Preparation method of 1-aminocyclopropyl methanol

Abstract

The invention discloses a preparation method of 1-aminocyclopropyl methanol, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: by taking cyclopropylamine as a raw material, carrying out benzophenone dimethyl ketal reaction to generate a cyclopropyl imine intermediate 1; deprotonating by adopting a lithium reagent, and then adding paraformaldehyde for reaction to obtain an intermediate 2; the preparation method comprises the following steps: adding 2-aminocyclopropanecarboxaldehyde into a reaction kettle, carrying out acidification to remove benzophenone, carrying out cyclization reaction with methylboronic acid, finally adding pinacol for exchange reaction, and distilling to remove a by-product, namely pinacol methylboronic acid ester, thereby obtaining 1-aminocyclopropanecarboxaldehyde. The method disclosed by the invention is simple in synthetic route, effectively solves the problem of separation and purification of the soluble aquatic product, and the obtained product is high in purity.

Description

Technical Field

[0001] The invention relates to a preparation method of 1-aminocyclopropylmethanol, and belongs to the technical field of pharmaceutical intermediate preparation. Background Art

[0002] 1-Aminocyclopropylmethanol (CAS: 107017-72-1), an amino alcohol compound containing a cyclopropyl group, is an important organic intermediate or raw material with a wide range of applications. 1-Aminocyclopropylmethanol is used as a primary raw material for pharmaceutical intermediates, such as aminopyridine benzamide derivatives [WO2022066917A]. Its chemical structure is as follows:

[0003]

[0004] After literature search, the main synthesis method of 1-aminocyclopropylmethanol [WO2006100208A; WO2015109109A; US201744182A; Synlett, 2019, 30, 464; Journal of Medicinal Chemistry, 2021, 64, 4071; WO2021252849A; WO 2022066917A] reported that 1-aminocyclopropylmethanol is mainly obtained by reduction reaction (reducing agent using lithium aluminum hydride, sodium borohydride or lithium borohydride, etc.) with 1-aminocyclopropylmethanol or 1-aminocyclopropylmethanol hydrochloride.

[0005] Since there are few synthetic methods at present and 1-aminocyclopropylmethanol has a wide range of uses, it is necessary to explore and study its synthetic route to provide a better process route with readily available raw materials, high product purity and economy. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing 1-aminocyclopropylmethanol. Cyclopropylamine is used as the raw material, and benzophenone dimethyl ketal reaction is performed to generate cyclopropylimine intermediate 1. A lithium reagent is then used to deprotonate the intermediate, and then paraformaldehyde is added to react to obtain intermediate 2. The intermediate is then acidified to remove the benzophenone, followed by a cyclization reaction with methylboronic acid, and finally, a pinacol exchange reaction is added. The byproduct methylboronic acid pinacol ester is distilled off to obtain 1-aminocyclopropylmethanol.

[0007] The preparation method of 1-aminocyclopropylmethanol of the present invention adopts the following technical scheme, and the synthetic route is as follows:

[0008]

[0009] The steps include:

[0010] A. Cyclopropylamine and benzophenone dimethyl ketal are reacted in the presence of p-toluenesulfonic acid to generate intermediate 1;

[0011] B. Add a lithiation reagent to intermediate 1 to remove protons at low temperature, and then react with paraformaldehyde to generate intermediate 2;

[0012] C. Intermediate 2 is hydrolyzed in the presence of an acid, followed by dehydration and condensation with boric acid to form a ring. After purification by distillation, it is exchanged with pinacol to obtain 1-aminocyclopropylmethanol.

[0013] Preferably, in the above step A, the molar ratio of cyclopropylamine, benzophenone dimethyl ketal and p-toluenesulfonic acid is 1:0.9-1.2:0.01-0.05.

[0014] Preferably, in the above step B, the deprotonation low temperature condition is -78°C to 0°C; and the reaction is carried out in methanol solvent.

[0015] Preferably, in the above step B, the lithiation reagent is selected from LDA, LiTMP or LiHMDS; and the reaction is carried out in tetrahydrofuran, 2-methylfuran or cyclopentyl methyl ether.

[0016] Preferably, in the above step B, the molar ratio of the intermediate 1, the lithiation reagent and the paraformaldehyde is 1:1-1.2:1-1.5.

[0017] Preferably, in the above step C, the acidification and hydrolysis is carried out in methanol, ethanol or isopropanol.

[0018] Preferably, in the above step C, the acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; and after acid hydrolysis, a base (sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate) is added to adjust the mixture to alkalinity.

[0019] Preferably, in the above step C, the boric acid is selected from methylboronic acid or trimethylboroxane.

[0020] Preferably, in the above step C, the molar ratio of the intermediate 2, acid, boric acid and pinacol is 1:2-5:1.1-1.6:1-1.2.

[0021] Beneficial effects of the present invention:

[0022] A. The present invention uses cheap and easily available cyclopropylamine as a raw material, has a reasonable overall route and a high yield, and provides a useful reference for the preparation of such compounds.

[0023] B. In step A of the present invention, methanol is used as the solvent, and the methanol can be completely recycled, thereby reducing costs and reducing the three wastes.

[0024] C. In step C of the present invention, pinacol is used to exchange methylboric acid again to generate methylboronic acid pinacol ester with a lower boiling point, which is easily separated and removed during distillation to obtain high-purity 1-aminocyclopropylmethanol, thereby solving the problem of effective separation of water-soluble products. Specific embodiments

[0025] Example 1

[0026]

[0027] Under nitrogen protection, cyclopropylamine (5.7 g, 0.1 mol), benzophenone dimethyl ketal (22.6 g, 0.099 mol) and p-toluenesulfonic acid (0.34 g, 0.002 mol) were mixed in 100 mL of methanol and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to recover methanol, and 50 mL of water was added to the residue for washing to obtain 21.9 g of intermediate 1 with a yield of 99% and an HPLC purity of 99.5%. 1 H NMR (400MHz, CDCl3): 7.58-7.42(m,5H), 7.36-7.28(m,5H), 2.90(m,1H), 1.05(m,2H), 0.86-0.78(m,2H).

[0028] Example 2

[0029]

[0030] Under nitrogen protection, intermediate 1 (22.1 g, 0.1 mol) was mixed in 200 mL of anhydrous THF, cooled to -70 ° C, and 110 mL of 1 M LDA tetrahydrofuran / hexane solution was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, and then 3.6 g (0.12 mol) of paraformaldehyde was added. The reaction was kept warm for 3 hours, and the temperature was naturally raised to -20 ° C. 120 mL of saturated ammonium chloride aqueous solution was added to quench the mixture, and then the temperature was raised to room temperature. The organic layer was separated and washed twice with 70 mL of water. The organic layer was dried and concentrated. The crude product was recrystallized from n-heptane and filtered to obtain 19.6 g of intermediate 2 with a yield of 78% and an HPLC index of 99.1%. 1 HNMR(400MHz, CDCl3):7.51-7.38(m,5H),7.34-7.22(m,5H),4.72(s,1H),3.42(m,2H),0.78-0.62(m,2H),0.61-0.45(m,2H).

[0031] Example 3

[0032]

[0033] Under nitrogen protection, intermediate 1 (22.1 g, 0.1 mol) was mixed in 200 mL of anhydrous THF, cooled to -50 ° C, and 1 M LiTMP (110 mL, 0.11 mol) / tetrahydrofuran solution was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, and then 3.6 g (0.12 mol) of paraformaldehyde was added. The reaction was kept warm for 3 hours, and the temperature was naturally raised to -20 ° C. 120 mL of saturated ammonium chloride aqueous solution was added to quench the mixture, and then the temperature was raised to room temperature. The layers were separated, and the organic layer was washed twice with 70 mL of water, dried and concentrated. The crude product was recrystallized from n-heptane, filtered, and dried to obtain 18.1 g of intermediate 2 with a yield of 72% and an HPLC index of 98.8%.

[0034] Example 4

[0035]

[0036] Under nitrogen protection, intermediate 2 (25.1g, 0.1mol) and 2M sulfuric acid (100mL) were mixed in 100mL methanol, and the reaction was allowed to proceed at room temperature for 4 hours. The mixture was then discarded after dichloromethane extraction. The aqueous layer was added with 3M sodium hydroxide solution, and the pH was adjusted to 10-11. 50mL sulfolane, methylboric acid (7.8g, 0.13mol) and 150mL toluene were added and refluxed to separate the water. When the system no longer had water to be separated, TLC detection showed that the reaction was cyclized. Toluene and excess methylboric acid (now present as a trimer) were removed by underpressure distillation, and then underpressure distillation was continued to obtain the cyclic intermediate. Pinacol (13g, 0.11mol) was then added and the mixture was warmed to 100-105°C for reaction. The methylboronic acid pinacol ester generated in the reaction process was continuously distilled out under a slight vacuum. The oil pump then continued to vacuumize for 40 minutes. After the reaction flask cooled, 7.7g 1-aminocyclopropylmethanol was obtained with a yield of 88% and a GC of 99.6%. 1 HNMR(400MHz, CDCl3):5.32-4.12(m,1H),3.28(s,2H),1.78(s,2H),0.52-0.27(m,4H).

[0037] Example 5

[0038]

[0039] Under nitrogen, intermediate 2 (25.1 g, 0.1 mol) and 3 M hydrochloric acid (100 mL) were mixed in 100 mL of methanol and reacted at room temperature for 4 hours. The mixture was extracted with dichloromethane and discarded. The aqueous layer was added with saturated sodium carbonate solution to adjust the pH to 10-11. 50 mL of sulfolane, methylboronic acid trimer (5.0 g, 0.04 mol), and 110 mL of toluene were added and refluxed to separate the water. When no more water was released from the system, TLC analysis showed that the reaction was complete. Toluene and excess methylboronic acid trimer were first removed by vacuum distillation, and then vacuum distillation was continued to obtain the cyclic intermediate. Pinacol (13 g, 0.11 mol) was then added and the temperature was raised to 100-105°C for reaction. Under slight vacuum, the methylboronic acid pinacol ester generated during the reaction was continuously distilled out. The oil pump was then vacuumed for 40 minutes. After cooling the reaction flask, 8.0 g of 1-aminocyclopropylmethanol was obtained, with a yield of 92% and a GC value of 99.2%.

[0040] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing 1-aminocyclopropylmethanol, characterized in that: The steps include: A. Cyclopropylamine and benzophenone dimethyl ketal are reacted in the presence of p-toluenesulfonic acid to generate intermediate 1; B. Add a lithiation reagent to intermediate 1 to remove protons at low temperature, and then react with paraformaldehyde to generate intermediate 2; C. Intermediate 2 is hydrolyzed in the presence of an acid, followed by dehydration and condensation with boric acid to form a ring. After purification by distillation, it is exchanged with pinacol to obtain 1-aminocyclopropylmethanol.

2. The method for preparing 1-aminocyclopropylmethanol according to claim 1, wherein: In step A, the molar ratio of cyclopropylamine, benzophenone dimethyl ketal and p-toluenesulfonic acid is 1:0.9-1:0.01-0.

05.

3. The method for preparing 1-aminocyclopropylmethanol according to claim 1, wherein: In step B, the deprotonation low temperature condition is -78°C to 0°C.

4. The method for preparing 1-aminocyclopropylmethanol according to claim 1, wherein: In step B, the lithiation reagent is selected from LDA, LiTMP or LiHMDS.

5. The method for preparing 1-aminocyclopropylmethanol according to claim 1, wherein: In step B, the molar ratio of the intermediate 1, the lithiating reagent and the paraformaldehyde is 1:1-1.2:1-1.

5.

6. The method for preparing 1-aminocyclopropylmethanol according to claim 1, wherein: In step C, the solvent is selected from methanol, ethanol or isopropanol.

7. The method for preparing 1-aminocyclopropylmethanol according to claim 1, wherein: In step C, the acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.

8. The method for preparing 1-aminocyclopropylmethanol according to claim 1, wherein: In step C, the boronic acid is selected from methylboronic acid or trimethylboroxane.

9. The method for preparing 2-bromo-4-chloro-3-fluorotoluene according to claim 1, wherein: In step C, the molar ratio of the intermediate 2, acid, boric acid and pinacol is 1:2-5:1.1-1.6:1-1.2.

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