Preparation method of viliciguat key intermediate

Abstract

The invention relates to the technical field of pharmaceutical and chemical engineering, in particular to a preparation method of a key intermediate of viliciguat, which improves the existing process and provides a novel synthetic route of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone [3, 4-B] pyridine-3-formonitrile, and the route has the advantages of short reaction time, high content, high yield, low cost and more convenient production operation. The route overcomes the technical difficulties that a five-membered ring is rearranged into a six-membered ring in the step S5, meanwhile, fluorine at the fifth position of a pyridine ring is introduced, the reaction conditions are mild, raw materials used in the synthesis method are cheaper and easier to obtain, the reaction temperature of each step is within 100 DEG C, the risk is small, and the heat efficiency is high.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical engineering, and in particular to a method for preparing a key intermediate of Vericipirax. Background Art

[0002] Vericipirat is a soluble guanylate cyclase (sGC) stimulator developed by Bayer in Germany and is an innovative drug for the treatment of heart failure. It can reduce the burden on the heart and slow down the development of heart failure by increasing intracellular cGMP levels and relaxing smooth muscles. Vericipirat can directly stimulate sGC and stabilize the binding of nitric oxide to sGC, thereby enhancing the L-ARG-NO-sGC-cGMP signaling pathway, improving myocardial and vascular function, preventing or even reversing left ventricular hypertrophy and fibrosis, slowing down ventricular remodeling, and reducing ventricular afterload through systemic and pulmonary vasodilation, thereby exerting a therapeutic effect on heart failure through the above mechanism. The compound 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carbonitrile is an important intermediate in the synthesis route of Vericipirat and a key intermediate in the existing process.

[0003] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention

[0004] The purpose of the present invention is to solve the problems in the prior art that the Vericipirax reaction steps are long, the reaction yield is low, and the catalyst is expensive, and a method for preparing a key intermediate of Vericipirax is provided.

[0005] In order to achieve the above-mentioned object, the present invention discloses a method for preparing a key intermediate of Vericipiracil. The structural formula of the key intermediate of Vericipiracil is

[0006] The synthetic route is as follows:

[0007]

[0008] The following steps are involved:

[0009] S1, cyclizing compound 1 in an organic solvent to obtain compound 2;

[0010] S2, compound 2 obtained in step S1 is catalyzed by an organic base to replace compound 3 with o-fluorobenzyl halide;

[0011] S3, reacting the compound 3 obtained in step S2 with cyanide and a catalyst to obtain a compound 4;

[0012] S4, dehydrating the compound 4 obtained in step S3 to obtain compound 5;

[0013] S5, rearrange the compound 5 obtained in step S4 and react under pressure to obtain compound 6, i.e., the target product.

[0014] In step S1, the organic solvent is any one or a combination of acetone, acetonitrile, tetrahydrofuran, and methanol.

[0015] In step S2, the organic base is any one or a combination of sodium hydroxide, sodium methoxide, and triethylamine.

[0016] In the step S2, the o-fluorobenzyl halide is any one or a combination of o-fluorobenzyl chloride, o-fluorobenzyl bromide and o-fluorobenzyl iodine.

[0017] In step S3, the catalyst is any one or a combination of triphenylphosphine, 18-crown-6-ether, and tetrabutylammonium chloride.

[0018] In the step S5, the rearrangement reaction pressure is 0.05-3 MPa.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: the preparation method of the key intermediate of Vericipirax in the present invention is improved by reducing the process cost by more than 50%, increasing the reaction yield by 30%, increasing the reactant content by 10%, reducing the reaction time by 50%, having a low reaction temperature and simple operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the H NMR spectrum of the product in Example 1;

[0021] Figure 2 is the liquid phase spectrum of the product in Example 1;

[0022] Figure 3 is the H NMR spectrum of the product in Example 2;

[0023] Figure 4 is the H NMR spectrum of the product in Example 3;

[0024] Figure 5 is the H NMR spectrum of the product in Example 4;

[0025] Figure 6 This is the H NMR spectrum of the product in Example 5. DETAILED DESCRIPTION

[0026] The above and other technical features and advantages of the present invention are described in more detail below in conjunction with the accompanying drawings.

[0027] Example 1

[0028]

[0029] At room temperature, 50g of raw material, 12g of hydrazine, and 300mL of methanol were added to a 500mL reaction bottle, and the temperature was raised to 65°C for reflux reaction for 8h. TLC detected that the raw material reaction was complete. The temperature was lowered and the methanol was concentrated, and then 300mL of dichloromethane was added, and 150mL of water was washed twice, and the dichloromethane was dried to obtain 36.6g of the target product with a yield of 95%.

[0030] Example 2

[0031]

[0032] At room temperature, 30 g of raw material, 10.7 g of sodium hydroxide, 200 mL of water, and 38.8 g of o-fluorobenzyl chloride were added to a 500 mL reaction bottle. Stirring was carried out at 35°C for 10 h. TLC showed that the raw material reaction was complete. Cooling and suction filtration were performed to obtain 50.7 g of the target product, with a yield of 90%.

[0033] Example 3

[0034]

[0035] At room temperature, 50 g of raw material, 16.9 g of potassium cyanide, 0.5 g of triphenylphosphine, and 250 mL of dichloromethane were added to a 500 mL reaction bottle, and stirred at 20°C for 4 h. TLC detected that the raw material reaction was complete. 200 mL of water was added for washing twice, and the solvent was concentrated to obtain 51.4 g of the target product with a yield of 92%.

[0036] Example 4

[0037]

[0038] At room temperature, 50 g of raw material, 17.2 g of sodium ethoxide, and 250 mL of ethanol were added to a 500 mL reaction bottle, and the temperature was raised to 80 °C for reflux reaction for 8 h. TLC detected that the raw material reaction was complete. The ethanol was concentrated and dried, and 150 mL of dichloromethane and 100 mL of water were added to wash twice. The solvent was concentrated and dried to obtain 41.4 g of the target product, with a yield of 89%.

[0039] Example 5

[0040]

[0041] At room temperature, 35 g of raw material, 11.8 g of sodium methoxide, and 350 mL of dichloromethane were added to a 500 mL autoclave, nitrogen was replaced, trifluoromethane was introduced to 0.2 MPa, and the reaction was stirred at 35 ° C for 12 hours. HPLC detected that the raw material reaction was complete. The solvent was concentrated and dried to obtain 33.5 g of the target product, with a yield of 85% and a purity of 97.7%.

[0042] Example 6

[0043] When only the solvent type or reactant equivalent in step S1 is changed, the reaction results are shown in Table 1 and Table 2

[0044] Table 1 Target product yields under different reaction solvents

[0045] Serial number Solvent type Total volume of solvent / times Reaction time / h Reaction temperature / ℃ Reaction results 1 Methanol 6 8 65 Yield 95% 2 acetone 6 8 65 Yield: 88% 3 Acetonitrile 6 8 65 Yield 85% 4 Tetrahydrofuran 6 8 65 Yield 86%

[0046] Table 2 Target product yields under different hydrazine equivalents

[0047]

[0048]

[0049] As shown in Table 1, the reaction solvent is methanol, the total volume of the solvent is 6 times, the amount of hydrazine used is 8.5eq, the reaction time is 8h, the reaction temperature is 65°C, and the reaction yield is the highest.

[0050] Example 7

[0051] When only the type or equivalent of the catalyst or reaction aid used in step S2 is changed, the reaction results are shown in Table 3 and Table 4.

[0052] Table 3 Target product yields under different organic base types and different organic base equivalents

[0053] Serial number Types of organic bases Organic base equivalent / eq Reaction time / h Reaction temperature / ℃ Reaction results 1 Sodium hydroxide 1.1 10 35 Yield 90% 2 Sodium Methanol 1.1 10 35 Yield 72% 3 Triethylamine 1.1 10 35 Yield 80% 4 Sodium hydroxide 1.5 10 35 Yield: 88% 5 Sodium hydroxide 1 10 35 Yield 85%

[0054] Table 4 Target product yield under different reaction aids

[0055] Serial number Reaction Auxiliary Agent Reaction equivalent / eq Reaction time / h Reaction temperature / ℃ Reaction results 1 2-Fluorobenzyl bromide 1.1 10 35 Yield 83% 2 2-Fluorobenzyl chloride 1.1 10 35 Yield 90% 3 o-Fluorobenzyl iodide 1.1 10 35 Yield 82% 4 2-Fluorobenzyl chloride 1.5 10 35 Yield 89% 5 2-Fluorobenzyl chloride 1 10 35 Yield 80%

[0056] It can be seen from Tables 3 and 4 that the reaction yield is the highest when 1.1 equivalents of sodium hydroxide are selected as the organic base, 1.1 equivalents of o-fluorobenzyl chloride are selected as the reaction auxiliary, the reaction time is 10 h, and the reaction temperature is 35° C.

[0057] Example 8

[0058] When only the type and equivalent of the catalyst in step S3 are changed, the reaction results are shown in Table 5

[0059] Table 5 Target product yields under different catalysts and different catalyst equivalents

[0060]

[0061] As shown in Table 5, when 0.1 equivalent of triphenylphosphine is selected as the reaction catalyst, the reaction time is 4 h, and the reaction temperature is 20° C., the reaction has the highest yield and is more economical.

[0062] Example 9

[0063] When only the reaction pressure or organic base equivalent in step S5 is changed, the reaction results are shown in Table 6

[0064] Table 6 Target product yields at different pressures and different sodium methoxide equivalents

[0065]

[0066] As shown in Table 6, the reaction yield is the highest when the reaction pressure is 0.2 MPa, the amount of sodium methoxide is 1.5 equivalents, the reaction time is 12 h, and the reaction temperature is 35°C.

[0067] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.

Claims

1. A method for preparing a key intermediate of Vericipirax, characterized in that: The structural formula of the key intermediate of Vericipirax is The synthetic route is as follows: The following steps are involved: S1, cyclizing compound 1 in an organic solvent to obtain compound 2; S2, compound 2 obtained in step S1 is catalyzed by an organic base to replace compound 3 with o-fluorobenzyl halide; S3, reacting the compound 3 obtained in step S2 with cyanide and a catalyst to obtain a compound 4; S4, dehydrating the compound 4 obtained in step S3 to obtain compound 5; S5, rearrange the compound 5 obtained in step S4 and react under pressure to obtain compound 6, i.e., the target product.

2. The method for preparing a key intermediate of Vericiguat according to claim 1, characterized in that: In step S1, the organic solvent is any one or a combination of acetone, acetonitrile, tetrahydrofuran, and methanol.

3. The method for preparing a key intermediate of Vericiguat according to claim 1, characterized in that: In step S2, the organic base is any one or a combination of sodium hydroxide, sodium methoxide, and triethylamine.

4. The method for preparing a key intermediate of Vericiguat according to claim 1, characterized in that: In the step S2, the o-fluorobenzyl halide is any one or a combination of o-fluorobenzyl chloride, o-fluorobenzyl bromide and o-fluorobenzyl iodine.

5. The method for preparing a key intermediate of Vericiguat according to claim 1, characterized in that: In step S3, the catalyst is any one or a combination of triphenylphosphine, 18-crown-6-ether, and tetrabutylammonium chloride.

6. The method for preparing a key intermediate of Vericiguat according to claim 1, characterized in that: In the step S5, the rearrangement reaction pressure is 0.05-3 MPa.

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