CN104910068A - 2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method - Google Patents
2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method Download PDFInfo
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- PPDYFTPCRSZNRD-UHFFFAOYSA-N 2-cyanopyridine-4-carbohydrazide Chemical compound NNC(=O)C1=CC=NC(C#N)=C1 PPDYFTPCRSZNRD-UHFFFAOYSA-N 0.000 title claims abstract description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- MPSVJNPESHZCIB-UHFFFAOYSA-N 2-cyanopyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C#N)=C1 MPSVJNPESHZCIB-UHFFFAOYSA-N 0.000 claims abstract description 16
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 13
- ORVHMLCJEKDDAX-UHFFFAOYSA-N methyl 2-cyanopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C#N)=C1 ORVHMLCJEKDDAX-UHFFFAOYSA-N 0.000 claims description 12
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 239000011261 inert gas Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000012795 verification Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UBVZQGOVTLIHLH-UHFFFAOYSA-N 4-[5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl]-pyridine-2-carbonitrile Chemical compound C1=NC(C#N)=CC(C=2N=C(NN=2)C=2C=CN=CC=2)=C1 UBVZQGOVTLIHLH-UHFFFAOYSA-N 0.000 description 3
- 229950004176 topiroxostat Drugs 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- SZNOQBMLXIQNKG-UHFFFAOYSA-N 2-cyanopyridine-4-carbonyl chloride Chemical compound ClC(=O)C1=CC=NC(C#N)=C1 SZNOQBMLXIQNKG-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QCWTWMJMLSKQCJ-UHFFFAOYSA-N Isonicotinic acid N-oxide Chemical compound OC(=O)C1=CC=[N+]([O-])C=C1 QCWTWMJMLSKQCJ-UHFFFAOYSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- JKRHDMPWBFBQDZ-UHFFFAOYSA-N n'-hexylmethanediimine Chemical compound CCCCCCN=C=N JKRHDMPWBFBQDZ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
技术领域 technical field
本发明属于制药领域，具体涉及一种2-氰基异烟酸酰肼1.5对甲苯磺酸盐的合成方法。 The invention belongs to the field of pharmacy, and in particular relates to a synthesis method of 2-cyanoisonicotinic acid hydrazide 1.5-p-toluenesulfonate.
背景技术 Background technique
托比司他（Topiroxostat）为富士制药和三和化学共同开发的新一代抗高尿酸血症药物，2-氰基异烟酰肼1.5对甲苯磺酸盐是合成Topiroxostat的关键中间体(中国专利2002819276.1)。文献报道(中国专利2002819276.1) 2-氰基异烟酰肼1.5对甲苯磺酸盐采用异烟酸N-氧化物为原料经过4步反应制备，其中，异烟酸N-氧化物与氯甲酸乙酯的反应需要在-15℃、无水、惰性气体保护下进行，反应条件较苛刻（图1-路线1）。也可以由2-氰基异烟酸甲酯为原料，直接与肼反应，获得2-氰基异烟酰肼，但是由于肼高毒易燃，工业生产存在安全隐患（图1-路线3）。 Topiroxostat (Topiroxostat) is a new generation of anti-hyperuricemia drug jointly developed by Fuji Pharmaceutical and Sanwa Chemicals. 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate is the key intermediate for the synthesis of Topiroxostat (Chinese patent 2002819276.1). Literature reports (Chinese patent 2002819276.1) 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate is prepared by using isonicotinic acid N-oxide as raw material through 4-step reaction, wherein, isonicotinic acid N-oxide and ethyl chloroformate The ester reaction needs to be carried out at -15°C, under the protection of anhydrous and inert gas, and the reaction conditions are relatively harsh (Figure 1-Route 1). It is also possible to use 2-cyanoisonicotinic acid methyl ester as a raw material and directly react with hydrazine to obtain 2-cyanoisonicotinic acid hydrazide. However, due to the high toxicity and flammability of hydrazine, there are potential safety hazards in industrial production (Figure 1-Route 3) .
为此，本发明采用2-氰基异烟酸甲酯为起始原料，经过碱如碳酸钠、碳酸钾等水解获得2-氰基异烟酸，在缩合剂如N，N’-二环己基碳二亚胺，1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐等的作用下，与叔丁氧基羰基肼缩合，缩合物用对甲苯磺酸一水合物水解获得目标化合物。由于2-氰基异烟酸甲酯分子中同时存在酯键和氰基，在强碱性条件下，酯键和氰基同时水解，无法获得预期产物2-氰基异烟酸。经过发明人多次试验，发现采用碳酸钠、碳酸钾等水解，可以方便的获得预期产物2-氰基异烟酸。2-氰基异烟酸与叔丁氧基羰基肼的缩合，可以采用氯化亚砜将2-氰基异烟酸先制备成2-氰基异烟酰氯，用2-氰基异烟酰氯与叔丁氧基羰基肼缩合，但是经过发明人多次试验，该方法收率很低，而且环境污染大，不适合工业生产。 For this reason, the present invention adopts 2-cyanoisonicotinic acid methyl ester as starting material, obtains 2-cyanoisonicotinic acid through alkali such as sodium carbonate, potassium carbonate etc. Under the action of hexyl carbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, etc., condense with tert-butoxycarbonylhydrazine, and use p-toluenesulfonic acid for the condensate Hydrate hydrolysis to obtain the target compound. Due to the simultaneous presence of ester bond and cyano group in the molecule of 2-cyanoisonicotinic acid methyl ester, under strong alkaline conditions, the ester bond and cyano group are hydrolyzed simultaneously, and the expected product 2-cyanoisonicotinic acid cannot be obtained. After several tests by the inventor, it is found that the expected product 2-cyanoisonicotinic acid can be easily obtained by hydrolysis with sodium carbonate, potassium carbonate, etc. For the condensation of 2-cyanoisonicotinic acid and tert-butoxycarbonylhydrazine, 2-cyanoisonicotinic acid can be prepared into 2-cyanoisonicotinic acid chloride by using thionyl chloride, and 2-cyanoisonicotinic acid chloride can be used to Condensation with tert-butoxycarbonyl hydrazine, but after many tests by the inventor, the method yield is very low, and the environmental pollution is large, so it is not suitable for industrial production.
发明内容 Contents of the invention
解决的技术问题：本发明提供一种2-氰基异烟酸酰肼1.5对甲苯磺酸盐的合成方法，采用2-氰基异烟酸甲酯为起始原料，经过3步反应，获得关键中间体2-氰基异烟酸酰肼1.5对甲苯磺酸盐，改进后的工艺不需要高温或者低温反应，反应条件温和，中间体无需提纯，操作简单，适合工业生产。 The technical problem to be solved: the present invention provides a kind of synthetic method of 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate, adopts 2-cyanoisonicotinic acid methyl ester as starting raw material, through 3 steps reaction, obtains The key intermediate 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate, the improved process does not require high temperature or low temperature reaction, the reaction conditions are mild, the intermediate does not need to be purified, the operation is simple, and it is suitable for industrial production.
技术方案：一种2-氰基异烟酸酰肼1.5对甲苯磺酸盐的合成方法，制备步骤为：采用2-氰基异烟酸甲酯为起始原料，经过碱水解获得2-氰基异烟酸，在缩合剂的作用下，与叔丁氧基羰基肼缩合得到缩合物；其中，2-氰基异烟酸甲酯与碱的物质的量之比为1:2-1:3，2-氰基异烟酸与叔丁氧基羰基肼的物质的量之比为1:1.5-1:3。 Technical solution : a method for synthesizing 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate, the preparation steps are: using 2-cyanoisonicotinic acid methyl ester as the starting material, and obtaining 2-cyanoic acid through alkali hydrolysis Isonicotinic acid, under the action of a condensing agent, condenses with tert-butoxycarbonylhydrazine to obtain a condensate; wherein, the ratio of the amount of 2-cyanoisonicotinic acid methyl ester to the base is 1:2-1: The amount ratio of 3,2-cyanoisonicotinic acid to tert-butoxycarbonylhydrazine is 1:1.5-1:3.
所述碱为碳酸钠或碳酸钾。 The base is sodium carbonate or potassium carbonate.
所述缩合剂为N，N’-二环己基碳二亚胺或1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐。 The condensing agent is N, N'-dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.
一种2-氰基异烟酸酰肼1.5对甲苯磺酸盐的合成方法，步骤为：2-氰基异烟酸甲酯0.05mol 、四氢呋喃50mL、异丙醇50mL、水30mL的混悬液中，室温搅拌下分批加入碳酸钠粉末0.1mol，加毕，室温继续搅拌反应2小时，滴加浓盐酸0.1mol，70℃过滤除去无机盐，滤液浓缩，得白色固体；2-氰基异烟酸0.05mol、四氢呋喃150mL、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐0.055mol， 1-羟基苯并三唑0.5 g，叔丁氧基羰基肼0.075mol，室温搅拌48小时，过滤除去不溶物，滤液浓缩，加入乙酸乙酯150mL，用水50mL洗涤，有机层用无水硫酸钠10.0g干燥，过滤，滤液加入对甲苯磺酸一水合物0.1mol，室温搅拌反应24小时，过滤，得白色固体。 A kind of synthesis method of 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate, the steps are: 0.05mol of 2-cyanoisonicotinic acid methyl ester, tetrahydrofuran 50mL, isopropanol 50mL, water 30mL suspension Add 0.1 mol of sodium carbonate powder in batches under stirring at room temperature. After the addition is complete, continue to stir at room temperature for 2 hours, add 0.1 mol of concentrated hydrochloric acid dropwise, filter at 70°C to remove inorganic salts, and concentrate the filtrate to obtain a white solid; 2-cyanoiso Nicotinic acid 0.05mol, tetrahydrofuran 150mL, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 0.055mol, 1-hydroxybenzotriazole 0.5 g, tert-butoxycarbonylhydrazine 0.075 mol, stirred at room temperature for 48 hours, filtered to remove insoluble matter, concentrated the filtrate, added 150 mL of ethyl acetate, washed with 50 mL of water, dried the organic layer with 10.0 g of anhydrous sodium sulfate, filtered, added 0.1 mol of p-toluenesulfonic acid monohydrate to the filtrate, Stir the reaction at room temperature for 24 hours, and filter to obtain a white solid.
有益效果：该工艺不需要高温或者低温反应，不需要惰性气体保护，所有反应溶剂不需要无水预处理、反应条件温和，中间体无需提纯，操作简单，适合工业生产。 Beneficial effects : the process does not require high-temperature or low-temperature reaction, does not require inert gas protection, does not require anhydrous pretreatment of all reaction solvents, has mild reaction conditions, does not require purification of intermediates, is simple to operate, and is suitable for industrial production.
附图说明 Description of drawings
图1为2-氰基异烟酰肼1.5对甲苯磺酸盐的合成路线图。 Figure 1 is a synthetic route diagram of 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate.
具体实施方式 Detailed ways
下面的实施例可使本专业技术人员可全面的理解本发明，但不以任何方式限制本发明。 The following examples allow those skilled in the art to fully understand the present invention, but do not limit the present invention in any way.
实施例1 2-氰基异烟酸的合成The synthesis of embodiment 1 2-cyanoisonicotinic acid
2-氰基异烟酸甲酯8.1g (0.05mol) 、四氢呋喃50mL、异丙醇50mL、水30mL的混悬液中，室温搅拌下分批加入碳酸钠粉末10.6 g(0.1mol)，加毕，室温继续搅拌反应2小时，滴加浓盐酸8.4mL(0.1mol)，70℃过滤除去无机盐，滤液浓缩，得白色固体7.2 g，收率97.3%。产物验证：7.98-7.99 (d, 1H), 8.18 (s, 1H), 8.70-8.72 (d, 1H).ESI-MS: 147.0 ([M-H]-) 。 8.1g (0.05mol) of methyl 2-cyanoisonicotinate, 50mL of tetrahydrofuran, 50mL of isopropanol, and 30mL of water were added in batches of 10.6 g (0.1mol) of sodium carbonate powder under stirring at room temperature, and the addition was completed. , continue stirring at room temperature for 2 hours, add 8.4 mL (0.1 mol) of concentrated hydrochloric acid dropwise, filter at 70°C to remove inorganic salts, and concentrate the filtrate to obtain 7.2 g of white solid, with a yield of 97.3%. Product verification: 7.98-7.99 (d, 1H), 8.18 (s, 1H), 8.70-8.72 (d, 1H). ESI-MS: 147.0 ([M-H]-) .
实施例2 2-氰基异烟酸的合成Example 2 Synthesis of 2-cyanoisonicotinic acid
2-氰基异烟酸甲酯8.1g (0.05mol) 、四氢呋喃50mL、异丙醇50mL、水30mL的混悬液中，室温搅拌下分批加入碳酸钾粉末20.1 g(0.15mol)，加毕，室温继续搅拌反应2小时，滴加浓盐酸12.8mL(0.15mol)，70℃过滤除去无机盐，滤液浓缩，得白色固体7.1 g，收率95.6%。产物验证：7.98-7.99 (d, 1H), 8.18 (s, 1H), 8.70-8.72 (d, 1H).ESI-MS: 147.0 ([M-H]-) 。 To the suspension of 8.1g (0.05mol) of methyl 2-cyanoisonicotinate, 50mL of tetrahydrofuran, 50mL of isopropanol and 30mL of water, add 20.1 g (0.15mol) of potassium carbonate powder in batches under stirring at room temperature, and complete the addition , continue to stir and react at room temperature for 2 hours, add 12.8 mL (0.15 mol) of concentrated hydrochloric acid dropwise, filter at 70°C to remove inorganic salts, and concentrate the filtrate to obtain 7.1 g of white solid, with a yield of 95.6%. Product verification: 7.98-7.99 (d, 1H), 8.18 (s, 1H), 8.70-8.72 (d, 1H). ESI-MS: 147.0 ([M-H]-) .
实施例3 2-氰基异烟酰肼1.5对甲苯磺酸盐的合成Example 3 Synthesis of 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate
使用实施例1或2所得2-氰基异烟酸7.4g (0.05mol)、四氢呋喃150mL、N，N’-二环己基碳二亚胺11.3g (0.055mol)， 4-二甲氨基吡啶0.1 g，叔丁氧基羰基肼9.9g (0.075mol)，室温搅拌48小时，过滤除去不溶物，滤液浓缩， 加入乙酸乙酯150mL，用水50mL洗涤，有机层用无水硫酸钠10.0g干燥，过滤，滤液加入对甲苯磺酸一水合物19.0g (0.1mol)，室温搅拌反应24小时，过滤，得白色固体15.5 g，收率73.8%。产物验证：1H-NMR(DMSO-d6) δ(ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98(d, 1H). ESI-MS: 163.0 ([M+H]+). Using 7.4g (0.05mol) of 2-cyanoisonicotinic acid obtained in Example 1 or 2, 150mL of tetrahydrofuran, 11.3g (0.055mol) of N,N'-dicyclohexylcarbodiimide, and 0.1g of 4-dimethylaminopyridine g, tert-butoxycarbonylhydrazine 9.9g (0.075mol), stirred at room temperature for 48 hours, filtered to remove insoluble matter, concentrated the filtrate, added 150mL of ethyl acetate, washed with 50mL of water, dried the organic layer with 10.0g of anhydrous sodium sulfate, filtered 19.0 g (0.1 mol) of p-toluenesulfonic acid monohydrate was added to the filtrate, stirred and reacted at room temperature for 24 hours, and filtered to obtain 15.5 g of white solid with a yield of 73.8%. Product verification: 1 H-NMR(DMSO-d 6 ) δ(ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98(d, 1H). ESI-MS: 163.0 ([M+H] + ).
实施例4 2-氰基异烟酰肼1.5对甲苯磺酸盐的合成Example 4 Synthesis of 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate
使用实施例1或2所得2-氰基异烟酸7.4g (0.05mol)、四氢呋喃150mL、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐10.5g (0.055mol)， 1-羟基苯并三唑0.5 g，叔丁氧基羰基肼19.8g (0.15mol)，室温搅拌48小时，过滤除去不溶物，滤液浓缩， 加入乙酸乙酯150mL，用水50mL洗涤，有机层用无水硫酸钠10.0g干燥，过滤，滤液加入对甲苯磺酸一水合物19.0g (0.1mol)，室温搅拌反应24小时，过滤，得白色固体15.6 g，收率74.3%。产物验证：1H-NMR(DMSO-d6) δ(ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98(d, 1H). ESI-MS: 163.0 ([M+H]+). Using the obtained 2-cyanoisonicotinic acid 7.4g (0.05mol), tetrahydrofuran 150mL, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 10.5g (0.055mol) obtained in Example 1 or 2 mol), 0.5 g of 1-hydroxybenzotriazole, 19.8 g (0.15 mol) of tert-butoxycarbonylhydrazine, stirred at room temperature for 48 hours, filtered to remove insoluble matter, concentrated the filtrate, added 150 mL of ethyl acetate, washed with 50 mL of water, organic The layer was dried with 10.0 g of anhydrous sodium sulfate, filtered, 19.0 g (0.1 mol) of p-toluenesulfonic acid monohydrate was added to the filtrate, stirred at room temperature for 24 hours, and filtered to obtain 15.6 g of white solid, yield 74.3%. Product verification: 1 H-NMR(DMSO-d 6 ) δ(ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98(d, 1H). ESI-MS: 163.0 ([M+H] + ).
实施例5 2-氰基异烟酰肼1.5对甲苯磺酸盐的合成Example 5 Synthesis of 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate
使用实施例1或2所得2-氰基异烟酸7.4g (0.05mol)、四氢呋喃150mL、N，N’-二环己基碳二亚胺11.3g (0.055mol)，叔丁氧基羰基肼9.9g (0.075mol)，室温搅拌72小时，过滤除去不溶物，滤液浓缩，加入乙酸乙酯150mL，用水50mL洗涤，有机层用无水硫酸钠10.0g干燥，过滤，滤液加入对甲苯磺酸一水合物19.0g (0.1mol)，室温搅拌反应24小时，过滤，得白色固体15.0 g，收率71.4%。产物验证：1H-NMR(DMSO-d6) δ(ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98(d, 1H). ESI-MS: 163.0 ([M+H]+)。 7.4 g (0.05 mol) of 2-cyanoisonicotinic acid obtained in Example 1 or 2, 150 mL of tetrahydrofuran, 11.3 g (0.055 mol) of N, N'-dicyclohexylcarbodiimide, and 9.9 g of tert-butoxycarbonylhydrazine g (0.075mol), stirred at room temperature for 72 hours, filtered to remove insoluble matter, concentrated the filtrate, added 150mL of ethyl acetate, washed with 50mL of water, dried the organic layer with 10.0g of anhydrous sodium sulfate, filtered, added p-toluenesulfonic acid monohydrate to the filtrate 19.0 g (0.1 mol) of the compound was stirred at room temperature for 24 hours, filtered to obtain 15.0 g of a white solid, and the yield was 71.4%. Product verification: 1 H-NMR(DMSO-d 6 ) δ(ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98(d, 1H). ESI-MS: 163.0 ([M+H] + ).
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