CN115925622A - Synthesis method of 3-cyanopyridine-2-ylcarbamic acid tert-butyl ester - Google Patents
Synthesis method of 3-cyanopyridine-2-ylcarbamic acid tert-butyl ester Download PDFInfo
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- RFHQQCPMIZEBHT-UHFFFAOYSA-N tert-butyl n-(3-cyanopyridin-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=NC=CC=C1C#N RFHQQCPMIZEBHT-UHFFFAOYSA-N 0.000 title claims description 27
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 28
- YYXDQRRDNPRJFL-UHFFFAOYSA-N 2-aminopyridine-3-carbonitrile Chemical compound NC1=NC=CC=C1C#N YYXDQRRDNPRJFL-UHFFFAOYSA-N 0.000 claims abstract description 27
- -1 3-cyanopyridine-2-yl tert-butyl Chemical group 0.000 claims abstract description 27
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 23
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 19
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 15
- LCZVKKUAUWQDPX-UHFFFAOYSA-N tert-butyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl]amino]acetate Chemical compound CC(=O)OC1=CC=CC=C1CN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1=CC=CC=C1OC(C)=O LCZVKKUAUWQDPX-UHFFFAOYSA-N 0.000 claims abstract description 12
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 claims abstract description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract 9
- 238000003756 stirring Methods 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000005457 ice water Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 17
- 238000001704 evaporation Methods 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000002244 precipitate Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000007792 addition Methods 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims 3
- 238000004807 desolvation Methods 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- TXQAZWIBPGKHOX-UHFFFAOYSA-N 1H-indol-3-amine Chemical compound C1=CC=C2C(N)=CNC2=C1 TXQAZWIBPGKHOX-UHFFFAOYSA-N 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 101710082513 C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 101710113864 Heat shock protein 90 Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000569 anti-influenzal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- HQUZGPRCOSFHKF-UHFFFAOYSA-N methanamine;pyridine Chemical class NC.C1=CC=NC=C1 HQUZGPRCOSFHKF-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- CWHFDTWZHFRTAB-UHFFFAOYSA-N phenyl cyanate Chemical compound N#COC1=CC=CC=C1 CWHFDTWZHFRTAB-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- ORUGTGTZBRUQIT-UHFFFAOYSA-N tert-butyl n-pyridin-2-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC=N1 ORUGTGTZBRUQIT-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pyridine Compounds (AREA)
Abstract
The invention discloses a method for synthesizing 3-cyanopyridine-2-yl tert-butyl carbamate, which is characterized by comprising the following steps: (1) Reacting the 2-chloronicotinonitrile with an ammonia solution to obtain 2-aminonicotinonitrile; (2) Reacting 2-amino nicotinonitrile with Boc anhydride to obtain (3-cyanopyridin-2-yl) nitrilic dicarboxylic acid di-tert-butyl ester; (3) The method has the advantages of simple process line, mild reaction condition, high yield, lower production cost and suitability for large-scale production.
Description
Technical Field
The invention relates to the field of medicine and pesticide intermediates, in particular to a synthetic method of (3-cyanopyridine-2-yl) tert-butyl carbamate.
Background
The (3-cyanopyridin-2-yl) carbamic acid tert-butyl ester is an important intermediate of medicines and pesticides; the pyridine methylamine type compound is a pyridine derivative with insecticidal activity, has the advantages of wide insecticidal spectrum, high efficiency, low toxicity, good systemic plant conductivity, long lasting period and the like, and plays an important role in creating novel high-efficiency pesticides. In addition, it can also synthesize 3-amino azaindole compounds. Azaindole derivatives are often found in natural products and have highly potent biological activity; among them, 3-aminoindole as a derivative of indole skeleton shows a wide range of biological activities such as antitumor, antimitotic agents antimalarial, anti-influenza and antimalarial activities. On the other hand, 3-amino nitrogen indoles also possess heat shock protein 90 (Hsp 90) which has been identified as potential antagonists and inhibitors of the C-X-C chemokine receptor type 4 (CXCR 4) receptor.
The synthesis of tert-butyl (3-cyanopyridin-2-yl) carbamate is reported in the literature, and only Tetrahedron,2003, vol.59, #31, p.5831-5836, the synthesis of which is reported in that 2- (tert-butoxycarbonylamino) pyridine and phenylcyanate are used as raw materials, and the reaction with butyllithium is carried out at ultralow temperature to obtain the target product with the yield of 31%. The method has the advantages of high raw material price, low yield and poor social and economic benefits; in addition, butyl lithium requires a relatively low temperature, the reagent is expensive and highly flammable, the operation is complex and unsafe, and the industrial cost is high; therefore, the process is not suitable for large-scale production.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthetic method of (3-cyanopyridine-2-yl) carbamic acid tert-butyl ester, which has the advantages of simple process line, mild reaction condition, high yield, lower production cost and suitability for large-scale production.
The technical scheme adopted by the invention for solving the technical problems is as follows: a synthetic method of (3-cyanopyridin-2-yl) carbamic acid tert-butyl ester comprises the following steps
(1) Reacting the 2-chloronicotinonitrile with an ammonia solution to obtain 2-aminonicotinonitrile;
(2) Reacting 2-aminonicotinonitrile with Boc anhydride to obtain (3-cyanopyridin-2-yl) nitrilodicarboxylic acid di-tert-butyl ester;
(3) Reacting di-tert-butyl 3-cyanopyridin-2-yl) nitriledicarboxylate with a base to remove one molecule of Boc to obtain tert-butyl (3-cyanopyridin-2-yl) carbamate.
The specific process of the step (1) is as follows: after the 2-chloronicotinonitrile is added into the ammonia solution, slowly raising the temperature to T1 under stirring, keeping the temperature to be more than or equal to 20 ℃ and less than or equal to 200 ℃ and reacting overnight under the T1, the next day, cooling to room temperature after the TLC detection reaction is completed, then reducing the pressure and evaporating the reaction mixed solution, pouring the residue into ice water, stirring for 1 hour, controlling the temperature to be not more than 5 ℃, forming a precipitate, filtering, and drying the filter cake to obtain the light yellow solid 2-aminonicotinonitrile.
Further, the ammonia solution is ethanol ammonia solution, methanol ammonia solution and ammonia water.
The specific process of the step (2) is as follows: dissolving 2-amino-3-cyanopyridine in a solvent, adding a catalyst N, N-dimethyl-4-aminopyridine, cooling to 5 ℃ in an ice water bath after adding, beginning to dropwise add di-tert-butyl dicarbonate, releasing heat in the reaction, controlling the temperature to be not higher than 15 ℃, controlling the temperature to react at T2, T2 being not lower than 10 ℃ and not higher than 100 ℃ after completing the dropwise adding, after TLC detection reaction is completed, evaporating the reaction mixed solution under reduced pressure, adding dichloromethane into the residue, stirring to dissolve the residue, washing with saturated salt twice, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain yellow solid (3-cyanopyridin-2-yl) di-tert-butyl nitridocarboxylate.
Further, the solvent is one or any combination of acetonitrile, 1,4-dioxane, tetrahydrofuran, DMF and DMSO.
Further, the mass ratio of the 2-amino-3-cyanopyridine to the di-tert-butyl dicarbonate is 1: (1-5).
The specific process of the step (3) is as follows: dissolving (3-cyanopyridin-2-yl) nitrilic dicarboxylic acid di-tert-butyl ester in a solvent, then adding basic carbonate, stirring for 1 hour at normal temperature after adding, then controlling the temperature to react at the temperature of more than or equal to T3 and less than or equal to 100 ℃, after TLC detection reaction is completed, evaporating reaction mixed liquor under reduced pressure, adding residue into water, stirring for dissolving, extracting for 3 times by using dichloromethane after stirring for dissolving, combining organic phases, washing the organic phases with saturated salt twice, drying by using anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain (3-cyanopyridin-2-yl) carbamic acid tert-butyl ester.
Further, the solvent is one or any combination of ethanol, methanol, isopropanol, 1,4-dioxane, tetrahydrofuran, DMF and DMSO; the basic carbonate is one of potassium carbonate, sodium carbonate, cesium carbonate and ammonium carbonate.
Further, the mass ratio of the (3-cyanopyridin-2-yl) nitrilic acid di-tert-butyl ester to the basic carbonate is 1: (1-7).
Compared with the prior art, the invention has the advantages that: the invention discloses a synthesis method of (3-cyanopyridine-2-yl) tert-butyl carbamate, which comprises the three steps of taking 2-chloronicotinonitrile as a raw material, firstly reacting with ammonia solution to obtain 2-aminonicotinonitrile, then reacting with Boc anhydride to obtain 3-cyanopyridine-2-yl) nitrilic dicarboxylic acid di-tert-butyl ester, and finally removing one molecule of Boc to obtain (3-cyanopyridine-2-yl) tert-butyl carbamate.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of tert-butyl (3-cyanopyridin-2-yl) carbamate synthesized by the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
A synthetic method of (3-cyanopyridin-2-yl) carbamic acid tert-butyl ester is characterized by comprising the following steps
(1) Reacting the 2-chloronicotinonitrile with an ammonia solution to obtain 2-aminonicotinonitrile;
(2) Reacting 2-aminonicotinonitrile with Boc anhydride to obtain (3-cyanopyridin-2-yl) nitrilodicarboxylic acid di-tert-butyl ester;
(3) Reacting di-tert-butyl 3-cyanopyridin-2-yl) nitrilodicarboxylate with alkali to remove one molecule of Boc to obtain tert-butyl (3-cyanopyridin-2-yl) carbamate, wherein the synthetic route is as follows:
the specific process of the step (1) is as follows: after the 2-chloronicotinonitrile is added into the ammonia solution, slowly raising the temperature to T1 under stirring, keeping the temperature to be more than or equal to 20 ℃ and less than or equal to 200 ℃ and reacting overnight under the T1, the next day, cooling to room temperature after the TLC detection reaction is completed, then reducing the pressure and evaporating the reaction mixed solution, pouring the residue into ice water, stirring for 1 hour, controlling the temperature to be not more than 5 ℃, forming a precipitate, filtering, and drying the filter cake to obtain the light yellow solid 2-aminonicotinonitrile. Wherein the ammonia solution is ethanol ammonia solution, methanol ammonia solution and ammonia water.
The specific process of the step (2) is as follows: dissolving 2-amino-3-cyanopyridine in a solvent, adding a catalyst N, N-dimethyl-4-aminopyridine, cooling to 5 ℃ in an ice water bath after adding, beginning to dropwise add di-tert-butyl dicarbonate, releasing heat in the reaction, controlling the temperature to be not higher than 15 ℃, controlling the temperature to react at T2, T2 being not lower than 10 ℃ and not higher than 100 ℃ after completing the dropwise adding, after TLC detection reaction is completed, evaporating the reaction mixed solution under reduced pressure, adding dichloromethane into the residue, stirring to dissolve the residue, washing with saturated salt twice, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain yellow solid (3-cyanopyridin-2-yl) di-tert-butyl nitridocarboxylate. Wherein the solvent is one or any combination of acetonitrile, 1,4-dioxane, tetrahydrofuran, DMF and DMSO; the mass ratio of 2-amino-3-cyanopyridine to di-tert-butyl dicarbonate is 1: (1-5).
The specific process of the step (3) is as follows: dissolving di-tert-butyl (3-cyanopyridin-2-yl) nitrilodicarboxylate in solvent, adding basic carbonate, stirring at normal temperature for 1 hr, and controlling the temperature at T3 and 10 deg.C
Reacting at the temperature of more than or equal to T3 and less than or equal to 100 ℃, after TLC detection reaction is complete, evaporating the reaction mixed solution under reduced pressure, adding the residue into water, stirring and dissolving the residue clearly, extracting the residue for 3 times by using dichloromethane, combining organic phases, washing the organic phases twice by using saturated salt solution, drying the organic phases by using anhydrous sodium sulfate, and performing desolventization under reduced pressure to obtain the (3-cyanopyridin-2-yl) carbamic acid tert-butyl ester. Wherein the solvent is one or any combination of ethanol, methanol, isopropanol, 1,4-dioxane, tetrahydrofuran, DMF and DMSO; the basic carbonate is one of potassium carbonate, sodium carbonate, cesium carbonate and ammonium carbonate. Wherein the mass ratio of di-tert-butyl (3-cyanopyridin-2-yl) nitrilecarboxylate to basic carbonate is 1: (1-7).
Example 1
1. Synthesis of 2-aminonicotinonitrile
Adding 3L of saturated ethanol ammonia solution and 120g (0.87 mol) of 2-chloronicotinonitrile into a 5L autoclave, slowly raising the temperature to 130 ℃ under stirring after the addition is finished, keeping the temperature for reaction overnight, detecting the reaction is finished the next day by TLC, and reducing the temperature of EA: PE =1:2 (Rf = 0.3) to room temperature, then evaporating the reaction mixture under reduced pressure, pouring the residue into 1kg of ice water, stirring for 1 hour, controlling the temperature to be not higher than 5 ℃, forming a precipitate, filtering, drying a filter cake to obtain 2-aminonicotinonitrile 90g of light yellow solid, and obtaining MP with the yield of 87 percent.
2. Synthesis of di-tert-butyl (3-cyanopyridin-2-yl) nitrilecarboxylate
Adding 300mL of tetrahydrofuran into a 1L reaction bottle, adding 24g (0.20 mol) of 2-amino-3-cyanopyridine and 2g of 4-dimethylaminopyridine under stirring at normal temperature, cooling to 5 ℃ in an ice water bath, starting to dropwise add 99g (0.45 mol) of di-tert-butyl dicarbonate (dissolved in 200mL of tetrahydrofuran), carrying out reaction heat release, controlling the temperature to be not higher than 15 ℃, stirring for 1 hour at room temperature after dropwise adding, and then heating to 35 ℃ for reaction overnight. The next day, the reaction was complete by TLC, EA: PE =1:2 (Rf = 0.6), cooled to room temperature, then the reaction mixture was evaporated to dryness under reduced pressure, 300mL dichloromethane was added to the residue, after stirring to dissolve it clearly, washed twice with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to give a residue, 200mL petroleum ether was added to the residue, the residue was cooled to 5 ℃ in an ice water bath, stirred for 0.5 hour to form a precipitate, filtered, and the filter cake was dried to give 61g of yellow solid with a yield of 95%.
3. Synthesis of tert-butyl (3-cyanopyridin-2-yl) carbamate
Adding 900mL of methanol into a 1L reaction bottle, adding 32g (0.10 mol) of (3-cyanopyridin-2-yl) nitrous dicarboxylic acid di-tert-butyl ester and 50g (0.36 mol) of potassium carbonate under stirring, stirring at normal temperature for reaction overnight, detecting the reaction completion by TLC the next day, then evaporating the reaction mixed solution under reduced pressure, adding 200mL of water into the residue, stirring and dissolving, extracting with dichloromethane (200mL x 3), combining organic phases, washing the organic phases twice with saturated saline (100 mL x 2), drying with anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a residue, adding 100mL of petroleum ether, cooling the residue to 5 ℃ in an ice water bath, stirring for 0.5 hour to form a precipitate, filtering, and drying a filter cake to obtain 20.5g of a white solid with the yield of 93%. The NMR spectrum of tert-butyl (3-cyanopyridin-2-yl) carbamate is shown in FIG. 1, 1H NMR (400MHz, DMSO-d 6): δ 1.58 (s, 9H), 7.15 (dd, J =7.6,4.8Hz, 1H), 7.90 (br.s, 1H) 7.97 (d, J =7.6Hz, 1H), 8.63 (d, J =4.8Hz, 1H).
Example 2
1. Synthesis of 2-aminonicotinonitrile
Adding 3L of saturated ethanol ammonia solution and 120g (0.87 mol) of 2-chloronicotinonitrile into a 5L autoclave, after the addition is finished, slowly raising the temperature to 170 ℃ under stirring, keeping the temperature for reaction overnight, and detecting the reaction completion by TLC the next day, wherein EA is PE =1:2 (Rf = 0.3), cooling to room temperature, then evaporating the reaction mixture under reduced pressure, pouring the residue into 1kg of ice water, stirring for 1 hour, controlling the temperature to be not higher than 5 ℃, forming a precipitate, filtering, and drying a filter cake to obtain a light yellow solid 2-aminonicotinonitrile 81g, MP 133-135 with the yield of 78 percent.
2. Synthesis of di-tert-butyl (3-cyanopyridin-2-yl) nitriledicarboxylate
Adding 300mL of tetrahydrofuran into a 1L reaction bottle, adding 24g (0.20 mol) of 2-amino-3-cyanopyridine and 2g of 4-dimethylaminopyridine under stirring at normal temperature, cooling to 5 ℃ in an ice water bath after the addition is finished, beginning to dropwise add 99g (0.45 mol) of di-tert-butyl dicarbonate (dissolved in 200mL of tetrahydrofuran), carrying out reaction heat release, controlling the temperature to be not higher than 15 ℃, and stirring at room temperature for reaction overnight after the dropwise addition is finished. The next day, TLC detects that the reaction is complete, EA: PE =1:2 (Rf = 0.6), cooling to room temperature, then evaporating the reaction mixture to dryness under reduced pressure, adding 300mL dichloromethane to the residue, stirring to dissolve, washing twice with saturated saline (100 mL. Times.2), drying with anhydrous sodium sulfate, desolventizing under reduced pressure, adding 200mL petroleum ether to the residue, cooling to 5 ℃ in an ice water bath, stirring for 0.5 hour to form a precipitate, filtering, and drying the filter cake to obtain 58g of yellow solid with yield of 90%.
3. Synthesis of tert-butyl (3-cyanopyridin-2-yl) carbamate
Adding 900mL of methanol into a 1L reaction bottle, adding 32g (0.10 mol) of (3-cyanopyridin-2-yl) nitrous dicarboxylic acid di-tert-butyl ester and 50g (0.36 mol) of potassium carbonate under stirring, stirring for 1 hour at normal temperature, then heating to 40 ℃ to react for 2 hours, detecting by TLC that the reaction is complete, cooling to room temperature, then evaporating the reaction mixture to dryness under reduced pressure, adding 200mL of water into the residue, stirring and dissolving, extracting by dichloromethane (200mL x 3), combining organic phases, washing the organic phases twice by saturated saline (100 mL x 2), drying by anhydrous sodium sulfate, removing the solution under reduced pressure to obtain a residue, adding 100mL of petroleum ether, cooling to 5 ℃ by an ice water bath, stirring for 0.5 hour to form a precipitate, filtering, drying the filter cake to obtain 19g of a white solid, and obtaining the yield of 87%.
Example 3
1. Synthesis of 2-aminonicotinonitrile
Adding 25wt% of concentrated ammonia water 3L and 120g (0.87 mol) of 2-chloronicotinonitrile into a 5L autoclave, after the addition is finished, slowly raising the temperature to 170 ℃ under stirring, keeping the temperature for reaction overnight, detecting the reaction completion by TLC the next day, and reducing the temperature of EA: PE =1:2 (Rf = 0.3) to room temperature, then evaporating the reaction mixture under reduced pressure, pouring the residue into 1kg of ice water, stirring for 1 hour, controlling the temperature to be not higher than 5 ℃, forming a precipitate, filtering, drying a filter cake to obtain a light yellow solid 2-aminonicotinonitrile 77g, MP 133-135, wherein the yield is 75 percent.
2. Synthesis of di-tert-butyl (3-cyanopyridin-2-yl) nitriledicarboxylate
Adding 300mL of tetrahydrofuran into a 1L reaction bottle, adding 24g (0.20 mol) of 2-amino-3-cyanopyridine and 2g of 4-dimethylaminopyridine into the reaction bottle under normal temperature and stirring, cooling the reaction bottle to 5 ℃ in an ice water bath, starting to dropwise add 99g (0.45 mol) of di-tert-butyl dicarbonate (dissolved in 200mL of tetrahydrofuran), carrying out reaction heat release, controlling the temperature to be not higher than 15 ℃, stirring the reaction bottle for 1 hour at room temperature after the dropwise addition is finished, and then heating the reaction bottle to 65 ℃ for reaction overnight. The next day, the reaction was complete by TLC detection, EA: PE =1:2 (Rf = 0.6), cooled to room temperature, then evaporated to dryness under reduced pressure, 300mL dichloromethane was added to the residue, after stirring to dissolve it clear, washed twice with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to give a residue, 200mL petroleum ether was added to the residue, cooled to 5 ℃ in an ice water bath, stirred for 0.5 hour to form a precipitate, filtered, and the filter cake was dried to give 56g of a yellow solid with a yield of 87%.
3. Synthesis of tert-butyl (3-cyanopyridin-2-yl) carbamate
Adding 900mL of methanol into a 1L reaction bottle, adding 32g (0.10 mol) of (3-cyanopyridin-2-yl) nitrous dicarboxylic acid di-tert-butyl ester and 50g (0.36 mol) of potassium carbonate under stirring, stirring for 1 hour at normal temperature, then heating to 65 ℃ to react for 2 hours, detecting by TLC that the reaction is complete, cooling to room temperature, then evaporating the reaction mixture to dryness under reduced pressure, adding 200mL of water into the residue, stirring and dissolving, extracting by dichloromethane (200mL x 3), combining organic phases, washing the organic phases twice by saturated saline (100 mL x 2), drying by anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a residue, adding 100mL of petroleum ether, cooling to 5 ℃ by an ice water bath, stirring for 0.5 hour to form a precipitate, filtering, and drying a filter cake to obtain 18g of a white solid with the yield of 81%.
The above description is not intended to limit the invention, nor is the invention limited to the examples set forth above. Those skilled in the art should also appreciate that they may make various changes, modifications, additions and substitutions within the spirit and scope of the invention.
Claims (9)
1. A synthetic method of (3-cyanopyridin-2-yl) carbamic acid tert-butyl ester is characterized by comprising the following steps
(1) Reacting the 2-chloronicotinonitrile with an ammonia solution to obtain 2-aminonicotinonitrile;
(2) Reacting 2-aminonicotinonitrile with Boc anhydride to obtain (3-cyanopyridin-2-yl) nitrilodicarboxylic acid di-tert-butyl ester;
(3) Reacting di-tert-butyl 3-cyanopyridin-2-yl) nitriledicarboxylate with a base to remove one molecule of Boc to obtain tert-butyl (3-cyanopyridin-2-yl) carbamate.
2. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 1, wherein the specific process of step (1) comprises: after the 2-chloronicotinonitrile is added into the ammonia solution, slowly raising the temperature to T1 under stirring, keeping the temperature to be more than or equal to 20 ℃ and less than or equal to 200 ℃ and reacting overnight under the T1, the next day, cooling to room temperature after the TLC detection reaction is completed, then reducing the pressure and evaporating the reaction mixed solution, pouring the residue into ice water, stirring for 1 hour, controlling the temperature to be not more than 5 ℃, forming a precipitate, filtering, and drying the filter cake to obtain the light yellow solid 2-aminonicotinonitrile.
3. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 2, wherein: the ammonia solution is ethanol ammonia solution, methanol ammonia solution and ammonia water.
4. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 1, wherein the specific process of the step (2) is as follows: dissolving 2-amino-3-cyanopyridine in a solvent, adding a catalyst N, N-dimethyl-4-aminopyridine, cooling to 5 ℃ in an ice water bath, starting to dropwise add di-tert-butyl dicarbonate, carrying out reaction heat release, controlling the temperature to be not higher than 15 ℃, controlling the temperature to react at T2, T2 being not lower than 10 ℃ and not higher than 100 ℃ after dropwise addition, carrying out TLC (thin-layer chromatography) detection reaction, evaporating reaction mixed solution under reduced pressure, adding dichloromethane into residues, stirring to dissolve the residues clearly, washing with saturated salt twice, drying with anhydrous sodium sulfate, and carrying out desolvation under reduced pressure to obtain yellow solid (3-cyanopyridine-2-yl) dinitrophthalic acid di-tert-butyl ester.
5. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 4, wherein: the solvent is one or any combination of acetonitrile, 1,4-dioxane, tetrahydrofuran, DMF and DMSO.
6. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 4, wherein: the mass ratio of the 2-amino-3-cyanopyridine to the di-tert-butyl dicarbonate is 1: (1-5).
7. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 1, wherein the specific process of the step (3) is as follows: dissolving (3-cyanopyridin-2-yl) nitrilic dicarboxylic acid di-tert-butyl ester in a solvent, then adding basic carbonate, stirring for 1 hour at normal temperature after adding, then controlling the temperature to react at the temperature of more than or equal to T3 and less than or equal to 100 ℃, after TLC detection reaction is completed, evaporating reaction mixed liquor under reduced pressure, adding residue into water, stirring for dissolving, extracting for 3 times by using dichloromethane after stirring for dissolving, combining organic phases, washing the organic phases with saturated salt twice, drying by using anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain (3-cyanopyridin-2-yl) carbamic acid tert-butyl ester.
8. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 7, wherein: the solvent is one or any combination of ethanol, methanol, isopropanol, 1,4-dioxane, tetrahydrofuran, DMF and DMSO; the basic carbonate is one of potassium carbonate, sodium carbonate, cesium carbonate and ammonium carbonate.
9. The method for synthesizing tert-butyl (3-cyanopyridin-2-yl) carbamate according to claim 7, wherein: the mass ratio of the (3-cyanopyridin-2-yl) nitrilic dicarboxylic acid di-tert-butyl ester to the basic carbonate is 1: (1-7).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1639165A (en) * | 2002-03-05 | 2005-07-13 | 伊莱利利公司 | Purine derivatives as kinase inhibitors |
| US20070249620A1 (en) * | 2004-07-02 | 2007-10-25 | Hitoshi Kurata | Urea Derivative |
| WO2022029063A1 (en) * | 2020-08-04 | 2022-02-10 | Bayer Aktiengesellschaft | Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines |
| CN114901280A (en) * | 2019-11-05 | 2022-08-12 | 德米拉公司 | MrgprX2 antagonists and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1639165A (en) * | 2002-03-05 | 2005-07-13 | 伊莱利利公司 | Purine derivatives as kinase inhibitors |
| US20070249620A1 (en) * | 2004-07-02 | 2007-10-25 | Hitoshi Kurata | Urea Derivative |
| CN114901280A (en) * | 2019-11-05 | 2022-08-12 | 德米拉公司 | MrgprX2 antagonists and uses thereof |
| WO2022029063A1 (en) * | 2020-08-04 | 2022-02-10 | Bayer Aktiengesellschaft | Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines |
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