CN115368219B - Preparation method of FGFR inhibitor key intermediate - Google Patents

Preparation method of FGFR inhibitor key intermediate Download PDF

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CN115368219B
CN115368219B CN202211309316.XA CN202211309316A CN115368219B CN 115368219 B CN115368219 B CN 115368219B CN 202211309316 A CN202211309316 A CN 202211309316A CN 115368219 B CN115368219 B CN 115368219B
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fgfr inhibitor
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庄晓晓
卢可伟
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Suzhou Kangchun Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention belongs to the field of drug synthesis, and particularly discloses a preparation method of a key intermediate 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol of an FGFR inhibitor, which comprises the following steps of taking 2,3,5, 6-tetrafluorobenzoic acid as a starting raw material, and acylating the starting raw material into methyl ester to obtain a compound II, substituting the compound II into methyl ester under the action of sodium alkoxide to obtain a compound III, decarboxylating the compound III to obtain a compound IV, substituting the compound IV with N, N-dimethylformamide at low temperature to obtain a compound V, and reacting the compound V with a reducing agent to obtain the 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol; the method has the advantages of novel route, simple and convenient operation, no need of separating isomers, high yield and good safety, and is suitable for industrial production.

Description

Preparation method of FGFR inhibitor key intermediate
Technical Field
The invention belongs to the field of drug synthesis, and particularly discloses a preparation method of a key intermediate 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol of an FGFR inhibitor.
Background
Fibroblast Growth Factor Receptors (FGFR) are one of the current focus targets for "pan-neoplastic" therapy. In recent years, the targeted therapy of malignant tumors is rapidly advanced, the development and marketing of targeted therapy of related drugs such as EGFR, HER-2, NTRK and the like are redefining the therapeutic pattern of malignant tumors, and the research and development of FGFR kinase inhibitors are also one of the hotspots. FGFR belongs to tyrosine kinase receptor, and is combined with Fibroblast Growth Factor (FGFs) to activate a series of downstream signal channels and participate in regulation of cell proliferation, migration and the like. When FGFR is abnormal, tumor generation and development are promoted by driving tumor cells to proliferate and survive and promoting angiogenesis. FGFR genetic alterations have been found to date in over ten malignancies, the most common of which are urothelial cancer, followed by breast cancer, endometrial cancer, and the like. Therefore, the development of FGFR inhibitors has wide market prospect. 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol is a key intermediate in the preparation of a series of FGFR inhibitors, and a representative compound thereof is ASP-5878 developed by Astilde pharmaceutical Japan, which has entered a first clinical trial worldwide. The structures of ASP-5878 and key intermediate (VI) are as follows:
Figure 827252DEST_PATH_IMAGE001
the search literature found two reports of the synthesis methods of 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol (compound VI), and the reaction routes are as follows:
Figure 48149DEST_PATH_IMAGE002
Figure 778601DEST_PATH_IMAGE003
it has been observed that both methods involve direct fluorination of the substrate, and the synthetic route of this method has the following problems: a large amount of fluoro reagent is used, atomic economics is not met, a large amount of waste is generated, pollution is serious, a large amount of monofluorine substitutes for impurities during fluoro reaction, product purification is difficult, yield is low, and industrial production cannot be achieved. Taken together, this synthetic route does not afford the desired 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol on a large scale. Therefore, it is necessary to develop a green synthesis method for preparing 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol which is efficient and environmentally friendly.
Disclosure of Invention
The invention aims to overcome the defects of the technology and provides a novel method for preparing the 2, 6-difluoro-3, 5-dimethoxy benzyl alcohol, which has the advantages of simple and convenient operation, low cost, high yield, safety, reliability and suitability for large-scale preparation.
The technical scheme of the invention is as follows:
a preparation method of a key intermediate of an FGFR inhibitor comprises the following steps:
a. 2,3,5, 6-tetrafluorobenzoic acid is taken as a starting material, and is acylated to form methyl ester to obtain a compound II;
b. the compound II is substituted under the action of sodium alkoxide to obtain a compound III;
c. decarboxylation of the compound III to obtain a compound IV;
d. reacting the compound IV with N, N-dimethylformamide and a lithiation reagent at low temperature, and substituting to obtain a compound V;
e. reacting the compound V with a reducing agent to obtain 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol;
the chemical reaction scheme is as follows:
Figure 186579DEST_PATH_IMAGE004
further, in the above preparation method of the key intermediate of the FGFR inhibitor, in the step a, the reaction reagent for acylation is acyl chloride, and an organic solvent is used as a reaction solvent.
Further, in the preparation method of the key intermediate of the FGFR inhibitor, the acyl chloride is selected from one of thionyl chloride, oxalyl chloride and phosphorus oxychloride; the organic solvent is selected from methanol; preferably, the reaction temperature is 0-60 ℃, and the molar ratio of the compound I to the acyl chloride is 1.
Further, in the preparation method of the key intermediate of the FGFR inhibitor, in the step b, the reaction temperature is 50-80 ℃; the sodium alkoxide is sodium methoxide; preferably, the molar ratio of compound II to sodium methoxide is 1:3.
further, in the preparation method of the key intermediate of the FGFR inhibitor, in the step c, the temperature of the decarboxylation reaction is 80-120 ℃; the reaction solvent is one selected from dimethyl sulfoxide, N, N-dimethylformamide and N, N-dimethylacetamide; the decarboxylation reagent is potassium fluoride or cesium fluoride. Preferably, the reaction temperature is 80-120 ℃; the molar ratio of the compound III to the decarboxylation reagent is 1.
Further, in the above preparation method of a key intermediate of the FGFR inhibitor, in step d, tetrahydrofuran or diethyl ether is used as a solvent; the lithiation reagent is lithium diisopropylamide.
Further, in the preparation method of the key intermediate of the FGFR inhibitor, in the step d, the low temperature range is-50 ℃ to-100 ℃; preferably, the reaction temperature is-78 ℃; the molar ratio of the compound IV to the lithiation reagent is 1:1.2.
further, in the above preparation method of the key intermediate of the FGFR inhibitor, in the step e, the solvent for the reaction is methanol or ethanol.
Further, in the above preparation method of a key intermediate of the FGFR inhibitor, in step e, the reducing agent is sodium borohydride or lithium borohydride; preferably, the reaction temperature is 0-30 ℃; the molar ratio of compound V to reducing agent is 1.5.
Further, the 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol is prepared by the preparation method of the key intermediate of the FGFR inhibitor.
The invention has the following beneficial effects:
the invention provides a brand-new industrialized route for synthesizing the FGFR inhibitor key intermediate 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol. The method has the advantages of mild route conditions, simple and convenient operation, stable process, convenient purification and easy scale-up production. More particularly, monosubstituted impurities which are difficult to separate and purify in the prior art are avoided to a limited extent, so that the whole process is simplified, the yield is improved, and the cost is lower. Meanwhile, the synthetic route provides a methodological reference for the synthesis of similar compounds, has good methodological significance for developing novel FGFR inhibitors, and provides assistance for the research and development of new FGFR drugs.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The reagents or instruments used in the examples of the present invention are not indicated by manufacturers, and are conventional reagents that are commercially available.
Example 1
Preparation of compound II: the reaction is as follows
Figure 759381DEST_PATH_IMAGE005
Adding 100g of raw material I into a 1000mL reaction bottle, adding 500mL of methanol, dropwise adding 63.50g of thionyl chloride into the reaction bottle in ice-water bath, heating to room temperature, stirring, and heating to 60 DEG o And C, reacting overnight, concentrating after the reaction is finished to remove the methanol, adding 500mL of ethyl acetate, washing with 500mL of saturated sodium bicarbonate solution, washing with 500mL of saturated sodium chloride solution, drying with anhydrous sodium sulfate, and spin-drying to obtain 100g of colorless solid, wherein the yield is 90.5%, and the purity is 97%. 1 HNMR(400MHz,DMSO-d6),δ:7.20-7.02(m,1H),3.96(s,3H)ppm。ESI-MS,m/z(%):209(M+H) + 。
Preparation of compound III: the reaction is as follows
Figure 569205DEST_PATH_IMAGE006
100g of II, 78g of sodium methoxide and 500mL of methanol are respectively added into a 1000mL reaction bottle and heated to 60 DEG o C reaction overnight, cooling to room temperature, spin-drying the reaction solution, adding 500mL of ethyl acetate and 500mL of saturated brine to the residue, washing, combining organic phases, drying over anhydrous sodium sulfate, and spin-drying to obtain compound V110g as a yellow solid, yield: 98.6 percent. 1 HNMR(400MHz,DMSO-d6),δ:6.62-6.58(m,1H),3.82(s,3H),3.72(s,6H)ppm。
ESI-MS,m/z(%):233(M+H) + .
Preparation of compound IV: the reaction is as follows
Figure 408241DEST_PATH_IMAGE007
Into a 1000mL reaction flask were added 150g of III, 600mL of dimethyl sulfoxide, 93g of potassium fluoride, and the mixture was heated to 100% o C, reacting overnight, cooling the system to room temperature after the reaction is finished, pouring the cooled system into 1500mL of water, extracting twice with 500mL of ethyl acetate, combining organic phases, washing with 500mL of saturated saline solution, drying with anhydrous sodium sulfate, and spin-drying to obtain 100g of yellow liquid, wherein the yield is as follows: 88.9 percent. 1 HNMR(400MHz,DMSO-d6),δ:6.54-6.48(m,1H),6.26-6.22(m,1H),3.65(s,6H)ppm。ESI-MS,m/z(%):175(M+H) + .
Preparation of compound V: the reaction is as follows
Figure 506779DEST_PATH_IMAGE008
50g of IV and 500mL of tetrahydrofuran are respectively added into a 1000mL reaction bottle, and the internal temperature is controlled to be reduced to-78 o C, adding 172mL of lithium diisopropylamide tetrahydrofuran solution (2M) dropwise, and after finishing adding, adding-78 o C stirring for 1h, adding N, N-dimethyl formamide 31.50g in drops, after the adding is finished, at-78 o C, stirring for 30min, and then slowly returning to the temperature. After TLC detection, saturated ammonium chloride solution 100mL is added to quench the reaction, ethyl acetate 300mL is added to extract twice, the organic phases are combined, washed twice with saturated saline solution 500mL, dried over anhydrous sodium sulfate and spin dried to obtain a yellow solid 55g, the yield is 94.8%. 1 HNMR(400MHz,CDCl3),δ:10.29(s,1H),6.80-6.84(m,1H),3.84(s,6H),ppm。
ESI-MS,m/z(%):203(M+H) + 。
Preparation of Compound VI: the reaction is as follows
Figure 86533DEST_PATH_IMAGE009
Adding V80g and methanol 600mL into a 1000mL reaction bottle, cooling to 0 in ice water bath o C-5 o C, adding 17.60g of sodium borohydride in batches, stirring for 1-2h at the normal temperature after adding, slowly adding 200mL of water, concentrating and removing methanolAlcohol, adding ethyl acetate 400mL for extraction twice, combining organic phases, washing twice with saturated saline solution 500mL, drying with anhydrous sodium sulfate, and spin-drying to obtain off-white solid 78g, with the yield of 96.5%. 1 HNMR(400MHz,CDCl3),
δ:6.62(t,1H),4.80(d,2H),3.88(s,6H),1.93(t,1H)ppm。ESI-MS,m/z(%):205(M+H) + 。
The above examples are only illustrative of a limited number of preferred embodiments of the present invention, and are described in more detail and detail, but are not to be construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention.

Claims (9)

1. A preparation method of a key intermediate of an FGFR inhibitor is characterized by comprising the following steps:
a. 2,3,5, 6-tetrafluorobenzoic acid is taken as a starting material, and is acylated to form methyl ester to obtain a compound II;
b. the compound II is substituted under the action of sodium alkoxide to obtain a compound III;
c. decarboxylating the compound III to obtain a compound IV;
d. reacting the compound IV with N, N-dimethylformamide and a lithiation reagent at low temperature, and substituting to obtain a compound V;
e. reacting the compound V with a reducing agent to obtain 2, 6-difluoro-3, 5-dimethoxybenzyl alcohol;
the chemical reaction scheme is as follows:
Figure 178784DEST_PATH_IMAGE001
。
2. the method for preparing a key intermediate of FGFR inhibitor according to claim 1, wherein in step a, the reaction reagent for acylation is acyl chloride, and an organic solvent is used as the reaction solvent.
3. The method for preparing a key intermediate of FGFR inhibitor according to claim 2, wherein the acid chloride is selected from one of thionyl chloride, oxalyl chloride and phosphorus oxychloride; the organic solvent is selected from methanol.
4. The method for preparing the key intermediate of the FGFR inhibitor according to claim 1, wherein the reaction temperature in step b is 50-80 ℃; the sodium alkoxide is sodium methoxide.
5. The method for preparing key intermediates of FGFR inhibitor according to claim 1, wherein in step c, the decarboxylation reaction temperature is 80-120 ℃; the reaction solvent is selected from one of dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide; the decarboxylation reagent is potassium fluoride or cesium fluoride.
6. The method for preparing key intermediates of FGFR inhibitor according to claim 1, wherein in step d, tetrahydrofuran or diethyl ether is used as solvent; the lithiating reagent is lithium diisopropylamide.
7. The method of claim 1, wherein the low temperature in step d is in the range of-50 ℃ to-100 ℃.
8. The method of claim 1, wherein the solvent for the reaction in step e is methanol or ethanol.
9. The method for preparing a key intermediate of an FGFR inhibitor according to claim 1, wherein in step e, the reducing agent is sodium borohydride or lithium borohydride.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104478742A (en) * 2014-11-24 2015-04-01 苏州乔纳森新材料科技有限公司 Fluoro compound and preparation method thereof
WO2016164703A1 (en) * 2015-04-09 2016-10-13 Eisai R & D Management Co., Ltd. Fgfr4 inhibitors
CN106459034A (en) * 2014-02-07 2017-02-22 普林斯匹亚生物制药公司 Quinolone derivatives as fibroblast growth factor receptor inhibitors
CN115151539A (en) * 2019-12-04 2022-10-04 因赛特公司 Derivatives of FGFR inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106459034A (en) * 2014-02-07 2017-02-22 普林斯匹亚生物制药公司 Quinolone derivatives as fibroblast growth factor receptor inhibitors
CN104478742A (en) * 2014-11-24 2015-04-01 苏州乔纳森新材料科技有限公司 Fluoro compound and preparation method thereof
WO2016164703A1 (en) * 2015-04-09 2016-10-13 Eisai R & D Management Co., Ltd. Fgfr4 inhibitors
CN115151539A (en) * 2019-12-04 2022-10-04 因赛特公司 Derivatives of FGFR inhibitors

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