阅读说明：本技术 一种1-氨甲基-1-环丙醇类化合物及其合成方法 (1-aminomethyl-1-cyclopropanol compound and synthetic method thereof ) 是由 张振兴 杨浩浩 于 2020-12-29 设计创作，主要内容包括：本发明公开了一种1-氨甲基-1-环丙醇类化合物的合成方法,包括以下步骤：(1)、在氮气保护下,将化合物(I)、THF以及DBU混合,得到第一混合物；将所述第一混合物与保护试剂混合,得到第二混合物；将所述第二混合物升温至回流,继续搅拌,得到第三混合物,将所述第三混合物经过后处理,得到中间体A；(2)、将所述中间体A、THF、二碘甲烷以及Zn-Cu试剂混合,得到第四混合物；在氮气保护下,将所述第四混合物通过回流搅拌,反应结束后,得到第五混合物,将所述第五混合物经过后处理得到中间体B纯品；(3)、将所述中间体B纯品溶于HCl/MeOH中,经过后处理后得到1-氨甲基-1-环丙醇盐酸盐。(The invention discloses a synthetic method of a 1-aminomethyl-1-cyclopropanol compound, which comprises the following steps: (1) under the protection of nitrogen, mixing the compound (I), THF and DBU to obtain a first mixture; mixing the first mixture with a protective reagent to obtain a second mixture; heating the second mixture to reflux, continuously stirring to obtain a third mixture, and carrying out aftertreatment on the third mixture to obtain an intermediate A; (2) mixing the intermediate A, THF, diiodomethane and a Zn-Cu reagent to obtain a fourth mixture; under the protection of nitrogen, refluxing and stirring the fourth mixture, obtaining a fifth mixture after the reaction is finished, and carrying out aftertreatment on the fifth mixture to obtain a pure intermediate B; (3) and dissolving the pure product of the intermediate B in HCl/MeOH, and performing post-treatment to obtain the 1-aminomethyl-1-cyclopropanol hydrochloride.)

1. A synthetic method of a 1-aminomethyl-1-cyclopropanol compound is characterized by comprising the following steps:

dissolving a compound (I) in THF (tetrahydrofuran) under the protection of nitrogen, and adding DBU (diethylene glycol) to obtain a first mixture;

mixing the first mixture with a protective reagent to obtain a second mixture;

heating the second mixture to reflux, continuously stirring, obtaining a third mixture after the reaction is finished, and carrying out aftertreatment on the third mixture to obtain an intermediate A, wherein the chemical reaction formula is as follows:

dissolving the intermediate A in THF, and adding diiodomethane and a Zn-Cu reagent to obtain a fourth mixture;

and under the protection of nitrogen, stirring the fourth mixture by reflux, obtaining a fifth mixture after the reaction is finished, and carrying out aftertreatment on the fifth mixture to obtain a pure intermediate B, wherein the chemical reaction formula is as follows:

and (3) dissolving the pure intermediate B in HCl/MeOH, adding ethyl acetate to carry out solvent replacement after the reaction is completed, removing most of ethyl acetate, cooling to room temperature, continuing stirring, filtering, washing and drying to obtain 1-aminomethyl-1-cyclopropanol hydrochloride, wherein the chemical reaction formula is shown as follows:

2. the method for synthesizing 1-aminomethyl-1-cyclopropanol compound according to claim 1, wherein in said compound (I), R1 is selected from H, R2 is selected from t-butyloxycarbonyl, trifluoroacetyl or trityl; the protective reagent is selected from tert-butyldimethylchlorosilane, trimethylchlorosilane or triethylchlorosilane.

3. The method for synthesizing 1-aminomethyl-1-cyclopropanol compounds according to claim 2, wherein said first mixture in step (1) further comprises a temperature reduction step before mixing with a protective reagent, wherein the temperature after temperature reduction is-5 to 0 ℃.

4. The method for synthesizing 1-aminomethyl-1-cyclopropanol compounds according to claim 2, wherein the reaction temperature is controlled not to exceed 10 ℃ and the reaction time is controlled to be 0.5h during the preparation of the second mixture in step (1); the reflux temperature is 68 ℃, and the reflux stirring time is 1.5 to 2 hours.

5. The method for synthesizing 1-aminomethyl-1-cyclopropanol compounds according to claim 2, wherein the post-treatment step in step (1) is specifically:

cooling the third mixture to-5-0 ℃, and then adjusting the third mixture to be neutral by using dilute hydrochloric acid, wherein the process temperature is controlled not to exceed 10 ℃;

standing for layering, extracting an aqueous layer by using 3x1L ethyl acetate, combining organic phases, and performing desolventizing to obtain the intermediate A.

6. The method for synthesizing 1-aminomethyl-1-cyclopropanol compounds according to claim 2, wherein the fourth mixture in step (2) further comprises a nitrogen substitution step before refluxing, and the number of nitrogen substitutions is 3; the reflux temperature is 68 ℃, and the reflux stirring time is 6 h.

7. The method for synthesizing 1-aminomethyl-1-cyclopropanol compounds according to claim 2, wherein the post-treatment step in step (2) is specifically:

cooling the fifth mixture to room temperature, filtering, washing a filter cake by THF, and performing desolventizing under reduced pressure to obtain a crude intermediate B;

and recrystallizing the intermediate crude product by ethyl acetate to obtain the intermediate B pure product.

8. The method for synthesizing 1-aminomethyl-1-cyclopropanol compound according to claim 2, wherein the reaction temperature in step (3) is room temperature and the reaction time is 1-2 h, preferably 1.5 h.

9. The method for synthesizing 1-aminomethyl-1-cyclopropanol compounds according to claim 2, wherein the step (3) further comprises removing most of the solvent before adding ethyl acetate for solvent replacement; the number of solvent replacements was 2; the stirring time is 2h after the temperature is reduced to the room temperature.

10. 1-aminomethyl-1-cyclopropanol prepared by the synthesis process according to any one of claims 1 to 9.

Technical Field

The invention relates to the field of medical intermediates, in particular to a 1-aminomethyl-1-cyclopropanol compound and a synthesis method thereof.

Background

The three-membered ring structure is an important pharmacophore in medicinal chemistry, and the group is applied to various medicinal structures. The 1-aminomethyl-1-cyclopropanol compound is used as an intermediate capable of providing a ternary ring structure, and has wide application in the field of new drug development. At present, the compounds are mainly prepared by a Kulinkovich reaction:

the method needs titanium tetraisopropoxide which is difficult to post-treat and ethyl magnesium bromide with high safety risk, and has harsh requirements on equipment and substrates in the operation process and difficult post-treatment, thereby causing difficult amplification and higher cost. And if R1 and R2 are benzyl, Pd catalytic hydrogenation deprotection is needed, and under the condition, the ring of the ternary ring structure is easy to open, so that the method is not suitable for scale-up production.

Disclosure of Invention

The invention aims to provide a synthetic method of a 1-aminomethyl-1-cyclopropanol compound, which solves one or more of the problems in the prior art.

On one hand, the invention provides a synthetic method of a 1-aminomethyl-1-cyclopropanol compound, which comprises the following steps:

dissolving N-Boc amino acetone in THF under the protection of nitrogen, and adding DBU to obtain a first mixture;

mixing the first mixture with a protective reagent to obtain a second mixture;

heating the second mixture to reflux, continuously stirring, obtaining a third mixture after the reaction is finished, and carrying out aftertreatment on the third mixture to obtain an intermediate A, wherein the chemical reaction formula is as follows:

dissolving the intermediate A in THF, and adding diiodomethane and a Zn-Cu reagent to obtain a fourth mixture;

and under the protection of nitrogen, stirring the fourth mixture by reflux, obtaining a fifth mixture after the reaction is finished, and carrying out aftertreatment on the fifth mixture to obtain a pure intermediate B, wherein the chemical reaction formula is as follows:

and (3) dissolving the pure intermediate B in HCl/MeOH, adding ethyl acetate to carry out solvent replacement after the reaction is completed, removing most of ethyl acetate, cooling to room temperature, continuing stirring, filtering, washing and drying to obtain 1-aminomethyl-1-cyclopropanol hydrochloride, wherein the chemical reaction formula is shown as follows:

in certain embodiments, in compound (I) R1 is selected from H, R2 is selected from t-butyloxycarbonyl, trifluoroacetyl or trityl; the protective agent is selected from tert-butyldimethylchlorosilane, trimethylchlorosilane or triethylchlorosilane.

Wherein: DBU, the 1, 8-diazabicycloundec-7-ene, is a sterically hindered amidine, basic and useful as a base or catalyst in organic synthesis. The general method for synthesizing DBU is that caprolactam and acrylonitrile are nucleophilic added to generate N- (2-cyanoethyl) caprolactam, N- (3-aminopropyl) caprolactam is obtained through catalytic hydrogenation, and DBU is obtained through 3-dehydration cyclization. In the synthesis, catalytic hydrogenation under pressure is generally required, and the requirement on reaction equipment is high.

THF, known by the name tetrahydrofuran, is a class of heterocyclic organic compounds, one of the most powerful polar ethers, used as a solvent in chemical reactions.

Tert-butyldimethylsilyl chloride, also known as TBDMSCl, is used as a protecting agent.

Trimethylchlorosilane, also known as TMSCl, is used as a protectant.

Triethylchlorosilane, also known as TESCl, is used as a protectant.

In certain embodiments, the first mixture of step (1) further comprises a temperature reduction step before mixing with the protecting agent, wherein the temperature after temperature reduction is from-5 to 0 ℃.

In certain embodiments, the reaction temperature is controlled not to exceed 10 ℃ and the reaction time is 0.5h during the preparation of the second mixture in step (1).

In certain embodiments, the reflux temperature in step (1) is 68 ℃ and the reflux stirring time is 1.5 to 2 h.

In certain embodiments, the post-treatment step in step (1) is specifically:

cooling the third mixture to-5-0 ℃, and then adjusting the third mixture to be neutral by using dilute hydrochloric acid, wherein the temperature in the process is controlled not to exceed 10 ℃;

standing for layering, extracting an aqueous layer by using 3x1L ethyl acetate, combining organic phases, and performing desolventizing to obtain the intermediate A.

In certain embodiments, the number of extractions is 3.

In certain embodiments, the fourth mixture in step (2) further comprises a nitrogen substitution step before refluxing, with a nitrogen substitution number of 3; the reflux temperature is 68 ℃, and the reflux stirring time is 6 h.

In certain embodiments, the post-treatment step in step (2) is specifically:

cooling the fifth mixture to room temperature, filtering, washing a filter cake by THF, and performing desolventizing under reduced pressure to obtain a crude intermediate B;

recrystallizing the intermediate crude product by ethyl acetate to obtain an intermediate B pure product.

In certain embodiments, the reaction temperature in step (3) is room temperature and the reaction time is from 1 to 2 hours, preferably 1.5 hours.

In certain embodiments, the step (3) further comprises removing a substantial portion of the solvent from the system prior to adding ethyl acetate to effect solvent replacement; the number of solvent replacements was 2; the stirring time is 2h after the temperature is reduced to the room temperature.

On the other hand, the synthesis method of the 1-aminomethyl-1-cyclopropanol compound provided by the invention is as follows:

dissolving N-Boc amino acetone in THF under the protection of nitrogen, and adding DBU to obtain a first mixture;

mixing the first mixture with a protective reagent to obtain a second mixture;

heating the second mixture to reflux, continuously stirring, obtaining a third mixture after the reaction is finished, and carrying out aftertreatment on the third mixture to obtain an intermediate A, wherein the chemical reaction formula is as follows:

dissolving the intermediate A in THF, and adding diiodomethane and a Zn-Cu reagent to obtain a fourth mixture;

and under the protection of nitrogen, stirring the fourth mixture by reflux, obtaining a fifth mixture after the reaction is finished, and carrying out aftertreatment on the fifth mixture to obtain a pure intermediate B, wherein the chemical reaction formula is as follows:

and (3) dissolving the pure intermediate B in HCl/MeOH, adding ethyl acetate to carry out solvent replacement after the reaction is completed, removing most of ethyl acetate, cooling to room temperature, continuing stirring, filtering, washing and drying to obtain 1-aminomethyl-1-cyclopropanol hydrochloride, wherein the chemical reaction formula is shown as follows:

has the advantages that: the synthesis method of the 1-aminomethyl-1-cyclopropanol compound has the advantages of low cost, low process requirements on production operation technology, high safety and strong operability, greatly reduces post-treatment difficulty and safe production risk, and is suitable for industrial production; meanwhile, the 1-aminomethyl-1-cyclopropanol compound prepared by the synthesis method has high purity and yield.

Detailed Description

The present invention will be described in further detail below with reference to embodiments.

Example 1

Step (1) Synthesis of intermediate A

Wherein, the chemical reaction equation is as follows:

the synthesis steps are as follows:

173.21g (1.0mol, 1.0eq.) of N-Boc amino acetone is dissolved in 1L of anhydrous tetrahydrofuran, 301.02g of 1, 8-diazabicycloundecen-7-ene (DBU) (1.2mol, 1.2eq.) is added into the anhydrous tetrahydrofuran, the system is protected by nitrogen, the temperature is reduced to-5 to 0 ℃, 165.79g of tert-butyldimethyl chlorosilane (TBDMSCl) (1.1mol, 1.1eq.) is slowly dropped into the anhydrous tetrahydrofuran, the temperature in the process is controlled not to exceed 10 ℃, the stirring is carried out for 0.5h after the addition is finished, then the system is heated to reflux, and the stirring is continued for 2 h. The reaction was complete as monitored by TLC until the starting material disappeared. Cooling the system to-5 to 0 ℃, then adjusting the system to be neutral by using 2N dilute hydrochloric acid, and controlling the process temperature to be not more than 10 ℃. Standing for layering, extracting the water layer with 3x1L ethyl acetate, combining the organic phases, and desolventizing to obtain 267.93g of intermediate A as a pale yellow solid with the yield of 93.2%.

Step (2) Synthesis of intermediate B

Wherein, the chemical reaction equation is as follows:

the synthesis steps are as follows:

250.00g (0.87mol, 1.0eq.) of intermediate A was dissolved in 2.5L tetrahydrofuran, to which was added 279.62g of diiodomethane (CH)₂I₂) (1.04mol,1.2eq.) and 224.36g of zinc copper reagent (Zn-Cu) (1.74mol,2.0eq.), replaced with nitrogen three times, then the system was stirred under reflux for 6h under nitrogen protection, and TLC monitoring confirmed the reaction was complete. After the reaction is finished, the system is cooled to room temperature, the system is filtered, filter cakes are washed by 250ml of tetrahydrofuran, decompression and desolventization are carried out to obtain 269.83g of (overweight) crude intermediate B, the crude product is recrystallized by 600ml of ethyl acetate to obtain 229.68g of pure intermediate B, white solid is obtained, and the yield is 87.6%.

Step (3) Synthesis of 1-aminomethyl-1-cyclopropanol hydrochloride (C)

Wherein, the chemical reaction equation is as follows:

the synthesis steps are as follows:

220.00g (0.73mol) of intermediate B were dissolved in 440ml (2v/w)2.5N HCl/MeOH, stirred at room temperature for 1.5h and TLC monitoring confirmed the end of the reaction. The system is decompressed and desolventized to remove most of the solvent, then 400ml of ethyl acetate is added into the system, the desolventization is continued, the obtained residue is stirred for 0.5h by 400ml of ethyl acetate, the filtration is carried out, the filter cake is washed by 200ml of ethyl acetate, and the drying is carried out to obtain 95.18g of the target product C (1-aminomethyl-1-cyclopropanol hydrochloride) as a white solid with the purity of 98.6 percent and the yield of 96.2 percent.

The nuclear magnetic hydrogen spectrum data of the 1-aminomethyl-1-cyclopropanol hydrochloride are as follows:

1H NMR(DMSO-d6,400MHz):δ4.50(s，1H)，3.35(s,2H)，0.79-0.63(m,2H)，0.59-0.56(m,2H)。

example 2

Step (1) Synthesis of intermediate A

169.10g (1.0mol, 1.0eq.) of N-trifluoroacetylaminoacetone is dissolved in 1L of anhydrous tetrahydrofuran, 301.02g of 1, 8-diazabicycloundecen-7-ene (DBU) (1.2mol, 1.2eq.) is added into the anhydrous tetrahydrofuran, the system is protected by nitrogen, the temperature is reduced to-5 to 0 ℃, 165.79g of trimethylchlorosilane (TMSCl) (1.1mol, 1.1eq.) is slowly dropped into the anhydrous tetrahydrofuran, the temperature in the process is controlled not to exceed 10 ℃, the stirring is carried out for 0.5h after the addition is finished, then the system is heated to reflux, and the stirring is continued for 2 h. The reaction was complete as monitored by TLC until the starting material disappeared. Cooling the system to-5 to 0 ℃, then adjusting the system to be neutral by using 2N dilute hydrochloric acid, and controlling the process temperature to be not more than 10 ℃. Standing for layering, extracting the water layer with 3 × 1L ethyl acetate, mixing the organic phases, and desolventizing to obtain 256.45g of intermediate A with a yield of 90.5%.

Step (2) Synthesis of intermediate B

250.00g (0.88mol, 1.0eq.) of intermediate A was dissolved in 2.5L tetrahydrofuran, and 282.84g of diiodomethane (CH) was added thereto₂I₂) (1.06mol,1.2eq.) and 226.93g of zinc copper reagent (Zn-Cu) (1.76mol,2.0eq.), replaced with nitrogen three times, then the system was stirred under reflux for 6h under nitrogen protection, and TLC monitoring confirmed the reaction was complete. After the reaction is finished, the system is cooled to room temperature, the system is filtered, filter cakes are washed by 250ml of tetrahydrofuran, decompression and desolventization are carried out to obtain 256.06g of (overweight) crude intermediate B, the crude product is recrystallized by 600ml of ethyl acetate to obtain 247.43g of pure intermediate B, and the yield is 94.3%.

Step (3) Synthesis of 1-aminomethyl-1-cyclopropanol hydrochloride (C)

245.00g (0.82mol) of intermediate B were dissolved in 490ml (2v/w)2.5N HCl/MeOH, stirred at room temperature for 1.5h and TLC monitoring confirmed the end of the reaction. The system is decompressed and desolventized to remove most of the solvent, then 400ml of ethyl acetate is added into the system, the desolventization is continued, the obtained residue is stirred for 0.5h by 400ml of ethyl acetate, the filtration is carried out, the filter cake is washed by 200ml of ethyl acetate, and the drying is carried out to obtain 94.07g of the target product C (1-aminomethyl-1-cyclopropanol hydrochloride) as a white solid with the purity of 98.8 percent and the yield of 92.4 percent.

The nuclear magnetic hydrogen spectrum data of the 1-aminomethyl-1-cyclopropanol hydrochloride are as follows:

1H NMR(DMSO-d6,400MHz):δ4.50(s，1H)，3.35(s,2H)，0.79-0.63(m,2H)，0.59-0.56(m,2H)。

example 3

Step (1) Synthesis of intermediate A

315.42g (1.0mol, 1.0eq.) of N-tritylaminoacetone is dissolved in 1L of anhydrous tetrahydrofuran, 301.02g of 1, 8-diazabicycloundecen-7-ene (DBU) (1.2mol, 1.2eq.) is added into the anhydrous tetrahydrofuran, the system is protected by nitrogen, the temperature is reduced to-5 to 0 ℃, 165.79g of triethylchlorosilane (TESCl) (1.1mol, 1.1eq.) is slowly dropped into the anhydrous tetrahydrofuran, the temperature in the process is controlled not to exceed 10 ℃, the stirring is carried out for 0.5h after the addition is finished, then the system is heated to reflux, and the stirring is continued for 2 h. The reaction was complete as monitored by TLC until the starting material disappeared. Cooling the system to-5 to 0 ℃, then adjusting the system to be neutral by using 2N dilute hydrochloric acid, and controlling the process temperature to be not more than 10 ℃. Standing for layering, extracting the water layer with 3x1L ethyl acetate, combining the organic phases, and desolventizing to obtain 396.59g of intermediate A with the yield of 92.3%.

Step (2) Synthesis of intermediate B

390.00g (0.91mol, 1.0eq.) of intermediate A were dissolved in 2.5L tetrahydrofuran, to which 291.95g diiodomethane (CH) was added₂I₂) (1.09mol,1.2eq.) and 234.67g of zinc copper reagent (Zn-Cu) (1.82mol,2.0eq.), replaced with nitrogen three times, then the system was stirred under reflux for 6h under nitrogen protection, and TLC monitoring confirmed the reaction was complete. After the reaction is finished, the system is cooled to room temperature, the system is filtered, filter cakes are washed by 250ml of tetrahydrofuran, decompression and desolventization are carried out to obtain 389.26g of (overweight) crude intermediate B, the crude product is recrystallized by 600ml of ethyl acetate to obtain 378.97g of pure intermediate B, and the yield is 94.1%.

Step (3) Synthesis of 1-aminomethyl-1-cyclopropanol hydrochloride (C)

370.00g (0.83mol) of intermediate B were dissolved in 440ml (2v/w)2.5N HCl/MeOH, stirred at room temperature for 1.5h and TLC monitored to determine the end of the reaction. The system is decompressed and desolventized to remove most of the solvent, then 400ml of ethyl acetate is added into the system, the desolventization is continued, the obtained residue is stirred for 0.5h by 400ml of ethyl acetate, the filtration is carried out, the filter cake is washed by 200ml of ethyl acetate, and the drying is carried out to obtain 93.26g of the target product C (1-aminomethyl-1-cyclopropanol hydrochloride) as a white solid with the purity of 98.1 percent and the yield of 90.5 percent.

The nuclear magnetic hydrogen spectrum data of the 1-aminomethyl-1-cyclopropanol hydrochloride are as follows:

1H NMR(DMSO-d6,400MHz):δ4.50(s，1H)，3.35(s,2H)，0.79-0.63(m,2H)，0.59-0.56(m,2H)。

in summary, the following steps: the invention provides a method for synthesizing 1-aminomethyl-1-cyclopropanol compounds by applying Simmons-Smith cyclopropanation reaction, which has the advantages of low cost, low process requirement on production operation technology, high safety and strong operability, greatly reduces post-treatment difficulty and safe production risk, and is suitable for industrial production; meanwhile, the 1-aminomethyl-1-cyclopropanol compound prepared by the synthesis method has high purity and yield.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these should be considered as within the scope of the present invention.