Preparation method for aliskiren

Abstract

The invention relates to a preparation method for aliskiren. The method includes: taking a known formula II compound as a raw material, subjecting the formula II compound and a reducing reagent to a reduction reaction in an organic solvent in the presence of a catalyst so as to generate aliskiren. Specifically, the reducing reagent is hydrogen, trialkyl substituted silane or formate; the catalyst is one of or a combination of several of palladium carbon, rhodium carbon, palladium carbon oxide, palladium hydroxide on carbon, palladium carbon, and platinum dioxide; the reduction reaction temperature is 0DEG C-100DEG C, and the pressure is 1-10bar. The method provided by the invention can prepare aliskiren by one-step reduction, and has the advantages of short reaction route, simple operation, good yield, and high product purity, thus being suitable for industrialized production.

Description

technical field

[0001] The invention relates to a preparation method of Aliskiren. Background technique

[0002] Aliskiren is one of the specific compounds reported in Chinese invention patent ZL200410034682.4, which has been successfully marketed. The chemical name of Aliskiren is (2S,4S,5S,7S-5-Amino-N-2-(carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyloctylamide), the structural formula is as follows:

[0003]

[0004] Aliskiren can block the RAAS system in the first link, reduce the activity of renin, reduce the generation of AngII, and play a role in lowering blood pressure and treating cardiovascular diseases. Judging from the current research, Aliskiren is a new generation of antihypertensive drugs that are potent, highly selective, orally effective and long-acting.

[0005] ZL200410034682.4 discloses the synthesis of δ-amino-γ-hydroxyl-ω-aryl-alkanamides through the following route:

[0006]

[0007] This ro...

Examples

Embodiment 1

[0030] Embodiment 1 is prepared formula IIa compound by formula IV compound

[0031]

[0032] The specific preparation process is as follows: Formula IV compound (1.0g, 2.09mmol), 3-amino-2,2-dimethylpropanamide (1.4g, 12.1mmol), 2-hydroxypyridine (0.1g, 1.05mmol) and Triethylamine (5ml) was heated to 95~105°C and reacted for 24h. After the reaction was detected by HPLC, it was cooled to room temperature, methyl tert-butyl ether was added to dilute the reaction mixture, and then the organic phase was washed with water and saturated brine. After the organic phase was dried and concentrated, the residue was subjected to flash column chromatography to obtain 1.06g of the compound of formula IIa, MS (m / z): 576 (M-H 2 O+1), HPLC (peak area purity) 96%, yield 85%.

Embodiment 2

[0033] Embodiment 2 is prepared formula IId compound by formula IV compound

[0034]

[0035] Concrete preparation process is as follows:

[0036] (1) Formula IV compound (1.0g, 2.09mmol), 3-amino-2,2-dimethylpropanamide (1.4g, 12.1mmol), 2-hydroxypyridine (0.1g, 1.05mmol) and triethyl Amine (5ml) was heated to 95~105°C and reacted for 24h. After the reaction was detected by HPLC, it was cooled to room temperature, methyl tert-butyl ether was added to dilute the reaction mixture, and then the organic phase was washed with water and saturated brine. After the organic phase was dried and concentrated, the residue was subjected to flash column chromatography to obtain 1.06 g of the compound of formula IIb, MS (m / z): 576 (M-H2O+1), HPLC (peak area purity) 96%, yield 85%.

[0037] (2) Dissolve the compound of formula IIb (1.0 g, 1.69 mmol) obtained in step (1) in 10 ml of ethanol, add 10% Pd / C (50 mg), and hydrogenate at 15-25°C under normal pressure. After the HPLC detection...

Embodiment 3

[0038] Example 3 Preparation of Aliskiren (compound of formula I) by formula IIa compound

[0039]

[0040] The specific preparation process is as follows: Dissolve the compound of formula IIa (1.0g, 1.69mmol) in 10ml of ethanol and 1ml of acetic acid, add 10% Pd / C (100mg), at 4bar pressure, 35-45 ℃, pass through hydrogen, carry out Reduction reaction, HPLC detection after the reaction is complete, filter to remove the catalyst, after the filtrate is concentrated, the residue is flash column chromatography to obtain Aliskiren 0.79g, MS (m / z): 552 (M+1), HPLC (peak area purity) 96%, yield 85%.

technical field

[0001] The invention relates to a preparation method of Aliskiren. Background technique

[0002] Aliskiren is one of the specific compounds reported in Chinese invention patent ZL200410034682.4, which has been successfully marketed. The chemical name of Aliskiren is (2S,4S,5S,7S-5-Amino-N-2-(carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyloctylamide), the structural formula is as follows:

[0003]

[0004] Aliskiren can block the RAAS system in the first link, reduce the activity of renin, reduce the generation of AngII, and play a role in lowering blood pressure and treating cardiovascular diseases. Judging from the current research, Aliskiren is a new generation of antihypertensive drugs that are potent, highly selective, orally effective and long-acting.

[0005] ZL200410034682.4 discloses the synthesis of δ-amino-γ-hydroxyl-ω-aryl-alkanamides through the following route:

[0006]

[0007] This ro...

Examples

Embodiment 1

[0030] Embodiment 1 is prepared formula IIa compound by formula IV compound

[0031]

[0032] The specific preparation process is as follows: Formula IV compound (1.0g, 2.09mmol), 3-amino-2,2-dimethylpropanamide (1.4g, 12.1mmol), 2-hydroxypyridine (0.1g, 1.05mmol) and Triethylamine (5ml) was heated to 95~105°C and reacted for 24h. After the reaction was detected by HPLC, it was cooled to room temperature, methyl tert-butyl ether was added to dilute the reaction mixture, and then the organic phase was washed with water and saturated brine. After the organic phase was dried and concentrated, the residue was subjected to flash column chromatography to obtain 1.06g of the compound of formula IIa, MS (m / z): 576 (M-H 2 O+1), HPLC (peak area purity) 96%, yield 85%.

Embodiment 2

[0033] Embodiment 2 is prepared formula IId compound by formula IV compound

[0034]

[0035] Concrete preparation process is as follows:

[0036] (1) Formula IV compound (1.0g, 2.09mmol), 3-amino-2,2-dimethylpropanamide (1.4g, 12.1mmol), 2-hydroxypyridine (0.1g, 1.05mmol) and triethyl Amine (5ml) was heated to 95~105°C and reacted for 24h. After the reaction was detected by HPLC, it was cooled to room temperature, methyl tert-butyl ether was added to dilute the reaction mixture, and then the organic phase was washed with water and saturated brine. After the organic phase was dried and concentrated, the residue was subjected to flash column chromatography to obtain 1.06 g of the compound of formula IIb, MS (m / z): 576 (M-H2O+1), HPLC (peak area purity) 96%, yield 85%.

[0037] (2) Dissolve the compound of formula IIb (1.0 g, 1.69 mmol) obtained in step (1) in 10 ml of ethanol, add 10% Pd / C (50 mg), and hydrogenate at 15-25°C under normal pressure. After the HPLC detection...

Embodiment 3

[0038] Example 3 Preparation of Aliskiren (compound of formula I) by formula IIa compound

[0039]

[0040] The specific preparation process is as follows: Dissolve the compound of formula IIa (1.0g, 1.69mmol) in 10ml of ethanol and 1ml of acetic acid, add 10% Pd / C (100mg), at 4bar pressure, 35-45 ℃, pass through hydrogen, carry out Reduction reaction, HPLC detection after the reaction is complete, filter to remove the catalyst, after the filtrate is concentrated, the residue is flash column chromatography to obtain Aliskiren 0.79g, MS (m / z): 552 (M+1), HPLC (peak area purity) 96%, yield 85%.

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