WO2017143627A1 - New method for preparing aliskiren intermediate - Google Patents

Abstract

The present application relates to a method for preparing an Aliskiren intermediate (III). The Aliskiren intermediate is prepared by carrying out a reduction reaction of a compound (IV) with sodium borohydride and boron trifluoride tetrahydrofuran.

Description

A new preparation method of aliskiren intermediate Technical field

The invention belongs to the field of medicinal chemical industry, and particularly relates to a novel preparation method of a synthetic condition-optimized blood pressure lowering drug aliskiren (Compound I) intermediate (Compound III).

Background technique

Cardiovascular diseases, including high blood pressure, are the number one death factor in the world and are known as "the number one killer of human health." The currently available antihypertensive drugs are mainly classified into the following categories: diuretics (thiazide drugs), β-blockers (lores), calcium antagonists (prime drugs), angiotensin Invertase inhibitors (Pulis), angiotensin II receptor antagonists (sartans). Only 25% of patients with hypertension can be controlled with current drugs. Aliskiren is the first non-peptide renin inhibitor approved by the FDA in 2007. It inhibits renin activity and reduces angiotensin I and angiotensin II levels in the body. And lowering blood pressure. Aliskiren is also unique in that it reduces plasma renin activity (PRA), which is not only a risk factor for myocardial infarction in hypertensive patients, but also closely related to target organ damage, reducing PRA protection of target organs. Role, this is also an important feature distinguishing renin inhibitors from other antihypertensive drugs.

Aligilen is a Novartis company, and the compound patent is US5559111A. It has been authorized in the domestic family patents CN1266118C and CN1153759C. The synthetic route is as follows:

Summary of the invention

In this patent, boron trifluoride tetrahydrofuran/sodium borohydride is used to reduce the carbonyl group, and the compound III is successfully prepared, which provides a new choice for the synthesis of the compound III. The method is milder than the boron trifluoride diethyl ether/sodium borohydride reaction condition. The industrialized operability is higher, the product purity is high, and the next step can be directly tested without purification.

The synthetic route of aliskiren intermediate III provided by the present invention is as follows:

The molar ratio of compound IV to boron trifluoride tetrahydrofuran is preferably 1:3 to 1:4;

The molar ratio of compound IV to sodium borohydride is preferably 1:2.5 to 1:3.5;

The above reaction is preferably carried out in an aprotic solvent, preferably a ketone, a lipid, an ether, an aromatic hydrocarbon, a halogenated alkane or the like, more preferably tetrahydrofuran, diethyl ether, diisopropyl ether, acetonitrile, acetone, N, N-di One of methyl formamide, dichloromethane, dimethyl sulfoxide or a mixture of any two. Most preferred is tetrahydrofuran or diethyl ether.

The reaction temperature is preferably 0 ° C to 30 ° C.

The above reaction step further includes post-treatment of the reactant, adding 3 to 4 times the amount of the compound IV (W/W) of hydrochloric acid (4N) to the reaction solution, and then extracting the product with ethyl acetate or dichloromethane; The ester or dichloromethane can be extracted 1 to 3 times, and the organic phase can also be washed with saturated sodium chloride or dried over anhydrous sodium sulfate.

The preparation method of the invention removes the compound III by column chromatography in the original research patent US 5559111A, and the reaction time only takes 1-2 hours, and after completion of the reaction, a high purity (more than 95%) product can be obtained after simple post-treatment. The next reaction can be carried out directly without further purification. The reaction process is mild, and can be carried out only at room temperature, has no effect on the chirality of the product, is simple to operate, and is suitable for industrial large-scale production.

detailed description

Example 1

Synthesis of Compound III: (R)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanol

Feeding ratio:

Material name	Moore ratio
Compound IV	1.0
Sodium borohydride	2.5
Boron trifluoride tetrahydrofuran	3.0

(R)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoic acid (155 g, 0.5 mol), sodium borohydride (47.4 g, 1.25 mol) was dissolved in tetrahydrofuran (775 ml), boron trifluoride tetrahydrofuran (210 g, 1.5 mol) was slowly added dropwise, and the temperature was controlled to be 20 to 30 ° C during the dropwise addition. After the completion of the dropwise addition, the reaction was stirred at the same temperature for 1 hour. After the completion of the reaction, 4N hydrochloric acid (465 ml) was added, and the mixture was stirred for 10 minutes, and then the mixture was combined with ethyl acetate. The organic phase was combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated. The rate was 97.3% and the HPLC purity was 96.6%.

Example 2

Synthesis of Compound III: (R)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanol

Feeding ratio:

Material name	Moore ratio
Compound IV	1.0
Sodium borohydride	3.5
Boron trifluoride tetrahydrofuran	4.0

(R)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoic acid (155 g, 0.5 mol), sodium borohydride (66.3 g, 1.75 mol) was dissolved in tetrahydrofuran (775 ml), boron trifluoride tetrahydrofuran (280 g, 2.0 mol) was slowly added dropwise, and the temperature was controlled to be 0 to 10 ° C during the dropwise addition. After the completion of the dropwise addition, the reaction was stirred at the same temperature for 2 hours. After the completion of the reaction, 4N hydrochloric acid (620 ml) was added, and the mixture was stirred for 10 minutes, and then the mixture was combined with dichloromethane. The organic phase was combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated. The rate was 98.0% and the HPLC purity was 97.1%.

Claims (3)

1. A method for preparing a compound III, which has the structural formula shown in the following figure, which is obtained by reacting a compound IV.

   
2. According to claim 1, in the process for the preparation of compound III from compound IV:

   (1) The reaction is preferably carried out in an aprotic solvent, preferably a ketone, a lipid, an ether, an aromatic hydrocarbon, a halogenated alkane or the like, more preferably tetrahydrofuran, diethyl ether, diisopropyl ether, acetonitrile, acetone, N, N. a mixture of dimethylformamide, dichloromethane, dimethyl sulfoxide or a mixture of any two, most preferably tetrahydrofuran or diethyl ether;

   (2) the molar ratio of the compound IV to boron trifluoride tetrahydrofuran is preferably 1:3 to 1:4;

   (3) the molar ratio of the compound IV to sodium borohydride is preferably 1:2.5 to 1:3.5;

   (4) the reaction temperature is preferably 0 ° C ~ 30 ° C;
3. After completion of the reaction of the parameter according to claim 2, the reaction system is acidified, and then the product is extracted by adding dichloromethane or ethyl acetate, followed by washing, drying and concentration to obtain the target product.