Preparation method of substituted benzoate derivative

Abstract

The invention provides a preparation method of a substituted benzoate derivative, which comprises the following steps: reacting zinc powder with a compound A in an organic solvent under the protection of inert gas to obtain a compound B containing a zinc reagent, coupling the compound B with a compound C under the action of a nickel catalyst and a metal Grignard reagent to generate a compound D, and separating the compound D from the compound C to obtain the substituted benzoate derivative. The method for preparing the final product is simple and efficient, the cost is reduced, and production is facilitated.

Description

Technical Field

[0001] The invention relates to a preparation method of a substituted benzoic acid ester derivative, belonging to the technical field of medicine and chemistry. Background Art

[0002] Orexin is a neuroendocrine hormone secreted by the hypothalamus that acts in the central nervous system. It exerts its biological effects by binding to orexin receptors. Orexin is of great significance to mammals, especially humans. It is widely involved in various regulatory activities of the central nervous system and has great significance in pathology. There are many types of mental disorders and diseases related to orexin and orexin receptors. These diseases have seriously affected social stability and the quality of life of patients and their families. In view of this, the current research on orexin receptor antagonists has become a hot spot for the research and development of drugs against central nervous system neurological and mental disorders and diseases.

[0003] Methyl 5-methyl-2-(2-pyrimidinyl)benzoate is an important intermediate of orexin receptor antagonist drugs and has been widely studied. Its chemical structure is shown below:

[0004]

[0005] Prior art mainly includes the following reports on the preparation method of 5-methyl-2-(2-pyrimidinyl)benzoic acid methyl ester:

[0006] The preparation of this compound is reported in patent CN107709318B, and the synthetic route is as follows:

[0007]

[0008] This route requires the use of bis-pinacol borate to first prepare the corresponding borate (methyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate), and then undergoes a coupling reaction with 2-chloropyrimidine to obtain the target product. This synthesis method requires the synthesis and separation of the corresponding borate, and then a catalytic reaction with precious metal palladium to obtain the target product. The two-step yield of this reaction is 36.4%, so this method has a low yield and a high cost.

[0009] This method is reported in the literature Organic Process Research & Development (2013), 17 (1), 61-68 and patents WO2008147518A, WO2019043407A, and WO2015083094A. It is also necessary to prepare the corresponding boric acid ester first. The synthetic route is as follows:

[0010]

[0011] The preparation method of the compound is disclosed in Letters in Organic Chemistry (2021), 18 (7), 501-506, and the synthesis route is as follows:

[0012]

[0013] This route uses n-butyl lithium, which has a high process risk, and uses a palladium catalyst, which is costly and not conducive to commercial production. Summary of the invention

[0014] In view of the defects of the prior art, the present invention provides a method for preparing a substituted benzoate derivative. The method for preparing the final product is simple, efficient, reduces costs, and is conducive to production.

[0015] In order to achieve the above object, the present invention adopts the following technical solutions:

[0016] The first aspect of the present invention provides a method for preparing a substituted benzoate derivative compound D, which comprises reacting zinc powder with compound A in an organic solvent under the protection of an inert gas to obtain a compound B containing a zinc reagent, and coupling compound B with compound C under the action of a nickel catalyst and a metal Grignard reagent to generate compound D, and the reaction formula is shown below:

[0017]

[0018] Where X 1 is selected from Cl, Br, I; X 2 Selected from Cl, Br, I, triflate, mesylate, p-toluenesulfonate;

[0019] A is a C or N atom;

[0020] R 1 is selected from benzyl and C1-C6 alkyl, and further the C1-C6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and n-hexyl;

[0021] R 2 is selected from H, C1-C4 alkyl, and substituted or unsubstituted aromatic groups, further the aromatic group is phenyl or pyridyl, and the substituent is C1-C4 alkyl, for example the C1-C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl;

[0022] Furthermore, the ring system formed by a connecting bond connected to the center of the ring in the formula represents that the connecting bond can be connected to R at any connectable position on the ring system. 2 Partially connected;

[0023] Furthermore, the preparation method of compound B satisfies one or more of the following conditions:

[0024] Furthermore, the preparation of the compound B is carried out under the action of an initiator, and the initiator is selected from at least one of 1,2-dibromoethane and trimethylsilyl chloride reagent, such as 1,2-dibromoethane;

[0025] Furthermore, the preparation of the compound B is carried out under the catalysis of a lithium salt, and the lithium salt is selected from at least one of lithium chloride, lithium bromide and lithium iodide, such as lithium chloride;

[0026] Further, the inert gas is nitrogen, argon or helium, such as nitrogen;

[0027] Further, the organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, acetone, acetonitrile, chloroform, methanol, ethanol and isopropanol, such as tetrahydrofuran;

[0028] Furthermore, the volume of the organic solvent mL is 1 to 20 times, for example, 5 to 10 times, the mass of compound A g;

[0029] Further, the molar ratio of the compound A to the zinc powder is 1:(1-5), for example 1:(2-3);

[0030] Further, the molar ratio of the compound A to the lithium salt is 1:(1-2.5), for example 1:(1-1.5);

[0031] Further, the molar ratio of the compound A to the initiator is 1:(0.05-0.3), for example 1:(0.1-0.2);

[0032] Further, the reaction temperature of the reaction is 50 to 90°C, such as 60 to 80°C, and another example is 65 to 70°C;

[0033] Furthermore, the reaction time of the reaction is 1 to 5 hours, such as 1 to 2 hours.

[0034] Furthermore, the preparation method of compound D satisfies one or more of the following conditions:

[0035] Further, the compound C is 2-chloropyrimidine, 2-bromopyrimidine, 2-iodopyrimidine, 2-pyrimidinyl trifluoromethanesulfonate, 2-pyrimidinyl methanesulfonate, 2-pyrimidinyl p-toluenesulfonate, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, 2-pyridyl trifluoromethanesulfonate, 2-pyridyl methanesulfonate, 2-pyridyl p-toluenesulfonate, 2-chlorobenzene, 2-bromobenzene, 2-iodobenzene, 2-phenyl trifluoromethanesulfonate, 2-phenyl methanesulfonate, 2-phenyl p-toluenesulfonate, for example, 2-chloropyrimidine, 2-bromopyrimidine, 2-iodopyrimidine, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, 2-chlorobenzene, 2-bromobenzene, 2-iodobenzene, more for example, 2-chloropyrimidine, 2-chloropyridine, 2-chlorobenzene;

[0036] Furthermore, the nickel catalyst is Ni(PPh 3 ) 2 Cl 2 、Ni(dppf)Cl 2 、Ni(dppe)Cl 2 、Ni(dppp)Cl 2 、Ni(dppb)Cl 2 、Ni(Py) 2 Cl 2 ,Ni(PCy 3 )Cl 2 One of the following, such as Ni(dppe)Cl 2 ;

[0037] Further, the molar ratio of the compound B to the nickel catalyst is 1:(0.01-0.2), for example, 1:(0.01-0.1); further, the metal Grignard reagent is selected from ethylmagnesium chloride, isopropylmagnesium chloride, cyclopropylmagnesium chloride, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, ethylmagnesium chloride-lithium chloride, sec-butylmagnesium chloride-lithium chloride, 2-butylmagnesium chloride-lithium chloride, isopropylmagnesium chloride-lithium chloride or isopropylmagnesium bromide-lithium chloride, for example, isopropylmagnesium chloride-lithium chloride;

[0038] Further, the molar ratio of the compound B to the metal Grignard reagent is 1:(0.01-0.1), for example, 1:(0.02-0.06);

[0039] Further, the reaction temperature is 20 to 60°C, for example 30 to 50°C, and for example 35 to 45°C;

[0040] Furthermore, the reaction time is 1 to 5 hours, for example 1 to 2 hours;

[0041] Furthermore, after the reaction is completed, post-treatment is selectively performed, the reaction mixture is cooled to 20-30° C., water and diatomaceous earth are added, filtered, separated, and concentrated to dryness.

[0042] Further, optionally, the above concentration to a dry product comprises the following purification steps: adding ethyl acetate, sodium sulfite and sodium chloride solution, stirring, and separating the liquids. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to a volume (mL) of 2 to 3 V of the compound A feed amount (g), heated to a clear solution (e.g., 70 to 80°C), cooled to 20 to 30°C for crystallization, filtered, and vacuum dried to obtain compound D.

[0043] Furthermore, a preferred synthetic route is provided, in an organic solvent under the protection of an inert gas, zinc powder is reacted with compound A1 to obtain compound B1 containing a zinc reagent, and compound B1 is coupled with compound C1 under the action of a nickel catalyst and a metal Grignard reagent to generate compound D1, and the reaction formula is shown below:

[0044]

[0045] Where X 1 is selected from Cl, Br, I; X 2 is selected from Cl, Br, I, trifluoromethanesulfonate, mesylate, p-toluenesulfonate; R 1 is selected from benzyl and C1-C6 alkyl, and further the C1-C6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and n-hexyl;

[0046] The preparation method and reaction conditions of each step of compound D1 refer to the preparation method of compound D in the first aspect of the present invention.

[0047] The second aspect of the present invention provides a method for preparing a compound B, which comprises reacting zinc powder with a compound A in an organic solvent under the protection of an inert gas to obtain a compound B containing a zinc reagent, and the reaction formula is as follows:

[0048]

[0049] Where X 1 , R 1 , R 2 As described in the first aspect of the present invention, the preparation method and reaction conditions of each step of preparing compound B from compound A are the same as those of preparing compound B from compound A in the first aspect of the present invention;

[0050] Furthermore, a preferred synthesis route is provided, the method comprising reacting zinc powder with compound A1 in an organic solvent under the protection of an inert gas to obtain compound B1 containing a zinc reagent, the reaction formula being as follows:

[0051]

[0052] Where X 1 , R 1 As described in the first aspect of the present invention;

[0053] Furthermore, the preparation methods and reaction conditions of each step of preparing compound B1 from compound A1 refer to the preparation of compound B from compound A in the first aspect of the present invention.

[0054] The third aspect of the present invention provides a method for preparing a substituted benzoate derivative, the method comprising coupling compound B with compound C under the action of a nickel catalyst and a metal Grignard reagent to generate compound D, and the reaction formula is as follows:

[0055]

[0056] Where X 1 , X 2 , A, R 1 , R 2 As described in the first aspect of the present invention, the preparation method and reaction conditions of each step of the reaction of compound B and compound C to prepare compound D are the same as those of the first aspect of the present invention to prepare compound D from compound B;

[0057] Furthermore, the ring system formed by a connecting bond connected to the center of the ring in the formula represents that the connecting bond can be connected to R at any connectable position on the ring system. 2 Partially connected;

[0058] Furthermore, a preferred synthetic route is provided, wherein compound B1 and compound C1 are coupled under the action of a nickel catalyst and a metal Grignard reagent to generate compound D1, and the reaction formula is shown below:

[0059]

[0060] Where X 1 , X 2 , R 1 As described in the first aspect of the present invention;

[0061] The preparation methods and reaction conditions of each step of the reaction of compound B1 with compound C1 to prepare compound D1 refer to the reaction of compound B with compound C to prepare compound D in the first aspect of the present invention.

[0062] The fourth aspect of the present invention provides a compound B, whose structure is shown below:

[0063]

[0064] Where X 1 Selected from Cl, Br, I;

[0065] R 1 is selected from benzyl and C1-C6 alkyl, and further the C1-C6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and n-hexyl;

[0066] R 2 It is selected from C1-C4 alkyl, and substituted or unsubstituted aromatic groups, further the aromatic group is phenyl or pyridyl, the substituent is C1-C4 alkyl, and the C1-C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-butyl.

[0067] For example, R 2 is a methyl group at the 5-position, and the structure of compound B1 is as follows:

[0068]

[0069] Where X 1 Selected from Cl, Br, I;

[0070] R 1 is selected from benzyl and C1-C6 alkyl, and further the C1-C6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and n-hexyl;

[0071] Beneficial technical effects of the present invention:

[0072] 1) The present invention uses nickel catalyst for coupling. Compared with the palladium catalytic coupling reported in the patent literature, the price of metal nickel is cheap. For example, the use of cheap Ni(dppe)Cl 2 Replace expensive Pd(dppf)Cl 2 , the reagent cost is reduced by at least 10%, and the problem of heavy metal residue is avoided. While ensuring the yield, the reaction cost can be significantly reduced.

[0073] 2) The preparation method uses an in-situ generated zinc reagent to replace the synthetic borate ester, which reduces the reagent cost, avoids the treatment and purification of the intermediate, and saves the reagents used for post-treatment and the production energy consumption.

[0074] 3) The preparation method of compound D of the present invention avoids the cumbersome step of separating the boron reagent in the prior art Suzuki coupling. At the same time, the process complexity and cost of Suzuki coupling are also high. Our method has the advantages of continuous synthesis, simple process, and further improves the synthesis efficiency; our reaction reduces the step of preparing boric ester, reduces the reagent cost by about 20%, reduces the production cost by about 30%, reduces the emission by about 30%, and reduces the production cycle by about 50%.

[0075] 4) The synthesis of compound D1.1 in the example uses a metal Grignard reagent as a catalyst, and the reaction yield is increased by 23% compared with the existing Suzuki coupling technology, achieving unexpected technical effects.

[0076] 5) Compound B can be used as an intermediate and can be used for the next step of reaction without any treatment; the operation is simpler and saves labor costs. The formation of intermediate compound B plays a key role in the smooth progress of subsequent reactions.

[0077] 6) The present invention optimizes the reaction conditions, enables the coupling reaction to proceed smoothly, and can obtain stable key intermediates, and significantly improves the yield. For example, using the conventional Negishi coupling reaction without adding a metal Grignard reagent, it is impossible to prepare compound D (including compound D1), and using the conventional Kumada coupling reaction, the intermediate is unstable and the reaction cannot proceed. The present invention unexpectedly found that the addition of a metal Grignard reagent allows the coupling reaction of the present invention to proceed smoothly and obtain a higher yield, thereby maximizing the reaction cost and efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 It is the HPLC spectrum of the compound D1.1 described in the present invention. DETAILED DESCRIPTION

[0079] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0080] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels. Specific embodiment:

[0082]

[0083] Add 7.7g lithium chloride to reaction flask 1, add 25g high-activity zinc powder to reaction flask 1, add 500mL tetrahydrofuran to reaction flask 1, replace with nitrogen 3 times, heat reaction flask 1 to 55-65℃, add 4.0mL 1,2-dibromoethane to reaction flask 1, heat reaction flask 1 to 65-70℃, add 50g compound A1.1 to reaction flask 1, stir reaction flask 1 for 1-2 hours, and cool reaction flask 1 to 0-10℃. Add 2.5g Ni(dppe)Cl 2Add reaction flask 2, add 25mL tetrahydrofuran to reaction flask 2; replace with nitrogen three times, add 7.0mL 1.3M isopropylmagnesium chloride-lithium chloride solution to reaction flask 2, stir for 5 minutes, add the solution in reaction flask 2 to reaction flask 1, add 25g 2-chloropyrimidine to reaction flask 1, heat the reaction to 35-45°C, and stir for 1-2 hours. Cool to 20-30°C, add 100mL water and 25g diatomaceous earth, filter, separate, and concentrate the organic phase to dryness. Add 500g ethyl acetate, add 250g 5% sodium sulfite 20% sodium chloride solution, and stir for 5-10min. Separate and wash the organic layer with 250mL saturated brine. The organic layer was dried and filtered using anhydrous sodium sulfate, and the filtrate was concentrated to 100-150 mL. The reactor was heated to a clear solution, and the temperature was slowly lowered to 20-30° C. for crystallization, and filtered. The filter cake was washed with ethyl acetate, and the filter cake was vacuum dried at 35-45° C. for 24 hours to obtain 35.2 g of solid compound D1.1 with a yield of 85.15% and a HPLC purity of 99.2%. The HPLC spectrum is as follows Figure 1 shown.

Claims

1. A method for preparing a compound D, comprising reacting zinc powder with a compound A in an organic solvent under the protection of an inert gas to obtain a compound B containing a zinc reagent, and coupling compound B with a compound C under the action of a nickel catalyst and a metal Grignard reagent to generate a compound D, the reaction formula being as follows: wherein X1 is selected from Cl, Br, I; X2 is selected from Cl, Br, I, trifluoromethanesulfonate, mesylate, p-toluenesulfonate; A is independently selected from C or N atoms; R1 is selected from benzyl or C1-C6 alkyl; R2 is selected from H, C1-C4 alkyl, and substituted or unsubstituted aromatic groups.

2. The method for preparing compound D according to claim 1, characterized in that: The R1 is selected from benzyl, C1-C6 alkyl, C1-C6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl; R2 is selected from H, C1~C4 alkyl, and substituted aromatic group or unsubstituted aromatic group, the aromatic group is phenyl or pyridyl, the substituted aromatic group is selected from the aromatic ring H is replaced by C1~C4 alkyl, the C1~C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl.

3. A method for preparing compound D, comprising coupling compound B with compound C under the action of a nickel catalyst and a metal Grignard reagent to generate compound D, the reaction formula is as follows: Wherein, X1, X2, A, R1, and R2 are defined as in claim 1.

4. The method for preparing compound D according to any one of claims 1 to 3, characterized in that: The nickel catalyst is one of Ni(PPh3)2Cl2, Ni(dppf)Cl2, Ni(dppe)Cl2, Ni(dppp)Cl2, Ni(dppb)Cl2, Ni(Py)2Cl2, Ni(PCy3)Cl2, for example Ni(dppe)Cl2.

5. The method for preparing compound D according to claim 1 or 3, characterized in that: The metal Grignard reagent is selected from ethylmagnesium chloride, isopropylmagnesium chloride, cyclopropylmagnesium chloride, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, ethylmagnesium chloride-lithium chloride, sec-butylmagnesium chloride-lithium chloride, 2-butylmagnesium chloride-lithium chloride, isopropylmagnesium chloride-lithium chloride or isopropylmagnesium bromide-lithium chloride, for example isopropylmagnesium chloride-lithium chloride.

6. The method for preparing compound D according to claim 1 or 3, characterized in that: The compound C is 2-chloropyrimidine, 2-bromopyrimidine, 2-iodopyrimidine, 2-pyrimidinyl trifluoromethanesulfonate, 2-pyrimidinyl methanesulfonate, 2-pyrimidinyl p-toluenesulfonate, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, 2-pyridyl trifluoromethanesulfonate, 2-pyridyl methanesulfonate, 2-pyridyl p-toluenesulfonate, 2-chlorobenzene, 2-bromobenzene, 2-iodobenzene, 2-phenyl trifluoromethanesulfonate, 2-phenyl methanesulfonate, 2-phenyl p-toluenesulfonate.

7. The method for preparing compound D according to claim 1 or 3, characterized in that: One or more of the following conditions are met: 1) The molar ratio of the compound B to the nickel catalyst is 1:(0.01-0.2), for example 1:(0.01-0.1); 2) The molar ratio of the compound B to the metal Grignard reagent is 1:(0.01-0.1), for example 1:(0.02-0.06); 3) the reaction temperature is 20 to 60°C, for example 30 to 50°C, for example 35 to 45°C; 4) The reaction time is 1 to 5 hours, for example 1 to 2 hours.

8. The preparation method according to claim 3, characterized in that: The R2 is a methyl group at the 5-position, and the A is a N atom.

9. The preparation method according to claim 1, characterized in that: The preparation method of compound B satisfies one or more of the following conditions: 1) The preparation of the compound B is carried out under the action of an initiator, wherein the initiator is selected from at least one of 1,2-dibromoethane and trimethylsilyl chloride reagent, for example, 1,2-dibromoethane; 2) The preparation of the compound B is carried out under the catalysis of a lithium salt, wherein the lithium salt is selected from at least one of lithium chloride, lithium bromide and lithium iodide, such as lithium chloride; 3) The inert gas is nitrogen, argon or helium, such as nitrogen; 4) the organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, acetone, acetonitrile, chloroform, methanol, ethanol and isopropanol; 5) The volume of the organic solvent used in mL is 1 to 20 times, for example, 5 to 10 times, the mass of compound A used in g; 6) The molar ratio of the compound A to the zinc powder is 1:(1-5), for example 1:(2-3); 7) The molar ratio of the compound A to the lithium salt is 1:(1-2.5), for example 1:(1-1.5); 8) The molar ratio of the compound A to the initiator is 1:(0.05-0.3), for example 1:(0.1-0.2); 9) The reaction temperature of the reaction is 50 to 90° C., for example 60 to 80° C., and for example 65 to 70° C.; 10) The reaction time of the reaction is 1 to 5 hours, for example 1 to 2 hours.

10. A compound B or compound B1, whose structure is shown below: wherein X1 is selected from Cl, Br, I; R1 is selected from benzyl or C1-C6 alkyl; preferably, C1-C6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl; R2 is selected from H, C1~C4 alkyl, and substituted aromatic group or unsubstituted aromatic group; preferably, the aromatic group is phenyl or pyridyl, the substituted aromatic group is selected from the aromatic ring H replaced by C1~C4 alkyl, and the C1~C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl.

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