WO2016202124A1

WO2016202124A1 - Riociguat intermediate and preparation method therefor

Info

Publication number: WO2016202124A1
Application number: PCT/CN2016/081940
Authority: WO
Inventors: 许学农
Original assignee: 苏州明锐医药科技有限公司
Priority date: 2015-06-16
Filing date: 2016-05-13
Publication date: 2016-12-22
Also published as: CN104892459A

Abstract

Disclosed are an intermediate, N-methyl-N-methyl formate-2-aminomalononitrile (II), for preparing Riociguat (I) and a preparation method therefor. Preparation steps comprise: 2-aminomalononitrile undergoes an n-methylation reaction to produce N-methyl-2-aminomalononitrile (IV), and N-methyl-2-aminomalononitrile (IV) undergoes an amidation reaction with methyl chloroformate or methyl bromoformate to produce N-methyl-N-methyl formate-2aminoalononitrile (II). The intermediate (II) undergoes a cyclization reaction with 1-(2- fluorobenzyl)-1H-pyrazol[3, 4-b]pyridine-3-formamidine (III) to produce Riociguat (I). The preparation method has readily available raw materials and a simple process and is economical, environmental friendly, and suitable for industrialized production.

Description

Leozepam intermediate and preparation method thereof

Technical field

The invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method for treating adult chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension (PAH) drug leopurin.

Background technique

Riociguat is the first soluble guanylate cyclase stimulator developed by Bayre and the first drug to be proven effective in patients with thromboembolic pulmonary hypertension (CTEPH). The drug was approved by the US FDA in October 2013 for the treatment of adult chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension (PAH) under the trade name Adempas. The successful development of this drug provides another important treatment option for patients with hypertension.

The chemical name of Riociguat (I) is: 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl Methyl-5-pyrimidine (methyl)carbamate, the structural formula of which is:

International patents WO2003095451 and WO2011147810, and the journals ChemMedChem. 2009, 4, 853-865 and Der Pharma Chemica, 2013, 5(4): 232-23, etc., report the synthesis of levozepam, the preparation steps of which include 2-bromo Benzyl fluorobenzene is used as a raw material, and an important intermediate 1-(2-fluorobenzyl)-1H is obtained by thiolation, pyrazole cyclization, pyridine cyclization, hydrolysis and amidation, dehydration nitrilation and thiolation. -pyrazolo[3,4-b]pyridine-3-carboxamidine (III); the intermediate is further subjected to pyrimidine cyclization, azo reduction, formamide and methylation to obtain levosimin (I ).

The international patents WO2012028647 and WO2011147810 and the like report another synthetic method of levozepam, and the main difference from the previous route is that the pyrimidine ring is formed in a different manner. It is obtained by introducing a halogen functional group at the 3-position of the pyrazolopyrimidine ring, and then coupling with a pyrimidine ring containing a halogen to obtain a pyrazolopyridine intermediate of a 3-substituted pyrimidine ring, which is further passed through a nitro group. The treatment of reduction, amino amidation, and methylation produces levosimin.

In addition, the international patent WO2013086935 and the Chinese patents CN104530044A, CN104086545A also report the preparation method of leopurin or an intermediate, and the contents of these documents are mainly found to be the intermediate 1-(2-fluorobenzyl)-1H-pyrazole. The preparation method of [3,4-b]pyridine-3-carboxamide (III) or its hydrochloride salt is optimized and improved as necessary.

Analysis of the preparation method of the currently disclosed leopurine, although the method is different, the basic idea is to sequentially pass through the pyrazole ring, incorporate the pyridine ring, form (or link) the pyrimidine ring, and then the functional group on the pyrimidine ring. The conversion is carried out, such as reduction of azo or nitro group, amidation of amino group and methylation, etc., to finally obtain a target compound. These methods all have the defects of rare raw materials, many steps and high cost. In particular, the above methods are all prepared by continuously changing and accumulating the functional groups of the starting materials. Obviously, such a synthetic idea does not conform to the modern green chemistry. The concept of economics.

In view of the existing process defects, the development of a simple process, economical and environmentally friendly and high-quality preparation technology, especially to find a process technology that can adapt to industrial production, has important practical significance for the economic and social benefits of the drug.

Summary of the invention

The object of the present invention is to provide a preparation method of Riociguat (I) which is easy to obtain raw materials, simple in process, economical and environmentally friendly, and suitable for industrial production.

In order to achieve the above object, the present invention firstly designs and prepares the compound N-methyl-N-methyl carbamate-2-aminomalononitrile as shown in Formula II.

The preparation method comprises the following steps: 2-aminomalononitrile (IV) is subjected to N-methylation to obtain N-methyl-2-aminomalononitrile (V), N-methyl-2-aminopropane Amidation of nitrile (V) with methyl chloroformate or methyl bromoformate affords methyl N-methyl-N-carboxylate-2-aminomalononitrile (II).

In addition, the present invention also proposes the following subsidiary technical solutions:

The methylation reagent for the N-methylation reaction is dimethyl sulfate, methyl iodide or formic acid/sodium borohydride.

When the methylation reagent of the N-methylation reaction is dimethyl sulfate, the acid binding agent is potassium carbonate, and the reaction solvent is toluene.

When the methylating agent for the N-methylation reaction is methyl iodide, the acid binding agent is potassium carbonate, and the reaction solvent is N,N-dimethylformamide.

When the methylation reagent of the N-methylation reaction is formic acid/sodium borohydride, the reaction solvent is formic acid; the molar ratio of the raw material 2-aminomalononitrile (IV) and sodium borohydride is 1:1.5-2.5. , preferably 1:2.0.

The molar ratio of the starting material of the amidation reaction, N-methyl-2-aminomalononitrile (V), to methyl chloroformate or methyl bromoformate is from 1:1.0 to 2.0, preferably from 1:1.2 to 1.5.

The acid binding agent of the amidation reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, lithium carbonate, potassium t-butoxide or sodium hydride. Preferred is triethylamine or pyridine.

The amidation reaction temperature is -25 to 25 ° C, preferably 5-10 ° C; the solvent is dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane Preferably, dichloromethane or tetrahydrofuran is used.

Meanwhile, the present invention also provides a method for preparing leooxime (I) by using the intermediate N-methyl-N-formic acid methyl ester-2-aminomalononitrile (II).

The preparation steps include: N-methyl-N-formic acid methyl ester-2-aminomalononitrile (II) and 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine- 3-carboquinone (III) is subjected to a cyclization reaction under the action of a base accelerator to obtain levosimin (I).

Wherein the cyclization reaction starting material N-methyl-N-formic acid methyl ester-2-aminomalononitrile (II) and 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b The molar ratio of pyridine-3-carboxamidine (III) is from 1:0.5 to 1.5, preferably from 1:0.75 to 1.0.

The alkali promoter of the cyclization reaction is sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate or cesium carbonate, preferably Sodium methoxide or tert-butyl Potassium alkoxide.

The temperature of the cyclization reaction is from 50 to 150 ° C, preferably from 100 to 140 ° C.

The solvent for the cyclization reaction is toluene, xylene, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably toluene or N,N- dimethylformamide.

Compared with the prior art, the preparation method of the leooxime (I) according to the invention has the characteristics of easy availability of raw materials, simple process and economical environmental protection, thereby facilitating the industrial production of the raw material medicine and promoting the development of its economic technology. .

detailed description

The technical solution of the present invention will be further described in the following with reference to a few preferred embodiments. For the preparation of the starting material 2-aminomalonitrile (IV), see the preparation of the same compound in Organic Syntheses, 48, 1-3, 1968; the starting material 1-(2-fluorobenzyl)-1H-pyrazole[3] For the preparation of 4-b]pyridine-3-carboxamidine (III), see the literature on the preparation of the same compound by ChemMedChem, 4(5), 853-865;

Embodiment 1:

2-Aminomalonitrile (IV) (8.1 g, 0.1 mol), dimethyl sulfate (25.2 g, 0.20 mol) and 150 mL of toluene were added to the reaction flask, and the mixture was heated to 35-45 ° C, and stirred until the system was dissolved. Potassium carbonate (27.6 g, 0.2 mol) was added in portions, and stirring was continued for 3 hours while maintaining the temperature, and the reaction was terminated by TLC. The solvent was evaporated under reduced pressure and the residue was crystalljjjjjjjjjjj The solid was added to ethyl acetate, and the mixture was diluted with EtOAc EtOAc (EtOAc) Malononitrile (V) 8.1 g, yield 85.3%; EI-MS m/z: 96 [M+H] ⁺ .

Embodiment 2:

2-Aminomalonitrile (IV) (8.1 g, 0.1 mol), anhydrous potassium carbonate (41.3 g, 0.3 mol) and N,N-dimethylformamide (150 mL) were added to a dry reaction flask at room temperature Methyl iodide (28.4 g, 0.2 mol) was slowly added dropwise, and the reaction was continued for 3-5 hours after completion of the dropwise addition, and the reaction was terminated by TLC. The organic layer was concentrated under reduced pressure.

Embodiment 3:

2-Aminomalonitrile (IV) (8.1 g, 0.1 mol) and 50 mL of formic acid were added to the reaction flask, and the temperature was raised to The reaction was stirred at 45-55 ° C for 5-6 hours, excess formic acid was recovered under reduced pressure, and the residue was dissolved in tetrahydrofuran, cooled to 0-5 ° C, sodium borohydride (7.6 g, 0.2 mol) was added in three portions, and the mixture was warmed to reflux. The reaction was carried out for 4-6 hours, and the reaction was completed by TLC. After cooling to room temperature, the reaction was quenched with EtOAc (EtOAc)EtOAc.

Embodiment 4:

N-methyl-2-aminomalononitrile (V) (9.5 g, 0.1 mol), triethylamine (20 g, 0.2 mol) and 100 mL of dichloromethane were added to the reaction flask, and the temperature was lowered to 5-8 ° C in an ice bath. Methyl chloroformate (14.3 g, 0.15 mol) was added dropwise with stirring. After the completion of the dropwise addition, the mixture was heated to reflux. stirring was continued for 4-6 hours, and the reaction was completed by TLC. The mixture was washed with water, saturated brine and water, and the organic layer was separated, dried over anhydrous sodium sulfate and evaporated. Methyl-N-formic acid methyl ester-2-aminomalononitrile (II) 13.3 g, yield 86.9%; mass spectrum (EI): EI-MS m/z: 154 [M+H] ⁺ , ¹ H NMR (CDCl ₃ ) 2.91 (s, 3H), 3.65 (s, 3H), 5.36 (s, 1H).

Embodiment 5:

Add 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (III) (2.7 g, 10 mmol), sodium methoxide (0.8 g, 15 mmol) to the reaction flask. And 35 mL of toluene, N-methyl-N-formic acid methyl ester-2-aminomalononitrile (II) (1.5 g, 10 mmol) was added with stirring, the temperature was raised to reflux, and the reaction was stirred for 6-8 hours, and the reaction was terminated by TLC. . The temperature was lowered, solids were precipitated, filtered, and the filter cake was washed with cold toluene. The crude product was recrystallized from water to give a pale-yellow solid (yield: 3.8 g, yield: 90.0%; EI-MS m/z: 423 [M+H] ⁺ , ¹ H NMR (DMSO-d ₆ ) δ 3.01 (s, 3H), 3.58 (s, 3H), 5.90 (s, 2H), 6.36 (brs, 4H), 7.10 (m, 1H), 7.54 (m, 2H), 7.63 (m, 2H), 8.76 ( Dd, 1H), 9.01 (dd, 1H).

Example 6:

1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (III) (2.7 g, 10 mmol) and potassium t-butoxide (1.7 g) were added to the reaction flask. , 15 mmol) and N,N-dimethylformamide 35 mL, gradually warmed to 120-130 ° C, stirred for 5-7 hours, and the reaction was terminated by TLC. Concentrated residue was recrystallized from methanol, and dried in vacuo to give an off-white solid Liao Xi gung (I) 3.9g, 92.4% yield of reduced pressure,; EI-MS m / z : 423 [M + H] +, 1 H NMR ( DMSO-d ₆ ) δ 3.01 (s, 3H), 3.58 (s, 3H), 5.90 (s, 2H), 6.36 (brs, 4H), 7.10 (m, 1H), 7.54 (m, 2H), 7.63 (m, 2H), 8.76 (dd, 1H), 9.01 (dd, 1H).

It should be noted that the above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to The person skilled in the art can understand the contents of the present invention and implement it according to the present invention, and cannot limit the scope of the present invention. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims

A compound of the formula N-methyl-N-formic acid methyl ester-2-aminomalononitrile
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 1, wherein the preparation method comprises the steps of: 2-aminomalononitrile by N-methylation reaction N-methyl-2-aminomalononitrile, N-methyl-2-aminomalononitrile and amidation of methyl chloroformate or methyl bromoformate to obtain methyl N-methyl-N-carboxylate -2-aminomalononitrile.
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 2, wherein the methylation reagent of the N-methylation reaction is dimethyl sulfate or methyl iodide. Or formic acid / sodium borohydride.
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 2, characterized in that the raw material of the amidation reaction is N-methyl-2-aminomalononitrile and chloroformic acid. The molar ratio of methyl ester or methyl bromoformate is from 1:1.0 to 2.0.
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 2, wherein the acid binding agent of the amidation reaction is triethylamine, pyridine or N-methylmorphine. Phenanthine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, lithium carbonate, potassium t-butoxide or sodium hydride.
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 2, wherein the amidation reaction temperature is from -25 to 25 ° C, and the solvent is dichloromethane, 1 , 2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane.
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 1, which is characterized in that the compound of the formula II is N-methyl-N-formic acid methyl ester-2-aminomalononitrile and 1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine is cyclized under the action of a base accelerator to prepare levozepam
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 7, wherein the cyclization reaction starting material N-methyl-N-formic acid methyl ester-2-aminopropane The molar ratio of dinitrile to 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine is from 1:0.5 to 1.5.
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 7, wherein the base accelerator of the cyclization reaction is sodium hydride, potassium hydride, sodium hydroxide or hydrogen. Potassium oxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate or cesium carbonate.
The compound N-methyl-N-formic acid methyl ester-2-aminomalononitrile according to claim 7, wherein the temperature of the cyclization reaction is from 50 to 150 ° C; the solvent of the cyclization reaction is Toluene, xylene, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.