Practical synthesis method for feritin inhibitor aliskiren

A synthetic method and high blood pressure technology, applied in the direction of chemical instruments and methods, preparation of carboxylic acid amides, preparation of organic compounds, etc., can solve the problems of shortening the steps of the reaction, racemic products, etc., and achieve shortening of the steps of the reaction, reaction Reasonable effect of process selection

Inactive Publication Date: 2007-08-15
上海药明康德新药开发有限公司
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  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The technical problem to be solved in the present invention is: optimize the synthetic route in document 1, use a kind of new synthetic method to convert intermediate A into target molecule Aliskiren, shorten the steps of the reaction and the yield is better; solve the prior art There is a racemic product problem when tert-butoxycarbonyl is removed in the middle; a new practical synthetic method of Aliskiren is provided

Method used

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  • Practical synthesis method for feritin inhibitor aliskiren
  • Practical synthesis method for feritin inhibitor aliskiren
  • Practical synthesis method for feritin inhibitor aliskiren

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Synthesis of Aliskiren:

[0034] The second step: (1S, 2S, 4S, 2’S)-(2-hydroxyl-4-hydroxymethyl-1-{2-[4-methoxyl-3-(3-methoxyl) Synthesis of -propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-tert-butyl carbonate

[0035] The method described in document 1 first prepares intermediate A, then intermediate A (16g, 25.4mmol) is dissolved in the absolute methanol of 200ml, adds the Pd / C catalyst (0.8g) of 5%, in 1 Atmospheric pressure, hydrogenation at 40°C for 12 hours. The catalyst was removed by filtration, spin-dried, and column chromatography (PE: EA = 3: 1) gave intermediate B (6 g, 17.8 mmol) and its diastereomer (3.8 g, 7.1 mmol), yield 98% . 1 HNMR (300ppm, CDCl3): δ6.78-6.68 (m, 3H), 4.71 (brs, 1H), 4.12-4.07 (t, J=6.3Hz, 2H), 3.82 (s, 3H), 3.72-3.44 ( m, 6H), 3.35(s, 3H), 2.64(brs, 2H), 2.50(m, 2H), 2.10(m, 2H), 1.72-1.45(m, 8H), 1.41(s, 9H), 0.90 (m, 12H); MS (m / z): 540 (M+H) + .

[0036] The second step: (1S, 3S, 1'S, 4'S)-{1-(4-isopropyl-5-oxo-tetr...

Embodiment 2

[0043] Synthesis of Aliskiren:

[0044] The first step: (1S, 2S, 4S, 2’S)-(2-hydroxy-4-hydroxymethyl-1-{2-[4-methoxy-3-(3-methoxy Synthesis of -propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-tert-butyl carbonate

[0045] The method described in document 1 first prepares intermediate A, then intermediate A (21g, 33.4mmol) is dissolved in the anhydrous methanol of 300ml, adds Raney Ni catalyst (2.1g), at 10 atmospheric pressure, 70 hydrogenation at °C for 12 hours. The catalyst was removed by filtration, spin-dried, and column chromatography (PE:EA=3:1) gave Intermediate B (11.4g, 21.2mmol) and its diastereomer (4.6g, 8.5mmol), yield 89 %. Its test data is as shown in the first step of the above-mentioned embodiment 1.

[0046] The second step: (1S, 3S, 1'S, 4'S)-{1-(4-isopropyl-5-oxo-tetrahydrofuryl-2-yl)-3-[4- Synthesis of methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-tert-butyl carbonate

[0047] According to the process conditions and operation steps ...

Embodiment 3

[0053] Synthesis of Aliskiren:

[0054] The first step: (1S, 4S, 2'S)-(2-hydroxy-4-hydroxymethyl-1-{2-[4-methoxy-3-(3-methoxy Synthesis of -propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-tert-butyl carbonate

[0055] The method described in document 1 first prepares intermediate A, then intermediate A (30g, 47.7mmol) is dissolved in the dehydrated alcohol of 400ml, adds the Pd / C catalyst (1.5g) of 5%, in 3 Atmospheric pressure, hydrogenation at room temperature for 12 hours. The catalyst was removed by filtration, spin-dried, and column chromatography (PE: EA = 3: 1) gave intermediate B (17.3 g, 32.1 mmol) and its diastereomer (7.1 g, 13.2 mmol), yield 95 %. Its test data is as shown in the first step of the above-mentioned embodiment 1.

[0056] The second step: (1S, 3S, 1'S, 4'S)-{1-(4-isopropyl-5-oxo-tetrahydrofuryl-2 base)-3-[4- Synthesis of methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-tert-butyl carbonate

[0057] According to the process conditio...

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Abstract

The invention discloses a synthesizing method of Alikelun of hypertension proteinogenase inhibitor, which comprises the following steps: adopting (1S, 4S, 2'S)-(4-benzyloxy methyl-2-hydroxy-1-{2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbonic tert-butyl as raw material; catalyzing; hydrogenating; removing benzyl; separating two R and S-typed diastereomers through column chromatography; obtaining (1S, 2S, 4S, 2'S)-(2-hydroxy-4-methylol-1-{2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbonic tert-butyl ester; oxidizing into (1S, 3S, 1'S, 4'S)-{1-(4-isopropyl-5-oxo-tetrahydrofuran-2-radical)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-amyl}-carbonic tert-butyl ester; proceeding amide ester exchange to obtain (1 S, 3S, 1'S, 4'S)-(4-(2-amino formyl-2-methyl-propyl amino formyl)-2-hydroxy-1-{2-[4-methoxy-3-(3-methoxy-propoxy-benzyl]-3-methyl-butyl}-5-methyl-hexyl) carbonic tert-butyl ester; removing terbu-carbonyl to produce Aliskiren.

Description

Technical field: [0001] The invention relates to a practical synthesis method of Aliskiren, an inhibitor of hypertensinogenase. Background technique: [0002] Cardiovascular disease, including hypertension, is the number one cause of death worldwide. According to the statistics of relevant experts: only 25% of patients with hypertension can be controlled with current drugs, so many companies are developing drugs for cardiovascular diseases such as antihypertension. According to the global antihypertensive drug sales of 35 billion US dollars in 2001, Datamonitor predicts that the global sales of antihypertensive drugs will reach 52 billion US dollars in 2007. [0003] An ideal antihypertensive drug has a good antihypertensive effect, is relatively cheap and reasonable, and has no or few side effects. Specifically, the ideal antihypertensive drug should be able to effectively lower blood pressure, can be taken orally once a day, is convenient to take, relatively cheap, has f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/22C07C231/00
Inventor 董华张治柳马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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