Preparation method of 1-isopropyl-4-piperidylamine

Abstract

The invention discloses a preparation method of 1-isopropyl-4-piperidylamine, and belongs to the field of synthesis of drug intermediates. According to the method, 4-aminopyridine is used as a raw material, and 1-isopropyl-4-piperidylamine is obtained through a salt forming reaction and a reduction reaction. The invention provides the preparation method of the 1-isopropyl-4-piperidylamine, and the method has the advantages of easily available raw materials, low price, controllable reaction process, simple operation, good product purity and high atom utilization rate, and accords with the green chemistry development concept.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical intermediate synthesis and relates to a preparation method of 1-isopropyl-4-piperidinamine. Background Art

[0002] 1-Isopropyl-4-piperidinamine, molecular formula: C8H 18 N2, molecular weight: 142.24, CAS: 127285-08-9, chemical structure is as follows:

[0003]

[0004] 1-Isopropyl-4-piperidinamine is an important intermediate in high-value-added pharmaceuticals and chemical industries. It is mainly used to synthesize the G9a protein inhibitor SPIN1. SPIN1 is a nuclear histone lysine methyltransferase that catalyzes the dimethylation of histone H3 lysine, a reversible modification associated with transcriptional gene silencing. SPIN1 can be used in the study of autoimmune diseases or cancer.

[0005] According to literature reports (Journal of Medicinal Chemistry (1999), 42 (14), 2706-2715, Journal of Medicinal Chemistry (2005), 48 (14), 4511-4525, WO2007052938A1, WO2017034245 A1), there is currently only one route for synthesizing 1-isopropyl-4-piperidinamine, and its synthetic route is as follows.

[0006]

[0007] This route uses 4-amino-1-benzylpiperidine as a raw material, protects the amino group with CBz or Boc, then removes the benzyl group, then undergoes a reductive amination reaction with acetone or a nucleophilic substitution reaction with 2-bromopropylamine, and finally removes the CBz or Boc protecting group to obtain 1-isopropyl-4-piperidinamine. This route is lengthy and requires two steps of adding and removing protecting groups, which increases the reaction steps, reduces the yield, and decreases the atom utilization, resulting in an overall yield of less than 60%, and is costly. The raw materials used in this reaction route are expensive, and the raw materials are synthesized by condensing N-benzylpiperidone with hydroxylamine hydrochloride and then reducing it. In summary, the existing route has limited industrial feasibility. It is necessary to design an industrially feasible route with cheaper raw materials, a shorter reaction route, high product quality, and low cost. Summary of the Invention

[0008] The present invention aims to overcome the deficiencies in the prior art and provides a method for preparing 1-isopropyl-4-piperidinamine.

[0009] This method uses cheap 4-aminopyridine as a raw material and undergoes a two-step reaction of salt formation and reduction to obtain 1-isopropyl-4-piperidinamine. The specific synthesis route is as follows:

[0010]

[0011] S1: 4-Aminopyridine and 2-bromopropane were added to a reaction flask, and a solvent was added. The temperature was raised to cause a salt-forming reaction to obtain intermediate 1 with a yield of 90%;

[0012] S2: Intermediate 1 is added to a solvent, a catalyst is added, and a reduction reaction is carried out under certain hydrogen pressure and temperature conditions to obtain 1-isopropyl-4-piperidinamine with a yield of 92%.

[0013] The solvent in step S1 is one or more of tetrahydrofuran, acetonitrile, 1,4-dioxane, ethylene glycol, ethanol, and isopropanol, preferably acetonitrile; the reaction temperature is 60-80° C., preferably 75° C.; the molar ratio of 4-aminopyridine to 2-bromopropane is 1:1-1.2, preferably 1:1.05.

[0014] The solvent described in step S2 is one of methanol, ethanol, isopropanol, and tert-butanol; the catalyst is one of 5% palladium carbon, 5% ruthenium carbon, 5% rhodium carbon, and 5% platinum carbon, preferably 5% ruthenium carbon, and the addition amount is 5% of the mass of intermediate 1; the hydrogen pressure is 4.0-6.0 MPa, and the reaction temperature is 80-95°C.

[0015] Beneficial effects of the present invention:

[0016] (1) The raw material 4-aminopyridine of the present invention is a bulk chemical and is cheap and readily available;

[0017] (2) The present invention can obtain 1-isopropyl-4-piperidinamine by two-step reaction with a total yield of 82.8%;

[0018] (3) The preparation process of the present invention does not require multiple steps of adding and removing protecting groups, thereby improving the atomic utilization rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the H NMR spectrum of intermediate 1;

[0020] Figure 2 is the mass spectrum of intermediate 1;

[0021] Figure 3 is the H NMR spectrum of 1-isopropyl-4-piperidinamine;

[0022] Figure 4 is the mass spectrum of 1-isopropyl-4-piperidinamine; DETAILED DESCRIPTION

[0023] Example 1:

[0024] Preparation of Intermediate 1: To a 3 L reaction flask, add 3-aminopyridine (200 g, 1 eq), 2-bromopropane (274.5 g, 1.05 eq), and acetonitrile (800 g). The reaction was heated to 80°C for 5 h, cooled to room temperature, and then further cooled to 5-10°C to precipitate a solid. The filter cake was filtered, washed with acetonitrile (200 g), and dried under vacuum to afford Intermediate 1 (415 g, 90% yield). 1 H NMR (400MHz, DMSO-d6): δ = 8.31 (d, J = 10.56, 2H), 8.09 (s, 2H), 6.91 (d, J = 8.08H z,2H),4.13(m,J=6.48Hz,1H),1.42(d,J=8.92,Hz,6H); HRMS(ESI-TOF)m / z:[M] + Calcd for C8H 13 N2 + 137.1073; Found 137.1096.

[0025] Preparation of 1-isopropyl-4-piperidinamine: Intermediate 1 (200 g) was added to a 5 L high-pressure reactor, ethanol (2 L) was added, 10.0 g of 5% ruthenium carbon was added, nitrogen was replaced three times, hydrogen was replaced three times, the reaction system pressure was maintained at 5.0 MPa, the temperature was slowly raised to 90 ° C, and the reaction was carried out for 6-7 hours. After the reaction was completed, palladium carbon was recovered by filtration, the filtrate was concentrated in vacuo, dichloromethane (500 g) and water (500 g) were added, the pH was adjusted to 9-10 with liquid caustic soda, the layers were separated, the organic phase was concentrated in vacuo to remove the solvent, and 1-isopropyl-4-piperidinamine (120.3 g, yield 92%, chemical purity 99.2%) was obtained by distillation under reduced pressure. 1 H NMR (400MHz, CDCl3): δ (ppm): 3.69-3.75 (m, 2H), 3.33-3.41 (m, J = 12.9Hz, 3H), 2.60-2.71 ( m,2H),2.31-2.41(m,2H),1.78-1.88(m,3H),1.39(d,J=6.6Hz,6H); HRMS(ESI-TOF)m / z:[M] + Calcd for C8H 13 N2 + 142.1470; Found 137.1491.

[0026] Example 2:

[0027] Preparation of Intermediate 1: To a 3 L reaction flask, add 3-aminopyridine (200 g, 1 eq), 2-bromopropane (313.7 g, 1.2 eq), and tetrahydrofuran (800 g). The reaction was heated to 70°C for 5 h, cooled to room temperature, and then further cooled to 5-10°C to precipitate a solid. The filter cake was filtered, washed with tetrahydrofuran (200 g), and dried under vacuum to afford Intermediate 1 (403.5 g, 87.5% yield).

[0028] Preparation of 1-isopropyl-4-piperidinamine: Intermediate 1 (200 g) was added to a 5 L autoclave, isopropanol (2 L) was added, 5% palladium carbon 10.0 g was added, nitrogen was replaced three times, hydrogen was replaced three times, the reaction system pressure was maintained at 5.0 MPa, the temperature was slowly raised to 90 ° C, the reaction was carried out for 5-6 hours, the reaction was completed, the palladium carbon was recovered by filtration, the filtrate was concentrated in vacuo, dichloromethane (500 g) and water (500 g) were added, the pH was adjusted to 9-10 with liquid caustic soda, the layers were separated, the organic phase was concentrated in vacuo to remove the solvent, and the reduced pressure distillation was continued to give 1-isopropyl-4-piperidinamine (118.3 g, yield 90.5%, chemical purity 99.1%).

[0029] Example 3:

[0030] Preparation of Intermediate 1: To a 3 L reaction flask, add 3-aminopyridine (200 g, 1 eq), 2-bromopropane (274.5 g, 1.05 eq), and ethanol (800 g). Heat to 80°C and react for 5 h. Cool to room temperature and continue cooling to 5-10°C to precipitate a solid. Filter and wash the filter cake with ethanol (200 g) to obtain the wet product of Intermediate 1. The undried intermediate 1 was directly put into a 10L high-pressure reactor, and ethanol (4L) was added, followed by 20.0g of 5% ruthenium carbon. The atmosphere was replaced with nitrogen three times and hydrogen three times. The pressure of the reaction system was maintained at 5.0MPa, and the temperature was slowly raised to 90°C. The reaction was carried out for 6-7 hours. After the reaction was completed, the ruthenium carbon was recovered by filtration, and the filtrate was concentrated in vacuo. Dichloromethane (1000g) and water (1000g) were added, and the pH was adjusted to 9-10 with liquid caustic soda. The layers were separated, and the organic phase was concentrated in vacuo to remove the solvent. The mixture was then distilled under reduced pressure to obtain 1-isopropyl-4-piperidinamine (252g, total yield of the two-step reaction was 83.5%, and chemical purity was 99.2%).

[0031] Example 4:

[0032] Preparation of Intermediate 1: To a 3 L reaction flask, add 3-aminopyridine (200 g, 1 eq), 2-bromopropane (274.5 g, 1.05 eq), and acetonitrile (800 g). The reaction was heated to 80°C for 5 h, cooled to room temperature, and then further cooled to 5-10°C to precipitate a solid. The filter cake was filtered, washed with acetonitrile (200 g), and dried under vacuum to afford Intermediate 1 (415 g, 90% yield).

[0033] Preparation of 1-isopropyl-4-piperidinamine: Intermediate 1 (200 g) was added to a 5 L autoclave, methanol (2 L) was added, 10.0 g of 5% rhodium on carbon was added, nitrogen was replaced three times, hydrogen was replaced three times, the reaction system pressure was maintained at 4.0 MPa, the temperature was slowly raised to 80 ° C, the reaction was carried out for 8-9 hours, the reaction was completed, the rhodium on carbon was recovered by filtration, the filtrate was concentrated in vacuo, dichloromethane (500 g) and water (500 g) were added, the pH was adjusted to 9-10 with liquid caustic soda, the layers were separated, the organic phase was concentrated in vacuo to remove the solvent, and 1-isopropyl-4-piperidinamine (114.7 g, yield 87.7%, chemical purity 99.1%) was obtained by distillation under reduced pressure.

[0034] Example 5:

[0035] Preparation of Intermediate 1: To a 3 L reaction flask, add 3-aminopyridine (200 g, 1 eq), 2-bromopropane (261.4 g, 1 eq), and acetonitrile (800 g). Heat to 80°C for 5 h, cool to room temperature, and continue cooling to 5-10°C to precipitate a solid. Filter the filter cake, wash it with acetonitrile (200 g), and dry it in vacuo to obtain Intermediate 1 (400 g, 86.8% yield).

[0036] Preparation of 1-isopropyl-4-piperidinamine: Intermediate 1 (200 g) was added to a 5 L high-pressure reactor, methanol (2 L) was added, 10.0 g of 5% ruthenium carbon was added, nitrogen was replaced three times, hydrogen was replaced three times, the reaction system pressure was maintained at 2.5 MPa, the temperature was slowly raised to 80° C., and the reaction was carried out for 13-14 hours. After the reaction was completed, the ruthenium carbon was recovered by filtration, the filtrate was concentrated in vacuo, dichloromethane (500 g) and water (500 g) were added, the pH was adjusted to 9-10 with liquid caustic soda, the layers were separated, the organic phase was concentrated in vacuo to remove the solvent, and 1-isopropyl-4-piperidinamine (107.8 g, yield 82.5%, chemical purity 99.2%) was obtained by continued distillation under reduced pressure.

[0037] Comparative Example:

[0038] Preparation of 1-benzyl-4-(BOC-amino)piperidine: 1-benzylpiperidin-4-amine (198.3 g) was added to dichloromethane (2 kg) at room temperature, followed by the addition of triethylamine (131.5 g) to the reaction system. Boc2O (283.7 g) was added dropwise while maintaining the temperature at 20-25° C. The reaction mixture was stirred at room temperature overnight, followed by the addition of water (1 kg) and stirring for 30 minutes. The layers were allowed to stand and the organic layer was washed with a 5% aqueous NaHCO3 solution (500 g) and a 10% brine solution (500 g), dried over anhydrous MgSO4, and concentrated in vacuo to afford 1-benzyl-4-(BOC-amino)piperidine (264.2 g, 91.1% yield, 98.6% purity) as a white solid.

[0039] Preparation of 4-tert-butoxycarbonylaminopiperidine: 1-benzyl-4-(BOC-amino)piperidine (100 g) was added to a 2 L high-pressure reactor, ethanol (500 g) was added, 5% palladium carbon 10.0 g was added, nitrogen was replaced three times, hydrogen was replaced three times, the reaction system pressure was maintained at 0.5 MPa, the temperature was slowly raised to 70 ° C, the reaction was completed for 5 hours, and the reaction was completed. The palladium carbon was recovered by filtration, the filtrate was concentrated in vacuo, and recrystallized from isopropyl ether to obtain 4-tert-butoxycarbonylaminopiperidine (61.2 g, yield 88.5%, chemical purity 98.9%).

[0040] Preparation of tert-butyl (1-isopropylpiperidin-4-yl)carbamate: 4-tert-Butyloxycarbonylaminopiperidine (200 g) was added to methanol (1 kg), followed by acetic acid (3 g). Acetone (100 g) was added dropwise at room temperature. After completion of the addition, the mixture was heated to 60°C and reacted for 3 hours. NaHB₄ (22.5 g) was then added in small portions over the entire reaction period, and the mixture was allowed to react at 60°C for 2 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was poured into water (600 g) and ethyl acetate (600 g), stirred for half an hour, separated, and the organic layer was washed with saturated Na₂CO₃ solution (200 g) and water (200 g). The mixture was dried over Na₂SO₄, and the solvent removed under reduced pressure to yield tert-butyl (1-isopropylpiperidin-4-yl)carbamate (190.5 g, yield 78.6%, purity 98.3%).

[0041] Preparation of 1-isopropyl-4-piperidinamine: tert-Butyl (1-isopropylpiperidin-4-yl)carbamate (242.4 g) was added to methanol (1 kg), and concentrated hydrochloric acid (12 M, 50 g) was added at room temperature. The reaction was stirred at room temperature for 12 hours. The solvent was concentrated in vacuo, and the residue was poured into water (600 g) and ethyl acetate (600 g). The pH was adjusted to 9-10 with 10% liquid caustic soda. The mixture was stirred for half an hour, separated, and the organic phase was dried over Na2SO4. The organic phase was concentrated in vacuo to remove the solvent and distilled under reduced pressure to give 1-isopropyl-4-piperidinamine (121.7 g, yield 85.6%, chemical purity 98.9%).

[0042] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without creative work are still within the scope of protection of the present invention.

Claims

1. A method for preparing 1-isopropyl-4-piperidinamine, characterized in that: The synthetic route of the preparation method is as follows: S1: 4-aminopyridine and 2-bromopropane were added to a reaction flask, and a solvent was added. The temperature was raised to cause a salt-forming reaction to obtain intermediate 1; S2: Intermediate 1 is added to a solvent, a catalyst is added, and a reduction reaction occurs under certain hydrogen pressure and temperature conditions to obtain 1-isopropyl-4-piperidinamine.

2. The method for preparing 1-isopropyl-4-piperidinamine according to claim 1, wherein The solvent in step S1 is one or more of tetrahydrofuran, acetonitrile, 1,4-dioxane, ethylene glycol, ethanol, and isopropanol; and the reaction temperature is 60-80°C.

3. The method for preparing 1-isopropyl-4-piperidinamine according to claim 1, wherein The molar ratio of the 4-aminopyridine to the 2-bromopropane is 1:1-1.

2.

4. The method for preparing 1-isopropyl-4-piperidinamine according to claim 1, wherein The solvent described in step S2 is one of methanol, ethanol, isopropanol, and tert-butanol; the catalyst is one of 5% palladium carbon, 5% ruthenium carbon, 5% rhodium carbon, and 5% platinum carbon, and the added amount is 5% of the mass of intermediate 1.

5. A method for preparing 1-isopropyl-4-piperidinamine according to claim 1, characterized in that: The hydrogen pressure in step S2 is 4.0-6.0 MPa, and the reaction temperature is 80-95°C.

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