A preparation method of anlotinib intermediate

Abstract

The present invention belongs to the field of pharmaceutical synthesis, and relates to a preparation method of an intermediate of anlotinib, specifically to a preparation method of the compound of formula IV, an intermediate of anlotinib. This preparation method significantly improves the yield of the compound of formula IV while reducing the feed amount of raw materials and the reaction temperature, and is suitable for industrial application.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis and relates to a method for preparing anlotinib intermediate. Background Art

[0002] Anlotinib Hydrochloride is a new type of small molecule multi-target tyrosine kinase inhibitor that can effectively inhibit multiple kinases such as VEGFR, PDGFR, FGFR, c-Kit, Met, etc., and has the effects of anti-tumor angiogenesis and inhibiting tumor growth. In 2015, it was granted orphan drug qualification for the treatment of ovarian cancer by the US FDA. Currently, clinical trials for various cancers are underway, including non-small cell lung cancer, soft tissue sarcoma, gastric cancer, colorectal cancer, medullary thyroid cancer, differentiated thyroid cancer, and esophageal squamous cell carcinoma, which have great market prospects. The structural formula of Anlotinib Hydrochloride is shown below:

[0003]

[0004] At present, the prior art discloses a number of synthetic routes of anlotinib. Among them, CN107771078A discloses that (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (compound of formula I) is subjected to condensation reaction and deprotection reaction to finally obtain anlotinib. The reaction route is as follows:

[0005]

[0006] In the reaction process, the compound of formula IV is a key intermediate, and its synthesis quality directly affects the synthesis efficiency and purity of anlotinib, and ultimately affects the quality of the product anlotinib hydrochloride. In the prior art, during the synthesis of the compound of formula IV, the feed amount of the reactant compound of formula II is relatively high (the molar ratio of the feed amount of the compound of formula I to the compound of formula II reaches about 1:2.5), the reaction temperature is high (reaching 80°C), and the reaction efficiency is low (the conversion rate of the compound of formula I is less than 50%), which significantly increases the production cost. Summary of the invention

[0007] In view of the above technical problems, the present invention improves the synthesis of the compound of formula IV, thereby achieving an increase in the conversion rate of the compound of formula I while reducing the feed amount of the compound of formula II and the reaction temperature, greatly improving the reaction yield, and being suitable for industrial application.

[0008] The present invention provides a method for synthesizing a compound of formula IV, comprising the following steps:

[0009] 1) In the presence of a base, the compound of formula II is subjected to an iodination reaction with an iodine reagent in an organic solvent to obtain a compound of formula III;

[0010] 2) Add the compound of formula I to the compound of formula III, and carry out a condensation reaction to obtain the compound of formula IV.

[0011]

[0012] Wherein, R is selected from H and C1-C6 alkoxy; in some embodiments, R is H.

[0013] Furthermore, the base in step 1) is an organic base.

[0014] In some embodiments, the organic base can be selected from any one or more of DIPEA, DMAP, trimethylamine, dimethylamine, triethylamine, diethylamine, tripropylamine, tributylamine, DABCO, DBU; in some preferred embodiments, the organic base is DIPEA.

[0015] Furthermore, the iodinating reagent in step 1) is selected from KI, NaI; in some preferred embodiments, the iodinating reagent is NaI.

[0016] In some embodiments, the organic solvent in step 1) is selected from DMF, acetone, DMSO, THF, DEM, HMPT, acetonitrile, NMP, DMI, DMPU; in some preferred embodiments, the organic solvent is acetone.

[0017] Furthermore, during the reaction processes of step 1) and step 2), the reaction temperature is controlled at 35-65 °C; in some preferred embodiments, the reaction temperature is controlled at 40-60 °C; in some most preferred embodiments, the reaction temperature is controlled at 50-60 °C.

[0018] In some embodiments, after adding the compound of formula I in step 2), a base scavenger is further added for reaction.

[0019] Furthermore, the base scavenger is selected from any one or more of triethylamine, DIEA, pyridine, DIPEA, DMAP, triethanolamine, tetrabutylammonium bromide, sodium acetate, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydroxide; in some preferred embodiments, the base scavenger is potassium carbonate.

[0020] In a specific embodiment, a method for synthesizing the compound of formula IV is provided, which comprises the following steps:

[0021]

[0022] 1) React the compound of formula II with NaI and DIPEA in acetone at a temperature controlled at 50-60 °C for 2-3 h to obtain the compound of formula III.

[0023] 2) Add the compound of formula I and potassium carbonate to the compound of formula III, and in a mixed solution of acetone and water, control the temperature at 50-60 °C and react for 15-30 h to obtain the compound of formula IV.

[0024] Furthermore, in the step 1), the molar ratio of the compound of formula II to NaI and DIPEA in the feed amount is 1:(1.2-2.0):(1.5-3.0), and in the step 2), the molar ratio of the compound of formula I to the compound of formula III and potassium carbonate in the feed amount is 1:(1.2-1.6):(3.0-6.0); in some preferred embodiments, in the step 1), the molar ratio of the compound of formula II to NaI and DIPEA in the feed amount is 1:1.5:2.0, and in the step 2), the molar ratio of the compound of formula I to the compound of formula III and potassium carbonate in the feed amount is 1:1.5:5.

[0025] Abbreviations and Definitions

[0026] For ease of reference, the following abbreviations are used and the abbreviations have the following meanings.

[0027] DIPEA: Diisopropylethylamine; DMAP: 4-N,N-Dimethylaminopyridine; DABCO: 1,4-Diazabicyclo[2.2.2]octane; DBU: 1,8-Diazabicycloundec-7-ene; KI: Potassium iodide; NaI: Sodium iodide; DMF: Dimethylformamide; THF: Tetrahydrofuran; DEM: Diethylene glycol monomethyl ether; HMPT: Hexamethylphosphoric triamide; NMP: N-Methylpyrrolidone; DMI: 1,3-Dimethyl-2-imidazolidinone; DMPU: 1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone.

[0028] "Organic base" refers to an organic compound that can provide electrons, including Lewis bases in organic compounds, including but not limited to DIPEA, DMAP, trimethylamine, dimethylamine, triethylamine, diethylamine, tripropylamine, tributylamine, DABCO, DBU.

[0029] "Iodinating reagent" is a reagent that provides iodine element for iodination reaction, including but not limited to KI, NaI.

[0030] "C1-C6 alkoxy" includes 1 to 6 saturated monovalent hydrocarbon groups having a straight-chain or branched-chain portion, including (but not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

[0031] "Acid-binding agent" is an organic base or inorganic base that can neutralize the acid generated by the reaction, including but not limited to triethylamine, DIEA, pyridine, DIPEA, DMAP, triethanolamine, tetrabutylammonium bromide, sodium acetate, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydroxide.

[0032] In the prior art, the preparation of the compound of Formula IV adopts a one-step reaction. However, due to the poor stability of the compound of Formula II itself, the compound of Formula II needs to be additionally added during the reaction process. And even if the feeding amount of the compound of Formula II is increased, the reaction efficiency is not high, only reaching about 50%.

[0033] The present invention provides a method for preparing the compound of Formula IV, an intermediate of anlotinib. This preparation method disassembles the synthesis of the compound of Formula IV into two-step reactions. First, the compound of Formula II undergoes an iodination reaction to obtain a more stable compound of Formula III, and then the compound of Formula III continues to react to obtain the compound of Formula IV. In addition, the present invention also provides a method for efficiently obtaining the compound of Formula III. Through the preparation method provided by the present invention, the yield of the compound of Formula IV can be significantly improved while reducing the feeding amount of the compound of Formula II and the reaction temperature, reducing the production cost, and being suitable for industrial application. Detailed implementation manners

[0034] The beneficial effects of the present invention are further described through the following examples, which should be understood that they are only examples and do not limit the present invention.

[0035] Example 1: Preparation of benzyl ((1-(iodomethyl)cyclopropyl)carbamate)

[0036]

[0037] Add acetone (200 mL), the compound of Formula II-1 (26.6 g, 88.9 mmol), NaI (20.0 g, 133.3 mmol), and DIPEA (23.0 g, 178.0 mmol) to a reaction flask, stir evenly, control the reaction temperature at 53 - 60 °C, reflux for 3 h, and detect that the reaction is complete to obtain the compound of Formula III-1, which is a thick substance.

[0038] Example 2: Preparation of benzyl 1-(((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)carbamate

[0039]

[0040] Cool the above reaction solution to room temperature, add acetone (200 mL), the compound of Formula I (20.0 g, 59.1 mmol), potassium carbonate (40.8 g, 295.2 mmol), and purified water (2 mL), stir evenly, control the reaction temperature at 53 - 60 °C, react for 8 - 16 h, monitor the reaction by HPLC until it is basically complete. After the reaction, control the water bath temperature at 30 - 40 °C and concentrate under reduced pressure to dryness to obtain the crude product of the compound of Formula IV-1.

[0041] Example 3: Purification of Benzyl 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate

[0042] To the crude product of the compound of Formula IV-1, 9 times the amount of purified water and 1 time the amount of absolute ethanol were added. After stirring at 55 - 65 °C for 1 h, filtration was carried out and the filter cake was collected; the above filter cake was added to a reaction flask, 10 times the amount of purified water was added and stirred evenly, then stirred at 55 - 65 °C for 1 h, filtered, and the filter cake was collected; 5 times the amount of absolute ethanol was added to the reaction flask, the filter cake from the previous step was added to the reaction flask and stirred evenly, then stirred at 70 - 78 °C for 1 h, cooled, and stirred at -5 - 5 °C for 6 h, filtered, and the filter cake was collected; the filter cake was slurried with 3 times the amount of absolute ethanol for 1 h, filtered, and the filter cake was collected again; the filter cake was dried in vacuo at 75 - 85 °C for 4 h, and the material was collected when the loss on drying was less than 1.0%. Finally, 30.5 g of the compound of Formula IV-1 was obtained, with a yield of 95.3%. By HPLC detection, the purity reached 99.2%.

[0043] Example 4: Effect of Different Bases on the Preparation Efficiency of Benzyl (1-(iodomethyl)cyclopropyl)carbamate

[0044]

[0045]

[0046] Under the condition of keeping other reaction conditions the same, the effects of different bases (including inorganic bases: potassium carbonate, cesium carbonate; organic base: DIPEA) on the preparation of the compound of Formula III-1 were studied. It was found that using an organic base, especially DIPEA, could significantly improve the conversion rate of the substrate (the compound of Formula II-1), as shown in the above table.

Claims

1. A method for synthesizing a compound of formula IV, which comprises, Step 1): In the presence of a base, the compound of formula II reacts with an iodinating reagent in an organic solvent to obtain a compound of formula III, and the base is an organic base; Step 2): Add the compound of formula I to the compound of formula III and carry out a condensation reaction to obtain a compound of formula IV, characterized in that, after adding the compound of formula I, continue to add an acid-binding agent for the reaction; wherein, R is selected from H and C1-C6 alkoxy.

2. The method for synthesizing a compound of formula IV according to claim 1, wherein R is H.

3. The method for synthesizing a compound of formula IV according to claim 1, characterized in that, the organic base is selected from any one or more of DIPEA, DMAP, trimethylamine, dimethylamine, triethylamine, diethylamine, tripropylamine, tributylamine, DABCO, or DBU.

4. The method for synthesizing a compound of formula IV according to claim 3, wherein the organic base is DIPEA.

5. The method for synthesizing a compound of formula IV according to claim 1, characterized in that, the iodinating reagent in step 1) is selected from KI or NaI.

6. The method for synthesizing a compound of formula IV according to claim 5, wherein the iodinating reagent is NaI.

7. The method for synthesizing a compound of formula IV according to claim 1, characterized in that, the organic solvent in step 1) is selected from DMF, acetone, DMSO, THF, DEM, HMPT, acetonitrile, NMP, DMI, or DMPU.

8. The method for synthesizing a compound of formula IV according to claim 7, wherein the organic solvent is acetone.

9. The method for synthesizing a compound of formula IV according to claim 1, characterized in that, during the reaction processes of step 1) and step 2), control the reaction temperature at 35-65 °C.

10. The method for synthesizing a compound of formula IV according to claim 9, wherein the reaction temperature is 40-60 °C.

11. The method for synthesizing a compound of formula IV according to claim 9, wherein the reaction temperature is 50-60 °C.

12. The method for synthesizing a compound of formula IV according to claim 1, characterized in that, the acid-binding agent is selected from any one or more of triethylamine, DIEA, pyridine, DIPEA, DMAP, triethanolamine, tetrabutylammonium bromide, sodium acetate, sodium carbonate, potassium carbonate, ammonium carbonate, or sodium hydroxide.

13. The method for synthesizing a compound of formula IV according to claim 1, characterized in that, the organic base in step 1) is DIPEA, the iodinating reagent is NaI, and the acid-binding agent in step 2) is potassium carbonate.

14. The method for synthesizing a compound of formula IV according to claim 13, characterized in that, in step 1), the molar ratio of the compound of formula II to NaI and DIPEA in the feed is 1:(1.2-2.0):(1.5-3.0), and in step 2) the molar ratio of the compound of formula I to the compound of formula III and potassium carbonate in the feed is 1:(1.2-1.6):(3.0-6.0).

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