CN103073548A - Preparation method for 6-tert-butyl-3-ethyl-4, 5-dihydro-1H-pyrazolo-[3, 4-c] pyridine-3, -6 (7H)-dicarboxylic acid diester - Google Patents
Preparation method for 6-tert-butyl-3-ethyl-4, 5-dihydro-1H-pyrazolo-[3, 4-c] pyridine-3, -6 (7H)-dicarboxylic acid diester Download PDFInfo
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- CN103073548A CN103073548A CN2013100477340A CN201310047734A CN103073548A CN 103073548 A CN103073548 A CN 103073548A CN 2013100477340 A CN2013100477340 A CN 2013100477340A CN 201310047734 A CN201310047734 A CN 201310047734A CN 103073548 A CN103073548 A CN 103073548A
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Abstract
The invention relates to a preparation method for 6-tert-butyl-3-ethyl-4, 5-dihydro-1H-pyrazolo-[3, 4-c] pyridine-3, -6 (7H)-dicarboxylic acid diester. The invention mainly aims to solve the technical problem that a suitable industrial synthesis method does not exist at present. The reaction formula of the preparation method is shown as follows: , the 6-tert-butyl-3-ethyl-4, 5-dihydro-1H-pyrazolo-[3, 4-c] pyridine-3, -6 (7H)-dicarboxylic acid diester and related derivatives obtained by the invention have important applications in medicinal chemistry and organic synthesis.
Description
Technical field
The present invention relates to the 6-tertiary butyl-3-ethyl-4, the 5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-preparation method of dicarboxylic diester.
Background technology
The 6-tertiary butyl-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-dicarboxylic diester and relevant derivative have important application, fabulous prospect is arranged in pharmaceutical chemistry and organic synthesis.At present the 6-tertiary butyl-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-the synthetic comparatively difficulty of dicarboxylic diester.Therefore, develop a raw material and be easy to get, easy to operate, reaction is easy to control, and the synthetic method that overall yield is fit to has meaning.
Summary of the invention
The objective of the invention is to develop and a kind ofly have raw material and be easy to get, easy to operate, can amplify, 6-tertiary butyl that yield is higher-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-synthetic method of dicarboxylic diester.Mainly solve the technical problem that is not fit at present Industrialized synthesis method.
Technical scheme of the present invention: a kind of 6-tertiary butyl-3-ethyl-4; 5-dihydro-1 h-pyrazole also (3; 4-c] pyridine-3;-6(7H)-preparation method of dicarboxylic diester; the present invention divided for three steps; at first, N-Boc-3-piperidone and ethyl diazoacetate are placed anhydrous tetrahydro furan or ether, under the nitrogen protection in-78
oC is to-60
oC drips LDA (THF) solution, and reacts 4-24 hour, acetic acid or ammonium chloride cancellation reaction, the concentrated crude product compound that obtains of isopropyl ether extraction
2, being directly used in next step, reaction formula is as follows:
Secondly, compound 2 and pyridine are placed isopropyl ether or ether, under the ice bath, drip phosphorus oxychloride, reaction solution stirring at room 8-24 hour, the sodium hydroxide adjust pH, ethyl acetate extraction, the sodium chloride solution washing is dry, obtain the crude product of compound 3, be directly used in next step, reaction formula is as follows:
At last, compound 3 and pyridine are dissolved in the ethyl acetate, this mixture is added drop-wise in the toluene of boiling, backflow 1-24 hour, the cooling concentration desolventizing, the residuum column chromatography purification obtains 6-tertiary butyl-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-and dicarboxylic diester, reaction formula is as follows:
The Chinese lexical or textual analysis of the present invention's abbreviation: LDA: lithium diisopropylamine; THF: tetrahydrofuran (THF); PY: pyridine; EtOAc: ethyl acetate.
Beneficial effect of the present invention: the invention provides a kind of synthetic 6-tertiary butyl-3-ethyl-4, the 5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-method of dicarboxylic diester, present method route is short, yield is higher, reaction is easy to amplify, and is easy to operate.
Embodiment
Reaction formula of the present invention is as follows:
Embodiment 1:a,N-Boc-3-piperidone (2.99 g, 15 mmol) and ethyl diazoacetate (1.72 g, 15 mmol) are placed anhydrous tetrahydro furan (20 mL), under the nitrogen protection in-78
oC, drip LDA ((15 mL, 1 M in THF) solution, and under this temperature, reacted 4 hours, acetic acid (1.5 mL) cancellation reaction, and under room temperature, stirred one hour, reaction solution is poured into water (40 mL), with isopropyl ether (20 mL) extraction, the organic phase NaHCO of mass percentage concentration 5%
3Washing, anhydrous sodium sulfate drying, the concentrated crude product compound that obtains
2(4 g) is directly used in next step.
Compound 2 (4 g) and pyridine (8 mL) are dissolved in the isopropyl ether (15 mL), under the ice bath, drip phosphorus oxychloride (2.3 g, 15 mmol), reaction solution stirring at room 8 hours, sodium hydroxide solution (5 mL, 0.1M) adds reaction solution, ethyl acetate (3 mL X 3) extraction, sodium chloride solution washing organic phase, dry concentrated, obtain compound 3(3 g) crude product, be directly used in next step.
At last with compound 3(3 g, 10 mmol) and pyridine (6 mL) be dissolved in the ethyl acetate (6 mL), this mixture is added drop-wise in the toluene (30 mL) of boiling, refluxed 1 hour, the cooling concentration desolventizing, the residuum column chromatography purification obtains 6-tertiary butyl-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-dicarboxylic diester (1.53 g, yield 51%).
1HNMR?(400?MHZ,?CDCl
3)?:?δ4.286-4.233?(q,?2H),?3.825?(s,?2H),?3.752-3.652?(m,?1H),?3.308-3.248?(t,?2H),?1.982-1.951?(d,?j?=?12.4?Hz,?2H),?1.767-1.694?(m,?2H),?1.466?(S,?9H),?1.318-1.283?(t,?3H)。
In the reaction of b, the first step, under the nitrogen protection in-69
oC drips LDA, 12 hours reaction times; 16 hours second step reaction times; Three-step reaction return time 12 hours; All the other same a obtain product yield 46%.
In the reaction of c, the first step, under the nitrogen protection in-60
oC drips LDA, 24 hours reaction times; 24 hours second step reaction times; Three-step reaction return time 24 hours; All the other same a obtain product yield 42%
Embodiment 2:N-Boc-3-piperidone (29.9 g, 150 mmol) and ethyl diazoacetate (17.2 g, 150 mmol) are placed anhydrous tetrahydro furan (200 mL), under the nitrogen protection in-78
oC, drip LDA ((150 mL, 1 M in THF) solution, and under this temperature, reacted 4 hours, acetic acid (15 mL) cancellation reaction, and under room temperature, stirred 1 hour, reaction solution is poured into water (400 mL), with isopropyl ether (200 mL) extraction, the organic phase NaHCO of mass percentage concentration 5%
3Washing, anhydrous sodium sulfate drying, the concentrated crude product compound that obtains
2(42 g) is directly used in next step,
Compound 2 (42 g) and pyridine (80 mL) are dissolved in the isopropyl ether (150 mL), under the ice bath, drip phosphorus oxychloride (23 g, 150 mmol), reaction solution stirring at room 8 hours, sodium hydroxide solution (50 mL, 0.1M) adds reaction solution, ethyl acetate (50 mL X 3) extraction, sodium chloride solution washing organic phase, dry concentrated, obtain compound 3(32 g) crude product, be directly used in next step.
At last with compound 3(30 g, 100 mmol) and pyridine (60 mL) be dissolved in the ethyl acetate (60 mL), this mixture is added drop-wise in the toluene (300 mL) of boiling, refluxed 3 hours, the cooling concentration desolventizing, the residuum column chromatography purification obtains 6-tertiary butyl-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-dicarboxylic diester (16 g, yield 52%).
1HNMR?(400?MHZ,?CDCl
3)?:?δ4.622(S,?2H),?4.417-4.364?(q,?2H),?3.670?(s,?2H),?2.658?(s,?2H),?1.494?(S,?9H),?1.412-1.377?(t,?3H)。
Embodiment 3:N-Boc-3-piperidone (299 g, 1.5 mol) and ethyl diazoacetate (172 g, 1.5 mol) are placed anhydrous tetrahydro furan (2 L), under the nitrogen protection in-78
oC, drip LDA ((1.5 L, 1 M in THF) solution, and under this temperature, react and spend the night, acetic acid (150 mL) cancellation reaction, and under room temperature, stirred 1 hour, reaction solution is poured into water (3 L), with isopropyl ether (1.5 L) extraction, the organic phase NaHCO of mass percentage concentration 5%
3Washing, anhydrous sodium sulfate drying, the concentrated crude product compound that obtains
2(440 g) is directly used in next step.
Compound 2 (440 g) and pyridine (800 mL) are dissolved in the isopropyl ether (1.5 L), under the ice bath, drip phosphorus oxychloride (230 g, 1.5 mol), the reaction solution stirred overnight at room temperature, sodium hydroxide solution (500 mL, 0.1M) adds reaction solution, ethyl acetate (300 mL X 3) extraction, sodium chloride solution washing organic phase, dry concentrated, obtain compound 3(310 g) crude product, be directly used in next step.
At last with compound 3(300 g, 1 mol) and pyridine (600 mL) be dissolved in the ethyl acetate (600 mL), this mixture is added drop-wise in the toluene (3 L) of boiling, backflow is spent the night, the cooling concentration desolventizing, and the residuum column chromatography purification obtains 6-tertiary butyl-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-dicarboxylic diester (152 g, yield 51%).
1HNMR?(400?MHZ,?CDCl
3)?:?δ4.622(S,?2H),?4.417-4.364?(q,?2H),?3.670?(s,?2H),?2.658?(s,?2H),?1.494?(S,?9H),?1.412-1.377?(t,?3H)。
Embodiment 4, and the first step reaction places ether with N-Boc-3-piperidone and ethyl diazoacetate, with ammonium chloride cancellation reaction, with extracted with diethyl ether compound 2; The second step reaction places ether with compound 2 and pyridine; All the other are with embodiment 1.
Claims (2)
1. the 6-tertiary butyl-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-preparation method of dicarboxylic diester, it is characterized in that may further comprise the steps:
The first step at first, places anhydrous tetrahydro furan or ether with N-Boc-3-piperidone and ethyl diazoacetate, under the nitrogen protection in-78
oC is to-60
oC, drip the tetrahydrofuran solution of lithium diisopropylamine, acetic acid or ammonium chloride solution cancellation reaction, the concentrated compound 2 crude product tertiary butyl 4-(1-diazo-2-oxyethyl group-2-oxoethyls that obtain of isopropyl ether or extracted with diethyl ether)-4-hydroxy piperidine-1-t-butyl formate, be directly used in next step;
Second step, compound 2 and pyridine are placed isopropyl ether or ether, under the ice bath, drip phosphorus oxychloride, the reaction solution stirring at room, the sodium hydroxide adjust pH, ethyl acetate extraction, the sodium chloride solution washing is dry, obtains compound 3 crude product tertiary butyl 4-(1-diazoes-2-oxyethyl group-2-oxoethyl)-5, the 6-dihydropyridine-1(2H)-t-butyl formate, be directly used in next step;
The 3rd step was dissolved in compound 3 and pyridine in the ethyl acetate, this mixture was added drop-wise in the toluene of boiling, reflux, the cooling concentration desolventizing, the residuum column chromatography purification obtains the 6-tertiary butyl-3-ethyl-4, the 5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3 ,-6(7H)-dicarboxylic diester; Reaction formula is as follows:
。
2. a kind of 6-tertiary butyl according to claim 1-3-ethyl-4,5-dihydro-1 h-pyrazole also (3,4-c] pyridine-3,-6(7H)-preparation method of dicarboxylic diester, it is characterized in that the first step reaction times is 4-24 hour, the second step stirring reaction time is 8-24 hour, the 3rd step reflux time 1-24 hour.
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| CN107200737A (en) * | 2017-06-29 | 2017-09-26 | 武汉药明康德新药开发有限公司 | The acid amides preparation method of tertbutyloxycarbonyl 3 (methylol) [1,2,3] triazole [1,5 a] piperidines 6 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823066A (en) * | 2003-07-10 | 2006-08-23 | 安万特医药股份有限公司 | Substituted tetrahydro-1h-pyrazolo [3,4-c]pyridines, compositions comprising them, and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823066A (en) * | 2003-07-10 | 2006-08-23 | 安万特医药股份有限公司 | Substituted tetrahydro-1h-pyrazolo [3,4-c]pyridines, compositions comprising them, and use |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107200737A (en) * | 2017-06-29 | 2017-09-26 | 武汉药明康德新药开发有限公司 | The acid amides preparation method of tertbutyloxycarbonyl 3 (methylol) [1,2,3] triazole [1,5 a] piperidines 6 |
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Owner name: TIANJIN YAOMING KANGDE NEW MEDICINE DEVELOPMENT CO Free format text: FORMER OWNER: TIANJIN YAOMING KANGDE NEW MEDICINE DEVELOPMENT CO., LTD. WUHAN YAOMING KANGDE NEW DRUGS DEVELOPMENT CO., LTD. YAOMINGKANGDE NEW MEDICINE DEVELOPMENT CO., LTD., WUXI SHANGHAI SYNTHEALL PHARMACEUTICAL CO., LTD. SHANGHAI STA PHARMACEUTICAL R + D CO., LTD. Effective date: 20141216 |
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Effective date of registration: 20141216 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant after: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Applicant after: Wuhan AppTec New Drug Development Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Wuhan AppTec New Drug Development Co., Ltd. Applicant before: Yaomingkangde New Medicine Development Co., Ltd., Wuxi Applicant before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant before: Shanghai STA Pharmaceutical R & D Co., Ltd. |
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Application publication date: 20130501 |