CN113816955B - RET kinase inhibitor intermediate and preparation method thereof - Google Patents
RET kinase inhibitor intermediate and preparation method thereof Download PDFInfo
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- CN113816955B CN113816955B CN202111147388.4A CN202111147388A CN113816955B CN 113816955 B CN113816955 B CN 113816955B CN 202111147388 A CN202111147388 A CN 202111147388A CN 113816955 B CN113816955 B CN 113816955B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
An intermediate of RET kinase inhibitor and a preparation method thereof relate to the field of pharmaceutical chemistry, the result of the intermediate of RET kinase inhibitor is shown as formula (7),
the preparation method comprises the following steps: step 1) reacting compound 5 with halogenated acrylonitrile in organic base and oxidant to obtain compound 6
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to an intermediate of an RET kinase inhibitor and a preparation method thereof.
Background
Selpercatinib(LOXO-292)
Is a potent, oral, highly selective inhibitor of rearrangement-during-transfection (RET) kinase and is useful in the treatment of cancer patients with RET abnormalities. The RET gene is a proto-oncogene that rearranges during transfection and is therefore known to encode a cell membrane receptor tyrosine kinase, an abnormality of which is a rare driver for many types of tumors. RET fusions are estimated to be present in approximately 2% of NSCLC, 1020% of Papillary Thyroid Carcinomas (PTCs) and other types of thyroid carcinomas, and other subgroups of cancers (e.g., colorectal cancers); RET point mutations are present in approximately 60% of Medullary Thyroid Carcinomas (MTC). RET fusion and RET point mutation cancers rely primarily on the activation of RET kinases to maintain their proliferation and survival, a dependence commonly referred to as "oncogene addiction," making such tumors highly sensitive to small molecule inhibitors that target RET.
U.S. Pat. No. US20180134702 reports that Selpercatinib can be synthesized from compound 7 by four-step reaction, the synthetic route is as follows:
the compound shown in the formula 7 is a key intermediate for synthesizing Selpercatinib, and compared with other intermediates, the route for synthesizing Selpercatinib is shortest and the efficiency is highest. However, the existing technology for synthesizing the compound shown in the formula 7 cannot obtain the compound shown in the single formula 7, isomers of the compound often exist and are difficult to separate, and the isomers cannot be completely converted into the Selpercatinib and finally exist as impurities, so that the synthesis method for synthesizing the Selpercatinib by using the compound shown in the formula 7 has no practical industrial application value. The invention aims to explore a preparation method of the compound shown in the formula (7) which has high purity, short synthetic route and high total yield and can be industrially produced.
Disclosure of Invention
In order to solve the technical problems of one aspect of the prior art, the invention provides a novel preparation method of an intermediate formula (1) for synthesizing the RET kinase inhibitor.
A method for preparing an RET kinase inhibitor intermediate of formula (7), comprising:
step 1) reacting compound 5 with halogenated acrylonitrile in organic base and oxidant to obtain compound 6
And 2) carrying out reduction reaction on the compound in the step 2) in a protic solvent in the presence of a reducing agent to obtain a compound 7.
In some embodiments, the organic base of step 1) may be selected from compounds containing nitrogen atoms, such as amines and nitrogen-containing heterocycles, and in some embodiments, the organic base is selected from one or more of 2,6 lutidine, 4 Dimethylaminopyridine (DMAP), 1,4 diazabicyclo [2.2.2] octane, 1,8 diazabicyclo [5.4.0] undec 7-ene (DBU), 1,5 diazabicyclo [4.3.0] undec 7-ene (DBN), triethylamine, diisopropylethylamine, and the like.
In some embodiments, the halogenated acrylonitrile of step 1) may be selected from bromoacrylonitrile, iodoacrylonitrile, or chloroacrylonitrile.
In some embodiments, the oxidizing agent of step 1) is selected from benzoquinone-based oxidizing agents, such as 2, 3 dichloro 5, 6 dicyan p-benzoquinone (DDQ).
In some embodiments, the molar ratio of the organic base to the compound of step 1) is no greater than 1; the molar ratio of compound 5 to oxidant is about 1.
In some embodiments, step 1) is performed in an aprotic solvent, such as a nitrile solvent, e.g., acetonitrile, propionitrile, etc., an ether solvent, e.g., tetrahydrofuran, diethyl ether, or methyl tert-butyl ether, etc.
In some embodiments, the reducing agent of step 2) is selected from Zn/NH4Cl, Zn/HCl, Zn/H2SO 4.
In some embodiments, the protic solvent of step 2) may be selected from alcoholic solvents, such as methanol, ethanol, isopropanol, and the like.
In some embodiments the reaction of step 2 is carried out at about 10 ℃ to about 30 ℃, in some embodiments the reaction of step 2 is carried out at about 15 ℃ to about 25 ℃.
In some embodiments, compound 5 is prepared by the following method:
and reacting the compound 3 in acid at the temperature of about 10-5 ℃, pouring the reaction liquid into ice water, separating out solid, filtering and washing to obtain a compound 4, and salifying the compound 4 and the compound 2 at room temperature to form a compound 5.
In some embodiments, the acid is not particularly limited, and any acid that can remove the Boc group on compound 3 can be used herein, such as trifluoroacetic acid, p-toluenesulfonic acid, and the like.
The reaction of the present invention may be monitored by High Performance Liquid Chromatography (HPLC) for an end point of the reaction, and the reaction is considered to be complete when the HPLC purity of the starting material is less than or equal to about 1% or about 0.5%, and the reaction time is usually less than 10 hours.
The room temperature in the present invention generally means a temperature of between 15 ℃ and 40 ℃, preferably between 25 ℃ and 35 ℃.
The invention has the following beneficial effects:
the invention adopts a brand new route to synthesize the compound 7, has high purity, can reach the purity of 99.5 percent without recrystallization after simple post-treatment, and has no isomer.
In industrial production, the intermediate is solid and convenient post-treatment, and the post-treatment in each step of the invention can obtain the product by simple extraction or filtration without repeated recrystallization or column chromatography.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, g means g, and ml means ml.
EXAMPLE 1 preparation of Compound 1
120.00g (0.690mol) of 3-bromo 5-hydroxypyridine, 2.4L of water and 219.42g (2.070mol) of sodium carbonate are put into a flask, 175.13g (0.690mol) of iodine is added in batches at 25 ℃, the reaction is continued for 2 hours, the reaction is monitored by HPLC, and the residual amount of raw materials is less than 0.5%; the reaction solution was poured into dilute hydrochloric acid, extracted 2 times with ethyl acetate, the organic phases were combined, and the solvent was distilled off under reduced pressure to give 210.00g of crude product (HPLC purity 93%), recrystallized from acetic acid and petroleum ether, filtered, and dried to give 167.61g of compound 1 (yellow solid, yield 81.0%).
EXAMPLE 2 preparation of Compound 3
Taking 150.00g of purified compound 1(0.500mol), 750mL of DMSO and 152.03g of potassium carbonate (1.100mol) in a flask, stirring in a water bath at 25 ℃, dropwise adding 138.74g of dimethyl sulfate (1.100mol), continuing to react for 5 hours, and monitoring the reaction by HPLC, wherein the residual amount of raw materials is less than 0.6%; the reaction solution was poured into 3.0L of ice water, diluted hydrochloric acid was added until no bubble was generated, extraction was performed 2 times with ethyl acetate, the organic phases were combined, washed 1 time with saturated sodium bicarbonate and saturated sodium chloride solutions, respectively, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 141.26g of compound 2 (grayish brown solid, yield 90%).
EXAMPLE 3 preparation of Compound 5
Putting 2.5L of trifluoroacetic acid into a flask, cooling to 0 ℃, adding 100.00g of compound 3(0.348mol) in batches for reacting for 2 hours, pouring the reaction liquid into ice water, separating out solids, filtering and washing to obtain a compound 4;
compound 4 was dissolved in 500mL of dichloromethane and 109.24g of Compound 2(0.348mol) was added to form a salt, which was reacted for 3 hours, filtered and dried in vacuo to give 139.51g of Compound 5 (pale yellow solid, yield 80%).
EXAMPLE 4 preparation of Compound 6
150.00g of Compound 5(0.299mol), 600mL of acetonitrile and 26.17g (0.299mol) of chloroacrylonitrile were placed in a flask, 136.56g (0.897mol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) was added dropwise thereto, 67.87g (0.299mol) of dichlorodicyanobenzoquinone (DDQ) was added thereto, and the mixture was reacted at room temperature for 10 hours, filtered, washed with water and dried under vacuum to obtain 100.58g of Compound 6 (pale yellow solid, yield 89.0%). 1H NMR (400MHz, CDCl3 δ ppm): Δ 3.97(s, 3H, OCH3), 8.00(s, 1H, Ar-H), 8.74(s, 1H, Ar-H).
EXAMPLE 5 preparation of Compound 7
120.00g of Compound 7(0.317mol) and 2.4L of methanol were put in a flask, stirred at 20 ℃ and added with 62.19g of zinc powder (0.951mol), 1.2L of saturated aqueous ammonium chloride solution was added dropwise thereto, reacted overnight, and the reaction was monitored by HPLC, and the remaining amount of the starting material was less than 0.5%, whereupon the reaction was terminated, filtered, washed with water and dried in vacuo to obtain 65.52g of Compound 7 (gray solid, yield 82.0%, purity by HPLC 99.5%).
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A process for the preparation of formula (7), comprising:
step 1) reacting compound 5 with halogenated acrylonitrile in organic base and oxidant to obtain compound 6
Step 2), carrying out reduction reaction on the compound 6 in a protic solvent in the presence of a reducing agent to obtain a compound 7; the organic base in the step 1) is one or more selected from 2, 6-dimethylpyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] undec-7-ene, triethylamine and diisopropylethylamine;
the oxidant in the step 1) is a benzoquinone oxidant.
2. The method according to claim 1, wherein the halogenated acrylonitrile in step 1) is selected from the group consisting of bromoacrylonitrile, iodoacrylonitrile and chloroacrylonitrile.
3. The process according to claim 1, wherein the step 1) is carried out in a nitrile solvent or an ether solvent.
4. The method of claim 1, wherein the reducing agent in step 2) is selected from Zn/NH4Cl, Zn/HCl, Zn/H2SO 4.
5. The method according to claim 1, wherein the protic solvent in step 2) is selected from alcoholic solvents.
6. The method according to claim 1, wherein the reaction in step 2 is carried out at 10 to 30 ℃.
7. The process of claim 1, compound 5 is prepared by:
and reacting the compound 3 in acid at the temperature of between 10 ℃ below zero and 5 ℃, pouring the reaction liquid into ice water, separating out solid, filtering and washing to obtain a compound 4, and salifying the compound 4 and the compound 2 at room temperature to form a compound 5.
8. A compound shown as follows
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Inventor after: Luo Shanmei Inventor after: Ye Zhaobao Inventor after: Chen Zhijun Inventor after: Wang Huangwei Inventor after: Chen Jiahui Inventor after: Zeng Yuandong Inventor after: Yang Hua Inventor before: Luo Shange Inventor before: Ye Zhaobao Inventor before: Chen Zhijun Inventor before: Wang Huangwei Inventor before: Chen Jiahui Inventor before: Zeng Yuandong Inventor before: Yang Hua |
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Address after: 361101 room 402A, qiangye building, industrial zone, Xiamen Torch High tech Zone (Xiang'an), Xiamen, Fujian Patentee after: Xiamen Yunfan Biotechnology Co.,Ltd. Address before: 361101 room 402A, qiangye building, industrial zone, Xiamen Torch High tech Zone (Xiang'an), Xiamen, Fujian Patentee before: XIAMEN YUNFAN PHARMACEUTICAL Co.,Ltd. |