Preparation method of a lenvatinib intermediate

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a lenvatinib intermediate. The present invention uses tert-butyl cyclopropylcarbamate as the starting material, and reacts with 4-amino-3-chlorophenol under the action of a catalyst to obtain the key intermediate of lenvatinib, 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea. This preparation method effectively avoids the use of reagents with strong toxicity such as chloroformate, making the reaction operation safer and more suitable for industrial scale-up production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a lenvatinib intermediate. Background Art

[0002] Lenvatinib (alias E7080), with the chemical name of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, is an oral multi-receptor tyrosine kinase inhibitor developed by Eisai Co., Ltd. in Japan. It was first launched in the United States on February 13, 2015, under the trade name Clinically, it is used for the treatment of aggressive, locally advanced or metastatic differentiated thyroid cancer, non-small cell lung cancer and potential treatment of other solid tumors. It was approved for marketing in China in September 2018 and began to be used for the first-line treatment of unresectable hepatocellular carcinoma (HCC), thus breaking the monopoly of sorafenib and adding another treatment option for unresectable HCC. Therefore, lenvatinib has great market prospects. Its chemical structural formula is as follows:[[]]

[0003]

[0004] At present, there are many disclosed synthetic processes for lenvatinib. Among them, US Patent No. US7253286 uses 3-chloro-4-cyanoaniline as a raw material, which is methyl etherified and then condensed with Meldrum's acid, heated and closed-loop in a biphenyl-diphenyl ether mixed solvent, and then hydrolyzed, chlorinated and ammoniated to obtain the key intermediate 4-chloro-7-methoxyquinoline-6-carboxamide. Using 3-chloro-4-aminophenol and phenyl chloroformate as starting materials, and then through an acylation reaction to obtain phenyl N-(2-chloro-4-hydroxyphenyl)carbamate, and then forming a urea with cyclopropylamine to obtain the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I). Finally, the two intermediates are catalyzed by potassium tert-butoxide to obtain the target compound lenvatinib. The synthetic route is as follows:[[]]

[0005]

[0006] As can be seen from the above, 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) can be used as a key intermediate for the preparation of lenvatinib in the above process. Therefore, 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) can directly affect the production, market supply and quality of this drug. The specific structural formula is as follows:[[]]

[0007]

[0008] In addition, Patent EP1683785A1, EP1698623A1, EP1797881A1, US7683172B2, WO2005044788, WO2006137474, CN100450998C, CN109456267A, CN101337930B and the literature "Synthesis of Lenvatinib", Chinese Journal of Medicinal Chemistry, 2015, 25(4): 285 - 288, "Synthesis of Lenvatinib", Chinese Journal of Pharmaceutical Industry, 2014, 45(6): 507 - 510, etc. all prepare the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) by the above method.

[0009] In addition, the literature "Improvement of the Synthetic Process of Receptor Tyrosine Kinase Inhibitor Lenvatinib", Chinese Journal of Medicinal Chemistry, 2016, 26(1): 29 - 32 extended the above process: starting from sulfanilic acid, first preparing a diazonium salt intermediate and then coupling it with m-chlorophenol and reducing it with zinc powder to obtain the intermediate 3-chloro-4-aminophenol, and then preparing the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) according to the above strategy. Although this method can successfully synthesize 4-amino-3-chlorophenol, the product yield is not high, the reaction conditions are harsh, it is easy to spray materials during the reaction, the intermediate products are easy to decompose and deteriorate, and 4-amino-3-chlorophenol is easy to oxidize and deteriorate during the purification process, making it not easy to operate. The synthetic route is as follows:

[0010]

[0011] The literature "Improvement of the Synthetic Process of Anticancer Drug Lenvatinib", Chemistry & Bioengineering, 2018, 35(10): 12 - 15 uses p-nitrophenyl chloroformate to activate the amino group and then prepares the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I). The synthetic route is as follows:

[0012]

[0013] However, the above routes all use chloroformates with certain toxicity to construct the urea functional group. Chloroformates not only have high toxicity, but are also not easily available in the market, and their preparation is relatively complex. Moreover, this route will produce phenol with relatively high toxicity in the subsequent reaction.

[0014] To solve the above problems and avoid the use of chloroformate, Chinese Patent Application CN109734661A discloses the following process: The related public process also uses 4-hydroxy-2-chloroaniline as the starting material, but first forms 4-hydroxy-2-chlorocyanamide with cyanogen bromide at low temperature, and then reacts 4-hydroxy-2-chlorocyanamide with propyl bromide at 100 °C for 8 h to synthesize the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) through the Ritter reaction. However, the overall yield of this route is relatively low, only 86%, and the related material cyanogen bromide is expensive, resulting in high production costs and difficult industrial scale-up production. The synthetic route is as follows:

[0015]

[0016] In summary, in view of the current preparation methods of the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) of lenvatinib having many deficiencies in terms of process safety, low yield, and high production costs. Therefore, it is still a problem to be solved at present to find a reaction route suitable for industrial production of the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) of lenvatinib with mild reaction conditions, simple operation process, high product yield, high purity, and low production cost. Summary of the Invention

[0017] Aiming at the problems existing in the current preparation technology of the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I) of lenvatinib, the present invention provides a new synthesis method of the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea of lenvatinib. This method can effectively avoid the above technical problems, and the obtained target product has high purity and yield, and is suitable for industrial production.

[0018] The specific technical solution of the present invention is as follows:

[0019]

[0020] A preparation method of the key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea of lenvatinib, comprising the following steps:

[0021] At room temperature, add the compound SM-1, base, and acid anhydride to an organic solvent, control the temperature at T1 for reaction. After detecting that the compound SM-1 has reacted completely, add triethylamine and the compound SM-2, continue to control the temperature at T1 for reaction. After detecting that the reaction is complete, pour the reaction solution into purified water, extract with an organic solvent, concentrate the organic phase under reduced pressure to dryness, and recrystallize with n-hexane-ethyl acetate to obtain the target product I.

[0022] Preferred embodiment: The base is one or a combination of 2-chloropyridine, 2-fluoropyridine, 2-bromopyridine, and triethylamine, and 2-chloropyridine is particularly preferred.

[0023] Preferred embodiment: The acid anhydride is one or a combination of trifluoromethanesulfonic anhydride (Tf2O) and acetic anhydride (Ac2O), and Tf2O is particularly preferred.

[0024] Preferred embodiment: The organic solvent is one or a combination of dichloromethane and chloroform, and dichloromethane is particularly preferred.

[0025] Preferred embodiment: The molar ratio of the compound SM-1, compound SM-2, base, acid anhydride, and triethylamine in the feed is 1: 2.5 - 4.0: 2.5 - 4.0: 1.3 - 2.0: 5.0 - 7.0, and 1: 3.0: 3.0: 1.5: 6.0 is particularly preferred.

[0026] Preferred embodiment: The reaction temperature T1 is 10 - 40 °C, preferably 20 - 25 °C.

[0027] Preferred embodiment: The organic solvent for extraction is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, and dichloromethane is particularly preferred.

[0028] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0029] 1. A simple and efficient method for preparing the key intermediate of lenvatinib, 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (I), is provided. The entire synthetic route is short, the operation steps are simple, the reaction conditions are mild, and the reaction yield is high.

[0030] 2. The use of highly toxic reagents such as chloroformate can be effectively avoided, making the reaction operation safer and more suitable for industrial scale-up production.

[0031] 3. In the experiment, the excess SM-2 can be recycled by acid-base extraction of the refined mother liquor to reduce production costs. Specific Embodiments

[0032] The present invention will be further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope of protection required by the present invention.

[0033] Example 1

[0034] At room temperature, compound SM-1 (15.72 g, 0.10 mol), 2-chloropyridine (34.06 g, 0.30 mol), and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to dichloromethane (150 ml). The reaction was carried out while controlling the temperature at 20 - 25°C. After detecting that the reaction of compound SM-1 was completed, triethylamine (60.71 g, 0.60 mol) and compound SM-2 (43.07 g, 0.30 mol) were added, and the reaction was continued while controlling the temperature at 20 - 25°C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml), the organic phase was separated, the aqueous phase was extracted with dichloromethane (500 ml × 2), the organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization with n-hexane - ethyl acetate, the target product I was obtained, with a yield of 97.2% and a purity of 99.92%.

[0035] Example 2

[0036] At room temperature, compound SM-1 (15.72 g, 0.10 mol), 2-chloropyridine (28.39 g, 0.25 mol), and acetic anhydride (15.31 g, 0.15 mol) were added to dichloromethane (150 ml). The reaction was carried out while controlling the temperature at 10 - 15°C. After detecting that the reaction of compound SM-1 was completed, triethylamine (60.71 g, 0.60 mol) and compound SM-2 (43.07 g, 0.30 mol) were added, and the reaction was continued while controlling the temperature at 10 - 15°C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml), the organic phase was separated, the aqueous phase was extracted with dichloromethane (500 ml × 2), the organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization with n-hexane - ethyl acetate, the target product I was obtained, with a yield of 94.3% and a purity of 99.68%.

[0037] Example 3

[0038] At room temperature, compound SM-1 (15.72 g, 0.10 mol), 2-chloropyridine (45.42 g, 0.40 mol), and acetic anhydride (15.31 g, 0.15 mol) were added to dichloromethane (150 ml). The reaction was carried out while controlling the temperature at 35 - 40°C. After detecting that the reaction of compound SM-1 was completed, triethylamine (60.71 g, 0.60 mol) and compound SM-2 (43.07 g, 0.30 mol) were added, and the reaction was continued while controlling the temperature at 35 - 40°C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml), the organic phase was separated, the aqueous phase was extracted with dichloromethane (500 ml × 2), the organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization with n-hexane - ethyl acetate, the target product I was obtained, with a yield of 95.1% and a purity of 99.60%.

[0039] Example 4

[0040] At room temperature, compound SM-1 (15.72 g, 0.10 mol), 2-fluoropyridine (29.13 g, 0.30 mol), and trifluoromethanesulfonic anhydride (36.68 g, 0.13 mol) were added to dichloromethane (150 ml), and the reaction was carried out at 20 - 25 °C. After detecting that the reaction of compound SM-1 was completed, triethylamine (50.60 g, 0.50 mol) and compound SM-2 (43.07 g, 0.30 mol) were added, and the reaction was continued at 20 - 25 °C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml), the organic phase was separated, the aqueous phase was extracted with dichloromethane (500 ml × 2), the organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization from n-hexane - ethyl acetate, the target product I was obtained with a yield of 94.6% and a purity of 99.70%.

[0041] Example 5

[0042] At room temperature, compound SM-1 (15.72 g, 0.10 mol), 2-bromopyridine (47.40 g, 0.30 mol), and trifluoromethanesulfonic anhydride (56.43 g, 0.20 mol) were added to dichloromethane (300 ml), and the reaction was carried out at 20 - 25 °C. After detecting that the reaction of compound SM-1 was completed, triethylamine (70.83 g, 0.70 mol) and compound SM-2 (43.07 g, 0.30 mol) were added, and the reaction was continued at 20 - 25 °C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml), the organic phase was separated, the aqueous phase was extracted with dichloromethane (500 ml × 2), the organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization from n-hexane - ethyl acetate, the target product I was obtained with a yield of 95.5% and a purity of 99.61%.

[0043] Example 6

[0044] At room temperature, compound SM-1 (15.72 g, 0.10 mol), triethylamine (30.36 g, 0.30 mol), and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to dichloromethane (150 ml), and the reaction was carried out at 20 - 25 °C. After detecting that the reaction of compound SM-1 was completed, triethylamine (60.71 g, 0.60 mol) and compound SM-2 (35.75 g, 0.25 mol) were added, and the reaction was continued at 20 - 25 °C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml), the organic phase was separated, the aqueous phase was extracted with dichloromethane (500 ml × 2), the organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization from n-hexane - ethyl acetate, the target product I was obtained with a yield of 94.6% and a purity of 99.71%.

[0045] Example 7

[0046] At room temperature, compound SM-1 (15.72 g, 0.10 mol), triethylamine (30.36 g, 0.30 mol), and trifluoromethanesulfonic anhydride (42.32 g, 0.15 mol) were added to chloroform (150 ml). The temperature was controlled at 20 - 25 °C for reaction. After detecting that the reaction of compound SM-1 was completed, triethylamine (60.71 g, 0.60 mol) and compound SM-2 (57.20 g, 0.40 mol) were added, and the reaction was continued at 20 - 25 °C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 2). The organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization from n-hexane - ethyl acetate, the target product I was obtained with a yield of 95.2% and a purity of 99.65%.

[0047] Example 8

[0048] At room temperature, compound SM-1 (15.72 g, 0.10 mol), 2-chloropyridine (24.98 g, 0.22 mol), and trifluoromethanesulfonic anhydride (28.21 g, 0.1 mol) were added to dichloromethane (150 ml). The temperature was controlled at 5 - 10 °C for reaction. After detecting that the reaction of compound SM-1 was completed, triethylamine (47.56 g, 0.47 mol) and compound SM-2 (31.46 g, 0.22 mol) were added, and the reaction was continued at 5 - 10 °C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 2). The organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization from n-hexane - ethyl acetate, the target product I was obtained with a yield of 88.6% and a purity of 98.82%.

[0049] Example 9

[0050] At room temperature, compound SM-1 (15.72 g, 0.10 mol), 2-chloropyridine (47.69 g, 0.42 mol), and trifluoromethanesulfonic anhydride (62.07 g, 0.22 mol) were added to dichloromethane (350 ml), and the reaction was carried out at a controlled temperature of 40 - 45 °C. After detecting that the reaction of compound SM-1 was completed, triethylamine (72.85 g, 0.72 mol) and compound SM-2 (60.06 g, 0.42 mol) were added, and the reaction was continued at a controlled temperature of 40 - 45 °C. After detecting that the reaction was completed, the reaction solution was poured into purified water (1500 ml), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (500 ml × 2), and the organic phase was washed with saturated brine (800 ml) and concentrated under reduced pressure to dryness. After recrystallization with n-hexane - ethyl acetate, the target product I was obtained with a yield of 89.3% and a purity of 97.56%.

Claims

1. A preparation method of a lenvatinib intermediate, characterized in that, The preparation method comprises the following steps: at room temperature, 15.72 g of compound SM-1, 34.06 g of 2-chloropyridine and 42.32 g of trifluoromethanesulfonic anhydride are added to 150 ml of dichloromethane, and the temperature is controlled at 20-25 °C for reaction. After detecting that the compound SM-1 has reacted completely, 60.71 g of triethylamine and 43.07 g of compound SM-2 are added, and the temperature is continuously controlled at 20-25 °C for reaction. After detecting that the reaction is complete, the reaction solution is poured into 1500 ml of purified water, the organic phase is separated, the aqueous phase is extracted twice with 500 ml of dichloromethane, the organic phase is washed with 800 ml of saturated brine and concentrated under reduced pressure to dryness, and the target product I is obtained after recrystallization with n-hexane-ethyl acetate; The reaction route is as follows: 。

Images