Preparation method for aliskiren

A compound and reaction time technology, applied in the field of preparation of aliskiren, can solve the problems of unsuitability for commercial production, low coupling yield, and difficult preparation of Grignard reagents, and achieve good industrial application value, short reaction route, The effect of cheap raw materials

Active Publication Date: 2012-02-15
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, the Grignard reagent of 4-methoxy-3-(3-methoxypropoxy)-bromobenzene is difficult to prepare, and the coupling yield is extremely low, so it is not suitable for commercial production

Method used

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  • Preparation method for aliskiren
  • Preparation method for aliskiren
  • Preparation method for aliskiren

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation of compound (I)

[0065] 22.64g (80mmol) of (3S, 5S, 1'S, 3'S)-5-(1'-azido-3'-hydroxymethyl-4'-methyl-pentyl)-3-isopropyl- Dihydrofuran-2-one was dissolved in 80ml of dichloromethane, 125mg (0.8mmol) of 2,2,6,6-tetramethylpiperidine oxide was added thereto, the temperature was lowered to below 0°C, and 71mL (96mmol) of ) molar concentration of 1.35mol / L sodium hypochlorite aqueous solution at 50 ° C for 2 hours. The reaction solution was cooled, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 20.68 g of compound (I) with a yield of 92%.

[0066] Preparation of compound (II)

[0067] Compound (I): 4-methoxy-3-(3-methoxypropoxy)-bromobenzene: metal reagent = 1: 1.4: 1.6 according to the molar ratio of the feed is carried out as follows, wherein the metal reagent is n-butyl Base Lithium:

[0068] Dissolve 3.85g (14mmol) of 4-methoxy-3-(3-methoxypropoxy)-bromobenzene in 14ml tetrahydrofuran, and add 1.6...

Embodiment 2

[0079] Preparation of compound (I)

[0080]11.3g (40mmol) of (3S, 5S, 1'S, 3'S)-5-(1'-azido-3'-hydroxymethyl-4'-methyl-pentyl)-3-isopropyl- Dihydrofuran-2-one was dissolved in 80ml of dichloromethane, 65mg (0.4mmol) of 2,2,6,6-tetramethylpiperidine oxide was added to it, the temperature was lowered to below 0°C, and 36mL (48mmol) of The molar concentration of (consumption) is 1.35mol / L sodium hypochlorite aqueous solution, react at 50 ℃ for 3 hours. The reaction solution was cooled, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 10 g of compound (I) with a yield of 89%.

[0081] Preparation of compound (II)

[0082] Compound (I): 4-methoxy-3-(3-methoxypropoxy)-bromobenzene: metal reagent = 1: 1.2: 1.4 according to the molar ratio of the feed is carried out as follows, wherein the metal reagent is n-butyl Base Lithium:

[0083] Dissolve 3.3g (12mmol) of 4-methoxy-3-(3-methoxypropoxy)-bromobenzene in 12ml of tetrahydro...

Embodiment 3

[0094] Preparation of compound (I)

[0095] Dissolve 3.1mL (35.9mmol) oxalyl chloride and 5.1mL (71.9mmol) dimethyl sulfoxide DMSO in dichloromethane, cool down to -65°C, add 6.2g (21.8mmol) (3S, 5S, 1'S, 3'S) -5-(1'-azido-3'-hydroxymethyl-4'-methyl-pentyl)-3-isopropyl-dihydrofuran-2-one in 22ml dichloromethane solution in- React at 65℃~-55℃ for 20 hours, add 3mL (21.8mmol) triethylamine, neutralize the reaction solution to neutrality, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate to obtain light yellow liquid compound (I) 4.9g, yield 80%.

[0096] Preparation of compound (II)

[0097] Compound (I): 4-methoxy-3-(3-methoxypropoxy)-bromobenzene: metal reagent = 1: 1.4: 2.0 according to the molar ratio of the feed to carry out the following operations, wherein the metal reagent is isopropyl Magnesium Chloride:

[0098] Dissolve 3.85g (14mmol) of 4-methoxy-3-(3-methoxypropoxy)-bromobenzene in 14ml of tetrahydrofuran, and add 1.0mol / L of isopropyl t...

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Abstract

The invention discloses a preparation method for aliskiren. The preparation method comprises the following steps of: preparing a compound (I) from (3S, 5S, 1'S, 3'S)-5-(1'-azido-3'-hydroxymethyl-4'-methyl-amyl)-3-isopropyl-dihydrofuran-2-ketone through catalytic oxidation; performing addition with 4-methoxyl-3-(3-methoxyl propoxy)-bromobenzene under the action of a metal reagent to obtain a compound (II); then performing catalytic hydrogenation and amino group protection to obtain a lactone compound (III), serving an important intermediate of the aliskiren; and finally condensing with 3-amino-2,2-methacrylamide and removing an amino protecting group to obtain the aliskiren. Compared with the prior art, the preparation method has the beneficial effects of cheap and readily available raw materials, short reaction route, easiness and convenience in operation, no special requirement on equipment, high yield, low cost and small environmental protection pressure, is suitable for commercial production and has a higher industrial application value.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of Aliskiren. Background technique [0002] The chemical name of Aliskiren Hemi-fumarate is (2S, 4S, 5S, 7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy -2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide (CAS No: 173334-58-2), is The antihypertensive drug developed by Novartis, Switzerland, was approved for marketing in the United States and the European Union in 2007. Aliskiren acts on the initial link of the renin-angiotensin system, which is different from the existing drugs acting on angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, and provides the ability to block the renin-angiotensin system. is an orally effective non-peptide renin inhibitor. [0003] The synthetic method of bibliography Aliskiren mainly contains following several kinds: [0004] The U.S. Patent No. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/22C07C231/12
CPCY02P20/55
Inventor 张兴贤庄程翰张拥军周雄飞周敦峰章丽刘良有卢宏强
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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