CN111978321A - Preparation method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof - Google Patents

Preparation method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof Download PDF

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CN111978321A
CN111978321A CN202010998826.7A CN202010998826A CN111978321A CN 111978321 A CN111978321 A CN 111978321A CN 202010998826 A CN202010998826 A CN 202010998826A CN 111978321 A CN111978321 A CN 111978321A
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粟骥
华瑞茂
闵鑫
周一鸣
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Hainan Fansheng Biotechnology Co ltd
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Abstract

The invention discloses a synthesis method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof. The process comprises a condensation reaction and a cyclization reaction. The condensation reaction takes (N-Boc-3-piperidone or derivatives thereof) as a substrate and N, N-dimethylformamide dimethyl acetal as a condensing agent and a solvent, and the condensation product shown in the structural formula II is obtained by reacting at 85 ℃. And then taking the compound shown in the formula II and hydrazine hydrate as substrates, adding the hydrazine hydrate, stirring, and reacting at 85 ℃ to obtain the compound shown in the formula III, namely 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof. The method is more economical compared with the old route, the substrate N-Boc-3-piperidone or the derivative thereof, N-dimethylformamide dimethyl acetal and hydrazine hydrate are very cheap, and the target product is expensive and has high added value; the reaction systems of the two steps are very simple, and the operation is convenient and fast and is easy to separate; high-pressure hydrogenation is not involved, and the safety is better compared with the old route.

Description

Preparation method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof
Technical Field
The invention belongs to the field of fine chemical engineering, and particularly relates to a synthesis method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof.
Background
Pyrazolo [4,3-b ] pyridine compounds, which are of interest to researchers because of their specific physiological activities and structural similarities to indoles, are important nitrogen-containing heterocycles. Many current antagonists of adrenotropin and adrenocorticotropic hormone releasing factor, etc. are molecules with their backbone (Bondavalli, f.et al.j.med.chem.2002,45,4875); and some active molecules of the pyrazolo [4,3-b ] pyridine structure are inhibitors of glycogen synthase kinase, cell cycle dependent kinases (Cardoso, c.r.et al.bioorg.med.chem.lett.2002,12, 9). Today, a large number of pyrazolo [4,3-b ] pyridine derivatives are synthesized, and 4,5,6, 7-tetrahydro-2H-pyrazole, which is a hydrogenated pyridine mother ring, is a very important class of derivatives. A series of chemokine receptor antagonist molecules shown in the following figure can be synthesized by taking 4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-b ] pyridine as a parent (U.S. Pat. No. 5,20140057937).
Figure BDA0002693501100000011
Generally, a protecting group is introduced on N on a pyrazole or pyridine mother ring, so that the selective modification and expansion can be carried out by using 4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-b ] pyridine as a skeleton. Tert-butyloxycarbonyl (-Boc) group has excellent stability to hydrogenation and alkali and mild leaving conditions, and additionally hydrogen on the nitrogen of the pyridine parent ring is easy to migrate, so 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine is mostly used as a raw material in the literature at present, but the route for synthesizing the raw material is to perform high-pressure catalytic hydrogenation on expensive 2H-pyrazolo [4,3-b ] pyridine, and introduce Boc protection on the nitrogen of the pyridine parent ring after hydrogenation of the pyridine parent ring (WO2014029732A 1).
Figure BDA0002693501100000012
We can find that although the current line seems simple, there are safety hazards in the high pressure hydrogenation experimental operation, and the conditions require a strongly acidic solvent. Considering that the starting material 2H-pyrazolo [4,3-b ] pyridine or the intermediate 4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-b ] pyridine is very expensive, the synthesis route of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine is considered to be low in practicability and efficiency.
Therefore, the method for developing the green, safe and convenient synthesis method of the 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and the derivatives thereof has higher economic value and better application prospect. This involves two important problems: firstly, how to synthesize a target product by using raw materials which are as cheap and easy to obtain as possible; secondly, how to improve the safety and convenience in the synthesis process.
Disclosure of Invention
The invention aims to provide a simple synthesis method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof.
The invention provides a synthesis method of a compound shown in a formula III (namely 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof), which comprises a condensation reaction and a cyclization reaction;
the method comprises the following specific steps:
dissolving the compound N-Boc-3-piperidone shown in the formula I or the derivative thereof in N, N-dimethylformamide dimethyl acetal (DMF-DMA) and stirring, and obtaining the compound shown in the formula II after the condensation reaction is finished;
dissolving the compound shown in the formula II in an organic solvent, adding hydrazine hydrate, stirring, and carrying out cyclization reaction to obtain the compound shown in the formula III.
Figure BDA0002693501100000021
In the above condensation reaction method, the reaction is carried out in a solvent; the solvent is N, N-dimethylformamide dimethyl acetal.
In the reaction step, the temperature is 75-100 ℃, and preferably 85 ℃; the time is 4 to 10 hours, preferably 6 hours. The completion of the reaction can be monitored by thin layer chromatography or gas chromatography.
The R groups of the reactant formula I, intermediate formula II, and final formula III include, but are not limited to, -H, alkyl, aryl, and the like.
After the reaction is finished, the reaction system can be subjected to simple separation and purification treatment according to a conventional method, and the preferred separation mode is as follows: extracting the stock solution after reaction with ethyl acetate and sodium chloride aqueous solution; then the organic phase is dried by anhydrous sodium sulfate and filtered; adding a certain amount of 100-200 meshes of silica gel into the filtrate, and carrying out reduced pressure concentration to remove the solvent to obtain the product-containing silica gel; then a layer of silica gel is filled in the funnel, and the mixture is washed by a mixed solvent (10:1) of petroleum ether and ethyl acetate, and then washed by a mixed solvent (3:1) of petroleum ether and ethyl acetate, the filtrate is collected and dried by spinning to obtain a product, namely the compound shown in the formula II, which can be directly used for next cyclization reaction.
The reaction conditions of the cyclization are as follows: and (3) dissolving the intermediate product of the compound shown in the formula II in an organic solvent, adding hydrazine hydrate, stirring, and carrying out cyclization reaction to obtain the compound shown in the formula III.
In the cyclization reaction method, the feeding molar amount of the hydrazine hydrate is 2.0-3.0 times, preferably 2.5 times of that of the compound shown in the formula II.
The reaction is carried out in a solvent; the solvent is methanol, ethanol, n-propanol or isopropanol, preferably ethanol.
In the reaction step, the temperature is 80-95 ℃, and preferably 85 ℃; the time is 1 to 2.5 hours, preferably 1.5 hours. The completion of the reaction can be monitored by thin layer chromatography or gas chromatography.
After the reaction is finished, the reaction system can be separated and purified according to a conventional method, and the preferable separation mode is as follows: extracting the reaction stock solution with saturated saline and ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent from the filtrate by rotation, drying in vacuum to obtain the product, namely the compound shown in the formula III, weighing, and calculating the yield.
The method for synthesizing 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof provided by the invention has the following characteristics: (1) is economical. N-Boc-3-piperidone and derivatives thereof, N-dimethylformamide dimethyl acetal and hydrazine hydrate which are reaction raw materials are common chemical raw materials or intermediates, the used solvent is very cheap and easy to obtain, and the product 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof obtained by the reaction are very expensive at present and are heterocyclic compounds with high added values. (2) Is convenient. In the first step of condensation reaction, N-dimethylformamide dimethyl acetal is not only a condensing agent but also a solvent, and the conditions are very simple; only an intermediate product II, hydrazine hydrate and a solvent exist in a cyclization reaction system, so that the system is simple and the operation is convenient and fast; the two-step separation and purification process is also very simple. (3) And (4) safety. The entire reaction path avoids a high pressure hydrogenation step, so safety is more reliable than in the old route.
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FIG. 1 is a scheme showing the synthesis of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine of the present invention
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The materials are commercially available from the open literature unless otherwise specified.
Example 1
0.300g N-Boc-3-piperidone (1.51mmol) was dissolved in 3.0mL of N, N-dimethylformamide dimethyl acetal and reacted at 85 ℃ for 6 hours. Diluting the reaction stock solution with 10.0mL of ethyl acetate, extracting twice with 8.0mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering, and adding silica gel into the filtrate for spin drying; then, a layer of silica gel was applied to the funnel, and the mixture was washed with 50.0mL of mixed eluent of petroleum ether and ethyl acetate (10:1), then washed with 80.0mL of mixed eluent of petroleum ether and ethyl acetate (3:1), and the filtrate was collected and spin-dried to obtain 0.320g of condensation product. The product of the previous step was dissolved in 3.0mL of ethanol, and 0.157g of hydrazine hydrate (3.15mmol) was added to react at 85 ℃ for 1.5 hours. Spin-drying the reaction stock solution under vacuum, diluting with 10.0mL of saturated sodium chloride aqueous solution, extracting twice with 8.0mL of ethyl acetate, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, adding petroleum ether, pulping, filtering, and drying to obtain 0.256g of the final product. The isolated yield of the desired product, 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine, was 76%.
Example 2
1.00g N-Boc-4-methyl-3-piperidone (4.69mmol) was dissolved in 10.0mL of N, N-dimethylformamide dimethyl acetal and reacted at 85 ℃ for 6 hours. Diluting the reaction stock solution with 30.0mL of ethyl acetate, extracting twice with 25.0mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering, and adding silica gel into the filtrate for spin drying; then a layer of silica gel was applied to the funnel, washed with 150.0mL of mixed eluent of petroleum ether and ethyl acetate (10:1), then washed with 200.0mL of mixed eluent of petroleum ether and ethyl acetate (3:1), and the filtrate was collected and spin-dried to obtain 1.02g of condensation product. The product of the previous step was dissolved in 10.0mL of ethanol, and 0.358g of hydrazine hydrate (9.50mmol) was added thereto, followed by reaction at 85 ℃ for 1.5 hours. Spin-drying the reaction stock solution under vacuum, diluting with 30.0mL of saturated sodium chloride aqueous solution, extracting twice with 30.0mL of ethyl acetate, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, adding petroleum ether, pulping, filtering, and drying to obtain 0.715g of the final product. The desired product, 7-methyl-6, 7-dihydro-2H-pyrazolo [4,3-b ] pyridine-4 (5H) -carboxylic acid tert-butyl ester, was isolated in 79% yield.
Example 3
1.00g N-Boc-4-ethyl-3-piperidone (4.40mmol) was dissolved in 10.0mL of N, N-dimethylformamide dimethyl acetal and reacted at 85 ℃ for 6 hours. Diluting the reaction stock solution with 30.0mL of ethyl acetate, extracting twice with 25.0mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering, and adding silica gel into the filtrate for spin drying; then, a layer of silica gel was applied to the funnel, and the mixture was washed with 150.0mL of mixed eluent of petroleum ether and ethyl acetate (10:1), then washed with 200.0mL of mixed eluent of petroleum ether and ethyl acetate (3:1), and the filtrate was collected and spin-dried to obtain 0.975g of condensation product. The product of the previous step was dissolved in 10.0mL of ethanol, and 0.325g of hydrazine hydrate (8.63mmol) was added thereto, followed by reaction at 85 ℃ for 1.5 hours. Spin-drying the reaction stock solution under vacuum, diluting with 30.0mL of saturated sodium chloride aqueous solution, extracting twice with 30.0mL of ethyl acetate, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, adding petroleum ether, pulping, filtering, and drying to obtain 0.855g of the final product. The isolated yield of the desired product, tert-butyl 7-ethyl-6, 7-dihydro-2H-pyrazolo [4,3-b ] pyridine-4 (5H) -carboxylate, was 86%.
Example 4
1.00g N-Boc-3-methyl-5-piperidone (4.69mmol) was dissolved in 10.0mL of N, N-dimethylformamide dimethyl acetal and reacted at 85 ℃ for 6 hours. Diluting the reaction stock solution with 30.0mL of ethyl acetate, extracting twice with 25.0mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering, and adding silica gel into the filtrate for spin drying; then a layer of silica gel was placed in the funnel, washed with 150.0mL of mixed eluent of petroleum ether and ethyl acetate (10:1), then washed with 200.0mL of mixed eluent of petroleum ether and ethyl acetate (5:1), and the filtrate was collected and spin-dried to obtain 0.558g of condensation product. The product of the previous step was dissolved in 10.0mL of ethanol, and 0.196g of hydrazine hydrate (5.20mmol) was added thereto, followed by reaction at 85 ℃ for 1.5 hours. Spin-drying the reaction stock solution under vacuum, diluting with 30.0mL of saturated aqueous sodium chloride solution, extracting twice with 30.0mL of ethyl acetate, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, adding petroleum ether, pulping, filtering, and drying to obtain 0.483g of final product. The isolated yield of the desired product, tert-butyl 6-methyl-6, 7-dihydro-2H-pyrazolo [4,3-b ] pyridine-4 (5H) carboxylate, was 83%.
Example 5
1.00g of tert-butyl 3-oxo-4-phenylpiperidine-1-carboxylate (3.63mmol) were dissolved in 10.0ml of N, N-dimethylformamide dimethyl acetal and reacted at 85 ℃ for 6 hours. Diluting the reaction stock solution with 30.0mL of ethyl acetate, extracting twice with 25.0mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering, and adding silica gel into the filtrate for spin drying; then, a layer of silica gel was applied to the funnel, and the mixture was washed with 150.0mL of mixed eluent of petroleum ether and ethyl acetate (10:1), then washed with 200.0mL of mixed eluent of petroleum ether and ethyl acetate (2:1), and the filtrate was collected and spin-dried to obtain 1.10g of the condensation product. The product of the previous step was dissolved in 10.0mL of ethanol, and 0.314g of hydrazine hydrate (8.32mmol) was added thereto, followed by reaction at 85 ℃ for 1.5 hours. Spin-drying the reaction stock solution under vacuum, diluting with 30.0mL of saturated sodium chloride aqueous solution, extracting twice with 30.0mL of ethyl acetate, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, adding petroleum ether, pulping, filtering, and drying to obtain 0.805g of the final product. The isolated yield of the desired product, tert-butyl 7-phenyl-6, 7-dihydro-2H-pyrazolo [4,3-b ] pyridine-4 (5H) -carboxylate, was 81%.

Claims (8)

1. A method for preparing the compound shown in the formula III comprises a condensation reaction and a cyclization reaction;
Figure FDA0002693501090000011
the method comprises the following specific steps:
dissolving the compound N-Boc-3-piperidone shown in the formula I or a derivative thereof in a solvent, stirring, and obtaining a compound shown in the formula II after the condensation reaction is finished;
dissolving the compound shown in the formula II in an organic solvent, adding hydrazine hydrate, stirring, and carrying out cyclization reaction to obtain the compound shown in the formula III.
The R groups of the reactant formula I, intermediate formula II, and final formula III include, but are not limited to, -H, alkyl, aryl, and the like.
2. The method of claim 1, wherein: the feeding molar amount of the hydrazine hydrate is 2.0-3.0 times of that of the compound shown in the formula II.
3. The method according to claim 1 or 2, characterized in that: the condensation reaction and the cyclization reaction are both carried out in a solvent.
4. The method of claim 3, wherein: in the condensation reaction step, a solvent is N, N-dimethylformamide dimethyl acetal;
in the cyclization reaction step, the solvent is selected from at least one of methanol, ethanol, n-propanol or isopropanol.
5. The method according to claim 1 or 2, characterized in that: in the condensation reaction step, the temperature is 75-100 ℃, and the time is 4-10 hours;
in the cyclization reaction step, the temperature is 80-95 ℃ and the time is 1-2.5 hours.
6. The method according to claim 1 or 2, characterized in that: in the reaction step, the reaction device is a closed reaction device or a reaction container with an additional reflux device.
7. The method according to claim 1 or 2, characterized in that: the method comprises the steps of separating and purifying a reaction system after the condensation reaction is finished to obtain a compound shown in a formula II;
and (3) separating and purifying the reaction system after the cyclization reaction is finished to obtain the compound shown in the formula III.
8. The method of claim 7, wherein:
the steps of separation and purification of the condensation reaction are as follows: (1) diluting the reaction stock solution with 8.0-15.0mL of ethyl acetate, and extracting twice with 5.0-12.0mL of saturated sodium chloride aqueous solution; (2) drying the organic phase with anhydrous sodium sulfate, filtering, adding silica gel into the filtrate, and spin-drying; (3) filling a layer of silica gel in a funnel, washing by using 40.0-60.0mL of mixed eluent of petroleum ether-ethyl acetate (10:1), washing by using 70.0-100.0mL of mixed eluent of petroleum ether-ethyl acetate (3:1), collecting filtrate, and spin-drying to obtain the compound shown in the formula II.
The steps of separation and purification of the cyclization reaction are as follows: (1) diluting the reaction stock solution with 8.0-15.0mL of saturated sodium chloride aqueous solution, and extracting twice with 5.0-12.0mL of ethyl acetate; (2) collecting the organic phase, drying with anhydrous sodium sulfate, and filtering; (3) and (3) adding petroleum ether into the filtrate after spin drying, pulping, filtering, and drying a filter cake to obtain the compound shown in the formula III.
CN202010998826.7A 2020-09-22 2020-09-22 Preparation method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof Pending CN111978321A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050245505A1 (en) * 2001-06-08 2005-11-03 Joseph Aszodi Novel heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents
CN104059063A (en) * 2014-04-03 2014-09-24 丽水绿氟科技有限公司 Preparation method of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine and derivatives of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine
CN109476664A (en) * 2017-05-17 2019-03-15 乐高化学生物科学股份有限公司 New compound as autotaxin inhibitors and the pharmaceutical composition comprising it
WO2020094749A1 (en) * 2018-11-09 2020-05-14 F. Hoffmann-La Roche Ag 5-[6-[[3-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile derivatives and similar compounds as tlr7-9 antagonists for treating systemic lupus erythematosus
US20200289516A1 (en) * 2017-08-24 2020-09-17 Asceneuron Sa Annulated glycosidase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050245505A1 (en) * 2001-06-08 2005-11-03 Joseph Aszodi Novel heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents
CN104059063A (en) * 2014-04-03 2014-09-24 丽水绿氟科技有限公司 Preparation method of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine and derivatives of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine
CN109476664A (en) * 2017-05-17 2019-03-15 乐高化学生物科学股份有限公司 New compound as autotaxin inhibitors and the pharmaceutical composition comprising it
US20200289516A1 (en) * 2017-08-24 2020-09-17 Asceneuron Sa Annulated glycosidase inhibitors
WO2020094749A1 (en) * 2018-11-09 2020-05-14 F. Hoffmann-La Roche Ag 5-[6-[[3-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile derivatives and similar compounds as tlr7-9 antagonists for treating systemic lupus erythematosus

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