CN103387509B - The preparation method of a kind of HCV protease inhibitor intermediate - Google Patents
The preparation method of a kind of HCV protease inhibitor intermediate Download PDFInfo
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- CN103387509B CN103387509B CN201210146447.0A CN201210146447A CN103387509B CN 103387509 B CN103387509 B CN 103387509B CN 201210146447 A CN201210146447 A CN 201210146447A CN 103387509 B CN103387509 B CN 103387509B
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Abstract
The present invention provides the preparation method of intermediate double cyclic lactone acid amides (I) of a kind of HCV protease inhibitor TMC435, namely taking a kind of Cinchonidune salt (IV) as raw material and chloro-formic ester compounds form mixed anhydride (III), again mixed anhydride is carried out condensation with N-methyl own enamine (NMHA) (II), thus obtain target product bicyclic lactone amide compound (I).
Description
Technical field
The present invention relates to the intermediate of a kind of HCV protease inhibitor TMC435 and the preparation method of derivative bicyclic lactone acid amides (I) thereof.
Background technology
In the major cause that hepatitis C virus (HCV) is suffering from chronic hepatopathy all over the world. After initial acute infection, the infected individuality of major part all can develop into chronic hepatitis, this is because HCV preferentially copies in liver cell instead of cytopathy directly occurs. Chronic hepatitis may develop into hepatic fibrosis, causes liver cirrhosis, end-stage liver disease and HCC(hepatocellular carcinoma) so that it is become the major cause of liver transplantation. The quantity of chronic hepatitis and accumulation patient makes the medical research focus that HCV becomes important. The duplication of HCV genome is subject to the mediation of multiple enzyme, has HCVNS3 serine protease and relevant cofactor NS4A thereof in described enzyme, and the multiple molten albumen cracking of its mediation HCV polyprotein matter, causes the generation of HCV replicative enzyme. NS3 serine protease be considered as virus replication necessary and the attractive target that become drug discovery.
It is a kind of cyclopentyl Macrocyclic HCV NS3/4A proteinase inhibitor having center quinolyl and replacing that TMC435 (has another name called TMC435350), and day takes once, and is used for the treatment of chronic hepatitis C, jointly researches and develops by Medivir and Johnson&Johnson. Clinical data shows, it is attractive especially in pharmacodynamics and pharmacokinetics, 1 type chronic hepatitis C patient can be made to keep higher lasting virological response (SVR) rate, have that treatment time is short, security, health giving quality and the feature such as tolerance is higher. Now in the whole world, multiple country carries out the clinical III phase and studies, and the fast passage (FastTrack) obtaining U.S. food Drug Administration (FDA) examines qualification, it is contemplated that listing in 2013.
Compound bicyclic lactone acid amides (I) is an important intermediate of preparation TMC435, document WO2010072742 and WO2007014926 (Johnson&Johnson application) discloses the synthetic method synthesizing TMC435 from compound (I), as shown in scheme 1.
Scheme 1
Document WO2010072742 (Johnson&Johnson application) discloses the preparation method of compound (I), as shown in scheme 2. Taking Cinchonidune (Cinchonidine) salt (IV) as starting raw material in scheme 2, amide coupling agents reacts with N-methyl own enamine (NMHA) (II), obtain bicyclic lactone acid amides (I), wherein, amide coupling agents comprises N-ethoxy carbonyl-2-oxyethyl group-1,2-dihydroquinoline (EEDQ), N-sec.-propyl-carbonyl-2-isopropoxy-1,2-dihydroquinoline, particularly its hydrochloride (IIDQ) etc. Another replacement scheme can also be used, Cinchonidune (Cinchonidine) salt (IV) is separable is Cinchonidune and bicyclic lactone, the latter and NMHA react in acid amides forming reactions described above, obtain bicyclic lactone acid amides (I). But, this kind of method reaction times is very long, and disposable receipts rate and purity are lower, temperature of reaction height, and needs to carry out the compound (I) that complicated post-processing operation just can obtain higher degree.
Scheme 2
Summary of the invention
For above-mentioned prior art Problems existing, the present invention has improved on the basis of scheme 2, object is to provide a kind of high-level efficiency to prepare the method for compound (I), the method overcome the disposable receipts rate of prior art and all lower shortcoming of purity, save cost, it is to increase economic benefit.
The present invention provides the preparation method of compound (I), it is characterized in that: Cinchonidune (Cinchonidine) salt (IV) dissolves with one or more mixed organic solvents, drip chlorination formic ether compounds ClC (=O) OR again, R is the alkyl of C1-C4, it is obtained by reacting mixed anhydride (III), add N-methyl own enamine (NMHA) (II) reaction again, obtain bicyclic lactone acid amides (I).
In the embodiment that another substitutes, Cinchonidune (Cinchonidine) salt (IV) can first be separated into Cinchonidune and bicyclic lactone, bicyclic lactone reacts with acid amides as above again, obtains bicyclic lactone acid amides (I).
Specific embodiment:
Embodiment 1
1000ml reaction flask adds compound (IV) 108g, add trichloromethane again, stirring and dissolving, it is cooled to-10 ~-5 �� of about C, drips and add methyl-chloroformate 31.8g, insulation reaction 3-5 hour, drip again and add the own enamine 30g of N-methyl, insulation reaction 1-2 hour, filtering, filter cake reclaims Cinchonidune. Filtrate is washed, layering, organic phase anhydrous sodium sulfate drying, filtration, and concentrated, obtaining light yellow oil (I) 57g, HPLC purity is 95%, and receipts rate is 90%.
Embodiment 2
1000ml reaction flask adds compound (IV) 108g, add toluene again, stirring and dissolving, it is cooled to-15 ~-10 �� of about C, drips and add Vinyl chloroformate 36.5g, insulation reaction 3-5 hour, drip again and add the own enamine 30g of N-methyl, insulation reaction 1-2 hour, filtering, filter cake reclaims Cinchonidune. Filtrate is washed, layering, organic phase anhydrous sodium sulfate drying, filtration, and concentrated, obtaining light yellow oil (I) 57g, HPLC purity is 94%, and receipts rate is 89%.
Embodiment 3
1000ml reaction flask adds compound (IV) 54g, add methylene dichloride again, stirring and dissolving, it is cooled to-5 ~ 0 �� of about C, drips and add isopropyl chlorocarbonate 20.6g, insulation reaction 3-5 hour, drip again and add the own enamine 15g of N-methyl, insulation reaction 1-2 hour, filtering, filter cake reclaims Cinchonidune. Filtrate is washed, layering, organic phase anhydrous sodium sulfate drying, filtration, and concentrated, obtaining light yellow oil (I) 28.6g, HPLC purity is 96%, and receipts rate is 91%.
Embodiment 4
Adding compound (IV) 54g in 500ml reaction flask, then add methyltetrahydrofuran 200g, dilute hydrochloric acid stirs layering, water layer 100g methylene dichloride back extraction, merges organic phase, adds 30g dried over mgso and filter after 2 hours. Filtrate is proceeded in 500ml reaction flask, stirring is cooled to 0 ~ 5 �� of about C, drip after adding a small amount of N-methylmorpholine (available triethylamine replacement), start to drip and add isopropyl chlorocarbonate 20.6g, insulation reaction 3-5 hour, then drip and add the own enamine 15g of N-methyl, insulation reaction 1-2 hour, filtering, filter cake reclaims Cinchonidune. Filtrate is washed, layering, organic phase anhydrous sodium sulfate drying, filtration, and concentrated, obtaining light yellow oil (I) 27g, HPLC purity is 89%, and receipts rate is 80%.
Claims (3)
1. a method for the bicyclic lactone acid amides shown in preparation formula (I), taking the Cinchonidune salt compound shown in formula (IV) as starting raw material,
It is characterized in that:
A, compound (IV) and the reaction of chloro-formic ester compound, form mixed anhydride (III), and wherein, R is the alkyl of C1-C4;
B, mixed anhydride (III) carry out condensation with compound (II) again,
Obtain product (I).
2. method according to claim 1, chloro-formic ester compound general formula is ClC (=O) OR, and wherein, R is the alkyl of C1-C4.
3. formula (III) compound:
Wherein, R is the alkyl of C1-C4.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210146447.0A CN103387509B (en) | 2012-05-11 | 2012-05-11 | The preparation method of a kind of HCV protease inhibitor intermediate |
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| CN201210146447.0A CN103387509B (en) | 2012-05-11 | 2012-05-11 | The preparation method of a kind of HCV protease inhibitor intermediate |
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| CN103387509A CN103387509A (en) | 2013-11-13 |
| CN103387509B true CN103387509B (en) | 2016-06-08 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007014926A1 (en) * | 2005-07-29 | 2007-02-08 | Tibotec Pharmaceuticals Ltd. | Macrocyclic inhibitors of hepatitis c virus |
| EP1881001A1 (en) * | 2006-07-20 | 2008-01-23 | Tibotec Pharmaceuticals Ltd. | HCV NS-3 serine protease inhibitors |
| CN101233131A (en) * | 2005-07-29 | 2008-07-30 | 泰博特克药品有限公司 | Macrocyclic inhibitors of hepatitis c virus |
| WO2008095999A1 (en) * | 2007-02-08 | 2008-08-14 | Tibotec Pharmaceuticals Ltd. | Pyrimidine substituted macrocyclic hcv inhibitors |
| CN101600713A (en) * | 2007-02-01 | 2009-12-09 | 泰博特克药品有限公司 | Be used to prepare the method and the intermediate of the macrocyclic protease inhibitor of HCV |
| WO2010072742A1 (en) * | 2008-12-23 | 2010-07-01 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Processes and intermediates for preparing a macrocyclic protease inhibitor of hcv |
-
2012
- 2012-05-11 CN CN201210146447.0A patent/CN103387509B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007014926A1 (en) * | 2005-07-29 | 2007-02-08 | Tibotec Pharmaceuticals Ltd. | Macrocyclic inhibitors of hepatitis c virus |
| CN101233131A (en) * | 2005-07-29 | 2008-07-30 | 泰博特克药品有限公司 | Macrocyclic inhibitors of hepatitis c virus |
| EP1881001A1 (en) * | 2006-07-20 | 2008-01-23 | Tibotec Pharmaceuticals Ltd. | HCV NS-3 serine protease inhibitors |
| CN101600713A (en) * | 2007-02-01 | 2009-12-09 | 泰博特克药品有限公司 | Be used to prepare the method and the intermediate of the macrocyclic protease inhibitor of HCV |
| WO2008095999A1 (en) * | 2007-02-08 | 2008-08-14 | Tibotec Pharmaceuticals Ltd. | Pyrimidine substituted macrocyclic hcv inhibitors |
| WO2010072742A1 (en) * | 2008-12-23 | 2010-07-01 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Processes and intermediates for preparing a macrocyclic protease inhibitor of hcv |
Non-Patent Citations (1)
| Title |
|---|
| Structure–activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350;Pierre Raboisson等;《Bioorganic & Medicinal Chemistry Letters》;20081231;第18卷;第4853-4858页 * |
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| CN103387509A (en) | 2013-11-13 |
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