CN105330604A - Teneligliptin key intermediate preparation method - Google Patents
Teneligliptin key intermediate preparation method Download PDFInfo
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- CN105330604A CN105330604A CN201510663300.2A CN201510663300A CN105330604A CN 105330604 A CN105330604 A CN 105330604A CN 201510663300 A CN201510663300 A CN 201510663300A CN 105330604 A CN105330604 A CN 105330604A
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- RTPIMXJIMMECPM-SDQBBNPISA-N CC/C=C(\N(C1C(C)=C(C)C=CC1)NI)/Br Chemical compound CC/C=C(\N(C1C(C)=C(C)C=CC1)NI)/Br RTPIMXJIMMECPM-SDQBBNPISA-N 0.000 description 1
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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
Abstract
The present invention discloses a preparation method of a teneligliptin key intermediate 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (compound I), and belongs to the technical field of medicine preparation. According to the method of the present invention, a compound IV is adopted as a raw material, and reacts with iodobenzene to obtain a compound III, the compound III reacts with N-Boc-piperazine to obtain a compound II, and the compound II reacts with a suitable acid to remove the Boc protection to obtain the compound I.
Description
Technical field
The present invention relates to medical manufacturing technology field, be specifically related to a kind of preparation method for Ge Lieting key intermediate.
Background technology
1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) 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-base)-1-piperazinyl]-2-pyrrolidyl] formyl radical] thiazolidine; commodity are called Tenelia, and this medicine is by Mitsubishi Tian Bianyu the-three company's joint study exploitation altogether.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-base)) piperazine mainly contains following methods
The patent W02002/014271 of Mitsubishi of Yuan Yan company pharmacy discloses a kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) preparation method (Scheme1) of piperazine, the method with the phosphorus oxychloride of severe toxicity for condensation reagent, yield is extremely low simultaneously, is not suitable for carrying out industrialized amplification and produces.
The patent W02012/165547 of Mitsubishi of Yuan Yan company pharmacy discloses another kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) preparation method (Scheme2) of piperazine, the method equally with the tetraphosphorus decasulfide of severe toxicity for condensation reagent, be not suitable for carrying out industrialized amplification and produce.
Patent CN102675321A discloses another kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) preparation method (Scheme3) of piperazine, the method step is many, and total recovery is low, is not suitable for carrying out industrial amplification production.
The present invention improves these defects.
Summary of the invention
The invention discloses a kind of for Ge Lieting key intermediate 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) preparation method of piperazine (Compound I), belong to medical manufacturing technology field, its preparation method is as shown in Scheme4, the method take compound IV as raw material, be obtained by reacting compound III, III and iodobenzene are obtained by reacting Compound II per, and II and N-Boc-piperazine is obtained by reacting Compound I.The method is simple to operate, avoids use poisonous reagent, and environmentally friendly, yield is high, is applicable to industrial amplification production.
Its detailed process is:
The preparation of compound III: compound IV in a solvent, under alkali effect, prepares compound III with compound iodobenzene generation nucleophilic substitution reaction.Described solvent is the mixture of one or more in acetonitrile, DMF or tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane or toluene or dimethylbenzene, preferred tetrahydrofuran (THF); Alkali is triethylamine or pyridine or sodium tert-butoxide or potassium tert.-butoxide or sodium hydride, preferred tertiary sodium butylate;
The preparation of Compound II per: compound III in a solvent, under alkali effect, prepares Compound II per with compound N-Boc-piperazine generation nucleophilic substitution reaction.Described solvent is the mixture of one or more in DMF or tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane or diethyl ether or diisopropyl ether or methyl tertiary butyl ether or benzene or toluene or dimethylbenzene, preferred dimethylbenzene; Alkali is triethylamine or pyridine or sodium tert-butoxide or potassium tert.-butoxide or sodium hydride, preferred sodium hydride.
The preparation of Compound I: Compound II per in a solvent, adds deprotecting regent, removes Boc protection and obtains Compound I.Described solvent is the mixture of one or more in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF) or methylene dichloride or chloroform or tetracol phenixin, preferred methylene dichloride; Deprotecting regent is trifluoroacetic acid or hydrochloric acid, preferred trifluoroacetic acid;
Embodiment
Below provide specific embodiments of the invention, to show possible implementation process, but do not limit the present invention.
Embodiment 1
(1) preparation of compound III a:
Compound IV (160g, 1mol) is joined in 900ml tetrahydrofuran (THF), slowly add sodium tert-butoxide (115.2g, 1.2mol) in batches, stir 20 minutes, drip iodobenzene (243.6g, 1.2mol).Mixture reflux stirs 4 hours, then stirred overnight at room temperature, TLC display reacts completely, and reaction solution is slowly poured in frozen water, adds ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate one time again, merges organic phase, dry, concentrate and obtain compound III a205.3g, yield is 87%.
(2) preparation of Compound II per a:
By compound N-Boc-piperazine (149.1g, 0.8mol) join in dimethylbenzene (1500ml), add sodium hydride (32g again, 0.8mol), stir 30 minutes, slowly add compound III a (188.8g, 0.8mol), mixture is heated to return stirring spend the night, TLC display reacts completely, then room temperature is cooled to, reaction solution is slowly poured in frozen water, separate dimethylbenzene layer, concentrated, add water and ethyl acetate again, extraction, separate organic phase, aqueous phase is extracted with ethyl acetate one time again, merge organic phase, dry, concentrate and obtain Compound II per a137g, yield is 92%.
(3) 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) preparation of piperazine:
By Compound II per a (136.88g, 0.4mol) join in methylene dichloride (1200ml), add trifluoroacetic acid (51.3g again, 0.45mol), stirred overnight at room temperature, TLC display reacts completely, slowly add saturated sodium bicarbonate aqueous solution until do not have bubble to produce, extraction, separate organic phase, dry, concentrated, crude product sherwood oil: ethyl acetate=20:80 carries out recrystallization and obtains off-white color 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) piperazine 78g, yield is 81%.
Embodiment 2
(1) preparation of compound III b:
Compound IV (160g, 1mol) is joined in 850ml acetonitrile, slowly add potassium tert.-butoxide (134.6g, 1.2mol) in batches, stir 30 minutes, drip iodobenzene (243.6g, 1.2mol).Mixture reflux stirs 4 hours, then stirred overnight at room temperature, TLC display reacts completely, and reaction solution is slowly poured in frozen water, adds ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate one time again, merges organic phase, dry, concentrate and obtain compound III b200.5g, yield is 85%.
(2) preparation of Compound II per b:
By compound N-Boc-piperazine (149.1g, 0.8mol) join N, in dinethylformamide (1550ml), add sodium tert-butoxide (76.8g again, 0.8mol), stir 40 minutes, slowly add compound III b (188.8g, 0.8mol), mixture is heated to return stirring spend the night, TLC display reacts completely, the most of N of decompression removing, dinethylformamide, again residuum is slowly poured in frozen water, add ethyl acetate, extraction, separate organic layer, water layer is extracted with ethyl acetate one time again, merge organic phase, wash two times with water, separate organic phase, dry, concentrate and obtain Compound II per b119g, yield is 80%.
(3) 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) preparation of piperazine:
By Compound II per b (102.66g, 0.3mol) join in methyl alcohol (1000ml), add trifluoroacetic acid (37.62g again, 0.33mol), stirred overnight at room temperature, TLC display reacts completely, the most of methyl alcohol of concentrated removing, more slowly add saturated sodium bicarbonate aqueous solution until do not have bubble to produce, then add ethyl acetate, extraction, separate organic phase, dry, concentrated, crude product sherwood oil: ethyl acetate=20:80 carries out recrystallization and obtains off-white color 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) piperazine 78g, yield is 73.2%.
Embodiment 3
(1) preparation of compound III c:
Compound IV (160g, 1mol) is joined 920ml1, in 4-dioxane, slowly adds sodium hydride (48g, 1.2mol) in batches, stir 25 minutes, drip iodobenzene (243.6g, 1.2mol).Mixture reflux stirs 4.5 hours, then stirred overnight at room temperature, TLC display reacts completely, and reaction solution is slowly poured in frozen water, adds ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate one time again, merges organic phase, dry, concentrate and obtain compound III c195.7g, yield is 83%.
(2) preparation of Compound II per c:
By compound N-Boc-piperazine (149.1g, 0.8mol) join in toluene (1700ml), add sodium tert-butoxide (76.8g again, 0.8mol), stir 40 minutes, slowly add compound III c (188.8g, 0.8mol), mixture is heated to return stirring spend the night, TLC display reacts completely, the most of N of decompression removing, dinethylformamide, again residuum is slowly poured in frozen water, add ethyl acetate, extraction, separate organic layer, water layer is extracted with ethyl acetate one time again, merge organic phase, wash two times with water, separate organic phase, dry, concentrate and obtain Compound II per b116g, yield is 78%.
(3) 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) preparation of piperazine:
By Compound II per c (102.66g, 0.3mol) join in ethanol (1000ml), add 6N hydrochloric acid (45ml) again, stirred overnight at room temperature, TLC display reacts completely, the most of ethanol of concentrated removing, slowly add saturated sodium bicarbonate aqueous solution again until do not have bubble to produce, add ethyl acetate again, extraction, separates organic phase, dry, concentrated, crude product sherwood oil: ethyl acetate=20:80 carries out recrystallization and obtains off-white color 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)) piperazine 74.69g, yield is 73.2%.
Claims (4)
1., for a preparation method for Ge Lieting key intermediate, it is characterized in that there is following reactions steps:
(1) compound IV in a solvent, under alkali effect, prepares compound III with compound iodobenzene generation nucleophilic substitution reaction;
Described solvent is the mixture of one or more in acetonitrile, DMF or tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane or toluene or dimethylbenzene, and alkali is triethylamine or pyridine or sodium tert-butoxide or potassium tert.-butoxide or sodium hydride;
(2) compound III in a solvent, under alkali effect, prepares Compound II per with compound N-Boc-piperazine generation nucleophilic substitution reaction;
Described solvent is N, dinethylformamide or tetrahydrofuran (THF) or 1, the mixture of one or more in 4-dioxane or diethyl ether or diisopropyl ether or methyl tertiary butyl ether or benzene or toluene or dimethylbenzene, alkali is triethylamine or pyridine or sodium tert-butoxide or potassium tert.-butoxide or sodium hydride;
(3) Compound II per is in a solvent, adds deprotecting regent, removes Boc protection and obtains Compound I:
Described solvent is the mixture of one or more in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF) or methylene dichloride or chloroform or tetracol phenixin; Deprotecting regent is trifluoroacetic acid or hydrochloric acid.
2. a kind of preparation method for Ge Lieting key intermediate as claimed in claim 1, is characterized in that, in described step (1), and the preferred tetrahydrofuran (THF) of described solvent; Described alkali preferred tertiary sodium butylate.
3. a kind of preparation method for Ge Lieting key intermediate as claimed in claim 1, is characterized in that, in described step (2), and the preferred dimethylbenzene of described solvent; The preferred sodium hydride of described alkali.
4. a kind of preparation method for Ge Lieting key intermediate as claimed in claim 1, is characterized in that, in described step (3), and the preferred methylene dichloride of described solvent; The preferred trifluoroacetic acid of described acid.
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| CN201510663300.2A CN105330604A (en) | 2015-10-14 | 2015-10-14 | Teneligliptin key intermediate preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349237A (en) * | 2016-08-15 | 2017-01-25 | 南通普悦生物医药有限公司 | Method for preparing hydrobromic acid teneligliptin |
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| CN102558058A (en) * | 2012-01-19 | 2012-07-11 | 陕西理工学院 | 1-aryl-3-substituent-5-substituted amino-4-pyrazole formamide compound and application thereof |
| WO2013068467A1 (en) * | 2011-11-09 | 2013-05-16 | Grünenthal GmbH | Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with a co-containing group as vanilloid receptor ligands |
| 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 |
| CN103880750A (en) * | 2014-03-18 | 2014-06-25 | 上海皓元生物医药科技有限公司 | Method for preparing key intermediate of Tenelia |
| CN104177295A (en) * | 2013-05-24 | 2014-12-03 | 南京华威医药科技开发有限公司 | Teneligliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl) piperazine preparation method |
-
2015
- 2015-10-14 CN CN201510663300.2A patent/CN105330604A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013068467A1 (en) * | 2011-11-09 | 2013-05-16 | Grünenthal GmbH | Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with a co-containing group as vanilloid receptor ligands |
| CN102558058A (en) * | 2012-01-19 | 2012-07-11 | 陕西理工学院 | 1-aryl-3-substituent-5-substituted amino-4-pyrazole formamide compound and application thereof |
| CN104177295A (en) * | 2013-05-24 | 2014-12-03 | 南京华威医药科技开发有限公司 | Teneligliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl) piperazine preparation method |
| 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 |
| CN103880750A (en) * | 2014-03-18 | 2014-06-25 | 上海皓元生物医药科技有限公司 | Method for preparing key intermediate of Tenelia |
Non-Patent Citations (2)
| Title |
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| GERHARD WOLBER ET AL.: "Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| TOMOHIRO YOSHIDA ET AL.: "Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor...", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349237A (en) * | 2016-08-15 | 2017-01-25 | 南通普悦生物医药有限公司 | Method for preparing hydrobromic acid teneligliptin |
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