Preparation method of naphthalene derivative with nitrogen heterocyclic ring

Abstract

The invention discloses a preparation method of a naphthalene derivative with a nitrogen-containing heterocyclic ring, which specifically comprises the following steps: carrying out cross-coupling reaction on a Grignard reagent generated by a reaction of a unitary halide and magnesium metal and a halogenated nitrogen-containing heterocyclic ring compound with a protected amino group, and then removing amino protection by acid and alkali to obtain the required naphthalene derivative with the nitrogen-containing heterocyclic ring. The method has the advantages of convenience in synthesis, simple process, high yield, low cost and the like, and is suitable for industrial production, the naphthalene derivative with the nitrogen heterocyclic ring prepared by the method can be used as a medical intermediate of a fatty acid binding protein inhibitor, and the method has important significance in research, development and production of the fatty acid binding protein inhibitor.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a naphthalene derivative having a nitrogen-containing heterocyclic ring. Background Art

[0002] Fatty acid binding protein ("FABP") inhibitors can be used to treat or prevent cardiovascular diseases, metabolic disorders, obesity or obesity-related diseases, diabetes, dyslipidemia, diabetic complications, impaired glucose tolerance or impaired fasting blood glucose, etc. Naphthalene derivatives with special structures and nitrogen-containing heterocycles can be used as pharmaceutical intermediates of fatty acid binding protein inhibitors (e.g., 1-43, 1-44 in patent US20120122837), such as 2-(naphthalene-2-ylmethyl)pyrrolidine or 3-(naphthalene-2-ylmethyl)azetidine and their isomers. However, these naphthalene derivatives with nitrogen-containing heterocycles are temporarily not commercially available, and there are relatively few research reports on their preparation methods. The development of methods suitable for industrial production of the above-mentioned naphthalene derivatives with nitrogen-containing heterocycles is of great significance for the research and development and production of fatty acid binding protein inhibitors. Summary of the invention

[0003] The technical problem to be solved by the present invention is to provide a method for preparing a naphthalene derivative having a nitrogen-containing heterocyclic ring which is simple to operate, has a high yield and is more suitable for industrial production.

[0004] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0005] A method for preparing a naphthalene derivative having a nitrogen-containing heterocyclic ring comprises the steps of firstly reacting a monohalogenated naphthalene with metal magnesium to generate a Grignard reagent, then reacting the Grignard reagent with a compound represented by formula (I), and removing a carbamate protecting group from the reaction product by acid or alkali to obtain a naphthalene derivative having a nitrogen-containing heterocyclic ring represented by formula (II);

[0006]

[0007] Wherein, R1 in formula (I) is a carbamate protecting group, X is a halogen atom, and m and n in formula (I) and formula (II) are independently 1, 2 or 3.

[0008] In an embodiment of the present invention, the monohalogenated naphthalene is a bromide of naphthalene, a chloride of naphthalene or an iodide of naphthalene.

[0009] In an embodiment of the present invention, X in the formula (I) is fluorine, iodine, bromine or chlorine.

[0010] In an embodiment of the present invention, the carbamate protecting group in the formula (I) is methoxyacyl, ethoxyacyl, tert-butyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl or trichloroethoxycarbonyl.

[0011] In the embodiment of the present invention, m in the formula (I) and formula (II) is 1 or 2, and n is 1.

[0012] According to some specific embodiments, the monohalide of naphthalene is a bromide of naphthalene, the carbamate protecting group in the formula (I) is tert-butyloxycarbonyl, and m in the formula (I) and the formula (II) is 1 or 2, and n is 1.

[0013] In an embodiment of the present invention, the initiator of the Grignard reaction is one or more of dimethoxyethoxyaluminum hydride (AlH(OMe)2Et2), ammonium persulfate, potassium persulfate, iodine, and 1,2-dibromoethane.

[0014] In an embodiment of the present invention, the reaction solvent of the Grignard reaction is one or more of cyclopentanehexyl methyl ether, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), 2-methyltetrahydrofuran (2-MeTHF), dioxane, and tert-butyl methyl ether.

[0015] In an embodiment of the present invention, the format reaction is performed under reflux.

[0016] In an embodiment of the present invention, the Grignard reagent reacts with the compound represented by formula (I) in the presence of a catalyst and a ligand, the catalyst is one or more of bis(triphenylphosphine)cobalt chloride, bis(triphenylphosphine)nickel chloride, and bis(triphenylphosphine)palladium chloride, and the ligand is one or more of tetramethylethylenediamine, diethylamine, diaminoethanol, and diethyl formate.

[0017] In an embodiment of the present invention, the reaction of the Grignard reagent with the compound represented by formula (I) is carried out in any one solvent of tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane or dimethylformamide or a mixed solvent of multiple thereof.

[0018] In an embodiment of the present invention, the reaction of the Grignard reagent with the compound represented by formula (I) is carried out at room temperature.

[0019] In an embodiment of the present invention, the reaction of removing the carbamate protecting group is carried out in any one solvent or a mixed solvent of multiple solvents of tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane or dimethylformamide;

[0020] In an embodiment of the present invention, the acid-base removal reaction of carbamate protecting groups is carried out at 35-45°C.

[0021] Furthermore, the acid-base removal of carbamate protecting groups is carried out at 38-42°C.

[0022] According to some specific embodiments of the present invention, the preparation method specifically comprises the following steps:

[0023] (1) Under a nitrogen atmosphere, a monohalide of naphthalene and metallic magnesium are subjected to a reflux reaction in the presence of an initiator and a first solvent, and after the reaction is completed, the first solvent is dried to obtain a Grignard reagent;

[0024] (2) under ice bath conditions, the Grignard reagent of step (1), the compound represented by formula (I), the catalyst and the ligand are mixed with a second solvent, the Grignard reagent of step (1) is added, and the reaction is carried out at room temperature. After the reaction is completed, the obtained reaction solution is extracted with ethyl acetate, washed with water, purified by column chromatography, and the purified product is used for the next reaction;

[0025] (3) The purified product obtained in step (2), the hydrochloric acid solution and the third solvent are mixed and reacted at 35 to 45° C. After the reaction is completed, the third solvent is dried by spin drying, redissolved in water, extracted with ethyl acetate, the pH of the aqueous phase is adjusted to 9 to 10 with a sodium hydroxide solution, extracted with dichloromethane, and the organic phase is dried over anhydrous Na2SO4. The dichloromethane is dried by spin drying to obtain a naphthalene derivative having a nitrogen-containing heterocyclic ring represented by formula (II).

[0026] Further preferably, the first solvent is cyclopentanehexyl methyl ether, the second solvent and the third solvent are tetrahydrofuran, respectively, the initiator is dimethoxyethoxyaluminum hydride, the catalyst is bis(triphenylphosphine)cobalt chloride, and the ligand is tetramethylethylenediamine.

[0027] Furthermore, the monohalide of naphthalene is added in batches, and the reflux reaction time is 0.5 to 2 hours.

[0028] Furthermore, the monohalogenated naphthalene is added within one hour to prevent overheating and incomplete reaction, and the reflux reaction time is controlled to be 0.8 to 1.5 hours.

[0029] Furthermore, in the step (2), the reaction time at room temperature is 6 to 10 hours.

[0030] Furthermore, in the step (2), the reaction time at room temperature is 7 to 9 hours.

[0031] Furthermore, in the step (3), the reaction time at 35-45° C. is 6-10 h.

[0032] Furthermore, in the step (3), the reaction time at 35-45° C. is 7-9 hours.

[0033] Furthermore, in the step (1), the molar ratio of the monocyclic halide to metallic magnesium is (0.95-1.05):1.

[0034] Furthermore, in the step (1), the ratio of the monocyclic halogenated compound to the first solvent is (0.008-0.015) mol: 1 ml.

[0035] Furthermore, in the step (1), the ratio of the initiator to the monohalide is (1-2) mL: 1 mol.

[0036] Furthermore, in the step (2), the molar ratio of the Grignard reagent, the compound represented by formula (I), the catalyst and the ligand is (2-3):1:(0.03-0.06):(0.03-0.06).

[0037] Compared with the prior art, the present invention has the following advantages:

[0038] The invention conducts a cross-coupling reaction between a Grignard reagent generated by the reaction of a monocyclic halogenated compound with metallic magnesium and a halogenated nitrogen-containing heterocyclic compound with protected amino groups, and then removes the amino group protection through acid and alkali to obtain the desired naphthalene derivative with nitrogen-containing heterocyclic ring. The invention has the advantages of convenient synthesis, simple process, high yield, low cost, etc., and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the NMR spectrum of the product 2-(naphthalen-2-ylmethyl)pyrrolidine in Example 1. DETAILED DESCRIPTION

[0040] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments and comparative examples.

[0041] The raw materials and ingredients used in the following examples and comparative examples are all commercially available.

[0042] Example 1

[0043] This example provides 2-(naphthalen-2-ylmethyl)pyrrolidine The preparation method, the method route and method adopted are as follows:

[0044]

[0045] Step 1: Under nitrogen atmosphere, magnesium chips (960 mg, 40 mmol) and cyclopentanehexyl methyl ether (CPME) (4.0 mL) were added to a 100 ml three-necked flask, 2-bromonaphthalene (0.28 g) and 0.06 mL dimethoxyethoxyaluminum hydride (AlH(OMe)2Et2 were added to initiate the reaction, and then the remaining 2-bromonaphthalene (8.0 g) was added to the reaction solution within one hour, and the mixture was then kept warm and refluxed for one hour, the solvent was spin-dried, and the resulting material was directly used in the next step.

[0046] Step 2: Under ice bath conditions, add tert-butyl 2-(iodomethyl)-1-pyrrolidinecarboxylate (3.5 g, 1 eq), bis(triphenylphosphine)cobalt chloride (Co(PPh3)2Cl2) (0.35 g, 0.05 eq) and tetramethylethylenediamine (TMEAD) (0.06 g, 0.05 eq) to a 100 ml three-necked flask, add 10 mL of THF tetrahydrofuran, stir to mix evenly, then add 2-naphthylmagnesium bromide (5.78 g, 2.5 eq) obtained in the previous step, stir the reaction until the temperature reaches room temperature, and react for 8 hours until the reaction is completed. The residue was extracted with EtOAc (2×20 mL), washed with water for several times, and the organic phases were combined, dried over anhydrous Na2SO4 and spin-dried. After re-dissolving in EA, it was purified by column chromatography (ethyl acetate / petroleum ether (V / V=1 / 10) as the eluent), and spin-dried to give tert-butyl 2-(naphthalene-2-ylmethyl)pyrrolidine-1-carboxylate (3.36 g, 98%).

[0047] Step 3: The tert-butyl 2-(naphthalene-2-ylmethyl)pyrrolidine-1-carboxylate (3.36 g) obtained in the previous step, tetrahydrofuran (20 mL), and 4N HCl (20 mL) were added to a 100 ml three-necked flask, stirred and reacted at 40° C. for 8 hours, the tetrahydrofuran solvent was spin-dried, and the mixture was extracted four times with ethyl acetate (4×30 mL). The pH of the aqueous phase was adjusted to 9.5 with sodium hydroxide solution, and then the organic phase was extracted with dichloromethane, dried over anhydrous Na2SO4, and spin-dried to obtain the product 2-(naphthalene-2-ylmethyl)pyrrolidine (2.1 g, 99.3%). The results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0048] 1 H NMR(400MHz,D2O)δ7.79(m,4H),7.44(m,3H),3.81(m,1H),3.28(dt,1H),3.15(m,3H),1.98(m,3H),1.70(m,1H).

[0049] Example 2

[0050] This example provides 3-(naphthalen-1-ylmethyl)pyrrolidine The preparation method of the invention is as follows: the steps are as follows: Example 1, except that the raw material 2-bromonaphthalene is replaced with 1-bromonaphthalene in the first step, and the raw material 2-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester is replaced with 3-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester in the second step, and the product 3-(naphthalene-1-ylmethyl)pyrrolidine (2.12 g, 97.4%) is finally obtained, and the results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0051] 1 H NMR(400MHz,D2O)δ7.96(m,3H),7.44(m,4H),2.91(m,6H),2.41(hept,1H),1.76(m,2H).

[0052] Example 3

[0053] This example provides 2-(naphthalen-1-ylmethyl)pyrrolidine The preparation method of the invention is as follows: the steps are as follows: Example 1, except that the raw material 2-bromonaphthalene is replaced with 1-bromonaphthalene in the first step, and the product 2-(naphthalene-1-ylmethyl)pyrrolidine (2.09 g, 97.3%) is finally obtained, and the results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0054] 1 H NMR(400MHz,D2O)δ7.94(m,3H),7.40(m,4H),3.27(m,1H),2.88(m,4H),1.70(m,4H).

[0055] Example 4

[0056] This example provides 3-(naphthalen-2-ylmethyl)pyrrolidine The preparation method of the invention is as follows: the steps are as in Example 1, except that the raw material 2-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester is replaced with 3-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester in the second step, and the product 3-(naphthalen-2-ylmethyl)pyrrolidine (2.15 g, 97.6%) is finally obtained, and the results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0057] 1 H NMR(400MHz,D2O)δ7.80(m,4H),7.44(m,3H),2.96(m,4H),2.73(d,2H),2.46(hept,1H),1.79(m,2H).

[0058] Example 5

[0059] This example provides 3-(naphthalen-1-ylmethyl)azetidine The preparation method of the invention is as follows: the steps are as follows: Example 1, except that the raw material 2-bromonaphthalene is replaced with 1-bromonaphthalene in the first step, and the raw material 2-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester is replaced with 3-(iodomethyl)azetidine-1-carboxylic acid tert-butyl ester in the second step, and the product 3-(naphthalene-1-ylmethyl)azetidine (1.92 g, 97.0%) is finally obtained, and the results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0060] 1 H NMR(400MHz,D2O)δ8.16(dd,1H),7.86(ddt,2H),7.42(m,4H),3.17(m,4H),2.86(d,2H),2.35(hept,1H).

[0061] Example 6

[0062] This example provides 3-(naphthalen-2-ylmethyl)azetidine The preparation method of the invention is as follows: the steps are as in Example 1, except that the raw material 2-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester is replaced with 3-(iodomethyl)azetidine-1-carboxylic acid tert-butyl ester in the second step, and the product 3-(naphthalene-2-ylmethyl)azetidine (1.94 g, 97.1%) is finally obtained, and the results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0063] 1 H NMR(400MHz,D2O)δ7.83(m,3H),7.52(m,3H),7.16(dd,1H),3.15(m,4H),2.66(d,2H),2.37(hept,1H).

[0064] Example 7

[0065] This example provides 2-(naphthalen-1-ylmethyl)azetidine The preparation method of the invention is as follows: the steps are as follows: Example 1, except that the raw material 2-bromonaphthalene is replaced with 1-bromonaphthalene in the first step, and the raw material 2-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester is replaced with 2-(iodomethyl)azetidine-1-carboxylic acid tert-butyl ester in the second step, and the product 2-(naphthalene-1-ylmethyl)azetidine (1.91 g, 96.9%) is finally obtained, and the results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0066] 1 H NMR(400MHz,D2O)δ8.15(dd,1H),7.88(ddt,2H),7.40(m,4H),3.27(dp,1H),2.99(m,4H),1.90(q,2H).

[0067] Example 8

[0068] This example provides 2-(naphthalen-2-ylmethyl)azetidine The preparation method of the invention is as follows: the steps are as in Example 1, except that the raw material 2-(iodomethyl)-1-pyrrolidinecarboxylic acid tert-butyl ester is replaced with 2-(iodomethyl)azetidine-1-carboxylic acid tert-butyl ester in the second step, and the product 2-(naphthalene-2-ylmethyl)azetidine (1.89 g, 96.8%) is finally obtained, and the results of hydrogen nuclear magnetic resonance spectrum are as follows:

[0069] 1 H NMR(400MHz,D2O)δ7.80(m,3H),7.49(m,3H),7.19(dd,1H),3.30(dp,1H),3.04(tdd,2H),2.74(m,2H),1.88(q,2H).

[0070] Example 9

[0071] This example provides another method for preparing 2-(naphthalene-2-ylmethyl)pyrrolidine, and the steps are basically the same as those in Example 1, except that the reaction solvent cyclopentylhexyl methyl ether in step 1 is replaced with DMF, and the reaction solvent tetrahydrofuran in steps 2 and 3 is replaced with 1,4-dioxane, and the remaining operations are exactly the same as those in Example 1, and the product 2-(naphthalene-2-ylmethyl)pyrrolidine (1.39 g, 64.6%) is finally obtained.

[0072] Example 10

[0073] This example provides another method for preparing 2-(naphthalene-2-ylmethyl)pyrrolidine, and the steps are basically the same as those in Example 1, except that the initiator dimethoxyethoxyaluminum hydride in step 1 is replaced with molecular iodine, and the remaining operations are exactly the same as those in Example 1, and the product 2-(naphthalene-2-ylmethyl)pyrrolidine (1.21 g, 56.1%) is finally obtained.

[0074] Embodiment 11

[0075] This example provides another method for preparing 2-(naphthalene-2-ylmethyl)pyrrolidine, and the steps are basically the same as those in Example 1, except that the ligand tetramethylethylenediamine in step 2 is replaced with ethyl diaminoformate, and the remaining operations are exactly the same as those in Example 1, and the product 2-(naphthalene-2-ylmethyl)pyrrolidine (1.72 g, 79.6%) is finally obtained.

[0076] The above detailed description of the present invention is intended to enable those skilled in the art to understand the contents of the present invention and implement them, but it does not limit the protection scope of the present invention. The present invention is not limited to the above embodiments, and any equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for preparing a naphthalene derivative having a nitrogen-containing heterocyclic ring, characterized in that: Firstly, a monohalogenated naphthalene compound is reacted with metal magnesium to generate a Grignard reagent, and then the Grignard reagent is reacted with a compound represented by formula (I), and the reaction product is subjected to acid-base treatment to remove the carbamate protecting group to obtain a naphthalene derivative having a nitrogen-containing heterocyclic ring represented by formula (II); Wherein, R1 in formula (I) is a carbamate protecting group, X is a halogen atom, and m and n in formula (I) and formula (II) are independently 1, 2 or 3.

2. The preparation method according to claim 1, characterized in that: The monohalogenated naphthalene is a bromide of naphthalene, a chloride of naphthalene or an iodide of naphthalene.

3. The preparation method according to claim 1, characterized in that: X in the formula (I) is fluorine, iodine, bromine or chlorine; and / or, the carbamate protecting group in the formula (I) is methoxyacyl, ethoxyacyl, tert-butyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl or trichloroethoxycarbonyl; And / or, in the formula (I) and formula (II), m is 1 or 2, and n is 1.

4. The preparation method according to claim 3, characterized in that: The monohalogenated naphthalene is a brominated naphthalene, the carbamate protecting group in the formula (I) is a tert-butyloxycarbonyl group, and m in the formula (I) and the formula (II) is 1 or 2, and n is 1.

5. The preparation method according to claim 1, characterized in that: The initiator of the Grignard reaction is one or more of dimethoxyethoxyaluminum hydride, ammonium persulfate, potassium persulfate, iodine, and 1,2-dibromoethane; And / or, the reaction solvent of the Grignard reaction is one or more of cyclopentanehexyl methyl ether, dimethyl sulfoxide, N,N-dimethylformamide, 2-methyltetrahydrofuran, dioxane, and tert-butyl methyl ether; And / or, the format reaction is performed under reflux.

6. The preparation method according to claim 1, characterized in that: The Grignard reagent reacts with the compound represented by formula (I) in the presence of a catalyst and a ligand, wherein the catalyst is one or more of bis(triphenylphosphine)cobalt chloride, bis(triphenylphosphine)nickel chloride, and bis(triphenylphosphine)palladium chloride, and the ligand is one or more of tetramethylethylenediamine, diethylamine, diaminoethanol, and diethylcarbamate; And / or, the reaction of the Grignard reagent with the compound represented by formula (I) is carried out in any one solvent of tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane or dimethylformamide or a mixed solvent of multiple thereof; And / or, the reaction of the Grignard reagent with the compound represented by formula (I) is carried out at room temperature.

7. The preparation method according to claim 1, characterized in that: The reaction of removing the carbamate protecting group is carried out in any one solvent or a mixed solvent of tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane or dimethylformamide; And / or, the acid-base removal of carbamate protecting groups is carried out at 35-45°C.

8. The preparation method according to claim 1, characterized in that: The preparation method specifically comprises the following steps: (1) Under a nitrogen atmosphere, a monohalide of naphthalene and metallic magnesium are subjected to a reflux reaction in the presence of an initiator and a first solvent, and after the reaction is completed, the first solvent is dried to obtain a Grignard reagent; (2) under ice bath conditions, the Grignard reagent of step (1), the compound represented by formula (I), the catalyst and the ligand are mixed with a second solvent, the Grignard reagent of step (1) is added, and the reaction is carried out at room temperature. After the reaction is completed, the obtained reaction solution is extracted with ethyl acetate, washed with water, purified by column chromatography, and the purified product is used for the next reaction; (3) The purified product obtained in step (2), the hydrochloric acid solution and the third solvent are mixed and reacted at 35 to 45° C. After the reaction is completed, the third solvent is dried by spin drying, redissolved in water, extracted with ethyl acetate, the pH of the aqueous phase is adjusted to 9 to 10 with a sodium hydroxide solution, extracted with dichloromethane, and the organic phase is dried over anhydrous Na2SO4. The dichloromethane is dried by spin drying to obtain a naphthalene derivative having a nitrogen-containing heterocyclic ring represented by formula (II).

9. The preparation method according to claim 8, characterized in that: The first solvent is cyclopentanehexyl methyl ether, the second solvent and the third solvent are tetrahydrofuran respectively, the initiator is dimethoxyethoxyaluminum hydride, the catalyst is bis(triphenylphosphine)cobalt chloride, and the ligand is tetramethylethylenediamine.

10. The preparation method according to claim 8, characterized in that: In the step (1), the monohalide of naphthalene is added in batches, and the reflux reaction time is 0.5 to 2 hours; In the step (2), the reaction time at room temperature is 6 to 10 hours; In the step (3), the reaction time at 35-45° C. is 6-10 hours.

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