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Aliskiren, its intermediates and medicinal salt, as well as preparation method thereof

A technology of intermediates and compounds, applied in the field of pharmaceutical synthesis, can solve the problems of difficult product separation and purification, high cost of reaction raw materials, low yield and purity, etc., and achieve the effect of easy crystallization, meeting industrial production and improving purity

Active Publication Date: 2012-06-06
NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, in the existing synthetic methods of Aliskiren or its intermediates, there are various degrees of high cost of reaction raw materials, complex reaction process, poor crystal form of intermediates, difficulty in product separation and purification, and low yield and purity. , long reaction time and other defects

Method used

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  • Aliskiren, its intermediates and medicinal salt, as well as preparation method thereof
  • Aliskiren, its intermediates and medicinal salt, as well as preparation method thereof
  • Aliskiren, its intermediates and medicinal salt, as well as preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Formula III 1 compound synthesis

[0048]

[0049] According to the method disclosed in patent WO2007045420A, the product Ia was synthesized as a synthetic raw material.

[0050] 1) Compound V 1 Synthesis

[0051]

[0052] in N 2Under protection, 26.45g (88.9mmol) of compound Ia was dissolved in 150mL of toluene, and 7.2ml of thionyl chloride and 0.5ml of DMF were slowly added dropwise at room temperature. The temperature rose to 37°C, heated to reflux for 2 hours after the dropwise addition, then lowered to room temperature, added 10ml of methanol dropwise, and stirred for 2 hours to obtain V 1 , the product does not need to be separated, and the next reaction is continued.

[0053] 2) by the azide compound V 1 Preparation of Amino Compound V by Pa / C Catalytic Hydrogenation 2

[0054]

[0055] The above obtained V 1 Move into the hydrogenation reactor, add 5g of catalyst Pd / C, react at normal temperature and pressure for 21 hours, the reac...

Embodiment 2

[0068] Example 2 Formula III 1 compound synthesis

[0069] According to the method disclosed in patent WO2007045420A, Ia was synthesized as a synthetic raw material.

[0070] 1) Preparation of Amino Compound Ib by Pa / C Catalytic Hydrogenation of Azide Compound Ia

[0071]

[0072] In the hydrogenation reactor, 26.45g of compound Ia was dissolved in 150ml of ethanol, 5g of 5% Pd / C catalyst was added, reacted at room temperature for 20 hours, then filtered, the filtrate was washed with water, and the organic phase was separated and concentrated to obtain compound Ib.

[0073] 2) Compound Ib reacts with phthaloyl chloride to synthesize amino-protected compound Ic 1

[0074]

[0075] Under the protection of nitrogen, 18.57g of compound Ib was dissolved in 95ml of tetrahydrofuran, the temperature was controlled to 0°C, 3.7g of triethylamine was added under stirring, and then 12.2g of phthaloyl chloride-THF solution was slowly added dropwise, maintaining the same temperat...

Embodiment 3

[0087] Example 3 Formula IV 1 compound synthesis

[0088]

[0089] Under nitrogen protection, add 150g (227mmol) III 1Compound and 80g (690mmol) compound BP-a, then add 111ml (79mmol) triethylamine, drop into 3.1g (32mmol) 2-hydroxypyridine, the reaction mixture is heated to 80 ℃, stirring reaction 24 hours, TLC detection reaction is complete, The reaction solution was diluted with saturated sodium bicarbonate, then extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a light yellow foamy substance, iso Recrystallized from propyl ether to obtain white solid substance IV 1 .

[0090] IV 1 :

[0091] H-NMR (400MHz, CDCl3): 0.86(q, 6H), 0.93(d, 3H), 1.01(d, 3H), 1.38(d, 6H), 1.96-2.00(m, 2H), 2.10(m, 2H), 2.15(m, 2H), 2.42(m, 2H), 2.81(m, 2H), 3.28(s, 3H), 3.28-3.81(m, 3H), 3.94(s, 3H),...

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Abstract

The invention mainly relates to aliskiren, its intermediates and a medicinal salt, as well as a preparation method thereof. The involved aliskiren and its intermediates are compounds as shown in formula I-V, wherein, the definitions of R and Z are stated in the specification. With the compound shown in formula Ia as a synthesis raw material, the compounds in formula I-V are synthesized through reduction, substitution and other reaction steps under the protection of nitrogen. These substances are precursors for synthesis of aliskiren, the precursor substances can be used to prepare aliskiren and its hemifumarate. The method for preparing aliskiren with the precursor substances has the advantages of low cost, easy crystallization and purification, as well as high purity, etc., and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to aliskiren, its intermediates, hemifumarate and preparation methods of these substances. Background technique [0002] The chemical formula of Aliskiren is C 30 h 53 N 3 o 6 , the chemical name is (2S, 4S, 5S, 7S)-5-amino-N-(2-carbamoyl-2methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methyl Oxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide, CAS №: 173334-57-1, molecular weight 551.76, chemical structural formula a: [0003] [0004] Aliskiren is a renin inhibitor that acts on the renin-angiotensin-aldosterone system. Clinically, Aliskiren is used in the form of hemifumarate, and is the first drug for the treatment of hypertension approved by the US FDA to directly inhibit the renal enzyme renin that causes blood pressure to increase. In 6 8-week placebo-controlled clinical studies on more than 2,000 patients with mild to moderate hypertension, it was proved that Aliskiren has the...

Claims

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Application Information

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IPC IPC(8): C07D405/06C07D209/48C07C237/22C07C231/12C07C57/15C07C51/41
Inventor 袁建栋徐安佗江锋焦玲玲
Owner NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD
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