CN103880750A - Method for preparing key intermediate of Tenelia - Google Patents
Method for preparing key intermediate of Tenelia Download PDFInfo
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- CN103880750A CN103880750A CN201410100009.XA CN201410100009A CN103880750A CN 103880750 A CN103880750 A CN 103880750A CN 201410100009 A CN201410100009 A CN 201410100009A CN 103880750 A CN103880750 A CN 103880750A
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- key intermediate
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- 0 ClCC*CCCl Chemical compound ClCC*CCCl 0.000 description 3
- FMKMKBLHMONXJM-UHFFFAOYSA-N Cc(cc1N)n[n]1-c1ccccc1 Chemical compound Cc(cc1N)n[n]1-c1ccccc1 FMKMKBLHMONXJM-UHFFFAOYSA-N 0.000 description 1
- FBCUUXMVVOANMV-UHFFFAOYSA-N Cc(cc1N2CCNCC2)n[n]1-c1ccccc1 Chemical compound Cc(cc1N2CCNCC2)n[n]1-c1ccccc1 FBCUUXMVVOANMV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing a key intermediate, namely 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine (represented by a formula I shown in a drawing), of Tenelia. According to the method, reaction is carried out in a manner of taking acetonitrile as a starting raw material, so as to obtain a compound V, cyclization reaction is carried out through adding the compound V to phenylhydrazine, so as to obtain a compound IV, and the compound I can be obtained directly through enabling the compound IV to react with bis(2-chloroethyl) amine or can also be obtained through enabling the compound IV to react with amino-protected bis(2-chloroethyl) amine so as to obtain a compound II and then removing protecting groups from the compound II.
Description
Technical field
The present invention relates to a kind of preparation method for Ge Lieting key intermediate, belong to organic synthesis field.
Background introduction
1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine has a wide range of applications in pharmaceutical chemistry and organic synthesis field, especially as a kind of important intermediate for Ge Lieting.For Ge Lieting chemistry 3-[[(2S by name; 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl)-1-piperazinyl]-2-pyrrolidyl] formyl radical] thiazolidine; commodity are called Tenelia, and this medicine is total to company's joint study by the Tian Bianyu of Mitsubishi the-tri-and develops.For Ge Lieting in September, 2011 in the granted listing of Japan, clinically for the treatment of type-II diabetes.
1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine mainly contains following methods
The patent W02002/014271 of Mitsubishi of Yuan Yan company pharmacy has announced the preparation method of a kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine, the method is take hypertoxic phosphorus oxychloride as condensation reagent, yield is extremely low simultaneously, is not suitable for carrying out industrialized amplification production.
The patent W02012/165547 of Mitsubishi of Yuan Yan company pharmacy has announced the preparation method of another kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine, the method, equally take hypertoxic tetraphosphorus decasulfide as condensation reagent, is not suitable for carrying out industrialized amplification production.
Our preparation method improves this defect.
Summary of the invention
The invention discloses a kind of preparation method for Ge Lieting key intermediate 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine (formula I); the method is take acetonitrile as starting raw material; reaction obtains compound V; V adds phenylhydrazine to carry out ring closure reaction to obtain compounds Ⅳ; IV can be through reacting and directly obtain Compound I with two (2-chloroethyl) amine; also can be through reacting and obtain Compound I I with two (2-chloroethyl) amine of amido protecting, then Compound I I obtains Compound I through Deprotection again.
The preparation method of 1-provided by the present invention (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine is as follows:
By the toluene solution intensification stirring reaction of acetonitrile and potassium tert.-butoxide, add other acetonitrile, temperature rising reflux, to reacting completely, is processed and is obtained compound V; The dilute hydrochloric acid solution of compound V and phenylhydrazine temperature rising reflux, to reacting completely, are processed and obtained compounds Ⅳ; Compounds Ⅳ is joined in organic bases, add compound III, pyroreaction is until raw material spot disappears, and reaction solution regulates PH to alkalescence, obtains Compound I I; II obtains Compound I through Deprotection again.
Wherein, P is hydrogen or tertbutyloxycarbonyl or benzyl or benzyl oxygen carbonyl
Described organic bases is diisopropyl ethyl amine or triethylamine;
Described high temperature is 80 ℃～120 ℃;
The scope of described adjusting pH value is 8～14.
The present invention designs environmental protection, and processing condition are reasonable, simple to operate, and reaction yield is high, and production cost is low, substantially without the three wastes, has larger implementary value and economic results in society.
In the mode of embodiment, the invention will be further described more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
Embodiment
Below provide specific embodiments of the invention, to show possible implementation process.
Embodiment 1:
(1) preparation of compound V:
In the reaction flask of 2L, drop into acetonitrile (41g, 1.0mol), potassium tert.-butoxide (112g, 1.0mol), toluene 1000ml, reaction solution heats up 80 ℃ and reacts 1 hour, then by acetonitrile (41g, 1.0mol) slowly drip in reaction solution, temperature rising reflux reaction 10 hours, cooling, reaction solution is poured in 1200ml frozen water, use ethyl acetate 300ml extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound V76g, yield: 93%.
(2) preparation of compounds Ⅳ:
In 2L there-necked flask, drop into compound V (73.8g, 0.9mol), phenylhydrazine (93.3g, 0.86mol), 1N hydrochloric acid (1000m1), temperature rising reflux reaction is spent the night, cooling, reaction solution regulates PH to alkalescence, uses ethyl acetate 300m1 extraction 3 times, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compounds Ⅳ 132.6g, yield: 89%.
(3) preparation of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine:
In the reaction flask of 1L, drop into compounds Ⅳ (130g, 0.75mol), two (2-chloroethyl) amine (102g, 0.72mol), diisopropyl ethyl amine (200m1), reaction solution heats up 80 ℃ and reacts 20 hours, cooling, use ethyl acetate 100ml extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains off-white color solid 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine 162g, yield: 93%.
Embodiment 2:
(1) preparation of Compound I IA:
In the reaction flask of 1L, drop into compounds Ⅳ (173g, 1.0mol), compound III A (261g, 0.95mol), diisopropyl ethyl amine (250m1), reaction solution heats up 120 ℃ and reacts 10 hours, cooling, use ethyl acetate 150ml extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains Compound I IA328.5g, yield: 92%.
(2) preparation of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine:
In 2L autoclave, drop into Compound I IA (301g, 0.8mol), ethanol 1L, adds palladium carbon, and pressure hydration stirs spends the night, and reacts complete.Filter, reaction solution evaporate to dryness, crude product obtains off-white color solid 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine: 193.7g, yield 82% with methylene dichloride recrystallization.
Embodiment 3:
(1) preparation of Compound I I B:
In the reaction flask of 1L, drop into compounds Ⅳ (173g, 1.0mol), compound III B (229g, 0.95mol), triethylamine (200m1), reaction solution heats up 80 ℃ and reacts 18 hours, cooling, use ethyl acetate 150ml extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains Compound I IB282.5g, yield: 87%.
(2) preparation of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine:
In 2L reaction flask, drop into Compound I IB (239.5g, 0.7mol), 5% hydrogenchloride ethyl acetate solution 1500ml, stirred overnight at room temperature, react complete, regulate PH to alkalescence, use ethyl acetate 150ml extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, after concentrating under reduced pressure, crude product obtains off-white color solid 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine: 170g, yield 96% with methylene dichloride recrystallization.
Embodiment 4:
(1) preparation of Compound I I C:
In the reaction flask of 1L, drop into compounds Ⅳ (173g, 1.0mol), compound III C (220.5g, 0.95mol), triethylamine (200m1), reaction solution heats up 120 ℃ and reacts 8 hours, cooling, use ethyl acetate 150ml extraction 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains Compound I I C287g, yield: 91%.
(2) preparation of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine:
In 2L autoclave, drop into Compound I I C (232g, 0.7mol), ethanol 1L, adds palladium carbon, and pressure hydration stirs spends the night, and reacts complete.Filter, reaction solution evaporate to dryness, crude product obtains off-white color solid 1-(3-methyl isophthalic acid-phenyl-1H-I pyrazoles-5-yl) piperazine: 144g, yield 85% with methylene dichloride recrystallization.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, without departing from the inventive concept of the premise; can also make some improvements and modifications, these improvements and modifications also should be considered within the scope of protection of the present invention.
Claims (2)
1. for a preparation method for Ge Lieting key intermediate, it is characterized in that this key intermediate (formula I) makes in the following manner:
By the toluene solution intensification stirring reaction of acetonitrile and potassium tert.-butoxide, add other acetonitrile, temperature rising reflux, to reacting completely, is processed and is obtained compound V; The dilute hydrochloric acid solution of compound V and phenylhydrazine temperature rising reflux, to reacting completely, are processed and obtained compounds Ⅳ; Compounds Ⅳ is joined in organic bases, add compound III, pyroreaction is until raw material spot disappears, and reaction solution regulates pH value to alkalescence, obtains Compound I I; II obtains Compound I through Deprotection again.
Wherein, P is hydrogen or tertbutyloxycarbonyl or benzyl or benzyl oxygen carbonyl
2. a kind of preparation method for Ge Lieting key intermediate as claimed in claim 1, is characterized in that,
Described organic bases is diisopropyl ethyl amine or triethylamine;
Described high temperature is 80 ℃～120 ℃;
The scope of described adjusting pH value is 8～14.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410100009.XA CN103880750A (en) | 2014-03-18 | 2014-03-18 | Method for preparing key intermediate of Tenelia |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410100009.XA CN103880750A (en) | 2014-03-18 | 2014-03-18 | Method for preparing key intermediate of Tenelia |
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| CN103880750A true CN103880750A (en) | 2014-06-25 |
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| CN201410100009.XA Pending CN103880750A (en) | 2014-03-18 | 2014-03-18 | Method for preparing key intermediate of Tenelia |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330604A (en) * | 2015-10-14 | 2016-02-17 | 湖南华腾制药有限公司 | Teneligliptin key intermediate preparation method |
| CN114181202A (en) * | 2021-12-17 | 2022-03-15 | 湖南省湘中制药有限公司 | Preparation method of brexpiprazole |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0977730A (en) * | 1995-09-14 | 1997-03-25 | Mitsui Toatsu Chem Inc | Production of diacetonitriles |
| CN1222511C (en) * | 2000-11-02 | 2005-10-12 | 惠氏公司 | I-aryl-or-I-alkylsulfonyl-heterocyclylbenzazoles as 5-hydroxytryptamine-b ligands |
| CN101318935A (en) * | 2008-07-21 | 2008-12-10 | 南通康鑫药业有限公司 | Method for preparing hydrochloric 1-(2-pyrimidine) diethylenediamine compound |
| CN101432278A (en) * | 2006-04-25 | 2009-05-13 | 布里斯托尔-迈尔斯斯奎布公司 | Diketo-piperazine and piperidine derivatives as antiviral agents |
| WO2012130299A1 (en) * | 2011-03-30 | 2012-10-04 | Prozymex A/S | Peptidase inhibitors |
| CN103275010A (en) * | 2013-05-30 | 2013-09-04 | 上海皓元生物医药科技有限公司 | Preparation method of 1-(3-methyl-1-phenyl-1H-pyrazolyl-5-yl)piperazine |
-
2014
- 2014-03-18 CN CN201410100009.XA patent/CN103880750A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0977730A (en) * | 1995-09-14 | 1997-03-25 | Mitsui Toatsu Chem Inc | Production of diacetonitriles |
| CN1222511C (en) * | 2000-11-02 | 2005-10-12 | 惠氏公司 | I-aryl-or-I-alkylsulfonyl-heterocyclylbenzazoles as 5-hydroxytryptamine-b ligands |
| CN101432278A (en) * | 2006-04-25 | 2009-05-13 | 布里斯托尔-迈尔斯斯奎布公司 | Diketo-piperazine and piperidine derivatives as antiviral agents |
| CN101318935A (en) * | 2008-07-21 | 2008-12-10 | 南通康鑫药业有限公司 | Method for preparing hydrochloric 1-(2-pyrimidine) diethylenediamine compound |
| WO2012130299A1 (en) * | 2011-03-30 | 2012-10-04 | Prozymex A/S | Peptidase inhibitors |
| CN103275010A (en) * | 2013-05-30 | 2013-09-04 | 上海皓元生物医药科技有限公司 | Preparation method of 1-(3-methyl-1-phenyl-1H-pyrazolyl-5-yl)piperazine |
Non-Patent Citations (2)
| Title |
|---|
| JUNJAPPA ET AL.: "Highly Regioselective Synthesis of 1-Aryl-3 (or 5)-alkyl/aryl-5 (or 3)-(N-cycloamino)pyrazoles", 《J. ORG. CHEM.》, vol. 70, no. 23, 15 October 2005 (2005-10-15), pages 9643 * |
| NILS GRIEBENOW ET AL.: "Identification and optimization of substituted 5-aminopyrazoles as potent and selective adenosine A1 receptor antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, no. 19, 1 August 2010 (2010-08-01), pages 5891 - 5894, XP027273585 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330604A (en) * | 2015-10-14 | 2016-02-17 | 湖南华腾制药有限公司 | Teneligliptin key intermediate preparation method |
| CN114181202A (en) * | 2021-12-17 | 2022-03-15 | 湖南省湘中制药有限公司 | Preparation method of brexpiprazole |
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Application publication date: 20140625 |