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Method for preparing aliskiren key intermediate by enzyme method

An enzymatic preparation and intermediate technology, applied in the field of biomedicine, can solve the problems of large discharge of organic three wastes, unsuitable for industrial production, high pressure conditions, etc., and achieves low production cost, good industrial application value, and easy availability of raw materials. Effect

Inactive Publication Date: 2018-06-22
上海韶屹生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route has long synthesis steps, uses expensive catalysts, requires high pressure conditions, and emits a large amount of organic waste, which is not suitable for industrial production

Method used

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  • Method for preparing aliskiren key intermediate by enzyme method
  • Method for preparing aliskiren key intermediate by enzyme method
  • Method for preparing aliskiren key intermediate by enzyme method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Preparation of 2,2-dimethyl-3-aminopropionamide

[0032] Step a)

[0033] 3-Nitropropionic acid (10g) and methanol (8L) were added to the reactor, concentrated sulfuric acid (2ml) was added dropwise, reacted for 0.5h under reflux conditions, and distilled under reduced pressure to obtain 3-nitropropionic acid methyl ester (11g), Put it directly into the next step.

[0034] Step b)

[0035] Add methyl 3-nitropropionate (11g), sodium methoxide (4.8g) and methanol (8L) into the reactor, react under reflux for 2h, then cool to 20-30°C, add dimethyl sulfate (11g) , stirred overnight at room temperature. The reaction solvent was distilled under reduced pressure, water (5 L) was added, extracted with ethyl acetate (3 L*3), dried, and distilled under reduced pressure to obtain methyl 2,2-dimethyl-3-nitropropionate (11.4 g).

[0036] Step c)

[0037] 2,2-Dimethyl-3-nitropropionic acid methyl ester (11.4g) was dissolved in methanol (10L), passed through ammonia, st...

Embodiment 2

[0040] Example 2 Preparation of 2,2-dimethyl-3-aminopropanamide

[0041] Step a)

[0042] 3-Nitropropionic acid (100g) and methanol (80L) were added in the reactor, concentrated sulfuric acid (20ml) was added dropwise, reacted under reflux conditions for 0.5h, and distilled under reduced pressure to obtain 3-nitropropionic acid methyl ester (110g), Put it directly into the next step.

[0043] Step b)

[0044] Add methyl 3-nitropropionate (110g), sodium methoxide (48g), and methanol (20L) into the reactor, react for 2 hours under reflux, then cool to 20-30°C, add dimethyl sulfate (110g), Stir overnight at room temperature. The reaction solvent was distilled under reduced pressure, water (15 L) was added, extracted with ethyl acetate (10 L*3), dried, and distilled under reduced pressure to obtain methyl 2,2-dimethyl-3-nitropropionate (114 g).

[0045] Step c)

[0046] 2,2-Dimethyl-3-nitropropionic acid methyl ester (114g) was dissolved in methanol (10L), passed through ammo...

Embodiment 3

[0049] Example 3 Preparation of 2,2-dimethyl-3-aminopropionamide

[0050] Step a), b), c) are the same as in Example 1;

[0051] Step d)

[0052] 2,2-Dimethyl-3-nitropropionamide (10.3g), nitroreductase enzyme powder (5mg), NADPH (0.5mg), Tris-HCl buffer (30mM, 0.05L, pH=6) , stirred at 70°C for 12h, filtered, extracted with ethyl acetate, dried and concentrated to obtain the crude product, which was recrystallized in petroleum ether to obtain the product 2,2-dimethyl-3-aminopropionamide (7.36g, yield 90%) , the product purity was 99.0%.

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Abstract

The invention discloses a method for preparing an aliskiren key intermediate by an enzyme method. 2,2-dimethyl-3-amino propenamide is obtained by using 3-nitropropionic acid as raw materials through esterification, methylation, ammonolysis and nitro-reduction reaction, wherein the 2,2-dimethyl-3-amino propenamide is prepared through reduction reaction under the effects of nitroreductase, coenzymeand buffer solution by the enzyme method. Compared with the prior art, the method provided by the invention has the advantages that the environment-friendly effect is good; the organic three-waste (waste water, waste solid and waste gas) discharging quantity is small; the raw materials can be easily obtained; the yield is higher; the production cost is greatly reduced; good industrial applicationvalues are realized.

Description

technical field [0001] The invention belongs to the field of biomedicine, in particular to a method for enzymatically preparing aliskiren key intermediates. Background technique [0002] Aliskiren is the first oral, non-peptide, direct renin inhibitor synthesized in recent years. The relative molecular mass is 609.8 (the free base is 551.8), the physical and chemical properties are stable, and the water solubility is high. In March 2007, the antihypertensive drug Aliskiren (trade name: Tekturna) was approved by the US Food and Drug Administration (FDA). In January 2008, the compound preparation composed of Aliskiren and Dihydrothiazide was also approved Approved by the FDA. [0003] Aliskiren can block the RAS system in the first link, reduce the activity of renin, reduce the production of AngII and aldosterone, without affecting the metabolism of bradykinin and prostaglandins, and play a role in lowering blood pressure and treating cardiovascular diseases. Judging from t...

Claims

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Application Information

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IPC IPC(8): C12P13/02
CPCC12P13/02
Inventor 许兴磊其他发明人请求不公开姓名
Owner 上海韶屹生物科技有限公司
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