CN102167680A - Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative - Google Patents
Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative Download PDFInfo
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- CN102167680A CN102167680A CN2011100700397A CN201110070039A CN102167680A CN 102167680 A CN102167680 A CN 102167680A CN 2011100700397 A CN2011100700397 A CN 2011100700397A CN 201110070039 A CN201110070039 A CN 201110070039A CN 102167680 A CN102167680 A CN 102167680A
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- 0 CC(C)(C)OC(N1CC(C)(CCC*C2)C2C2(CC2)CC1)=O Chemical compound CC(C)(C)OC(N1CC(C)(CCC*C2)C2C2(CC2)CC1)=O 0.000 description 1
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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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Abstract
The invention discloses a preparation method of an octahydrocyclopenta[c]pyrrole carboxylic acid derivative. The method comprises the following steps: octahydrocyclopenta[c]pyrrole protected by N is used as raw material, one of tetrahydrofuran, methyl tert-butyl ether and dioxane is used as solvent, chiral organic ligand is added to react with lithium alkylide for 2-3 hours at -50 DEG C to -78 DEG C, then the reaction product reacts with carbon dioxide or ethyl chloroformate to obtain the octahydrocyclopenta[c]pyrrole carboxylic acid derivative. The preparation method of the octahydrocyclopenta[c]pyrrole carboxylic acid derivative has short synthetic route and high yield and can be used to realize mass production successfully.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, relate in particular to the also preparation method of [c] pyrroles carboxylic acid derivative of a kind of octahydro cyclopentyl.
Background technology
Hepatitis C (HCV) virus is since 1989 find, global PI toxicity hepatitis C patients is about 1.7 hundred million, and infect based on hepatitis C virus 1 type year new cases 300～4,000,000, accounts for 70%.Hepatitis C is mainly by blood-borne, and the average infection rate in the whole world is 3%, and Chinese infection rate is about 3.2%, domestic antibody to hepatitis C positive person about 4,000 ten thousand (1b, 2a).Hepatitis C easily transfers to chronic, and as not treating, number turnover is up to 75%～85%.Behind the hepatitis C infection 20～30 years, 10%～20% transfers liver cirrhosis to; Hepatitis C infection 30 years, 1～3% develops into liver cancer.According to statistics, global 27% liver cirrhosis and 25% liver cancer derive from hepatitis C.Liver cancer is occurred frequently in China, occupies second.
The decision-making resource company (Decision Resources) of the U.S. points out that in research report in 2007 hepatitis C virus treatment market will increase nearly five times in following 10 years, increases to more than 10,000,000,000 dollars in 2017 from about 2,000,000,000 dollars in 2007.As the China of developing country, because to the understanding deficiency of hepatitis C, it is out in the cold or treat as other hepatitis much to infect the case of hepatitis C, and along with the raising of medical level, its market potential demand is huge.The standard treatment of current treatment hepatitis C is polyoxyethylene glycol Interferon, rabbit and ribavirin (ribavirin) combination therapy, this therapy can be greater than 70% to HCV gene 2 types and 3 type infected patient curative ratios, but only is 40%～50% to HCV gene 1 type infected patient curative ratio.The treatment erious adverse reaction of polyoxyethylene glycol Interferon, rabbit and ribavirin, price is high, and patient tolerability is poor.
Present anti-hepatitis C drug research is very active, and the main pharmaceuticals in the whole world all has oneself studies the project that suppresses hepatitis C.Research HCV virus replication necessary NS3/NS4A multifunctional protein enzyme (serine protease) inhibitor is at present nearest from market in carrying out the HCV medicine of clinical trial.NS3/NS4A proteinase inhibitor of greatest concern surely belongs to the VX950(Telaprevir of Vertex company development at present).VX950 has now entered the III clinical trial phase.VX950 very likely becomes first inhibition hepatitis C virus small molecules medicine of drugs approved by FDA.The VX950 complex structure, it contains five chiral centres, is made up of 4 alpha-non-natural amino acids.There are problems such as route is long, yield is low in its key intermediate, octahydro cyclopentyl also [c] pyrroles-2-carboxylic acid synthetic, bring difficulty to scale operation.
Summary of the invention
The technical problem to be solved in the present invention provides the also preparation method of [c] pyrroles carboxylic acid derivative of a kind of octahydro cyclopentyl, and this method synthetic route is short, yield is high, and scale operation can be realized smoothly.
In order to solve the problems of the technologies described above; octahydro cyclopentyl of the present invention is the preparation method of [c] pyrroles carboxylic acid derivative also; comprise step: the octahydro cyclopentyl that the N that represents with the following structural formula I protects also [c] pyrroles is a raw material; with a kind of in tetrahydrofuran (THF), methyl tertiary butyl ether or the dioxane is solvent; add the chirality organic ligand; at-50 ℃～-78 ℃; with lithium alkylide reaction 2～3 hours; again with carbon dioxide or Vinyl chloroformate reaction; obtain also [c] pyrroles carboxylic acid derivative of the octahydro cyclopentyl shown in the following structural formula II, its reaction formula is as follows:
Preferably, described octahydro cyclopentyl also [c] pyrroles's N protecting group P is a tertbutyloxycarbonyl, and N-tertbutyloxycarbonyl octahydro cyclopentyl also [c] pyrroles's (III) structural formula is as follows:
Preferably, described chirality organic ligand comprises (+) Tocosamine or (+)-3-methyl-ten dihydro-1,5-methylene-pyridine-[1,2-a] [1,5] diazocine.
Preferably; with the octahydro cyclopentyl of N protection also [c] pyrroles be raw material; with a kind of in tetrahydrofuran (THF), methyl tertiary butyl ether or the dioxane is solvent; add the chirality organic ligand; at-78 ℃; with lithium alkylide reaction 2～3 hours, with carbon dioxide or Vinyl chloroformate reaction, obtain also [c] pyrroles carboxylic acid derivative of octahydro cyclopentyl again.
Preferably, described lithium alkylide is a s-butyl lithium; Preferred, described lithium alkylide is the cyclohexane solution that contains s-butyl lithium.
Preferably, described solvent is a methyl tertiary butyl ether.
Octahydro cyclopentyl of the present invention is the preparation method of [c] pyrroles carboxylic acid derivative also, and synthetic route is short, yield is high, and scale operation can be realized smoothly.
Embodiment
The invention provides the also preparation method of [c] pyrroles carboxylic acid derivative of a kind of octahydro cyclopentyl.Octahydro cyclopentyl also [c] pyrroles carboxylic acid derivative is the important intermediate of preparation VX950 and other medicine; its chemical structural formula is as shown in the formula (V); R1 wherein is a kind of of alkoxyl group, hydroxyl or Chiral Amine; R2, R3 are a kind of in hydrogen, fluorine, the hydroxyl, and N protecting group (P) is tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or chirality carbalkoxy.This compound is an optical purity.Preparation method of the present invention is from the octahydro cyclopentyl of N protection [c] pyrroles also, and low temperature is through the highly basic dehydrogenation, under chiral environment and the electrophilic group reaction, introduces the chirality carboxyls at 2, obtains also [c] pyrroles carboxylic acid derivative of octahydro cyclopentyl.
The inventive method concrete steps comprise: the octahydro cyclopentyl that the N that represents with the following structural formula I protects also [c] pyrroles is a raw material; with a kind of in tetrahydrofuran (THF), methyl tertiary butyl ether or the dioxane is solvent; add the chirality organic ligand; at-50 ℃～-78 ℃; with lithium alkylide reaction 2～3 hours; with carbon dioxide or Vinyl chloroformate reaction, obtain also [c] pyrroles carboxylic acid derivative of the octahydro cyclopentyl shown in the following structural formula II again, its reaction formula is as follows:
The inventive method synthetic route is short, yield is high.The key intermediate chirality octahydro cyclopentyl of VX950 also [c] pyrroles-2-carboxylic acid (IV) can be directly from the octahydro cyclopentyl of the whirlpool that disappears also [c] pyrroles (I) obtain in a step.In a preferred embodiment of the invention; the octahydro cyclopentyl of employing N-tertbutyloxycarbonyl (N-Boc) protection also [c] pyrroles (III) is a raw material; with (+)-Tocosamine as the chirality organic ligand; after the reaction of-78 ℃ and s-butyl lithium (s-BuLi); then with carbon dioxide reaction; the octahydro cyclopentyl that obtains chirality is [c] pyrroles-2-carboxylic acid (IV, wherein R also
1=OH), its reaction formula is as follows:
The present invention is further detailed explanation below by embodiment.
Embodiment 1
N-Boc octahydro cyclopentyl is [c] pyrroles III (0.42 g also, 2 mmol) and (+)-Tocosamine (0.56 g) be dissolved in (20 mL) in the methyl tertiary butyl ether, be cooled to-78 ℃ with the dry ice-propanone cryostat, be added dropwise to s-butyl lithium (cyclohexane solution that contains 1.4 M s-butyl lithium, 2.1 mL).After 3 hours, feed exsiccant carbonic acid gas (0.5 hour)-78 ℃ of stirrings.Reaction is raised to room temperature gradually, and stirring is spent the night.Be cooled to 0-5 ℃, add HCl (1N), transfer pH to 2-3, use ethyl acetate extraction 2 times, merge organic layer, after water and salt solution respectively wash 2 times, anhydrous sodium sulfate drying filters, behind the evaporated under reduced pressure solvent, residue separates through silica gel column chromatography, gets also [c] pyrroles-2-carboxylic acid IV (0.33 g) of N-tertbutyloxycarbonyl octahydro cyclopentyl.
Embodiment 2
N-Boc octahydro cyclopentyl is [c] pyrroles III (4.2 g, 20 mmol) and (+)-3-methyl-ten dihydro-1 also, 5-methylene-pyridine-[1,2-a] [1,5] diazocine (4.07 g, 21 mmol) is dissolved in (150 mL) in the methyl tertiary butyl ether, is cooled to-78 with the dry ice-propanone cryostat
oC is added dropwise to s-butyl lithium (cyclohexane solution of 1.4 M, 15 mL, 21 mmol).-78
oC stirred cryostat after 3 hours, fed exsiccant carbonic acid gas (0.5 hour).Reaction is raised to room temperature gradually, and stirring is spent the night.Be cooled to 0-5
oC adds HCl (1N), transfers pH to 2-3, with ethyl acetate extraction (2 x, 200 mL), merges organic layer.After organic layer water and salt solution respectively washed 2 times, anhydrous sodium sulfate drying filtered, and behind the evaporated under reduced pressure solvent, residue separates through silica gel column chromatography, got also [c] pyrroles-2-carboxylic acid IV (2.9 g) of chirality N-tertbutyloxycarbonyl octahydro cyclopentyl.
Embodiment 3
N-Boc octahydro cyclopentyl is [c] pyrroles III (1.39 g, 6.6 mmol) and (+)-3-methyl-ten dihydro-1 also, 5-methylene-pyridine-[1,2-a] [1,5] diazocine (1.54 g, 7.92 mmol) is dissolved in (20 mL) in the ether, is cooled to-50 with the dry ice-propanone cryostat
oC is added dropwise to s-butyl lithium (cyclohexane solution of 1.4 M, 5.66 mL, 7.92 mmol).-50
oC stirred cryostat after 2 hours, added ether (10 mL) solution of Vinyl chloroformate (1.25 mL, 13.2 mmol).Reaction is raised to room temperature gradually, and stirring is spent the night.Be cooled to 0-5
oC adds HCl (1 N), transfers pH to 5-6, with ethyl acetate extraction (2 x, 50 mL), merges organic layer.After each washing of organic layer water and salt solution, anhydrous sodium sulfate drying filters, and behind the evaporated under reduced pressure solvent, separates (10% ethyl acetate and normal hexane) through silica gel column chromatography, gets also [c] pyrroles-2-carboxylic acid, ethyl ester (0.62 g) of chirality N-tertbutyloxycarbonyl octahydro cyclopentyl
The above embodiment has only expressed embodiments of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to claim of the present invention.Should be pointed out that for the person of ordinary skill of the art without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (9)
1. the octahydro cyclopentyl preparation method of [c] pyrroles carboxylic acid derivative also; it is characterized in that; comprise step: the octahydro cyclopentyl that the N that represents with the following structural formula I protects also [c] pyrroles is a raw material; with a kind of in tetrahydrofuran (THF), methyl tertiary butyl ether or the dioxane is solvent; add the chirality organic ligand; at-50 ℃～-78 ℃; with lithium alkylide reaction 2～3 hours; again with carbon dioxide or Vinyl chloroformate reaction; obtain also [c] pyrroles carboxylic acid derivative of the octahydro cyclopentyl shown in the following structural formula II, its reaction formula is as follows:
2. preparation method according to claim 1 is characterized in that, described octahydro cyclopentyl also [c] pyrroles's N protecting group P is a tertbutyloxycarbonyl.
3. preparation method according to claim 1 and 2 is characterized in that, described chirality organic ligand comprises (+) Tocosamine or (+)-3-methyl-ten dihydro-1,5-methylene-pyridine-[1,2-a] [1,5] diazocine.
4. preparation method according to claim 1 and 2; it is characterized in that; with the octahydro cyclopentyl of N protection also [c] pyrroles be raw material; with a kind of in tetrahydrofuran (THF), methyl tertiary butyl ether or the dioxane is solvent; add the chirality organic ligand ,-78 ℃ and lithium alkylide reaction 2～3 hours; with carbon dioxide or Vinyl chloroformate reaction, obtain also [c] pyrroles carboxylic acid derivative of octahydro cyclopentyl again.
5. preparation method according to claim 1 and 2 is characterized in that, described lithium alkylide is a s-butyl lithium.
6. preparation method according to claim 5 is characterized in that, described lithium alkylide is the cyclohexane solution that contains s-butyl lithium.
7. preparation method according to claim 4 is characterized in that, described lithium alkylide is the cyclohexane solution that contains s-butyl lithium.
8. preparation method according to claim 1 and 2 is characterized in that, described solvent is a methyl tertiary butyl ether.
9. preparation method according to claim 7 is characterized in that, described solvent is a methyl tertiary butyl ether.
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| CN201110070039.7A CN102167680B (en) | 2011-03-23 | 2011-03-23 | Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875648A (en) * | 2012-09-26 | 2013-01-16 | 深圳翰宇药业股份有限公司 | Method for preparing telaprevir |
| US10300050B2 (en) | 2016-02-05 | 2019-05-28 | Achieve Pharma Uk Limited | Succinate salt of cytisine and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101291909A (en) * | 2005-08-19 | 2008-10-22 | 弗特克斯药品有限公司 | Processes and intermediates |
| WO2010126881A1 (en) * | 2009-04-27 | 2010-11-04 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101291909A (en) * | 2005-08-19 | 2008-10-22 | 弗特克斯药品有限公司 | Processes and intermediates |
| WO2010126881A1 (en) * | 2009-04-27 | 2010-11-04 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
Non-Patent Citations (1)
| Title |
|---|
| 孙亮: "《STN》", 20 March 2014, article "STN" * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875648A (en) * | 2012-09-26 | 2013-01-16 | 深圳翰宇药业股份有限公司 | Method for preparing telaprevir |
| CN102875648B (en) * | 2012-09-26 | 2014-02-19 | 深圳翰宇药业股份有限公司 | Method for preparing telaprevir |
| US10300050B2 (en) | 2016-02-05 | 2019-05-28 | Achieve Pharma Uk Limited | Succinate salt of cytisine and use thereof |
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Granted publication date: 20140702 Termination date: 20170323 |