A process for the synthesis of a pharmaceutical intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a medicine intermediate. The synthesis method takes compound A as a starting material, and obtains target product H through four steps of acyl chlorination, substitution, condensation and reduction. The synthesis route is low in raw material cost, easy to obtain, few in reaction steps, simple in operation process, low in reaction condition, low in cost, and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine synthesis, and more particularly to the synthesis of a medicine intermediate. BACKGROUND

[0002] Larotrectinib molecule as a small molecule inhibitor of tropomyosin receptor kinase (TRK) has strong selectivity to TRK, and at present, studies have modified it into a PET imaging molecule, such as a F-labeled larotrectinib molecular probe reported in patent CN109705124B. 18 The metabolic distribution of the Larotrectinib molecule targetable observation probe in vivo is observed to evaluate the status of solid tumors and the treatment effect or post-treatment status.

[0003]

[0004] At present, there are three synthetic routes for larotrectinib. ① Patent US8513263 uses pyrrolidine-1-carboxylic tert-butyl ester as a raw material, and through substitution, nitration, reduction, and reaction with (S)-3-hydroxypyrrolidine, larotrectinib is obtained, with a total yield of only 18%, and expensive (-)-delphinidin, palladium acetate and other reagents are used in the synthesis, the synthesis cost is high, and low-temperature reaction is involved. ② Qiu Xianhua et al. use 2,5-difluorobenzaldehyde and (R)-tert-butylsulfinamide as raw materials, and through 9 steps, larotrectinib is obtained. This route has a long synthesis step, many by-products, complicated operation and difficult to obtain raw materials, and high industrialization cost. ③ Patent CN107987082A uses 5-chloro-3-nitropyrazolopyrimidine as a raw material, and through reduction, acylation, and nucleophilic substitution reaction, larotrectinib is obtained. The reduction process uses a zinc powder-hydrochloric acid reduction system, which not only increases the corrosion of the equipment, but also pollutes the environment, and is not suitable for large-scale production. SUMMARY

[0005] The present application aims to provide a novel synthesis method for a key intermediate of larotrectinib, (S)-N-{5-[(R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-amino (i.e. compound H).

[0006]

[0007] The object of the present application can be achieved by the following technical solutions:

[0008] A synthesis method of a medicine intermediate, the specific method is as follows:

[0009] (1) compound A is subjected to acyl chloride reaction to obtain compound B,

[0010]

[0011] wherein the compound A is reacted with a chlorinating agent under the action of a catalyst to obtain compound B.

[0012] Further, the molar ratio of the reaction of the compound A with the chlorinating agent is 1:1-1.5.

[0013] Further, the catalyst is dimethylformamide; the chlorinating agent is selected from one of oxalyl chloride, thionyl chloride or dichlorosulfoxide; the reaction solvent is selected from one of dichloromethane, diethyl ether, benzene, tetrahydrofuran, chloroform, acetonitrile or toluene; and the reaction temperature is 0-50°C.

[0014] Preferably, the chlorinating agent is oxalyl chloride, the reaction solvent is dichloromethane, and the reaction temperature is 10-30°C.

[0015] (2) compound B is reacted with compound C to obtain compound D,

[0016]

[0017] wherein the compound B is reacted with the compound C under alkaline conditions.

[0018] Further, the molar ratio of the reaction of the compound B, the compound C and the base is 1:1-2:1-2.

[0019] Further, the base is triethylamine or diisopropylethylamine; the reaction solvent is selected from one or two of dichloromethane, tetrahydrofuran, ethanol or benzene; and the reaction temperature is -20°C-20°C.

[0020] Preferably, the molar ratio is 1:1.5:1.5, the base is triethylamine, the reaction solvent is dichloromethane, and the reaction temperature is 0-10°C.

[0021] (3) compound D is condensed with compound F to obtain compound G,

[0022]

[0023] wherein the compound D is condensed with the compound F in an alcohol solution.

[0024] Further, the molar ratio of the reaction of the compound D with the compound F is 1:1-1.5, and the reaction temperature is 50-90°C.

[0025] Preferably, the molar ratio is 1:1, the alcohol is ethanol, and the reaction temperature is 70-80°C.

[0026] 4) compound G is reduced to obtain product H,

[0027]

[0028] The reducing condition is iron powder-ammonium chloride system, iron powder-acetic acid system or palladium carbon / H2 system.

[0029] Further, when the iron powder-ammonium chloride system is used, alcohol and water are used as solvents, and the reaction is refluxed under nitrogen protection for 4-8 h; when the iron powder-acetic acid system is used, water is used as solvent, and the reaction is stirred at room temperature for 3-4 h; when the palladium carbon / H2 system is used, alcohol is used as solvent at room temperature, 5% palladium / carbon catalyst is added, and the reaction is carried out under hydrogen for 12 h.

[0030] Preferably, the alcohol is methanol or ethanol.

[0031] The present application discloses a novel synthesis method of a laroitinib intermediate, which can obtain the target product H from compound A through acyl chloride, substitution, condensation and reduction. DETAILED DESCRIPTION

[0032] The features and properties of the present application are further described in detail below in combination with examples. The specific conditions not mentioned in the examples are carried out according to conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments not mentioned by the manufacturer are conventional products that can be purchased on the market.

[0033] The features and properties of the present application are further described in detail below in combination with examples.

[0034] Example 1

[0035] 1) Synthesis of compound B

[0036]

[0037] In a 50 mL round-bottom flask, compound A (2.5 mmol), oxalyl chloride (3.2 mmol), 0.5 mL of dimethylformamide and 20 mL of dichloromethane were sequentially added, and the reaction was carried out at room temperature for 30 min. The reaction was monitored by TLC, and after the reaction was completed, compound B was obtained by concentration under reduced pressure, with a yield of 95%.

[0038] 2) Synthesis of compound D

[0039]

[0040] In a 50 mL round bottom flask, compound B (2 mmol) and triethylamine (3 mmol) were added in sequence, dissolved in 10 mL of dichloromethane, and a solution of compound C (3 mmol) in 10 mL of dichloromethane was slowly added dropwise under ice water bath conditions. After the addition was completed, stirring was continued for 3 h, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was quenched with methanol and evaporated under reduced pressure. Compound D was obtained by purification, with a yield of 83%.

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.38 (m, 1H), 7.23 (m, 3H), 6.08 (d, J =15.0 Hz, 1H), 5.01 (m, 1H), 3.69 (m, 2H), 3.06 (d, J = 1.1 Hz, 6H), 2.14 –2.03 (m, 2H), 1.96 – 1.80 (m, 2H)。

[0042] 3) Synthesis of compound G

[0043]

[0044] Compound D (1.5 mmol) and compound F (1.5 mmol) were refluxed in 200 mL of ethanol for 6 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, and compound G was obtained by purification, with a yield of 75%.

[0045] 4) Synthesis of product H

[0046]

[0047] Compound G (1 mmol) was dissolved in 2 mL of acetic acid and 1 mL of water, and then iron powder (3 mmol) was added. Stirring was performed at room temperature for 3 h, and the reaction was monitored by TLC. After the reaction was completed, the pH of the reaction mixture was adjusted to 8 using a sodium hydroxide solution, and then ethyl acetate was added to filter the mixture using diatomite. The organic phase was washed with water, and product H was obtained by concentration, with a yield of 94%.

[0048] LC-MS: [M / 2+H] + = 158.60

[0049] 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 7.9 Hz, 1H), 7.88 (s, 1H), 7.36(m, 1H), 7.22 (m, 1H), 7.17 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 5.91 (d, J =7.5 Hz, 1H), 5.67 (d, J = 7.3 Hz, 1H), 5.14 – 5.07 (m, 1H), 3.78 – 3.64 (m,2H), 2.12 – 1.93 (m, 4H)。

[0050] Example 2

[0051] 1) Preparation of compounds B, D, G according to Example 1.

[0052] 2) Synthesis of product H

[0053]

[0054] Compound G (1 mmol), iron powder (10 mmol) were added to 250 mL of ethanol, nitrogen was bubbled, heated to reflux, while dropwise adding ammonium chloride (10 mmol) in 250 mL of water, dropwise in 1 h, continue refluxing for 6 h, TLC monitoring reaction. Reaction was completed, concentrated under reduced pressure, the concentrate was diluted with water, extracted with dichloromethane 3 times, the organic phase was combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give product H, yield 90%.

[0055] Example 3

[0056] 1) Preparation of compounds B, D, G according to Example 1.

[0057] 2) Synthesis of product H

[0058]

[0059] Compound G (1 mmol) was added to 20 mL of ethanol solution, 5% palladium / carbon catalyst (0.1 mmol) was added under N2, then the mixture was stirred at room temperature under hydrogen atmosphere for 12 h. The reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, purified to give product H, yield 85%.

[0060] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method of synthesis of a pharmaceutical intermediate, characterized by, The synthesis steps are: 1) acyl chlorination reaction of compound A to obtain compound B, 2) reaction of compound B with compound C to obtain compound D, 3) condensation of compound D with compound F to obtain compound G, 4) reduction of compound G to obtain product H, 。 2. The method of synthesis of claim 1, wherein, In step (1), compound A reacts with a chlorinating agent under the action of a catalyst to obtain compound B; the reaction solvent is selected from one of dichloromethane, diethyl ether, benzene, tetrahydrofuran, chloroform or toluene.

3. The method of synthesis of claim 2, wherein, The catalyst is dimethylformamide; the chlorinating agent is selected from one of oxalyl chloride, thionyl chloride or dichlorosulfoxide.

4. The method of synthesis of claim 1, wherein, In step (2), compound B reacts with compound C under alkaline conditions; the reaction solvent is selected from one or two of dichloromethane, tetrahydrofuran, ethanol or benzene.

5. The method of synthesis of claim 4, wherein, The base is triethylamine or diisopropylethylamine.

6. The method of synthesis of claim 1, wherein, In step (3), compound D reacts with compound F in an alcohol solution to condense.

7. The method of synthesis of claim 6, wherein, The alcohol is ethanol.

8. The method of synthesis of claim 1, wherein, The reduction conditions of step (4) are iron powder-ammonium chloride system, iron powder-acetic acid system or palladium on carbon / H2 system.

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