetidine is used as a raw material to perform reductive amination with various aldehydes in the presence of a metal catalyst. Background Art

[0002] In 2012, Dijcks, FA, et al. reported that N-substituted azetidine derivatives are effective in preventing or treating ovulatory dysfunction, uterine cancer, endometrial cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy and breast cancer. In particular, estrogen receptor-positive breast cancer, more particularly, estrogen receptor-positive, hormone therapy-resistant breast cancer. In 2016, Peter JK et al. reported a new class of 2H-chromene compounds, which have an effect on conditioning caused by estrogen and other endocrine disorders. This class of 2H-chromene compounds also includes N-substituted azetidine derivatives.

[0003] In fact, a large part of the N-substituted azetidine derivatives mentioned in the above two patents have oxygen atoms substituted at the 3-position of azetidine, that is, the patent mentioned N-substituted-3-hydroxyazetidine compounds. In 2017, Myles, DC et al. reported a series of indole compounds, which have a conditioning effect on estrogen and other endocrine disorders. Some of these compounds also contain N-substituted-3-hydroxyazetidine compounds.

[0004] It can be seen that N-substituted-3-hydroxyazetidine compounds are a class of relatively valuable compounds in medicinal chemistry. However, there are relatively few methods for synthesizing such compounds, which are mainly obtained by ring-closing benzylamine or diphenylmethylamine with epichlorohydrin; or by esterifying azetidine with acyl chloride / anhydride and then reducing it with LiAlH4. The defects existing in the prior art are: many reaction steps (6-7 steps), the need for dangerous reducing agents, harsh reaction conditions (anhydrous and oxygen-free), cumbersome post-treatment and low yield.

[0005] Therefore, it is very necessary to develop a method for synthesizing N-substituted-3-hydroxyazetidine compounds with simple steps, mild conditions, low cost and environmental friendliness. Summary of the invention

[0006] In order to overcome the above technical defects, the present invention uses N-protected group-3-hydroxyazetidine or 3-hydroxyazetidine as a raw material in the presence of a metal catalyst to carry out reductive amination with various aldehydes, that is, the reaction is carried out in a one-pot method, and deprotection and protection are carried out simultaneously.

[0007] The preparation method of an N-substituted-3-hydroxyazetidine compound of the present invention comprises the following steps: in the presence of a metal catalyst, compound A and aldehyde B are subjected to a catalytic hydrogenation reaction in an organic solvent to obtain an N-substituted-3-hydroxyazetidine compound C;

[0008]

[0009] Wherein: R1 is selected from benzyl, diphenylmethyl, hydrogen, Cbz, p-methoxybenzyl, 2,4-dimethoxybenzyl; R2 is selected from hydrogen, substituted C1-C8 straight or branched saturated hydrocarbon, C3-C 10 Cycloalkyl or heterocyclic group; the substituent in the substituted C1-C8 straight or branched saturated hydrocarbon group is selected from at least one of hydrogen, halogen, C1-C8 straight or branched alkyl or perfluoroalkyl, C1-C4 straight or branched alkoxy, and phenyl; the heterocyclic group heteroatom is selected from N, S or O, and the number of heteroatoms is an integer of 1-3.

[0010] Furthermore, in the above technical solution, R1 is selected from benzyl, diphenylmethyl or hydrogen; R2 is selected from hydrogen, C1-C8 straight or branched saturated hydrocarbon group, C3-C 10 Cyclic or heterocyclic group; the substituent in the substituted C1-C8 straight or branched saturated hydrocarbon group is selected from at least one of halogen, C1-C8 straight or branched alkyl or perfluoroalkyl, C1-C4 straight or branched alkoxy, and phenyl; the heteroatom of the heterocyclic group is selected from N, S or O, and the number of heteroatoms is an integer of 1-3.

[0011] Furthermore, in the above technical scheme, R1 is selected from benzyl, diphenylmethyl or hydrogen; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 3-fluoro-n-propyl, cyclopropylmethyl, 3-methoxy-n-propyl, isopropylmethyl, cyclobutylmethyl or 3-tetrahydrofuranylmethyl.

[0012] Furthermore, in the above technical solution, the metal catalyst is Pd / C, Pd(OH)2 / C, Pd(OH)2, different loads of Pd, different loads of Pd(OH)2, PtO2, 5-20% Pt / C, Rany-Ni, Rh / C with different metal and water contents. Under the preferred conditions, the catalyst is 5-20% Pd(OH)2 / C, Pd(OH)2.

[0013] Furthermore, in the above technical solution, the reducing agent is 0.1-100 atm hydrogen atmosphere, ammonium formate, sodium formate, potassium formate, formic acid, NaBH4, KBH4, LiBH4, NaBH(OAc)3, NaBH3CN. Under preferred conditions, the reducing agent is hydrogen or ammonium formate.

[0014] Furthermore, in the above technical solution, the reaction temperature is 0 to 100° C. Under preferred conditions, the reaction temperature is 29 to 55° C.

[0015] Furthermore, in the above technical solution, the reaction feeding method is selected from directly feeding all materials into the reaction bottle for reaction, or feeding the materials in sequence according to the intermediate process.

[0016] Furthermore, in the above technical solution, the organic solvent is selected from alcohol, water or a mixture of two or more of alcohol / water.

[0017] Furthermore, in the above technical solution, the alcohol is selected from methanol, ethanol, propanol or isopropanol. Under preferred conditions, the reaction solvent is methanol.

[0018] Furthermore, in the above technical scheme, the most preferred scheme of the present invention is: R1 is selected from benzyl, diphenylmethyl or hydrogen; R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 3-fluoro-n-propyl, cyclopropylmethyl, 3-methoxy-n-propyl, isopropylmethyl, cyclobutylmethyl or 3-tetrahydrofuranylmethyl; the catalyst is 10% Pd(OH)2 / C; the reaction material feeding method is: all the reaction materials are added into the reaction bottle at one time when the reaction is fed; the reducing agent is hydrogen; and the reaction temperature is 29-55°C.

[0019] The core technology of the present invention is: in the presence of reducing salts such as hydrogen or ammonium formate, a metal catalyst is used to catalyze the deprotection of N-protected group-3-hydroxyazetidine to obtain 3-hydroxyazetidine, which is very unstable and easy to deteriorate. The present invention uses a "one-pot method" to continue the reaction of 3-hydroxyazetidine with an aldehyde compound at 0°C-100°C to obtain a product. This process can be carried out separately, or all materials can be put into the reaction at one time and then directly reacted to obtain.

[0020] Advantageous Effects of the Invention

[0021] The N-substituted-3-hydroxyazetidine compounds prepared by the present invention utilize the two reactions of deprotection of A and protection of B. The conditions of the present invention have the advantages of mild conditions, readily available and low-priced raw materials, simple operation, no need to separate intermediates, high final product yield, and environmental friendliness.

[0022] The invention uses cheap and readily available N-protected group-3-hydroxyazetidine or 3-hydroxyazetidine hydrochloride, in the presence of a metal catalyst, hydrogen or formate as a reducing agent, and aldehyde (RCHO) as a raw material to obtain the target product through a one-pot reaction, thereby overcoming the defects of the prior art such as multiple reaction steps (6-7 steps), the need for dangerous reducing agents, harsh reaction conditions (anhydrous and oxygen-free), complicated post-treatment, and low yield. DETAILED DESCRIPTION

[0023] The present invention is further described below by way of examples, the purpose of which is only to provide a better understanding of the content of the present invention. Therefore, the examples given do not limit the scope of protection of the present invention.

[0024] In the following examples, the N-dibenzhydryl-3-hydroxyazetidine used was produced by Anergy Company with a purity of 98%, and the Pd(OH)2 / C was produced by Wokai Company with a content of 10%; hydrogen was provided by Shanghai Yizhi Industrial Gas Co., Ltd. with a purity of 99.9%, and methanol was provided by Shanghai Runjie Chemical Reagent Co., Ltd. as an analytical grade reagent.

[0025] Example 1

[0026]

[0027] In a 5000mL three-necked flask, 500mL methanol, 500g raw material SM1, 1000mL methanol, 250mL propionaldehyde (1.7eq), 10g Pd(OH)2 / C and 500mL methanol were added in sequence. Hydrogen was replaced three times, and then hydrogenated at normal pressure. The initial reaction temperature was 29°C. As the reaction proceeded, the temperature of the reaction system gradually increased, reaching a maximum temperature of 55°C, and the hydrogen absorption rate was very fast. After 8 to 9 hours of reaction, the hydrogen absorption rate suddenly became very slow. TLC (CH2Cl2 / MeOH=10 / 1), adding ammonia water, UV and iodine cylinder showed that the raw material almost completely disappeared, and only one new point was generated. Stop stirring, filter with two layers of filter paper, recover the catalyst, and store it in water. The filtrate was spin-dried, and then 500mL of water was added, and the solution was washed with petroleum ether three times. The aqueous phase was spin-dried, and the residue was distilled under reduced pressure to obtain the product TM, a colorless viscous liquid with a yield of 60%. 1 H NMR(300MHz,CDCl3)δ:5.51(br s,1H),4.39(m,1H),3.62-3.56(m,2H),2.90-2.85(m,2H),2.41(t,J=7.5Hz,2H),1.34(t,J=7.2Hz,2H),0.87(t,J=7.8Hz,3H).

[0028] Example 2

[0029]

[0030] In a 5000mL three-necked flask, add 500mL methanol, 230g raw material SM2, 500mL methanol, 500mL methanol and sodium bicarbonate (176g) in sequence. Stir open for 30min, then add 250mL propionaldehyde (1.7eq), 10g Pd(OH)2 / C. Replace with hydrogen three times, then hydrogenate at normal pressure. The initial reaction temperature is 29°C. As the reaction proceeds, the temperature of the reaction system gradually increases, reaching a maximum temperature of 55°C, and the hydrogen absorption rate is very fast. After 6 to 7 hours of reaction, the hydrogen absorption rate suddenly becomes very slow. TLC (CH2Cl2 / MeOH=10 / 1), add ammonia water, ultraviolet and iodine cylinder show that the raw material almost completely disappears, and only one new point is generated. Stop stirring, filter with two layers of filter paper, recover the catalyst, and store in water. The filtrate is spin-dried, and the residue is distilled under reduced pressure to obtain the product SM, a colorless viscous liquid with a yield of 55%.

[0031] Example 3

[0032]

[0033] In a 3000mL three-necked flask, add 500mL methanol, 500g raw material SM1, 500mL methanol, 10g Pd(OH)2 / C and 500mL methanol in sequence. Hydrogen replacement three times, then hydrogenation at normal pressure. The initial reaction temperature is 29°C. As the reaction proceeds, the temperature of the reaction system gradually increases, the highest temperature rises to 55°C, and the hydrogen absorption rate is very fast. After 6 to 7 hours of reaction, the hydrogen absorption rate suddenly becomes very slow. TLC (CH2Cl2 / MeOH=10 / 1), add ammonia water, ultraviolet and iodine cylinder show that the raw material almost completely disappears, and only one new point is generated. Add 250mL propionaldehyde (1.7eq) to the reaction system, continue hydrogenation at normal pressure, and after 3 to 4 hours of reaction, the hydrogen absorption rate suddenly becomes very slow. Stop stirring, filter with two layers of filter paper, recover the catalyst, and store it in water. The filtrate is spin-dried, and the residue is distilled under reduced pressure to obtain the product TM, a colorless viscous liquid with a yield of 55%.

[0034] Example 4

[0035]

[0036] In a 5000mL three-necked flask, 500mL methanol, 500g raw material SM1, 500mL methanol, 10g Pd(OH)2 / C and 500mL methanol were added in sequence. Hydrogen was replaced three times, and then hydrogenation was carried out under normal pressure. The initial reaction temperature was 29°C. As the reaction proceeded, the temperature of the reaction system gradually increased, reaching a maximum temperature of 55°C, and the hydrogen absorption rate was very fast. After 6 to 7 hours of reaction, the hydrogen absorption rate suddenly became very slow. TLC (CH2Cl2 / MeOH=10 / 1), adding ammonia water, UV and iodine cylinder showed that the raw material almost completely disappeared, and only one new point was generated. The system was filtered to remove the catalyst. The filtrate was dried to obtain a viscous oily substance. 2000mL 1,2-dichloroethane and 250mL propionaldehyde (1.7eq) were added to the reaction system, and NaBH(OAc)3 was added in batches under ice water cooling. After 16 hours of reaction, water was added to quench the reaction. Separate the liquid, and extract the organic layer with water twice. The aqueous layer was distilled under reduced pressure to obtain the product TM, a colorless viscous liquid, with a yield of 30%.

[0037] Example 5

[0038]

[0039] In a 5000mL three-necked flask, add 2000mL 1,2-dichloroethane, 230g raw material SM2 and sodium bicarbonate (176g) in sequence. Stir open for 30min, then add 250mL propionaldehyde (1.7eq), add NaBH(OAc)3 in batches under ice water cooling, and heat to 25-35℃ for reaction after addition. After stirring for 16 hours, add water to quench the reaction. Separate the liquids, and extract the organic layer with water twice. The aqueous layer is distilled under reduced pressure to obtain the product TM, a colorless viscous liquid with a yield of 35%.

[0040] The embodiments are described in detail, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A method for preparing an N-substituted-3-hydroxyazetidine compound, characterized in that: The method comprises the following steps: in the presence of a metal catalyst, compound A and aldehyde B are subjected to a catalytic hydrogenation reaction in an organic solvent to obtain an N-substituted-3-hydroxyazetidine compound C; Wherein: R1 is benzyl, diphenylmethyl, hydrogen, Cbz, p-methoxybenzyl, 2,4-dimethoxybenzyl; R2 is hydrogen, substituted C1-C8 straight chain or branched saturated hydrocarbon, C3-C 10 Cycloalkyl or heterocyclic group; the substituent in the substituted C1-C8 straight or branched saturated hydrocarbon group is selected from at least one of hydrogen, halogen, C1-C8 straight or branched alkyl or perfluoroalkyl, C1-C4 straight or branched alkoxy, and phenyl; the heterocyclic group heteroatom is selected from N, S or O, and the number of heteroatoms is an integer of 1-3.

2. The method for preparing the N-substituted-3-hydroxyazetidine compound according to claim 1, characterized in that: R1 is selected from benzyl, diphenylmethyl or hydrogen; R2 is selected from hydrogen, C1-C8 straight or branched saturated hydrocarbon, C3-C 10 Cyclic or heterocyclic group; the substituent in the substituted C1-C8 straight or branched saturated hydrocarbon group is selected from at least one of halogen, C1-C8 straight or branched alkyl or perfluoroalkyl, C1-C4 straight or branched alkoxy, and phenyl; the heteroatom of the heterocyclic group is selected from N, S or O, and the number of heteroatoms is an integer of 1-3.

3. The method for preparing the N-substituted-3-hydroxyazetidine compound according to claim 1, characterized in that: The metal catalysts are Pd / C, Pd(OH)2 / C, Pd(OH)2, different loaded Pd, different loaded Pd(OH)2, PtO2, 5-20% Pt / C, Rany-Ni, and Rh / C with different metal and water contents.

4. The method for preparing the N-substituted-3-hydroxyazetidine compound according to claim 1, characterized in that: The reducing agent is 0.1-100 atm hydrogen atmosphere, ammonium formate, sodium formate, potassium formate, formic acid, NaBH4, KBH4, LiBH4, NaBH(OAc)3, NaBH3CN.

5. The method for preparing the N-substituted-3-hydroxyazetidine compound according to claim 1, characterized in that: The reaction temperature is 0-100°C.

6. The method for preparing the N-substituted-3-hydroxyazetidine compound according to claim 1, characterized in that: The reaction feeding method is selected from directly feeding all the materials into the reaction bottle for reaction, or feeding the materials in sequence according to the intermediate process.

7. The method for preparing the N-substituted-3-hydroxyazetidine compound according to claim 1, characterized in that: The organic solvent is selected from alcohol, water or a mixture of two or more of alcohol / water.

8. The method for preparing the N-substituted-3-hydroxyazetidine compound according to claim 7, characterized in that: The alcohol is selected from MeOH, ethanol, propanol or isopropanol.

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