Preparation method of Latricinib intermediate
The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of a Latricinib intermediate.
Latrotinib (Larotretinib) is a potent, oral, selective inhibitor of Tropomyosin Receptor Kinase (TRKs) developed by LoxoOncology, a biomedical company located in Stanford, USA. The U.S. Food and Drug Administration (FDA) granted the orphan drug status of this experimental drug treatment for solid tumors carrying NTRK gene fusions in month 5 2017.
The chemical name of the latsatinib is (S) -N- ((R) -2- (2, 5-difluorophenyl) tetrahydropyrrolidin-1-yl) pyrazolo [1, 5-a ] pyrimidine-3-yl) -3-hydroxytetrahydropyrrolidine-1-formamide, and the chemical structure of the latsatinib is as follows:
methods for preparing the latrine have been reported, and international patents WO2010/048314 and WO2016/077841 report methods for preparing the latrine, and provide methods for preparing (R) -2- (2, 5-difluorophenyl) tetrahydropyrrolidine (I), an important intermediate thereof.
From the synthetic route, the method relates to chiral ligands, metallic lithium/zinc reagents, noble metal palladium reagents, tri-n-butylphosphonium tetrafluoroborate and other raw materials or catalysts, and simultaneously relates to harsh reaction conditions of low temperature, no oxygen, no water and the like, and the method has various steps and is not beneficial to industrial production.
Although patents US2016/0168156, US2015/0368238 and CN104672121, etc. also report some synthetic methods for this compound, the atom economy of the preparation process is reduced due to the use of chiral sulphoxides or other resolving reagents. Therefore, a new preparation method of the (R) -2- (2, 5-difluorophenyl) tetrahydropyrrolidine (I) serving as the intermediate of the Latricinib, which has the advantages of readily available raw materials, convenient operation, mild conditions and reduced side reactions and environmental pollution, is needed.
Disclosure of Invention
The invention aims to provide a preparation method of a novel Latricinib intermediate (R) -2- (2, 5-difluorophenyl) pyrrolidine, which comprises the steps of carrying out addition reaction on a chiral induction reagent taking chiral Betti base (Betti base) as a parent nucleus and a Grignard reagent, and carrying out debenzylation reaction on the obtained product to obtain a target product. The method has the advantages of simpler preparation steps of the target product, easily obtained raw materials, less side reaction and suitability for industrial production.
In order to achieve the purpose, the invention adopts the following main technical scheme: a preparation method of a Latricinib intermediate (R) -2- (2, 5-difluorophenyl) pyrrolidine (I),
the preparation method is characterized by comprising the following steps: taking (7aS,12R) -12-phenyl-7 a,8,9, 10-tetrahydro-12H-naphthol [1,2-e ] pyrrolo [2,1-b ] [1,3] oxazine (II) aS a raw material, carrying out addition reaction with 2, 5-difluorophenyl magnesium bromide (III) to obtain 1- [ (R) - [ (2R) -2- (2, 5-difluorophenyl) -1-tetrahydropyrrolyl ] phenylmethyl ] -2-naphthol (IV), and carrying out debenzylation reaction on the obtained 1- [ (R) - [ (2R) -2- (2, 5-difluorophenyl) -1-tetrahydropyrrolyl ] phenylmethyl ] -2-naphthol (IV) to obtain a Latricinib intermediate (R) -2- (2, 5-difluorophenyl) tetrahydropyrrolidine (I).
In addition, the invention also comprises the following auxiliary technical scheme:
the feeding molar ratio of the addition reaction raw materials (7aS,12R) -12-phenyl-7 a,8,9, 10-tetrahydro-12H-naphthol [1,2-e ] pyrrolo [2,1-b ] [1,3] oxazine (II) and 2, 5-difluorophenyl magnesium bromide (III) is aS follows: 1.0: 1.0-2.0, preferably 1.0: 1.4-1.6.
The temperature of the addition reaction is 0-60 ℃, and preferably 25-35 ℃.
The solvent for the addition reaction is toluene, diethyl ether, isopropyl ether, dichloromethane, 1, 2-dichloroethane, 2-methyltetrahydrofuran or tetrahydrofuran, preferably tetrahydrofuran.
The reaction system of the debenzylation reaction is a catalytic hydrogenation reduction system or a cerium ammonium nitrate oxidation system.
When the reaction system of the debenzylation reaction is a catalytic hydrogenation reduction system, the catalyst for catalytic hydrogenation is palladium carbon, raney nickel, palladium hydroxide carbon or platinum carbon, preferably palladium carbon.
When the reaction system of the debenzylation reaction is a catalytic hydrogenation reduction system, the solvent of the debenzylation reaction is methanol, ethanol, isopropanol, dichloromethane, ethyl acetate or isopropyl acetate, and preferably methanol or ethanol.
When the reaction system of the debenzylation reaction is a ceric ammonium nitrate oxidation system, the solvent of the debenzylation reaction is acetonitrile/water, dichloromethane/water or tetrahydrofuran/water, and acetonitrile/water is preferred; the volume ratio is 1-5: 1, preferably 2: 1.
Compared with the prior art, the invention has the advantages that: a target product is simply and quickly prepared by adopting a chiral induction reagent through classical addition, debenzylation and other reactions. Compared with the existing preparation method of the product, the reaction process is shortened, noble metal catalysts and other expensive reagents are reduced, severe reaction conditions such as no oxygen, no water and the like are avoided, the reaction yield and the operation controllability are improved, the production of the Latricinib intermediate (I) is more controllable, the cost is reduced, and the development of the economic technology of the bulk drug is promoted.
The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments. Wherein the chiral inducing reagent (7aS,12R) -12-phenyl-7 a,8,9, 10-tetrahydro-12H-naphthol [1,2-e ] pyrrolo [2,1-b ] [1,3] oxazine (II) can be prepared aS described in Synlett (2004), (1), 122-124 "or" Tetrahedron: asymmetry (2004), 15(3), 475-.
The first embodiment is as follows:
adding (7aS,12R) -12-phenyl-7 a,8,9, 10-tetrahydro-12H-naphthol [1,2-e ] into a dry reaction bottle under nitrogen atmosphere]Pyrrolo [2,1-b][1，3]Oxazine (II) (3.0g, 10mmol) and dried tetrahydrofuran 30mL, cooled to 0 deg.C, and 2, 5-difluorophenylmagnesium (III) bromide (3.2g, 15mmol) in tetrahydrofuran 30mL was added dropwise. Heating to 25-35 ℃, keeping the temperature, stirring and reacting for 3-5 hours, and detecting by TLC to finish the reaction. The reaction was quenched with 25mL of saturated ammonium chloride, extracted three times with dichloromethane, and the organic phases were combined, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Concentrating, recrystallizing the residue with ethyl acetate to obtain white solid 1- [ (R) - [ (2R) -2- (2, 5-difluorophenyl) -1-tetrahydropyrrolyl]Phenylmethyl group]3.5g of 2-naphthol (IV), yield 84.3%, FAB-MS m/z: 416[ M + H ]]+。
adding 1- [ (R) - [ (2R) -2- (2, 5-difluorophenyl) -1-tetrahydropyrrolyl into a hydrogenation reaction bottle]Phenylmethyl group]2-Naphthol (IV) (2.1g, 5mmol), 10% palladium on carbon (Pd/C) (0.32g, 0.3mmol) and 25mL of methanol, and hydrogen was introduced at room temperature and normal pressure until hydrogen was no longer absorbed, and the introduction of hydrogen was stopped. Filtering to recover the catalyst, and recovering the solvent under reduced pressure to obtain 0.79g of (R) -2- (2, 5-difluorophenyl) pyrrolidine (I) as a reddish oil with the yield of 86.3 percent; 1H NMR (CDCl)3)δ7.24(m，1H)，6.94(m，1H)，6.85(m，1H)，4.40(t，J＝7.6Hz，1H)，3.16(m，1H)，3.04(m，1H)，2.21-2.30(m，1H)，1.77-1.95(m，3H)，1.57-1.67(m，1H)；EI-MS m/z：184[M+H]+。
adding 1- [ (R) - [ (2R) -2- (2, 5-difluorophenyl) -1-tetrahydropyrrolyl into a reaction bottle]Phenylmethyl group]60mL of a mixed solvent of (2.1g, 3mmol) of (IV) -2-naphthol, (4.1g, 7.5mmol), ammonium ceric nitrate and acetonitrile and water (volume ratio 2: 1), and the mixture was stirred at room temperature for 5 to 7 hours, and the reaction was terminated by TLC. After filtration, sodium hydrogencarbonate solution was added to the filtrate and extracted three times with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrating under reduced pressure to obtain reddish oily substance (R) -0.76g of 2- (2, 5-difluorophenyl) pyrrolidine (I), yield 83.0%; 1H NMR (CDCl)3)δ7.24(m，1H)，6.94(m，1H)，6.85(m，1H)，4.40(t，J＝7.6Hz，1H)，3.16(m，1H)，3.04(m，1H)，2.21-2.30(m，1H)，1.77-1.95(m，3H)，1.57-1.67(m，1H)；EI-MSm/z：184[M+H]+。
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.