CN103387509A - Preparation method of HCV protease inhibitor intermediate - Google Patents
Preparation method of HCV protease inhibitor intermediate Download PDFInfo
- Publication number
- CN103387509A CN103387509A CN2012101464470A CN201210146447A CN103387509A CN 103387509 A CN103387509 A CN 103387509A CN 2012101464470 A CN2012101464470 A CN 2012101464470A CN 201210146447 A CN201210146447 A CN 201210146447A CN 103387509 A CN103387509 A CN 103387509A
- Authority
- CN
- China
- Prior art keywords
- compound
- iii
- bicyclic lactone
- preparation
- cinchonidune
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of an intermediate bicyclic lactone amide (I) of HCV protease inhibitor TMC435. According to the invention, a cinchonidine salt (IV) is adopted as a raw material, and forms mixed anhydride (III) with a chloroformate compound; and the mixed anhydride is subjected to condensation with N-methyl-cyclohexene amine (NMHA) (II), such that the target product bicyclic lactone amide compound (I) is obtained.
Description
Technical field:
The present invention relates to the preparation method of intermediate and the derivative bicyclic lactone acid amides (I) thereof of a kind of HCV proteinase inhibitor TMC435.
Background technology:
Hepatitis C virus (HCV) is the major cause of suffering from chronic hepatopathy all over the world.After initial acute infection, most of infected individuality all can develop into chronic hepatitis, and this is because HCV preferentially copies rather than cytopathy directly occurs in liver cell.Chronic hepatitis may develop into hepatic fibrosis, causes liver cirrhosis, latter stage hepatopathy and HCC (hepatocellular carcinoma), make it become the major cause of liver transplantation.Chronic hepatitis and accumulation patient's quantity makes HCV become important medical research focus.HCV is genomic copies the mediation that is subject to plurality of enzymes, and HCV NS3 serine protease and relevant cofactor NS4A thereof are arranged in described enzyme, and the multiple proteolytic cleavage of its mediation HCV polyprotein, cause the generation of HCV replicative enzyme.The NS3 serine protease is considered to the necessary and attractive target that become drug discovery of virus replication.
TMC435 (having another name called TMC435350) is a kind of cyclopentyl Macrocyclic HCV NS3/4A proteinase inhibitor that the center quinolyl replaces that has, and day clothes once, are used for the treatment of chronic hepatitis C, by Medivir and Johnson﹠amp; Johnson researches and develops jointly.Clinical data shows, it is attractive especially aspect pharmacodynamics and pharmacokinetics, can make 1 type patients with chronic hepatitis C keep higher lasting virological response (SVR) rate, has short, security for the treatment of time, health giving quality and tolerance than high.Now a plurality of countries carry out the clinical III phase and study in the whole world, and the fast passage (Fast Track) that has obtained U.S. food Drug Administration (FDA) examines qualification, estimate listing in 2013.
Compound bicyclic lactone acid amides (I) is the important intermediate of preparation TMC435, document WO2010072742 and WO2007014926 (Johnson﹠amp; The Johnson application) disclose from the synthetic method of the synthetic TMC435 of compound (I), as shown in scheme 1.
Scheme 1
Document WO2010072742 (Johnson﹠amp; The Johnson application) preparation method of compound (I) is disclosed, as shown in scheme 2.In scheme 2 take Cinchonidune (Cinchonidine) salt (IV) as starting raw material, (II) react with N-methyl hexamethyleneamine (NMHA) in the acid amides coupler, obtain bicyclic lactone acid amides (I), wherein, the acid amides coupler 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.Also can use another replacement scheme, Cinchonidune (Cinchonidine) salt (IV) is separable is Cinchonidune and bicyclic lactone, and the latter and NMHA form reaction in reaction at acid amides described above, obtain bicyclic lactone acid amides (I).But this method reaction times is very long, and disposable yield and purity are lower, and temperature of reaction is high, and need to carry out complicated post-processing operation and just can obtain the compound (I) of higher degree.
Scheme 2
Summary of the invention:
Problem for above-mentioned prior art existence, the present invention improves on the basis of scheme 2, purpose is to provide a kind of high-level efficiency to prepare the method for compound (I), the method has overcome all lower shortcomings of the disposable yield of prior art and purity, save cost, improved economic benefit.
The 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 again chloro-formic ester compounds ClC (=O) OR, R is the alkyl of C1-C4, reaction obtains mixed anhydride (III), add again N-methyl hexamethyleneamine (NMHA) (II) to react, obtain bicyclic lactone acid amides (I).
In another embodiment that substitutes, Cinchonidune (Cinchonidine) salt (IV) can first be separated into Cinchonidune and bicyclic lactone, and bicyclic lactone reacts with acid amides as above again, obtains bicyclic lactone acid amides (I).
Specific embodiment:
Embodiment 1
Add compound (IV) 108g in the 1000ml reaction flask, add again trichloromethane, stirring and dissolving, be cooled to-10 ~-5 ° of C left and right, drip methyl-chloroformate 31.8g, insulation reaction 3-5 hour, drip again N-methyl hexamethyleneamine 30g, insulation reaction 1-2 hour, filter, and filter cake reclaims Cinchonidune.The filtrate washing, layering, organic phase is with anhydrous sodium sulfate drying, filtration, and is concentrated, obtains light yellow oil (I) 57g, and HPLC purity is 95%, and yield is 90%.
Embodiment 2
Add compound (IV) 108g in the 1000ml reaction flask, then add toluene, stirring and dissolving, be cooled to-15 ~-10 ° of C left and right, drip Vinyl chloroformate 36.5, insulation reaction 3-5 hour, then drip N-methyl hexamethyleneamine 30g, insulation reaction 1-2 hour, filter, and filter cake reclaims Cinchonidune.The filtrate washing, layering, organic phase is with anhydrous sodium sulfate drying, filtration, and is concentrated, obtains light yellow oil (I) 57g, and HPLC purity is 94%, and yield is 89%.
Embodiment 3
Add compound (IV) 54g in the 1000ml reaction flask, then add methylene dichloride, stirring and dissolving, be cooled to-5 ~ 0 ° of C left and right, drip isopropyl chlorocarbonate 20.6, insulation reaction 3-5 hour, then drip N-methyl hexamethyleneamine 15g, insulation reaction 1-2 hour, filter, and filter cake reclaims Cinchonidune.The filtrate washing, layering, organic phase is with anhydrous sodium sulfate drying, filtration, and is concentrated, obtains light yellow oil (I) 28.6g, and HPLC purity is 96%, and yield is 91%.
Embodiment 4
Add compound (IV) 54g in the 500ml reaction flask, then add methyltetrahydrofuran 200g, dilute hydrochloric acid stirs layering, and water layer, with the back extraction of 100g methylene dichloride, merges organic phase, adds the 30g dried over mgso to filter after 2 hours.Filtrate is changed in the 500ml reaction flask, stirring is cooled to 0 ~ 5 ° of C left and right, after dripping a small amount of N-methylmorpholine (available triethylamine replacement), start to drip isopropyl chlorocarbonate 20.6g, insulation reaction 3-5 hour, then drip N-methyl hexamethyleneamine 15g, insulation reaction 1-2 hour, filter, filter cake reclaims Cinchonidune.The filtrate washing, layering, organic phase is with anhydrous sodium sulfate drying, filtration, and is concentrated, obtains light yellow oil (I) 27g, and HPLC purity is 89%, and yield is 80%.
Claims (4)
1. take the Cinchonidune salt compound shown in formula (IV) as starting raw material, the method for the bicyclic lactone acid amides shown in preparation formula (I),
It is characterized in that:
A, compound (IV) and the reaction of chloro-formic ester compounds, form mixed anhydride (III),
B, mixed anhydride (III) again and compound (II) carry out condensation,
Obtain product (I).
2. method according to claim 1, after comprising compound (IV) first being separated into Cinchonidune and bicyclic lactone, with bicyclic lactone with organic solvent dissolution after, add again the reaction of chloro-formic ester compounds, form mixed anhydride (III), again and compound (II) carry out condensation, obtain product (I).
3. according to claim 1-2 described methods, described chloro-formic ester compounds are that (=O) OR, wherein, R is the alkyl of C1-C4 to ClC.
4. formula (III) compound:
Wherein, R is the alkyl of C1-C4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210146447.0A CN103387509B (en) | 2012-05-11 | 2012-05-11 | The preparation method of a kind of HCV protease inhibitor intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210146447.0A CN103387509B (en) | 2012-05-11 | 2012-05-11 | The preparation method of a kind of HCV protease inhibitor intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103387509A true CN103387509A (en) | 2013-11-13 |
| CN103387509B CN103387509B (en) | 2016-06-08 |
Family
ID=49531941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210146447.0A Active CN103387509B (en) | 2012-05-11 | 2012-05-11 | The preparation method of a kind of HCV protease inhibitor intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103387509B (en) |
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 |
|---|
| PIERRE RABOISSON等: "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", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 18, 31 December 2008 (2008-12-31), pages 4853 - 4858, XP029441726, DOI: doi:10.1016/j.bmcl.2008.07.088 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103387509B (en) | 2016-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Talele et al. | Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase | |
| Qiu et al. | Synthesis and biological evaluation of Matijing-Su derivatives as potent anti-HBV agents | |
| CN107033087B (en) | 1H-indazole-4-amine compounds and use thereof as IDO inhibitors | |
| CN108727378A (en) | Novel isoquinoline compound and its medical usage | |
| DeGoey et al. | Discovery of pyrido [2, 3-d] pyrimidine-based inhibitors of HCV NS5A | |
| BRPI0718798A2 (en) | HEPATITIS C VIRUS MACROCYCLIC INHIBITORS | |
| JP2012528877A5 (en) | ||
| CN103130710B (en) | Anti-enteric virus71 (EV71) hexanolactam aldehyde compound and its production and use | |
| EA200901573A1 (en) | Heteroaryl Thiazole Substituents | |
| CN108794487A (en) | Double and ring nucleoid capsid inhibitor and its purposes as drug for treating hepatitis B | |
| EP3239160B1 (en) | Tizoxanide phosphate and alkane sulfonate and pharmaceutical applications thereof | |
| US10538507B2 (en) | Preparation process for high-purity dabigatran etexilate | |
| WO2009127949A8 (en) | 4- [3- (aryloxy) benzylidene] -3-methyl piperidine aryl carboxamide compounds useful as faah inhibitors | |
| CN103387509B (en) | The preparation method of a kind of HCV protease inhibitor intermediate | |
| CN107459511A (en) | Ketone compounds of 4 imino group oxazolidine of anti-enteric virus71 (EV71) 2 and its production and use | |
| CN105237516A (en) | Preparation method of Ledipasvir | |
| Jiang et al. | Synthesis and antiviral activity of a series of novel N-phenylbenzamide and N-phenylacetophenone compounds as anti-HCV and anti-EV71 agents | |
| CN104030998B (en) | 4-Polyfluoroalkyl-4,5-bis-substituted isoxazoles derivative and preparation method thereof | |
| CN108129366A (en) | Antiviral compound, preparation method and its usage | |
| JP7154659B2 (en) | Fused ring-containing compound, use thereof and pharmaceutical composition containing same | |
| CA2887420C (en) | Matrix metalloproteinase inhibitors and methods for the treatment of pain and other diseases | |
| CN101239958A (en) | Arylthioureas compounds with antivirus activity, preparation method and use thereof | |
| CN102643266A (en) | New preparation method of Lenalidomide B crystal form | |
| CN102796084A (en) | Application of active substance to treatment of hepatitis C and preparation method thereof | |
| CN109535213A (en) | The preparation of Suo Feibuwei |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |