A method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source

Abstract

The present application relates to a method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source, which comprises mixing a pyridine quaternary phosphonium salt, a copper catalyst and a ligand, adding an organic solvent and a reducing agent under a carbon dioxide atmosphere, quenching after reaction by acidification, obtaining a crude product of isonicotinic acid compounds, and further preparing isonicotinic acid methyl compounds after esterification. The method has excellent functional group compatibility, and can be used for precise late-stage carbon-hydrogen bond carboxylation modification of complex molecules such as pyridine drugs. Based on the method, isonicotinic acid compounds can also be synthesized by one-pot method directly from pyridine compounds. The synthesis practicability of the method is verified on a kilogram scale, showing significant industrial application potential.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and in particular relates to a method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source. Background Technology

[0002] Since the industrial era, excessive carbon dioxide emissions have triggered a series of severe climate problems, seriously threatening the safety and stability of the human living environment. However, from a chemical perspective, carbon dioxide is also a cheap, readily available, renewable, and green source of C1. Utilizing carbon dioxide resources through organic synthesis to transform it into high-value-added chemicals is of great significance.

[0003] The pyridine skeleton is one of the most prevalent heterocyclic skeletons in drugs and bioactive natural products. Research on pyridine has long been a focus of synthetic chemists. Isonicotinic acid compounds, in particular, are core building blocks of many bioactive molecules, and are even precursors for the drug isoniazid. However, current synthesis of isonicotinic acid compounds still primarily relies on the oxidation of 4-methylpyridine, which involves demanding conditions, complex steps, and makes the synthesis of complex isonicotinic acid molecules particularly difficult. Therefore, using carbon dioxide as a carboxyl source to prepare isonicotinic acid compounds aligns with green chemistry principles and facilitates the efficient development of novel isonicotinic acid compounds. As novel, simple, and high-value-added pyridine functionalization precursors, developing their carboxylation reactions with carbon dioxide for the efficient preparation of novel isonicotinic acid compounds is of significant research importance. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source.

[0005] The technical solution adopted in this invention is: a methyl isonicotinic acid compound with any of the following structures;

[0006]

[0007] An isonicotinic acid compound with any of the following structures;

[0008]

[0009] A method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source involves mixing pyridine quaternary phosphate salt, a copper catalyst, and a ligand, adding an organic solvent and a reducing agent under a carbon dioxide atmosphere, and then quenching the reaction with acid to obtain crude isonicotinic acid compounds.

[0010] Preferably, the crude isonicotinic acid compound is further esterified to obtain isonicotinic acid methyl ester compounds.

[0011] Preferably, the pyridine ring of the pyridine quaternary phosphonium salt has one or more of the following groups: aryl, cyano, ester, alkynyl, halogen atom, alkyl, and alkyloxy group;

[0012] Preferably, the aryl group is a phenyl group with or without substituents. When the phenyl group has substituents, the substituents are halogens (fluorine, chlorine, bromine) or alkyl groups (alkyl group is C1). m H (2m+1) - where 1≤m≤6), alkyloxy group (alkyl group is C1) m H (2m+1) - where 1≤m≤6), one or more of ester and cyano groups.

[0013] Preferably, the ester group is a methyl ester group or an ethyl ester group; the alkynyl group is a phenylacetynyl group; the halogen atom is one or more of fluorine, chlorine and bromine atoms; and the alkyl group is C. m H (2m+1) - where 1 ≤ m ≤ 6; alkyloxy group is C m H (2m+1) O-, where 1≤m≤6.

[0014] Preferably, the copper catalyst is one or a combination of copper inorganic salts, copper alkoxides, copper carboxylates and copper ketones; more preferably, it is a copper halide salt, and even more preferably, it is cuprous chloride.

[0015] Preferably, the ligand is one or more combinations of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), triphenylphosphine, N,N'-dibenzyloxalyldiamine, N,N,N',N'-tetramethylethylenediamine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline and 2,2'-bipyridine;

[0016] The preferred formulation is N,N,N',N'-tetramethylethylenediamine or 4,7-diphenyl-1,10-phenanthroline.

[0017] Preferably, the phenanthroline and bipyridine skeleton may or may not contain the same or different substituents such as alkyl, alkoxy, and aryl groups.

[0018] Preferably, the alkyl group is C m H (2m+1) - where 1 ≤ m ≤ 6; alkyloxy group is C m H (2m+1) O-, where 1≤m≤6; aryl is phenyl.

[0019] Preferably, the solvent is one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and acetonitrile; more preferably, it is N,N-dimethylacetamide.

[0020] Preferably, the reducing agent is one or more of the following: a 1-2 mol / L diethylzinc solution, samarium powder, bis(pentamethylcyclopentadiene)cobalt, and cobalt dicene, and more preferably a 2 mol / L diethylzinc toluene solution.

[0021] Preferably, the specific preparation method is as follows:

[0022] Step 1: Add pyridine quaternary phosphonium salt, copper catalyst, and ligand to the reaction vessel; the molar ratio of pyridine quaternary phosphonium salt, copper catalyst, and ligand is 1:0.05-0.1:0.1-1;

[0023] Step 2: Replace the reaction atmosphere in the container with a carbon dioxide atmosphere, add solvent and reducing agent using a syringe, and stir the reaction at room temperature;

[0024] Step 3: After the reaction is complete, add a dioxane solution of hydrogen chloride at a concentration of 1-4 mol / L for acid quenching. After stirring, extract with ethyl acetate and water to purify the organic phase product and obtain crude isonicotinic acid compounds.

[0025] Preferably, it further includes step 4;

[0026] Step 4: Add ether and methanol to the crude isonicotinic acid compound product. The volume ratio of ether to methanol is 4:1. Slowly add a hexane solution of trimethylsilyldiazomethane at a concentration of 1-4 mol / L. Stir the reaction at room temperature and separate and purify by column chromatography to obtain isonicotinic acid methyl ester compounds.

[0027] Preferably, a prefabrication step is included before step 1, as follows:

[0028] Preparative steps: Add pyridine compound and dichloromethane to a reaction vessel under an argon atmosphere, cool to -78°C, add trifluoromethanesulfonic anhydride dropwise, add triphenylphosphine powder after the reaction, add triethylamine dropwise after the reaction, heat to room temperature, add water to quench the reaction, purify the organic phase product to obtain pyridine phosphonium salt, which can be used in the reaction in step 1.

[0029] Isonicotinic acid compounds prepared by a method using carbon dioxide as a carboxyl source.

[0030] Isonicotinic acid methyl ester compounds prepared by a method using carbon dioxide as a carboxyl source.

[0031] The advantages and positive effects of this invention are: a novel method for synthesizing isonicotinic acid compounds by reacting pyridine quaternary phosphate substrates with carbon dioxide; this method uses carbon dioxide as a green C1 resource, is catalyzed by inexpensive copper metal, and prepares isonicotinic acid compounds in an organic solution at room temperature and atmospheric pressure; the reaction process is novel and the conditions are simple and mild.

[0032] This reaction exhibits excellent functional group compatibility, a broad substrate range, and for the first time enables one-pot, one-step carboxylation conversion of some complex pyridine drug molecules.

[0033] Furthermore, this reaction can prepare a series of novel isonicotinic acid compounds in high yields on a gram-scale basis, demonstrating significant application potential in both industrial production and new drug development. Detailed Implementation

[0034] The embodiments of the present invention will be described below.

[0035] This invention relates to a method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source. The method involves mixing pyridine quaternary phosphate, a copper catalyst, and a ligand, adding an organic solvent and a reducing agent under a carbon dioxide atmosphere at 1 standard atmosphere, quenching the reaction with acid, extracting and concentrating to obtain a crude isonicotinic acid compound, and then separating and purifying it after esterification to obtain isonicotinic acid methyl ester compounds.

[0036] Specifically, pyridine quaternary phosphate, copper catalyst, and ligand are mixed, and an organic solvent and diethylzinc solution are added under a carbon dioxide atmosphere at 1 atm. The reaction yields crude isonicotinic acid compounds, which are then esterified with trimethylsilyldiazomethane and purified by column chromatography to obtain isonicotinic acid methyl ester products. The reaction first involves the reaction of the reducing agent diethylzinc with cuprous chloride to generate an active zero-valent copper species. This zero-valent copper species reacts with pyridine quaternary phosphate via single-electron transfer to give monovalent pyridine copper (Py-4-CuL). The C-Cu bond of this intermediate is then inserted into the carbon dioxide, generating a monovalent pyridine carboxylated copper intermediate (PyCO2CuL). This intermediate is then converted to pyridine carboxylated zinc (PyCO2ZnEt) under the action of diethylzinc, thus regenerating the zero-valent copper species and completing the catalytic cycle. The pyridine carboxylated zinc species is protonated to obtain isonicotinic acid products, which are then subjected to a post-treatment esterification step to obtain isonicotinic acid methyl ester products.

[0037] This novel reaction method, compared to the harsh traditional oxidation methods using 4-methylpyridine compounds, offers simpler and milder conditions and exhibits groundbreaking functional group tolerance. Furthermore, this method is simple, mild, and can prepare a series of previously unreported high-value-added isonicotinic acid and isonicotinic acid methyl ester compounds.

[0038]

[0039] According to the above reaction formula, the specific preparation steps are as follows:

[0040] Step 1: Add pyridine quaternary phosphonium salt, copper catalyst, and ligand to the reaction vessel; the molar ratio of pyridine quaternary phosphonium salt, copper catalyst, and ligand is 1:0.05-0.1:0.1-1;

[0041] Step 2: Replace the reaction atmosphere in the container with a carbon dioxide atmosphere, add the solvent and reducing agent with a syringe under a carbon dioxide gas stream, and stir the reaction at room temperature;

[0042] Step 3: After the reaction is complete, add a solution of dioxane containing hydrogen chloride at a concentration of 1-4 mol / L for acidification. Stir for 10 minutes, extract with 150 mL of ethyl acetate and 50 mL of water, dry the organic phase with anhydrous sodium sulfate, and remove ethyl acetate by rotary evaporation to obtain crude isonicotinic acid compounds.

[0043] Step 4: Add diethyl ether (4 mL) and methanol (1 mL) to the crude product, and slowly add 2 mL of a hexane solution of trimethylsilyldiazomethane with a concentration of 1-4 mol / L. Stir the reaction at room temperature, remove the solvent, and then separate by column chromatography to obtain isonicotinic acid methyl ester products.

[0044] The pyridine quaternary phosphonium salt structure is shown in the reaction formula, where R represents an aryl group (preferably a phenyl group with or without substituents), a cyano group, an ester group (preferably a methyl ester group or an ethyl ester group), an alkynyl group (preferably a phenylethynyl group), a halogen atom (preferably fluorine, chlorine, or bromine), or an alkyl group (C). m H (2m+1) - where 1≤m≤6), alkyloxy (C m H (2m+1) O-, where 1≤m≤6) or more; when the above aryl group has a substituent, the substituent is a halogen (fluorine, chlorine, bromine), an alkyl group (C m H (2m+1) - where 1≤m≤6), alkyloxy (C m H (2m+1) O-, where 1≤m≤6), ester group (methyl ester group and ethyl ester group) and cyano group, one or more of them.

[0045] The copper catalyst is one or a combination of copper inorganic salts, copper alkoxides, copper carboxylates and copper ketones; preferably a copper halide, and more preferably cuprous chloride.

[0046] The ligand is one or more combinations of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), triphenylphosphine, N,N'-dibenzyloxalyldiamine, N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, and 2,2'-bipyridine. The phenanthroline and bipyridine skeleton may or may not contain an alkyl group (C). m H (2m+1) - where 1≤m≤6), alkoxy (C m H (2m+1)O-, where 1≤m≤6), phenyl or other similar or different substituents. Preferably, it is N,N,N',N'-tetramethylethylenediamine or 4,7-diphenyl-1,10-phenanthroline.

[0047] In step two, the solvent is one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and acetonitrile; preferably N,N-dimethylacetamide.

[0048] In step two, the reducing agent is one or more of the following: a 1-2 mol / L diethylzinc solution, samarium powder, bis(pentamethylcyclopentadiene)cobalt, and cobalt dicene, preferably a 2 mol / L diethylzinc toluene solution.

[0049] In some embodiments of the present invention, the pyridine compound can be phosphated first and then carboxylated according to the above steps to directly synthesize isonicotinic acid compounds from the pyridine compound in a one-pot process, as shown in the following reaction formula.

[0050]

[0051] The process includes a preparative step before step 1, where pyridine quaternary phosphide is synthesized from pyridine compounds via a C4 site selective carbon-hydrogen bond phosphating reaction. The preparative step involves adding pyridine compounds and dichloromethane to a reaction vessel under an argon atmosphere, cooling to -78°C, adding trifluoromethanesulfonic anhydride dropwise, reacting with triphenylphosphine powder, reacting with triethylamine, heating to room temperature, quenching the reaction with water, and purifying the organic phase product to obtain pyridine quaternary phosphine, which can be used in step 1 to prepare isonicotinic acid methyl ester compounds.

[0052] In the above preparation method, the pyridine quaternary phosphate substrate is prepared by selective phosphating at position 4 starting from pyridine. The preparation steps are simple and exhibit excellent selectivity. This method provides an efficient indirect synthesis of isonicotinic acid compounds from pyridine, enabling the preparation of isonicotinic acid compounds using carbon dioxide as the C1 source. It also allows for precise late-stage carboxylation modification of complex pyridine drugs, providing an effective pathway for the development of novel isonicotinic acid drugs. Furthermore, the practical value of this method has been validated on a gram-scale, demonstrating significant industrial application prospects.

[0053] The above method can be used to prepare compounds with structures as shown in Formula 1-28.

[0054]

[0055]

[0056]

[0057] Among them, the compounds shown in formulas 4, 5, 7, 8, 12, 13, 14, 15, 24, 25, 26, 27 and 28 are new isonicotinic acid compounds.

[0058] It is also possible to prepare compounds with structures as shown in Formulas 29-32.

[0059]

[0060] Formulas 31 and 32 are novel isonicotinic acid compounds.

[0061] The present invention will now be described. Experimental methods that do not specify the operation steps are performed in accordance with the corresponding product manuals. Unless otherwise specified, the instruments, reagents and consumables used in the embodiments can be purchased from commercial companies.

[0062] Example 1:

[0063]

[0064] Preparation of methyl 2-phenylisonicotinic acid (compound of formula 1):

[0065] In a 50 mL Schlenk tube, 0.3 mmol of p-2-phenylpyridine quaternary phosphate substrate (Formula 1a) and 0.03 mmol of cuprous chloride were added sequentially. The reaction flask was then completely purged with carbon dioxide, and 1 mL of N,N-dimethylacetamide, 0.3 mmol of N,N,N',N'-tetramethylethylenediamine, and 0.6 mL of diethylzinc solution (2.0 mol / L toluene solution) were added sequentially under a 1 atm carbon dioxide stream. The mixture was then stirred at room temperature for 12 hours. After the reaction was complete, the solution was acidified with 2 mL of 1 mol / L dioxane hydrochloride solution, stirred for 5 minutes, and then extracted with 150 mL of ethyl acetate and 50 mL of water. The extract was dried and concentrated to obtain crude 2-phenylisonicotinic acid.

[0066] Add 4 mL of diethyl ether and 1 mL of methanol to the above crude 2-phenylisonicotinic acid. Slowly add 2 mL of trimethylsilyldiazomethane solution (2.0 mol / L n-hexane solution) while stirring. After reacting for 5 minutes, concentrate the solution by rotary evaporation, prepare a dry sample, and separate and purify by column chromatography with petroleum ether / ethyl acetate as the developing solvent to obtain the target product methyl 2-phenylisonicotinic acid as shown in Formula 1, with a yield of 83%.

[0067] 1 H NMR (CDCl3, 400MHz): δ8.82(d,J=4.8Hz,1H),8.29(s,1H),8.05(d,J=7.2Hz,2H),7.76(d,J=4.8Hz,1H),7.51-7.42(m,3H),3.97(s,3H).

[0068] Example 2:

[0069]

[0070] Preparation of methyl 2-(p-Tolyl)isonicotinic acid (compound 2):

[0071] The preparation process was the same as in Example 1, except that 2-(p-tolyl)pyridine quaternary phosphonium salt (compound of formula 1b) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(p-tolyl)isonicotinic acid methyl ester as shown in formula 2 was obtained with a yield of 77%.

[0072] 1 H NMR (CDCl3, 600MHz): δ8.82 (d, J = 4.2Hz, 1H), 8.27 (s, 1H), 7.95 (d, J = 7.8Hz, 2H),7.75(d,J=4.2Hz,1H),7.30(d,J=7.8Hz,2H),3.98(s,3H),2.42(s,3H).

[0073] Example 3:

[0074]

[0075] Preparation of methyl 2-(4-chlorophenyl)isonicotinic acid (compound of formula 3):

[0076] The preparation process was the same as in Example 1, except that 2-(4-chlorophenyl)pyridine quaternary phosphonium salt (compound of formula 1c) was used instead of compound 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(4-chlorophenyl)isonicotinic acid methyl ester of formula 3 was obtained after treatment, with a yield of 86%.

[0077] 1 H NMR (CDCl3, 400MHz): δ8.82 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 3.99 (s, 3H).

[0078] Example 4:

[0079]

[0080] Preparation of methyl 2-(4-bromophenyl)isonicotinic acid (compound of formula 4):

[0081] The preparation process was the same as in Example 1, except that 2-(4-bromophenyl)pyridine quaternary phosphonium salt (compound of formula 1d) was used instead of compound 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(4-bromophenyl)isonicotinic acid methyl ester of formula 3 was obtained after treatment, with a yield of 74%.

[0082] 1 H NMR (CDCl3, 400MHz): δ8.81 (dd, J1=5.2, J2=0.8Hz, 1H), 8.25 (t, J=1.2Hz1H), 7.92 (d ,J=8.4Hz,1H),7.77(dd,J1=5.0,J2=1.4Hz,1H),7.60(d,J=8.8Hz,2H),3.98(s,3H).

[0083] Example 5:

[0084]

[0085] Preparation of methyl 2-(4-(methoxycarbonyl)phenyl)isonicotinic acid (compound 5):

[0086] The preparation process was the same as in Example 1, except that 2-(4-(methoxycarbonyl)phenyl)pyridine quaternary phosphonium salt (compound of formula 1e) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product methyl 2-(4-(methoxycarbonyl)phenyl)isonicotinic acid, as shown in formula 5, was obtained with a yield of 70%.

[0087] 1 H NMR (CDCl3, 600MHz): δ8.83(d,J=4.8Hz,1H),8.31(s,1H),8.12(d,J=7.2Hz,4H),7.79(d,J=4.2Hz,1H),3.97(s,3H),3.93(s,3H).

[0088] Example 6:

[0089]

[0090] Preparation of methyl 2-([1,1'-biphenyl]-4-yl)isonicotinic acid (compound of formula 6):

[0091] The preparation process was the same as in Example 1, except that 2-([1,1'-biphenyl]-4-yl)pyridine quaternary phosphonium salt (compound of formula 1f) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-([1,1'-biphenyl]-4-yl)isonicotinic acid methyl ester, as shown in formula 6, was obtained with a yield of 85%.

[0092] 1H NMR (CDCl3, 600MHz): δ8.85 (d, J = 4.2Hz, 1H), 8.34 (s, 1H), 8.15 (d, J = 7.8Hz, 2H), 7.77 (d, J = 2.4Hz, 1H), 7.74(d,J=7.8Hz,2H),7.67(d,J=7.2Hz,2H),7.47(t,J=6.8Hz,2H),7.38(t,J=6.6Hz,1H),3.99(s,3H).

[0093] Example 7:

[0094]

[0095] Preparation of methyl 2-(4-vinylphenyl)isonicotinic acid (compound of formula 7):

[0096] The preparation process was the same as in Example 1, except that 2-(4-vinylphenyl)pyridine quaternary phosphonium salt (compound of formula 1g) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(4-vinylphenyl)isonicotinic acid methyl ester of formula 7 was obtained after treatment, with a yield of 86%.

[0097] 1 H NMR (CDCl3, 600MHz): δ8.79(d,J=4.2Hz,1H),8.26(s,1H),8.02(d,J=7.8Hz,2H),7.72(d,J=4.2Hz,1H),7.51( d,J=7.8Hz,2H),6.75(dd,J1=17.4,J2=10.8Hz,1H),5.82(d,J=18Hz,1H),5.30(d,J=10.8Hz,1H),3.95(s,3H).

[0098] Example 8:

[0099]

[0100] Preparation of methyl 2-(3-(phenylethynyl)phenyl)isonicotinic acid:

[0101] The preparation process was the same as in Example 1, except that 2-(3-(phenylethynyl)phenyl)pyridine quaternary phosphonium salt (compound of formula 1h) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(3-(phenylethynyl)phenyl)isonicotinic acid methyl ester, as shown in formula 8, was obtained with a yield of 90%.

[0102] 1H NMR (CDCl3, 600MHz): δ8.85(d,J=4.8Hz,1H),8.32(s,1H),8.24(s,1H),8.04(d,J=7.8Hz,1H),7.80(d,J=4.8H z,1H),7.61(d,J=7.2Hz,1H),7.57(d,J=5.4Hz,2H),7.49(t,J=7.8Hz,1H),7.36(d,J=6.6Hz,3H),4.00(s,3H).

[0103] Example 9:

[0104]

[0105] Preparation of methyl 2-(3-bromophenyl)isonicotinic acid:

[0106] The preparation process was the same as in Example 1, except that 2-(3-bromophenyl)pyridine quaternary phosphonium salt (compound of formula 1i) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(3-bromophenyl)isonicotinic acid methyl ester as shown in formula 9 was obtained with a yield of 83%.

[0107] 1 H NMR (CDCl3, 600MHz): δ8.80 (d, J = 4.8Hz, 1H), 8.22 (d, J = 13.2Hz, 2H), 7.94 (d, J = 7.2Hz ,1H),7.77(d,J=4.2Hz,1H),7.54(d,J=7.8Hz,1H),7.33(t,J=7.8Hz,1H),3.97(s,3H).

[0108] Example 10:

[0109]

[0110] Preparation of methyl 2-(3-(trifluoromethyl)phenyl)isonicotinic acid (compound of formula 10):

[0111] The preparation process was the same as in Example 1, except that 2-(3-(trifluoromethyl)phenyl)pyridine quaternary phosphonium salt (compound of formula 1j) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(3-(trifluoromethyl)phenyl)isonicotinic acid methyl ester, as shown in formula 10, was obtained with a yield of 78%.

[0112] 1H NMR (CDCl3, 600MHz): δ8.84(s,1H),8.34(s,1H),8.30(s,1H),8.22(d,J=7.2H z,1H),7.81(s,1H),7.68(d,J=7.2Hz,1H),7.60(t,J=7.2Hz,1H),3.99(s,3H).

[0113] Example 11:

[0114]

[0115] Preparation of methyl 2-(2,4-difluorophenyl)isonicotinic acid (compound 11):

[0116] The preparation process was the same as in Example 1, except that 2-(2,4-difluorophenyl)pyridine quaternary phosphonium salt (compound of formula 1k) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(2,4-difluorophenyl)isonicotinic acid methyl ester of formula 11 was obtained after treatment, with a yield of 71%.

[0117] 1 H NMR (CDCl3, 600MHz): δ8.83 (d, J = 4.8Hz, 1H), 8.29 (s, 1H), 8.01 (q, J = 8.4Hz, 1H), 7.79 (d, J = 4.4Hz, 1H), 7.02-6.91 (m, 2H), 3.97 (s, 3H).

[0118] Example 12:

[0119]

[0120] Preparation of methyl 2-(4-bromo-3-methoxyphenyl)isonicotinic acid (compound 12):

[0121] The preparation process was the same as in Example 1, except that 2-(4-bromo-3-methoxyphenyl)pyridine quaternary phosphonium salt (compound of formula 11) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(4-bromo-3-methoxyphenyl) isonicotinic acid methyl ester, as shown in formula 12, was obtained with a yield of 84%.

[0122] 1 H NMR (CDCl3, 600MHz): δ8.76-8.75 (m, 1H), 8.26 (d, J = 2.4Hz, 1H), 8.17 (s, 1H), 7.95 (dd, J1 = 8.6Hz, J 2=2.2Hz,1H),7.70(dd,J1=5.0Hz,J2=1.4Hz,1H),6.96(d,J=8.8Hz,1H),3.96(s,3H),3.93(s,3H).

[0123] Example 13:

[0124]

[0125] Preparation of methyl 2-(naphth-2-yl)isonicotinic acid (compound of formula 13):

[0126] The preparation process was the same as in Example 1, except that 2-(naphth-2-yl)pyridine quaternary phosphonium salt (compound of formula 1m) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(naphth-2-yl)isonicotinic acid methyl ester of formula 13 was obtained after treatment, with a yield of 84%.

[0127] 1 H NMR (CDCl3, 600MHz): δ8.75 (d, J = 3.6Hz, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.07 (d, J = 7.8Hz, 1H),7.83(d,J=7.2Hz,2H),7.75(s,1H),7.66(d,J=2.4Hz,1H),7.40(s,2H),3.87(s,3H).

[0128] Example 14:

[0129]

[0130] Preparation of methyl 2-(anthracite-9-yl)isonicotinic acid (compound of formula 14):

[0131] The preparation process was the same as in Example 1, except that 2-(anthracene-9-yl)pyridine quaternary phosphonium salt (compound of formula 1n) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(anthracene-9-yl)isonicotinic acid methyl ester, as shown in formula 14, was obtained with a yield of 83%.

[0132] 1 H NMR (CDCl3, 600MHz): δ9.09 (d, J = 5.4Hz, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 8.07 ( d,J=8.4Hz,2H),8.03(d,J=4.8Hz,1H),7.54(d,J=9.0Hz,1H),7.48(t,J=7.2Hz 2H),7.40(t,J=7.2Hz,1H),3.96(s,3H).

[0133] Example 15:

[0134]

[0135] Preparation of methyl 2-(9,9-dimethyl-9H-fluoren-2-yl)isonicotinic acid (compound of formula 15):

[0136] The preparation process was the same as in Example 1, except that 2-(9,9-dimethyl-9H-fluoren-2-yl)pyridine quaternary phosphonium salt (compound of formula 1o) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(9,9-dimethyl-9H-fluoren-2-yl)isonicotinic acid methyl ester, as shown in formula 15, was obtained with a yield of 79%.

[0137] 1 H NMR (CDCl3, 600MHz): δ8.87(d,J=4.8Hz,1H),8.37(s,1H),8.19(s,1H),8.06(d,J=7.8Hz,1H),7.84 (d,J=7.8Hz,1H),7.79-7.77(m,2H),7.48(d,J=6.6Hz,1H),7.36(s,2H),4.00(s,3H),1.58(s,6H).

[0138] Example 16:

[0139]

[0140] Preparation of methyl 2-(thien-2-yl)isonicotinic acid (compound of formula 16):

[0141] The preparation process was the same as in Example 1, except that 2-(thiophene-2-yl)pyridine quaternary phosphonium salt (compound of formula 1p) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(thiophene-2-yl)isonicotinic acid methyl ester of formula 16 was obtained after treatment, with a yield of 75%.

[0142] 1 H NMR (CDCl3, 600MHz): δ8.68 (d, J = 4.8Hz, 1H), 8.17 (s, 1H), 7.67-7.65 (m, 2H), 7.42 (d, J = 4.8Hz, 1H), 7.12 (t, J = 3.8Hz 1H), 3.97 (s, 3H).

[0143] Example 17:

[0144]

[0145] Preparation of methyl 2-(thiophene-3-yl)isonicotinic acid (compound of formula 17):

[0146] The preparation process was the same as in Example 1, except that 2-(thiophene-3-yl)pyridine quaternary phosphonium salt (compound of formula 1q) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(thiophene-3-yl)isonicotinic acid methyl ester of formula 17 was obtained after treatment, with a yield of 69%.

[0147] 1 H NMR (CDCl3, 600MHz): δ8.70(d,J=4.8Hz,1H),8.11(s,1H),7.95(d,J=1.8Hz,1H),7.68-7.64(m,2H),7.37(dd,J1=4.8Hz J2=3.0Hz,1H),3.93(s,3H)..

[0148] Example 18:

[0149]

[0150] Preparation of methyl 2-(benzofuran-2-yl)isonicotinic acid (compound 18):

[0151] The preparation process was the same as in Example 1, except that 2-(benzofuran-2-yl)pyridine quaternary phosphonium salt (compound of formula 1r) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-(benzofuran-2-yl)isonicotinic acid methyl ester of formula 18 was obtained after treatment, with a yield of 87%.

[0152] 1 H NMR (CDCl3, 600MHz): δ8.62 (d, J=2.4Hz 1H),8.22(s,1H),7.58–7.57(m,1H),7.48(d,J=7.2Hz,1H),7.41(d,J=7.8Hz ,1H),7.31(s,1H),7.19(t,J=7.4Hz,1H),7.10(t,J=7.2Hz,1H),3.82(s,3H).

[0153] Example 19:

[0154]

[0155] Preparation of methyl 2-cyanoisonicotinic acid (compound 19):

[0156] The preparation process was the same as in Example 1, except that 2-cyanopyridine quaternary phosphonium salt (compound of formula 1s) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product methyl 2-cyanoisonicotinic acid, as shown in formula 19, was obtained with a yield of 74%.

[0157] 1H NMR (CDCl3, 600MHz): δ8.87 (d, J=4.8Hz, 1H), 8.21 (s, 1H), 8.06 (dd, J1=4.8Hz, J2=1.2Hz, 1H), 3.99 (s, 3H).

[0158] Example 20:

[0159]

[0160] Preparation of methyl 3-chloroisonicotinic acid (compound 20):

[0161] The preparation process was the same as in Example 1, except that 3-chloropyridine quaternary phosphonium salt (compound of formula 1t) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product methyl 3-chloroisonicotinic acid, as shown in formula 20, was obtained with a yield of 44%.

[0162] 1 H NMR (CDCl3, 400MHz): δ8.72 (s, 1H), 8.59 (d, J = 2.8Hz, 1H), 7.75 (d, J = 4.4Hz, 1H), 3.96 (s, 3H).

[0163] Example 21:

[0164]

[0165] Preparation of methyl 2-cyano-3-methylisonicotinic acid (compound 21):

[0166] The preparation process was the same as in Example 1, except that 2-cyano-3-methylpyridine quaternary phosphonium salt (compound of formula 1u) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-cyano-3-methylisonicotinic acid methyl ester of formula 21 was obtained after treatment, with a yield of 52%.

[0167] 1 H NMR (CDCl3, 400MHz): δ8.64 (d, J = 4.8Hz, 1H), 7.87 (d, J = 4.8Hz, 1H), 3.96 (s, 3H), 2.78 (s, 3H).

[0168] Example 22:

[0169]

[0170] Preparation of methyl 2-cyano-6-methylisonicotinate (compound 22):

[0171] The preparation process was the same as in Example 1, except that 2-cyano-6-methylpyridine quaternary phosphonium salt (compound of formula 1v) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2-cyano-6-methylisonicotinic acid methyl ester of formula 22 was obtained after treatment, with a yield of 65%.

[0172] 1 H NMR (CDCl3, 600MHz): δ8.64 (d, J = 4.8Hz, 1H), 7.87 (d, J = 4.8Hz, 1H), 3.96 (s, 3H), 2.78 (s, 3H).

[0173] Example 23:

[0174]

[0175] Preparation of methyl 5-cyano-2-methylisonicotinate (compound of formula 23):

[0176] The preparation process was the same as in Example 1, except that 5-cyano-2-methylpyridine quaternary phosphonium salt (compound of formula 1w) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product methyl 5-cyano-2-methylisonicotinate of formula 23 was obtained after treatment, with a yield of 46%.

[0177] 1 H NMR (CDCl3, 400MHz): δ8.91(s,1H),7.82(s,1H),4.02(s,3H),2.70(s,3H).

[0178] Example 24:

[0179]

[0180] Preparation of methyl 5-methyl-2-phenylisonicotinic acid (compound of formula 24):

[0181] The preparation process was the same as in Example 1, except that 5-methyl-2-phenylpyridine quaternary phosphonium salt (compound of formula 1x) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product methyl 5-methyl-2-phenylisonicotinic acid ester of formula 24 was obtained after treatment, with a yield of 58%.

[0182] 1 H NMR (CDCl3, 400MHz): δ8.82(d,J=4.8Hz,1H),8.26(s,1H),7.95(d,J=8.0Hz,2H),7 .74(dd,J1=4.8Hz,J2=1.4Hz,1H),7.29(d,J=8.0Hz,2H),3.98(s,3H),2.41(s,3H).

[0183] Example 25:

[0184]

[0185] Preparation of methyl 2-methyl-5-(phenylethynyl)isonicotinic acid (compound 25):

[0186] The preparation process was the same as in Example 1, except that 2-methyl-5-(phenylethynyl)pyridine quaternary phosphonium salt (compound of formula 1y) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product methyl 2-methyl-5-(phenylethynyl)isonicotinic acid, as shown in formula 25, was obtained with a yield of 66%.

[0187] 1 H NMR (CDCl3, 600MHz): δ8.78(s,1H),7.64(s,1H),7.58-7.56(m,2H),7.36–7.35(m,3H),3.98(s,3H),2.62(s,3H).

[0188] Example 26: Carboxylic acid methyl esterification of pterostilbene derivatives

[0189]

[0190] Preparation of (E)-2-(4-(3,5-dimethoxystyryl)phenyl)isonicotinic acid methyl ester (compound of formula 26):

[0191] The preparation process was the same as in Example 1, except that (E)-2-(4-(3,5-dimethoxystyryl)phenyl)pyridine quaternary phosphonium salt (compound of formula 1z) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product E)-2-(4-(3,5-dimethoxystyryl)phenyl)isonicotinic acid methyl ester, as shown in formula 26, was obtained with a yield of 66%.

[0192] 1 H NMR (CDCl3, 400MHz): δ8.82 (d, J = 5.2Hz, 1H), 8.30 (s, 1H), 8.07 (d, J = 8.4Hz, 2H), 7.75 (dd, J1 = 4.8Hz, J2 = 1.2Hz, 1H),7.62(d,J=8.0Hz,2H),7.12(s,2H),6.69(d,J=2.0Hz,2H),6.41(t,J=2.0Hz,1H),3.99(s,3H),3.83(s,6H).

[0193] Example 27: Bisacodyl carboxylic acid methyl esterification

[0194]

[0195] Preparation of (4-(methoxycarbonyl)pyridin-2-yl)methylene)bis(4,1-phenylene)diacetate (compound 27):

[0196] The preparation process was the same as in Example 1, except that (4-(methoxycarbonyl)pyridin-2-yl)methylene)bis(4,1-phenylene)diacetate quaternary phosphonium salt (compound of formula 1aa) was used instead of compound 1aa. The reaction was carried out at room temperature for 12 hours, and the target product (4-(methoxycarbonyl)pyridin-2-yl)methylene)bis(4,1-phenylene)diacetate as shown in formula 27 was obtained with a yield of 45%.

[0197] 1 H NMR (CDCl3, 400MHz): δ8.74(d,J=5.4Hz,1H),7.70(s,2H),7.19(d,J=8.4Hz,4H),7.03(d,J=8.4Hz,4H),5.71(s,1H),3.92(s,3H),2.28(s,6H).

[0198] Example 28: Loratadine carboxylic acid methyl esterification

[0199]

[0200] Preparation of methyl-8-chloro-11-(1-(ethoxycarbonyl)piperidin-4-ylidene)-6-11-dihydro-5H-benzo[5,6]cycloheptane[1,2-b]pyridine-4-carboxylic acid (compound of formula 28):

[0201] The preparation process was the same as in Example 1, except that loratadine quaternary phosphonium salt (compound of formula 1ab) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product methyl-8-chloro-11-(1-(ethoxycarbonyl)piperidin-4-ylidene)-6-11-dihydro-5H-benzo[5,6]cycloheptane[1,2-b]pyridine-4-carboxylic acid, as shown in formula 28, was obtained with a yield of 39%.

[0202] 1 H NMR (CDCl3, 600MHz): δ8.50 (s, 1H), 7.52 (s, 1H), 7.26-7.20 (m, 2H), 7.12 (d, J = 7.2Hz, 1H), 4.04 (d, J = 5.4Hz, 2H), 3.89 (s ,2H),3.67-3.58(m,2H),3.34-3.15(m,4H),2.92(t,J=11.4Hz,1H),2.38-2.24(m,3H),2.06(d,J=12Hz1H),1.18(s,3H).

[0203] Example 29:

[0204]

[0205] One-pot preparation of 2-phenylisonicotinic acid (compound of formula 29):

[0206]

[0207] A magnetic flask was filled with a magnet and purged to an argon atmosphere. 2-Phenyridine (compound of formula 1A, 10 mmol) and 100 mL of dichloromethane were added under an argon flow. The mixture was cooled to -78 °C, and then trifluoromethanesulfonic anhydride (11 mmol) was added dropwise using a syringe. After 0.5 h, triphenylphosphine powder (11 mmol) was added under an argon flow. The reaction was continued for another 0.5 h, and then triethylamine (11 mmol) was added dropwise using a syringe. The mixture was gradually brought to room temperature and stirred for another 0.5 h until the reaction was complete. The reaction was quenched with 150 mL of water, extracted, and separated. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude 2-phenylpyridine phosphate product.

[0208] In a 500 mL Schlenk flask, crude p-2-phenylpyridine phosphate and cuprous chloride (1 mmol) were added sequentially. The reaction flask was then completely purged with carbon dioxide. Under a 1 atm carbon dioxide stream, 30 mL of N,N-dimethylacetamide, 10 mmol of N,N,N',N'-tetramethylethylenediamine, and 20 mL of diethylzinc solution (2.0 mol / L toluene solution) were added sequentially, followed by stirring at room temperature for 12 hours. After the reaction was complete, the mixture was acidified with 1 mol / L dioxane hydrochloride solution, stirred for 5 minutes, and then extracted with ethyl acetate and water. After drying and concentration, crude 2-phenylisonicotinic acid was obtained. The crude product was prepared by dry chromatography and purified by column chromatography using ethyl acetate and acetic acid as the developing solvent, yielding the target product 2-phenylisonicotinic acid (Formula 29) in 58% yield.

[0209] 1 H NMR (DMSO-d6, 600MHz): δ13.74 (s, 1H), 8.85 (d, J = 4.8Hz, 1H), 8.28 (s, 1H), 8.11 (d ,J=7.8Hz,2H),7.77(d,J=4.8Hz,1H),7.51(t,J=7.5Hz,2H),7.46(t,J=7.2Hz,1H).

[0210] Example 30:

[0211]

[0212] One-pot preparation of 2-(3-bromophenyl)isonicotinic acid (compound of formula 30):

[0213] The preparation process was the same as in Example 29, except that 2-(3-bromophenyl)pyridine (compound of formula 1B) was used instead of 2-phenylpyridine. Phosphating and carboxylation were carried out in a one-pot process. After post-treatment separation and purification, 1.28 g of the target product 2-(4-vinylphenyl)isonicotinic acid, as shown in formula 30, was obtained, with a yield of 44%.

[0214] 1 H NMR (DMSO-d6, 400MHz): δ13.82 (s, 1H), 8.86 (d, J = 4.8Hz, 1H), 8.32 (d, J = 6.0Hz, 2H), 8.1 3(d,J=8.0Hz,1H),7.81(d,J=4.0Hz,1H),7.67(d,J=8.4Hz,1H),7.49(d,J=7.8Hz,1H)..

[0215] Example 31:

[0216]

[0217] One-pot preparation of 2-(4-vinylphenyl)isonicotinic acid (compound of formula 31):

[0218] The preparation process was the same as in Example 29, except that 2-(4-vinylphenyl)pyridine (compound of formula 1C) was used instead of 2-phenylpyridine. Phosphating and carboxylation were carried out in a one-pot process. After post-treatment separation and purification, 1.28 g of the target product 2-(4-vinylphenyl)isonicotinic acid, as shown in formula 30, was obtained, with a yield of 57%.

[0219] 1 H NMR (DMSO-d6, 400MHz): δ13.76 (s, 1H), 8.85-8.84 (m, 1H), 8.30 (s, 1H), 8.12 (d, J = 6.8Hz, 2H), 7.77-7.76 (m, 1 H), 7.62 (d, J = 6.8Hz, 2H), 6.81 (dd, J1 = 17.5, J2 = 10.9Hz, 1H), 5.94 (d, J = 17.6Hz, 2H), 5.34 (d, J = 10.9Hz, 2H).

[0220] Example 32:

[0221]

[0222] Preparation of 2-(bis(4-acetoxyphenyl)methyl)isonicotinic acid (compound of formula 32):

[0223] The preparation process was the same as in Example 29, except that 2-(bis(4-acetoxyphenyl)methyl)pyridine (compound of formula 1D) was used instead of 2-phenylpyridine, and DBU was used instead of triethylamine. Phosphating and carboxylation were carried out in a one-pot process. After post-treatment separation and purification, 0.97 g of the target product 2-(bis(4-acetoxyphenyl)methyl)isonicotinic acid, as shown in formula 32, was obtained, with a yield of 23%.

[0224] 1 H NMR (DMSO-d6, 400MHz): δ13.68(s,1H),8.76(d,J=5.2Hz,1H),7.75(s,1H),7.69(dd,J1=5 .2,J2=1.2Hz,1H),7.28(d,J=8.4Hz,4H),7.07(d,J=8.4Hz,4H),5.89(s,1H),2.24(s,6H).

[0225] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the patent coverage of the present invention.

Claims

1. A method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source, characterized in that: The pyridine quaternary phosphonium salt, copper catalyst and ligand were mixed, and an organic solvent and reducing agent were added under a carbon dioxide atmosphere. The reaction was then quenched by acidification to obtain crude isonicotinic acid compounds. The structure of pyridine quaternary phosphonium salt is as follows As shown, R represents one or more of aryl, cyano, methyl ester, ethyl ester, phenylethynyl, halogen atom, alkyl of 1-6 carbons, and alkyloxy of 1-6 carbons; when the aryl group has a substituent, the substituent is one or more of halogen, alkyl of 1-6 carbons, alkyloxy of 1-6 carbons, methyl ester, ethyl ester, and cyano. The copper catalyst is cuprous chloride; the ligand is N , N , N ', N '-Tetramethylethylenediamine; reducing agent is diethylzinc.

2. The method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source according to claim 1, characterized in that: The crude isonicotinic acid compounds were further esterified to obtain isonicotinic acid methyl ester compounds.

3. The method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source according to claim 1, characterized in that: The solvent is N , N -Dimethylformamide, N , N -Dimethylacetamide, N A combination of one or more of methylpyrrolidone and acetonitrile.

4. The method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source according to any one of claims 1-3, characterized in that: The specific preparation method is as follows: Step 1: Add pyridine quaternary phosphonium salt, copper catalyst, and ligand to the reaction vessel; the molar ratio of pyridine quaternary phosphonium salt, copper catalyst, and ligand is 1:0.05~0.1:0.1~1; Step 2: Replace the reaction atmosphere in the container with a carbon dioxide atmosphere, add solvent and reducing agent using a syringe, and stir the reaction at room temperature; Step 3: After the reaction is complete, add a dioxane solution of hydrogen chloride (1-4 mol / L) for acid quenching. After stirring, extract with ethyl acetate and water to purify the organic phase product and obtain crude isonicotinic acid compounds.

5. The method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source according to claim 4, characterized in that: It also includes step 4; Step 4: Add diethyl ether and methanol to the crude isonicotinic acid compound product in a volume ratio of 4:

1. Slowly add a hexane solution of trimethylsilyldiazomethane at a concentration of 1-4 mol / L. Stir the reaction at room temperature and separate and purify by column chromatography to obtain isonicotinic acid methyl ester compounds.

6. The method for preparing isonicotinic acid compounds using carbon dioxide as a carboxyl source according to claim 4, characterized in that: The process before step 1 includes a prefabrication step, as detailed below: Preparative steps: Add pyridine compound and dichloromethane to a reaction vessel under an argon atmosphere, cool to -78°C, add trifluoromethanesulfonic anhydride dropwise, add triphenylphosphine powder after the reaction, add triethylamine dropwise after the reaction, heat to room temperature, add water to quench the reaction, purify the organic phase product to obtain pyridine phosphonium salt, which can be used in the reaction in step 1.

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