Preparation method of sulfonate analogue

Abstract

The present invention relates to a method for preparing sulfonate analogs, in particular in the presence of an enzyme. The preparation method provided by the invention overcomes the defects in the prior art, greatly reduces the production cost, improves the product yield, greatly improves the process safety, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical synthesis, and particularly relates to a preparation method of a sulfonate analogue. BACKGROUND

[0002] The sulfonate analogue of the present application can be used as a chemical raw material and as a key starting material for preparing a pharmaceutical compound. The compound has chirality, and in the industrial or pharmaceutical synthesis field, high-purity chiral compounds of the sulfonate analogue often need to be prepared and separated. However, due to the physicochemical properties or structural characteristics of the compound itself, the preparation or separation is often limited, the efficiency is low, the yield is not high, the cost is high, and industrial production cannot be realized. Therefore, how to obtain high-purity and high-yield chiral isomers of the compound sulfonate analogue through an industrialized preparation method is a technical problem that the chemical and pharmaceutical fields desire to solve.

[0003] The sulfonate analogue can be used as a key starting material for preparing a RET inhibitor and plays a key role in the preparation of the RET inhibitor. Patent WO2020228756A1 discloses a series of di-cyclic derivatives, which exhibit outstanding pharmacological properties and have strong inhibitory effect on RET kinase activity, but have poor inhibitory effect on KDR kinase activity. In addition, patent WO2024027690A1 discloses a preparation method of the sulfonate analogue. However, the preparation method of the compound in the patent is complex, especially the isomers are separated by chemical reagents, which not only has a long step but also has high cost and low total yield of the product, and is not suitable for industrial production. Therefore, how to obtain a preparation method of the sulfonate analogue which is simple in process, low in cost and high in yield and suitable for industrial production is a technical problem that the chemical industry needs to solve. SUMMARY

[0004] The present application provides a preparation method of a sulfonate analogue shown in formula SMB to solve the above technical problems.

[0005]

[0006] The preparation method mainly comprises the following steps:

[0007] A preparation method of a compound of formula B2-a, wherein the compound B1 is subjected to selective esterification with an enzyme to obtain the compound of formula B2-a.

[0008]

[0009] The reaction is carried out in an organic solvent, wherein the organic solvent is selected from one or more of methyl tert-butyl ether, isopropanol, tetrahydrofuran, toluene, ethyl acetate, acetonitrile, isopropyl ether, dioxane, and vinyl acetate, and preferably one or both of toluene and vinyl acetate.

[0010] said enzyme is selected from the group consisting of lipase, catalase, transaminase, racemase, epoxidase, preferably lipase.

[0011] said lipase is selected from the group consisting of phosphatase, solid sterolase or carboxylic esterase, preferably carboxylic esterase.

[0012] said lipase is selected from the group consisting of plant lipase, microbial lipase or animal lipase, preferably animal lipase, which can be porcine pancreatic lipase. The activity of the selected enzyme is 15-35 units / mg (unit is the activity unit of enzyme), as a preferred solution, the CAS number of the selected enzyme is 9001-62-1. As an example of commercial source, such as the enzyme with the product number L812481 of the Sigma-Aldrich reagent, the enzyme with the product number L874984 of the Sigma-Aldrich reagent, and the enzyme with the product number M95858 of the Merck company, those skilled in the art can understand that the same or similar enzyme as the above examples can be prepared by the current commercial enzyme extraction and preparation process, and can be applied to the preparation process of the present application.

[0013] The ratio Kg / Kg between the mass Kg of the lipase and the mass Kg of the compound B1 is 0.5:1-2:1, preferably 0.5:1-1.5:1, more preferably 1:1-1.5:1, further preferably 1:1.

[0014] The ratio L / Kg between the volume L of the toluene and the mass Kg of the compound B1 is 25:1-15:1, preferably 22:1-17:1, further preferably 20:1.

[0015] The ratio L / Kg between the volume L of the vinyl acetate and the mass Kg of the compound B1 is 6:1-2:1, preferably 5:1-3:1, further preferably 4:1.

[0016] The reaction temperature is 10-50°C, preferably 20-40°C, more preferably 25-35°C, further preferably 25-30°C.

[0017] In some embodiments of the present application, the above-mentioned compound B2-a is subjected to a sulfonylation reaction with compound A1 to generate compound B3;

[0018]

[0019] The solvent used for the compound B2-a is selected from the group consisting of dichloromethane, acetonitrile, toluene, tetrahydrofuran, ethyl acetate, dioxane, preferably dichloromethane;

[0020] The solvent used for the compound A1 is selected from the group consisting of dichloromethane, acetonitrile, toluene, tetrahydrofuran, ethyl acetate, dioxane, preferably dichloromethane;

[0021] The molar ratio of the compound B2-a to the compound A1 is 1:1-1:1.5, preferably 1:1-1:1.2, more preferably 1:1.

[0022] The catalyst used in the reaction is selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, preferably 4-dimethylaminopyridine.

[0023] In some embodiments of the present application, the above-mentioned B3 compound is reacted with an inorganic salt to obtain SMB after removing TMS;

[0024]

[0025] The inorganic salt used in the reaction is selected from potassium fluoride, cesium fluoride, sodium fluoride, tetrabutylammonium fluoride, preferably potassium fluoride.

[0026] The specific lipase, reaction solvent, reaction temperature and reaction ratio screened in the present application all achieve good experimental results, and the isomer content is low.

[0027] The preparation method of the present application, especially the isomer resolution by lipase, greatly reduces the production cost, improves the product yield, and greatly improves the process safety, and is suitable for industrial production. DETAILED DESCRIPTION

[0028] The following are specific embodiments of the present application, which are only illustrative and do not limit the scope of application of the present application

[0029] Example 1

[0030] First step: enzyme catalysis process

[0031]

[0032] 1) B1 20g was added to 400mL of toluene, 20g of lipase (L812481 or M95858 enzyme, CAS number 9001-62-1, enzyme activity needs to be maintained at 15-35 units / mg) and 80mL of vinyl acetate were added, and the internal temperature was kept at 25-30℃. After stirring for 30-35h, the target configuration of the product was obtained, 99.92%: isomer 0.08%, ee value 99.8%.

[0033] 2) The reaction solution was filtered to remove most of the carboxylate enzyme, and the filtrate was concentrated at 50-60℃ to obtain B2, 25g, of which the target product B2-a was 8g, with a mass yield of 40%.

[0034]

[0035] 1H NMR (400 MHz, DMSO) δ 5.21 (s, 1H), 4.84 (t, J = 6.2 Hz, 1H), 3.29 (dd, J = 6.2, 2.4 Hz, 2H), 1.27 (s, 3H), 0.13 (s, 9H).

[0036] ESI-MS (M+NH4) + : 190.1 m / z.

[0037] Second step: sulfonylation process

[0038]

[0039] 1) The product 25 g of the previous step was dissolved in DCM 125 mL, DMAP 11.3 g was added, and the temperature was lowered to 0-10 °C, and stirred for 20 min;

[0040] 2) After dissolving 10.5 g of naphthalene sulfonyl chloride in 60 mL of DCM, it was slowly added to the reaction solution, and the temperature was controlled <10 °C during the addition process. After the addition was completed, the reaction solution was stirred at 0-10 °C for 2 h, and TLC (EA: PE = 1:5) was used for monitoring.

[0041] The TLC showed that there was no remaining product from the previous step;

[0042] 3) The reaction solution was filtered, and the filter cake was washed with DCM twice, 10 mL*2. The filtrate was added to 170 mL of 1M aqueous hydrochloric acid solution, and the organic phase was extracted. The organic phase was further washed with water twice, 170 mL*2;

[0043] 4) The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to obtain 65 g of crude product B3, which was directly used for the next step.

[0044]

[0045] 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 1.9 Hz, 1H), 8.26 (dd, J = 8.2, 1.4 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.15-8.10 (m, 1H), 7.88 (dd, J = 8.7, 2.0 Hz, 1H), 7.76 (m, J = 21.1, 8.2, 6.9, 1.4 Hz, 2H), 5.89 (s, 1H), 3.91 (s, 2H), 1.29 (s, 3H), 0.08 (s, 9H).

[0046] ESI-MS (M+NH4) + : 380.22 m / z.

[0047] Third step: hydrolysis process

[0048]

[0049] 1) Reactor was charged with 65 g of the product from previous step, dissolved in 325 mL of solvent methanol, and 31.4 mL of concentrated hydrochloric acid was added slowly, stirred at room temperature overnight.

[0050] 2) TLC (EA:PE = 1:5) showed that the starting material was substantially completely converted, 325 mL of DCM and 325 mL of water were added to extract, the aqueous phase was added to 325 mL of DCM to extract, the organic phase was combined, the organic phase was washed with 325 mL of water, and the crude product B3 was obtained by concentration, 53 g, which was directly used.

[0051] Fourth step: TMS removal process

[0052]

[0053] 1) The crude product from the previous step, 53 g, was added to the reaction bottle, 100 mL of solvent DMF was added, and 13.9 g of acetic acid was added, and stirred at room temperature;

[0054] 2) KF 6.8 g was dissolved in 100 mL of water, added to the reaction solution, stirred at 25-30°C for 12-15 h, and then controlled, the starting material was completely converted and the TMS was removed, the reaction solution was extracted with 400 mL of EA and 400 mL of water to obtain the organic phase, the aqueous phase was extracted with 200 mL of EA once, the organic phase was combined, washed with 200 mL*2 of water twice, and dried with anhydrous sodium sulfate, and the organic phase was concentrated, and dried at room temperature under vacuum overnight to obtain the crude product 12.8 g;

[0055] 3) The crude product was purified: 11 mL of DCM was added, and the solution was clarified at 50°C, 120 mL of n-hexane was added dropwise, and the solid was precipitated, and the slurry was continued at 50°C for 0.5-1 h, and then the slurry was continued at 10-20°C for 1-2 h, and the solid was dried after filtration to obtain 8.8 g, the total molar yield of the three steps was 65.2%, the mass yield was 109.9%, the target configuration was 99.92%, the isomer was 0.08%, and the ee value was 99.8%.

[0056]

[0057] 1 H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.89 (dd, J = 8.7, 2.0 Hz, 1H), 7.82-7.71 (m, 2H), 5.88 (s, 1H), 3.91 (s, 2H), 1.29 (s, 3H).

[0058] ESI-MS: 207.0 m / z.

[0059] Example 2

[0060] Screening of enzymes for resolution of compound of formula B2-a

[0061] The following lipases were screened: enzyme No. 1, Macrolin part No. L812480 (enzyme activity 100 units / mg), enzyme No. 2, Macrolin part No. L874984 (enzyme activity 20 units / mg), enzyme No. 3, Sigma part No. L3126 (enzyme activity > 125 units / mg), enzyme No. 4, Macrolin part No. L812481 (enzyme activity 15-35 units / mg), with other parameters fixed, vinyl acetate (4 v), catalyst: lipase (100%, mass ratio), reaction system: methyl tert-butyl ether (20 v), and the results are shown in Table 1:

[0062] Table 1 Screening of enzyme-catalyzed lipase types

[0063] No. Enzyme No. Reaction temperature / °C Reaction time / h Isomer content / % 1 Enzyme No. 1 30 24 20 2 Enzyme No. 2 30 24 3.0 3 Enzyme No. 3 30 24 80 4 Enzyme No. 4 30 24 0.3

[0064] As can be seen from Table 1, a total of four common lipases on the market were screened, and the reaction was carried out at 30°C for 24 h, among which enzymes No. 2 and No. 4 had better reaction effects, and the isomer content was below 5%, so enzymes No. 2 and No. 4 were selected as the catalysts for enzyme catalysis.

[0065] Example 3

[0066] Effect of reaction temperature on resolution of compound of formula B2-a with enzymes

[0067] With other reaction parameters fixed, vinyl acetate (4 v), catalyst: lipase (enzyme No. 4, 100%, mass ratio), reaction system: methyl tert-butyl ether (20 v), reaction temperature (25°C, 30°C, 35°C, 40°C, 50°C) was screened in parallel, and the results are shown in Table 2.

[0068] Table 2 Screening of reaction temperature

[0069]

[0070]

[0071] As can be seen from Table 2, the reaction was carried out at different temperatures for 24 h, and good experimental effects were achieved at each temperature, and the isomer content was below 5%. When the reaction temperature was 25-35°C, the isomer content was stable, and the content was about 0.3%.

[0072] Example 4

[0073] Effect of reaction solvent on enzymatic resolution of compound of formula B2-a

[0074] Fixing other parameters, vinyl acetate (4v), catalyst: lipase (enzyme No. 4, 100%, mass ratio), reaction temperature: 30℃, parallel screening of reaction solvent, and the results are shown in Table 3.

[0075] Table 3 Screening of reaction solvent

[0076]

[0077] As can be seen from Table 3, the screened solvent of the present application achieves good experimental results, and the isomer content is low, especially methyl tert-butyl ether, toluene and isopropyl ether, and the isomer content is below 0.5%.

[0078] Example 5

[0079] Effect of reaction ratio on enzymatic resolution of compound of formula B2-a

[0080] Fixing other parameters, catalyst: lipase (enzyme No. 4), reaction system: toluene (20v), parallel screening of vinyl acetate and lipase dosage, and the results are shown in Table 4.

[0081] Table 4 Screening of vinyl acetate and lipase dosage

[0082]

[0083] As can be seen from Table 4, under the condition of 30℃ for 24h, different reaction ratios of enzyme No. 4 and vinyl acetate all achieve good experimental results, especially when the enzyme dosage is 1.0 (mass ratio) and the vinyl acetate dosage is 4.0 (volume ratio), the isomer content is low, and the product content is high.

Claims

1. Process for the preparation of a compound of formula B2-a, characterized in that, Compound B1 is subjected to selective esterification reaction in the presence of an enzyme to obtain compound B2-a; The reaction is carried out in an organic solvent selected from one or more of methyl tert-butyl ether, isopropyl alcohol, tetrahydrofuran, toluene, ethyl acetate, acetonitrile, isopropyl ether, dioxane, vinyl acetate, preferably one or both of toluene and vinyl acetate.

2. The process for the preparation of a compound of formula B2-a according to claim 1, characterized in that, Compound B2-a is subjected to sulfonylation reaction with compound A1 to obtain compound B3; wherein R1is selected from a phenyl or naphthalene ring group, optionally the phenyl or naphthalene ring group can be further substituted by C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, nitro or halo.

3. The process for the preparation of a compound of formula B2-a according to claim 2, characterized in that, Compound B3 is reacted with an inorganic salt to obtain SMB after removing TMS; 4. The process of claim 1 for the preparation of a compound of formula B2-a, wherein The enzyme is selected from lipase, catalase, transaminase, racemase, epoxidase, preferably lipase; More preferably, the lipase is selected from plant lipase, microbial lipase or animal lipase, preferably animal lipase, more preferably animal lipase with enzyme activity of 15-35 units / mg, further preferably porcine pancreas lipase with enzyme activity of 15-35 units / mg, or preferably lipase with CAS number 9001-62-1.

5. The process of claim 1 for the preparation of a compound of formula B2-a, wherein The mass ratio of the lipase to compound B1 is 0.5:1-2:1, preferably 0.5:1-1.5:1, more preferably 1:1-1.5:1, further preferably 1:1; Preferably, the volume to mass ratio of toluene to compound B1 is 25:1-15:1, preferably 22:1-17:1, further preferably 20:1; Preferably, the volume to mass ratio of vinyl acetate to compound B1 is 6:1-2:1, preferably 5:1-3:1, further preferably 4:

1.

6. The process of claim 1 for the preparation of a compound of formula B2-a, wherein The reaction temperature is 10-50℃, preferably 20-40℃, further preferably 25-30℃.

7. The process of claim 2 for the preparation of a compound of formula B2-a, wherein A catalyst is also used in the reaction, wherein the catalyst is selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, preferably 4-dimethylaminopyridine.

8. The process of claim 2 for the preparation of a compound of formula B2-a, wherein The molar ratio of compound B2-a to compound A1 is 1:1-1:1.5, preferably 1:1-1:1.2, more preferably 1:

1.

9. The process of claim 3 for the preparation of a compound of formula B2-a, wherein The step (c) is carried out in the presence of an inorganic salt, wherein the inorganic salt is selected from potassium fluoride, cesium fluoride, sodium fluoride, tetrabutylammonium fluoride, preferably potassium fluoride.

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