CN1554647A - Process for synthesizing ritonavir - Google Patents
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- CN1554647A CN1554647A CNA2003101210916A CN200310121091A CN1554647A CN 1554647 A CN1554647 A CN 1554647A CN A2003101210916 A CNA2003101210916 A CN A2003101210916A CN 200310121091 A CN200310121091 A CN 200310121091A CN 1554647 A CN1554647 A CN 1554647A
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Abstract
The present invention relates to the synthesis process of Ritonavir as one proteinase inhibitor for resisting AIDS. The synthesis process includes the condensation between benzylamino alcohol and valine NCA to obtain valyl benzylamino alcohol, the reaction between valyl benzylamino alcohol and ditert-butyl dicarbonate to obtain tert-butoxy acyl valyl benzylamino alcohol, the hydrogenolysis and debenzylation of tert-butoxy acyl valyl benzylamino alcohol in ammonium formate and Pd-C to obtain tert-butoxy acyl valyl amino alcohol, the active esterification reaction between tert-butoxy acyl valyl amino alcohol and 5-methylol thiazole, subsequent hydrolysis to obtain thiazolyl-5-methoxycarbonyl valyl amino alcohol, and the reaction of thiazolyl-5-methoxycarbonyl valyl amino alcohol and isopropyl thiazolyl methylamine under the action of BTC to obtain final product Ritonavir. The present invention has lowered cost and raised atomic utilization.
Description
(1) technical field
The present invention relates to a kind of synthetic method of ritonavir as one proteinase inhibitor for resisting AIDS.
(2) background technology
Ritonavir, chemical name: (5S, 8S, 10S, 11S)-10-hydroxy-2-methyl-5-(1-first and second bases)-1-[2-(1-first and second bases)-4-thiazolyl]-3,6-dioxy-8,11-two (phenmethyl)-2,4,7,12-four azepines tridecyl-13-carboxylic acid, 5-thiazole methyl esters (CAS No.155213-67-5) is the proteinase inhibitor (Proc.Natl.Acad.Sci.USA of a kind of anti-AIDS HIV-1 and HIV-2,1995,92,2484).The ritonavir structural formula is as follows:
From the ritonavir structural analysis, can be divided into four fragments.I is a 5-hydroxyl thiazole fragment, and IV is a sec.-propyl thiazole methylamine fragment, and III is the Xie Ansuan fragment, and II is the chiral amino alcohol fragment.According to patent and bibliographical information, ritonavir synthetic comprises following process: (a) two thiazole fragments (I and IV) is synthetic, (b) in the middle of chiral amino alcohol fragment (II) synthetic, (c) each segmental method of attachment.The segmental method of attachment of each that report is concluded three kinds: 1) benzyl ammonia alcohol 1 hydrogenolysis under palladium catalysis obtains diamino alcohol 2; under the borane reagent effect, obtain single acylate 3 with 4 reactions of 5-hydroxymethylthiazole Acibenzolar; obtain ritonavir (Patent US5541206) with 5 condensations again, synthetic route is as follows:
2) adopt uncle's fourth oxanamide protection method, connect 5-hydroxymethylthiazole base and sec.-propyl thiazole methylamine Xie Ansuan base according to this.Benzyl ammonia alcohol 1 is through uncle's fourth oxygen acidylate; go benzyl to obtain 6, is connected thiazole methoxycarbonyl base again with 5-hydroxymethylthiazole Acibenzolar 4 reaction and obtains 7,7 and go to protect through acid catalysis; be connected with sec.-propyl thiazole methylamine Xie Ansuan 5 and obtain ritonavir (Patent US5567823), synthetic route is as follows:
3) Xie Ansuan N-carboxylic acid inner-acid anhydride (NCA) and 1 condensation connect sec.-propyl thiazole methylamine 10 again, obtain intermediate 11.After the palladium catalytic hydrogenolysis is removed benzyl, generate ritonavir (Patent WO0121603) with 4 condensations of 5-hydroxymethylthiazole Acibenzolar, synthetic route is as follows:
Selective problems when the limitation of method 1 is the single acidylate of diamino alcohol under borane reagent protection and bring the trouble of the purification process of product thus.In addition, during preparation compound 5, Xie Ansuan need be changed into corresponding ester protection, generate carbamide compound, be hydrolyzed into sec.-propyl thiazole methylamine Xie Ansuan 5 again with 10 reactions of sec.-propyl thiazole methylamine; Method 2 adopts uncle's fourth oxanamide protection methods, has solved the selective problems when connecting two thiazole fragments step by step, but insufficient be that the preparation of compound 5 is loaded down with trivial details, reactions steps is more; The great advantage of method 3 is that reactions steps is short, and what auxiliary reagent was used lacks, the atom utilization height.But can influence the other end thiazole methylamine base when removing benzyl owing to the hydrogenolysis of compound 11, hydrogenolysis goes the benzyl selective conditions wayward.
(3) summary of the invention
The object of the present invention is to provide a kind of uncle's of utilization fourth oxygen acyl group protection method, hydrogenolysis to remove benzyl, react the strong synthetic (5S of specificity; 8S; 10S; 11S)-and 10-hydroxy-2-methyl-5-(1-first and second bases)-1-[2-(1-first and second bases)-4-thiazolyl]-3,6-dioxy-8,11-two (phenmethyl)-2; 4; 7,12-four azepines tridecyl-13-carboxylic acid, the new way of 5-thiazole methyl esters (ritonavir).
The present invention with (5S)-5-amino-2-(N, N-dibenzyl) amino-3-hydroxyl-1,6-phenylbenzene hexane 1 is a raw material for 2S, 3S, and synthetic route is as follows:
Reaction process is as follows:
1) benzyl ammonia alcohol 1 obtains valyl ammonia benzyl ammonia alcohol 9 with Xie Ansuan N-carboxylic acid inner-acid anhydride (NCA) 8 condensations, and weak polar solvent is adopted in reaction, and said weak polar solvent is a methylene dichloride, chloroform or 1,2-ethylene dichloride; Alkali reagent is a tertiary amine, and said tertiary amine is a triethylamine, temperature of reaction-30～0 ℃;
2) valyl ammonia benzyl ammonia alcohol 9 obtains uncle's fourth oxygen acyl valyl ammonia benzyl ammonia alcohol 12 with the di-tert-butyl dicarbonic acid ester reaction, non-protonic solvent is adopted in reaction, said non-protonic solvent is an ethyl acetate, and methylene dichloride or chloroform, used alkali are yellow soda ash or solution of potassium carbonate;
3) compound 12 hydrogenolysis in ammonium formiate and Pd-C is removed benzyl, obtains uncle's fourth oxygen acyl valyl amino alcohol 13, and reaction is made solvent with alcohol, and said alcohol is methyl alcohol or ethanol, 60～80 ℃ of temperature of reaction;
4) uncle's fourth oxygen acyl valyl amino alcohol 13 and 5-hydroxymethylthiazole Acibenzolar 4 reacting by heating in weak polar solvent, 40～70 ℃ of temperature of reaction, reaction 5～12h, then hydrochloric acid hydrolysis goes uncle's fourth oxygen formyl radical to obtain thiazole-5-methoxycarbonyl valyl amino alcohol 14, the aryl of 5-hydroxymethylthiazole Acibenzolar 4 can be phenyl or substituted-phenyl, preferably p-nitrophenyl; Said weak polar solvent is an ethyl acetate;
5) compound 14 triphosgene (BTC) effect down with 10 reactions of sec.-propyl thiazole methylamine, obtain the final product ritonavir, reaction solvent employing halohydrocarbon, temperature of reaction-35～-70 ℃, said halohydrocarbon is methylene dichloride or chloroform.
The present invention has saved the esterification protection carboxyl and the hydrolysis of Xie Ansuan and has gone to protect step.Utilize uncle's fourth oxygen acyl group protection method, hydrogenolysis is removed benzyl, and the reaction specificity is strong.At last with triphosgene with two amine connect the finished product.Saved twice in the reaction and used chloro-formic ester, be beneficial to and reduce cost the raising atom utilization.
(4) embodiment
The invention will be further described below by embodiment.
(696mg 1.5mmol) is dissolved in anhydrous methylene chloride (30ml) to step 1 benzyl ammonia alcohol 1.Be cooled to-20 ℃.Slowly drip N-carboxylic acid inner-acid anhydride 8 dichloromethane solution (2.25ml, 2.25mmol).Finish, (0.27ml, dichloromethane solution 30ml 1.92mmol) lasts 10min slowly to drip triethylamine.-13～-17 ℃ of reaction 2h.Concentrated hydrochloric acid is transferred pH=4.Saturated solution of sodium bicarbonate is transferred pH=8～9.Washing.Anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains 991mg valyl ammonia benzyl ammonia alcohol.
1H?NMR(CDCl
3，500MHz)δ7.05-7.35(m，20H)，4.12(m，1H)，3.90(d，J＝13.3Hz，2H)，3.57(dt，J＝2.2×8.1Hz，1H)，3.38(d，J＝14.2Hz，2H)，3.10(d，J＝4.1Hz，1H)，3.04(dd，J＝14.2×5.8Hz，1H)，2.62-2.82(m，4H)，2.15(m，1H)，1.57(m，2H)，1.53(m，2H)，1.35(m，1H)，0.88(d，J＝6.9Hz，3H)，0.63(d，J＝6.9Hz，3H).
MS(ESI)：564.3(M+1).
Step 2 valyl ammonia benzyl ammonia alcohol 9 (crude product 991mg 1.5mmol) is dissolved in the ethyl acetate (20ml), add 10% salt of wormwood (5ml) and di-tert-butyl dicarbonic acid ester (436mg, 2.0mmol).Stirring at room reaction 30min.Branch vibration layer.Wash organic phase with water, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains crude product 1.282g.The rapid column chromatography separation obtains 707mg compound 12.Two step yields 71%.
1H?NMR(CDCl
3，500MHz)δ7.00-7.35(m，20H)，6.55(d，J＝10.5Hz，1H)，5.03(d，J＝6.5Hz，1H)，4.52(s，1H)，4.03(m，1H)，3.85(d，J＝13.1Hz，2H)，3.52(t，J＝8.5Hz，1H)，3.35(d，J＝13.3Hz，2H)，3.05(dd，J＝14.4×5.7Hz，1H)，2.70-2.90(m，4H)，2.55(m，1H)，2.14(m，1H)，1.75(d，J＝8.5Hz，2H)，1.44(s，9H)，0.93(d，J＝6.8Hz，3H)，0.83(d，J＝6.5Hz，3H).
MS(ESI)：664.9(M+1).
(665mg 1.0mmol) is dissolved in methyl alcohol (15ml) to step 3 uncle fourth oxygen acyl valyl ammonia benzyl ammonia alcohol 12, adds 10%Pd-C (200mg) and ammonium formiate (700mg, 11mmol) methyl alcohol (15ml) solution.Be heated to 75 ℃, insulation backflow 7h.Solution diatomite heat filtering.Concentrating under reduced pressure.Add hot ethyl acetate (20ml) dissolving.Wash successively with 10% solution of potassium carbonate and water in 50 ℃.Obtain directly next step reaction of ethyl acetate solution of compound 13.
1H?NMR(DMSO-d
6，500MHz)δ7.70(d，J＝9.5Hz，1H)，7.10-7.30(m，10H)，6.45(d，J＝8.5Hz，1H)，4.45(bs，1H)，4.04(m，1H)，3.67(t，J＝8.3Hz，1H)，3.43(s，1H)，2.58-2.78(m，4H)，2.42(m，1H)，1.77(m，1H)，1.62(m，1H)，1.50(m，1H)，1.36(s，9H)，1.20(m，2H)，0.74(d，J＝6.8Hz，3H)，0.71(d，J＝6.8Hz，3H).
MS(ESI)：484.1(M+1).
(308mg 1.1mmol) is dissolved in compound 13 (484mg, ethyl acetate 1.0mmol) (20ml) solution to step 4 5-hydroxymethylthiazole Acibenzolar 4.Be heated with stirring to 60 ℃.Insulated and stirred 12h.Be cooled to 30 ℃.Add 3 of strong aquas.Stir 3h.10% solution of potassium carbonate washing 3 times, washing.Drip concentrated hydrochloric acid (0.3ml) in the solution.Be heated to 50 ℃, insulated and stirred reaction 3h.Concentrating under reduced pressure obtains solid.Solid adds ethyl acetate (20ml), transfers pH=10 with 10% ammoniacal liquor.Stir 10min.Branch vibration layer.Organic layer 25% sodium-chlor washing 2 times.Anhydrous sodium sulfate drying.Concentrating under reduced pressure.Obtain 489mg thiazole-5-methoxycarbonyl valyl amino alcohol 14.Rapid column chromatography separates, and obtains 433mg compound 14.Two step yields are 82%.
1H?NMR(CDCl
3，500MHz)δ?8.75(s，1H)，7.80(s，1H)，7.5(d，J＝8.5Hz，1H)，7.00-7.35(m，10H)，5.65(d，J＝9.3Hz，1H)，5.22(s，2H)，4.15(m，1H)，3.80(m，1H)，3.67(m，1H)，3.06(d，J＝2.3Hz，1H)，2.60-2.95(m，4H)，2.10(s，1H)，1.50-1.70(m，2H)，1.62(m，1H)，1.26(s，2H)，0.80(d，J＝6.3Hz，3H)，0.42(d，J＝6.6Hz，3H).
MS(ESI)：525.4(M+1).MS
2：525.2(M+1)(86)，507.3(86)，481.3(100)，463.3(13)，410.3(61).
(99mg 0.33mmol) mixes with methylene dichloride (15ml) step 5 triphosgene (BTC).Be cooled to-65 ℃.Thiazole-5-methoxycarbonyl valyl amino alcohol 14 (513mg, 0.97mmol) and triethylamine (0.145ml 1.03mmol) is dissolved in methylene dichloride (20ml), is cooled to-70 ℃.Amino alcohol 14 and triethylamine dichloromethane solution slowly are added drop-wise in the dichloromethane solution of triphosgene, last 30min.In-60～-70 ℃ of stirring reaction 4h.Prepare in addition thiazole methylamine 10 (170mg, 1mmol) and triethylamine (0.225ml, methylene dichloride 1.60mmol) (15ml) solution is cooled to-70 ℃, slowly is added drop-wise to reaction soln, lasts 30min.Add at-30～-40 ℃ of stirring reaction 3h.Add 10% citric acid stopped reaction.Branch vibration layer.The washing organic phase.Anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product 585mg.Rapid column chromatography separate ritonavir 461mg, productive rate 65%.
1H?NMR(DMSO-d
6，500MHz)δ9.05(s，1H)，7.85(s，1H)，7.70(d，J＝9.0Hz，1H)，7.1-7.3(m，11H)，6.88(d，J＝10.5Hz，1H)，6.02(d，J＝8.5Hz，1H)，5.16(d，J＝13.5Hz，1H)，5.12(d，J＝13.0Hz，1H)，4.60(bs，1H)，4.50(q，J＝15.0Hz，2H)，4.15(m，1H)，3.95(m，1H)，3.85(m，1H)，3.60(bs，1H)，3.25(m，1H)，2.85(s，3H)，2.55-2.70(m，4H)，1.90(m，1H)，1.45(m，2H)，1.30(d，J＝7.5Hz，6H)，0.75(d，J＝7.5Hz，6H).
MS(ESI)：721.4(M+1).
Claims (2)
1. the method for a synthetic ritonavir is with (2S, 3S, 5S)-and 5-amino-2-(N, N-dibenzyl) amino-3-hydroxyl-1,6-phenylbenzene hexane 1 is a raw material, synthetic (5S, 8S, 10S, 11S)-and 10-hydroxy-2-methyl-5-(1-first and second bases)-1-[2-(1-first and second bases)-4-thiazolyl]-3,6-dioxy-8,11-two (phenmethyl)-2,4,7,12-four azepines tridecyl-13-carboxylic acid, 5-thiazole methyl esters (ritonavir) is characterized in that synthetic route is as follows:
Reaction process is as follows:
1) benzyl ammonia alcohol 1 obtains valyl ammonia benzyl ammonia alcohol 9 with Xie Ansuan N-carboxylic acid inner-acid anhydride (NCA) 8 condensations, and weak polar solvent is adopted in reaction, and said weak polar solvent is a methylene dichloride, chloroform or 1,2-ethylene dichloride; Alkali reagent is a tertiary amine, and said tertiary amine is a triethylamine, temperature of reaction-30～0 ℃;
2) valyl ammonia benzyl ammonia alcohol 9 obtains uncle's fourth oxygen acyl valyl ammonia benzyl ammonia alcohol 12 with the di-tert-butyl dicarbonic acid ester reaction, non-protonic solvent is adopted in reaction, said non-protonic solvent is an ethyl acetate, and methylene dichloride or chloroform, used alkali are yellow soda ash or solution of potassium carbonate;
3) compound 12 hydrogenolysis in ammonium formiate and Pd-C is removed benzyl, obtains uncle's fourth oxygen acyl valyl amino alcohol 13, and reaction is made solvent with alcohol, and said alcohol is methyl alcohol or ethanol, 60～80 ℃ of temperature of reaction;
4) uncle's fourth oxygen acyl valyl amino alcohol 13 and 5-hydroxymethylthiazole Acibenzolar 4 reacting by heating in weak polar solvent, 40～70 ℃ of temperature of reaction, reaction 5～12h, then hydrochloric acid hydrolysis goes uncle's fourth oxygen formyl radical to obtain thiazole-5-methoxycarbonyl valyl amino alcohol 14, the aryl of 5-hydroxymethylthiazole Acibenzolar 4 can be phenyl or substituted-phenyl, and said weak polar solvent is an ethyl acetate;
5) compound 14 triphosgene (BTC) effect down with 10 reactions of sec.-propyl thiazole methylamine, obtain the final product ritonavir, reaction solvent employing halohydrocarbon, temperature of reaction-35～-70 ℃, said halohydrocarbon is methylene dichloride or chloroform.
2. the method for a kind of synthetic ritonavir as claimed in claim 1 is characterized in that the aryl of 5-hydroxymethylthiazole Acibenzolar 4 is p-nitrophenyls.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008027932A3 (en) * | 2006-08-31 | 2008-07-31 | Abbott Lab | Cytochrome p450 oxidase inhibitors and uses thereof |
| US7786153B2 (en) | 2005-03-02 | 2010-08-31 | Abbott Laboratories Inc. | Compounds that are useful for improving pharmacokinetics |
| CN103896870A (en) * | 2014-04-23 | 2014-07-02 | 南京靖龙药物研发有限公司 | Preparation method of deuterium labeled Ritonavir |
| CN104311503A (en) * | 2014-11-03 | 2015-01-28 | 东北制药集团股份有限公司 | Method for preparing anti-HIV (human immunodeficiency virus) medicine ritonavir |
-
2003
- 2003-12-24 CN CN 200310121091 patent/CN1247554C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7786153B2 (en) | 2005-03-02 | 2010-08-31 | Abbott Laboratories Inc. | Compounds that are useful for improving pharmacokinetics |
| US8524753B2 (en) | 2005-03-02 | 2013-09-03 | Abbvie Inc. | Compounds that are useful for improving pharmacokinetics |
| US8741938B2 (en) | 2005-03-02 | 2014-06-03 | Abbvie Inc. | Compounds that are useful for improving pharmacokinetics |
| WO2008027932A3 (en) * | 2006-08-31 | 2008-07-31 | Abbott Lab | Cytochrome p450 oxidase inhibitors and uses thereof |
| EP2465856A3 (en) * | 2006-08-31 | 2012-12-12 | Abbott Laboratories | Cytochrome P450 oxidase inhibitors and uses thereof |
| CN103896870A (en) * | 2014-04-23 | 2014-07-02 | 南京靖龙药物研发有限公司 | Preparation method of deuterium labeled Ritonavir |
| CN103896870B (en) * | 2014-04-23 | 2016-08-24 | 南京靖龙药物研发有限公司 | A kind of preparation method of deuterated ritonavir |
| CN104311503A (en) * | 2014-11-03 | 2015-01-28 | 东北制药集团股份有限公司 | Method for preparing anti-HIV (human immunodeficiency virus) medicine ritonavir |
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Assignee: Anhui Biochem United Pharmaceutical Co., Ltd. Assignor: Xiamen University Contract fulfillment period: 2008.10.28 to 2018.10.27 contract change Contract record no.: 2008351000064 Denomination of invention: Process for synthesizing ritonavir Granted publication date: 20060329 License type: Exclusive license Record date: 2008.12.9 |
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