CN101967130A - Synthesis method of ritonavir midbody - Google Patents
Synthesis method of ritonavir midbody Download PDFInfo
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Abstract
The invention discloses a synthesis method of (2S,3S,5C)-5-(Butyloxycarbonylamino)-2-(N-5- thiazolyl-carbomethoxy) amino-1,6-diphenyl-3-hydroxyhexane which is prepared from (2S,3S,5C)-2-amino-3-hydroxy-5-(Butyloxycarbonylamino)-1,6-diphenylhexane and 5-thiazolylmethyl-4-nitrobenzophenone carbonic ester through the nucleophilic substitution reaction, wherein the (2S,3S,5C)-2-amino-3-hydroxy-5-(Butyloxycarbonylamino)-1,6-diphenylhexane is prepared through the reducing step, the amino protection step and the catalytic reduction step on (S,Z)-5-amino-2-(dibenzylamino)-1,6-diphenylhexane-4-alkene-3-ketone. The synthesis method is an in situ synthesis method, not only reduces the reaction steps but also reduce the time consumption brought by intermediate product separation, improves the yield and does not influence the purity and the quality of the product.
Description
Technical field
The present invention relates to a kind of improved synthetic method, relate to a kind of ritonavir intermediate particularly---(2S, 3S, 5S)-and 5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1, the synthetic method of 6-phenylbenzene-3-hydroxyl hexane.
Background technology
Ritonavir can be treated late period or non-progressive acquired immune deficiency syndrome (AIDS) patient separately or with the other medicines coupling, and has following structure:
When synthesizing ritonavir, need make the intermediate of ritonavir in advance---(2S, 3S, 5S)-and 5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1,6-phenylbenzene-3-hydroxyl hexane (compound VI), structure is as follows:
The method for preparing compound VI relate to (2S, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1,6-phenylbenzene hexane (compound IV) and 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V).
In above-mentioned reaction, for reducing (2S, 3S, 5S)-and 2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1, by product quantity and by product kind that 6-phenylbenzene hexane (compound IV) produces when reacting with 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) guarantee the compound VI yield, can obtain highly purified (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1, the core place of 6-phenylbenzene hexane (compound IV).In existing disclosed method; compound IV is by (S; Z)-and 5-amino-2-(dibenzyl amino)-1,6-phenylbenzene hexane-4-alkene-3-ketone (Compound I) obtains the protection of Compound I I, t-butoxycarbonyl amino through reduction and obtains that compound III and catalytic reduction debenzylation step obtain.In order to improve the purity of compound IV, after the debenzylation step, compound IV earlier with succsinic acid react (2S, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1,6-phenylbenzene hexane succinate (compound VI I), again by (2S, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1, after desalting, 6-phenylbenzene hexane succinate (compound VI I) further obtains compound VI with 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) reaction.This synthetic method (2S, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1,6-phenylbenzene hexane (compound IV) needs to use earlier the method into succinate refining, obtain purity and reach (2S more than 99%, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1, the pure product of 6-phenylbenzene hexane succinate, succinate is removed in alkali cleaning then, this salify purified method, complex steps, length consuming time needs to consume a large amount of organic solvents, intermediate product (2S, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1, the separation of 6-phenylbenzene hexane succinate has also improved cost.Therefore, need a kind of more economical synthetic method.
The route of synthesis of existing open compound IV is as follows:
Summary of the invention
The invention provides the synthetic method of a kind of ritonavir intermediate " (2S; 3S; 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1; 6-phenylbenzene-3-hydroxyl hexane (compound VI) ", this synthetic method is an in-situ synthetic method, and it has not only reduced reactions steps, has also reduced intermediate product and has separated the time loss that is brought, improve yield, and do not influenced degree of purity of production and quality.
The technical solution used in the present invention is as follows:
The synthetic method of ritonavir intermediate is characterized in that, comprises the steps:
A, (S, Z)-5-amino-2-(dibenzyl amino)-1,6-phenylbenzene hexane-4-alkene-3-ketone (Compound I) through carbonyl reduction, C=C reduce (2S, 3S, 5S)-and 5-amino-2-(N, N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane (Compound I I);
B, (2S, 3S, 5S)-5-amino-2-(N, the N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane (Compound I I), adopt tertbutyloxycarbonyl BOC protect (2S, 3S, 5S)-and 2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound III);
C, (2S, 3S, 5S)-2-(N, the N-dibenzyl amino)-and 3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound III) is taken off benzyl through catalysis, obtains (2S, 3S, 5S)-and 2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound IV) crude product is through alkali cleaning, sodium-chlor is washed, use the normal heptane crystallization again, filter wet product, obtain pure product after the oven dry;
D, (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1, the pure product of 6-phenylbenzene hexane (compound IV) and 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) are through nucleophilic substitution, and crystallization filters, get (2S after the oven dry, 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1,6-phenylbenzene-3-hydroxyl hexane (compound VI).
In the preferred embodiment of the present invention, (the 2S that obtains among the step C, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane crude product ethyl acetate stirring and dissolving successively with 5%～10% sodium carbonate solution and the washing of 8%～10% sodium chloride solution, concentrates again, the normal heptane crystallization, filter wet product.By above-mentioned mode, not only reduced reactions steps, also reduce intermediate product and separated the time loss that is brought.
In the preferred embodiment of the present invention, (S, Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-reductive agent that uses in 4-alkene-3-ketone (Compound I) reduction process can be one or more in boron-tetrahydrofuran (THF), boron-dimethyl thioether, sodium borohydride, POTASSIUM BOROHYDRIDE or the lithium hydroxide.
In the preferred embodiment of the present invention, (S, Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-reduction of 4-alkene-3-ketone (Compound I) carries out under acidic conditions, used acid can be one or more in hydrochloric acid, sulfuric acid, sulfonic acid, acetic acid or the methylsulfonic acid.
In the preferred embodiment of the present invention, (2S, 3S, 5S)-2-(N, the N-dibenzyl amino)-and 3-hydroxyl-5-(tert.-butoxy formamido group)-1, the debenzylation of 6-phenylbenzene hexane (compound III) is realized by one or more the catalyzed reaction in the palladium catalyst charcoal, Palladous chloride, rhodium carbon, platinum oxide.
In the preferred embodiment of the present invention, the temperature of reaction of nucleophilic substitution is 25 ℃～100 ℃ in the steps d, and optimum temps is 60 ℃～80 ℃.
The synthetic method of ritonavir intermediate provided by the invention " (2S; 3S; 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1; 6-phenylbenzene-3-hydroxyl hexane (compound VI) " is an in-situ synthetic method, it has not only reduced reactions steps, also reduced intermediate product and separated the time loss that is brought, improved yield, and do not influenced degree of purity of production and quality.
Embodiment
The present invention will be further described below in conjunction with embodiment, but do not constitute any limitation of the invention.
Embodiment 1
1, (2S, 3S, 5S)-5-amino-2-(N, N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane (Compound I I) synthetic
In the 1000ml four-hole boiling flask that thermometer, mechanical stirring and dropping funnel are housed, add sodium borohydride 3.8g and glycol dimethyl ether 154.7ml, stir and be cooled to-10 ℃.Dropping contains the ethylene glycol dimethyl ether solution (methylsulfonic acid: glycol dimethyl ether=15.5ml: 24ml), control interior temperature and be no more than 5 ℃ of methylsulfonic acid.After drip finishing, drip again Virahol (19ml), ethylene glycol bisthioglycolate methyl alcohol 35.7ml and (S, Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-mixed solution of 4-alkene-3-ketone (Compound I) 14.6g, temperature is no more than 0 ℃ in the control.After dripping end, after reacting completely, drip the ethylene glycol dimethyl ether solution (containing trolamine 14.3g) of trolamine again in reaction below 0 ℃ more than 12 hours, temperature is no more than 5 ℃ in the control, stirs 30 minutes.Slowly drip the dimethylacetamide solution (containing sodium borohydride 3.1g) of sodium borohydride again, slowly be warming up to room temperature, insulated and stirred 2 hours.After reacting completely, in reaction solution, slowly add entry, add methyl tertiary butyl ether under the room temperature, standing demix.With 10% aqueous sodium hydroxide solution 476ml washing, aqueous ammonium chloride solution 476ml washing and sodium chloride solution 593ml wash organic layer successively.The organic layer that obtains is used anhydrous magnesium sulfate drying 2 hours, and solvent evaporated obtains lurid oily product under 30 ℃ of water-baths.
2, (2S, 3S, 5S)-2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound III) synthetic
Upwards the step concentrates oily matter adding methyl alcohol 15ml, and stirring and dissolving adds triethylamine 6.47g, water 79ml, tert-Butyl dicarbonate 7g stirs 2h, after reacting completely, standing demix, organic layer water 86ml washing, organic layer concentrating under reduced pressure solvent obtains light yellow oil.
3, (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound IV) synthetic
Upwards the step concentrates oily matter and adds ethanol 190ml, and 40 ℃ of stirring and dissolving add ammonium formiate 10.4g, Pd/C 7g, and back flow reaction 4 hours is until the raw material complete reaction.Filter, get the compound IV crude product.The compound IV crude product is with going into ethyl acetate 170ml dissolving, slowly add 10% sodium carbonate solution 100ml washing, 10% sodium-chlor 100ml washing, organic layer is evaporated to dried for 50 ℃, add normal heptane 110ml, stir, filter wet product, dry to such an extent that purity is 99.5% pure product of compound IV for 50 ℃.
4, (2S, 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) is amino-1,6-phenylbenzene-3-hydroxyl hexane (compound VI) synthetic
To thermometer is housed, the 1000ml four-hole boiling flask of mechanical stirring and dropping funnel adds (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound IV) 20g and 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) 14.5g, ethyl acetate 300ml, heating in water bath is to refluxing, 60 ℃ of insulation reaction 12～14 hours, be cooled to room temperature, add ammoniacal liquor 3g, stirred 1 hour, add 4% sodium hydroxide solution 100ml * 3 again, sodium chloride solution 100ml * 2, organic layer is evaporated to dried for 50 ℃, get golden yellow oily matter, add ethyl acetate/normal heptane crystallization.
Embodiment 2
Embodiment 2 as different from Example 1, (2S, 3S, 5S)-2-(N, the N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound III) adopts following mode synthetic: the step that makes progress concentrates oily matter and adds methyl tertiary butyl ether 40ml, stirring and dissolving adds salt of wormwood 8.77g, water 79ml, tert-Butyl dicarbonate 7g, stir 2h, after reacting completely, standing demix, organic layer water 86ml washing, organic layer concentrating under reduced pressure solvent obtains light yellow oil.
Embodiment 3
Embodiment 3 as different from Example 1, (2S, 3S, 5S)-and 2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound IV) adopts following mode synthetic: upward the step concentrates and adds methyl alcohol 190ml, 40 ℃ of stirring and dissolving in the oily matter, add Pd/C 7g, feed the air in the hydrogen exchange autoclave, hydrogen pressure reaches 0.5Mpa in still, reacts 4 hours until the raw material complete reaction.Filter, concentrate, get the compound IV crude product.Add ethyl acetate 170ml, stirring and dissolving slowly adds 5% sodium carbonate solution 100ml washing, 8% sodium-chlor 100ml washing, 60 ℃ of organic layers are evaporated to dried, add normal heptane 110ml, stir, filter wet product, dry to such an extent that purity is 99.6% pure product of compound IV for 50 ℃.
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (7)
1. the synthetic method of ritonavir intermediate is characterized in that, comprises the steps:
A, (S, Z)-5-amino-2-(dibenzyl amino)-1,6-phenylbenzene hexane-4-alkene-3-ketone through carbonyl reduction, C=C reduce (2S, 3S, 5S)-5-amino-2-(N, N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane;
B, (2S, 3S, 5S)-5-amino-2-(N, N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane, adopt tertbutyloxycarbonyl BOC protect (2S, 3S, 5S)-and 2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane;
C, (2S, 3S, 5S)-2-(N, the N-dibenzyl amino)-and 3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane is taken off benzyl through catalysis, obtains (2S, 3S, 5S)-and 2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane crude product is through alkali cleaning, sodium-chlor is washed, use the normal heptane crystallization again, filter wet product, obtain pure product after the oven dry;
D, (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1, pure product of 6-phenylbenzene hexane and 5-thiazolyl methyl-4-nitrophenyl carbonate is through nucleophilic substitution, and crystallization filters, get (2S after the oven dry, 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1,6-phenylbenzene-3-hydroxyl hexane.
2. according to the synthetic method of the ritonavir intermediate described in the claim 1, it is characterized in that: (the 2S that obtains among the step c, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane crude product ethyl acetate stirring and dissolving successively with 5%～10% sodium carbonate solution and the washing of 8%～10% sodium chloride solution, concentrates again, the normal heptane crystallization, filter wet product.
3. according to the synthetic method of the ritonavir intermediate described in the claim 1, it is characterized in that: (S among the step a, Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-reductive agent that uses in 4-alkene-3-ketone reduction process is one or more in boron-tetrahydrofuran (THF), boron-dimethyl thioether, sodium borohydride, POTASSIUM BOROHYDRIDE or the lithium hydroxide.
4. according to the synthetic method of the ritonavir intermediate described in the claim 3, it is characterized in that: (S among the step a, Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-reduction of 4-alkene-3-ketone carries out under acidic conditions, used acid is one or more in hydrochloric acid, sulfuric acid, hydrofluoric acid, sulfonic acid, acetic acid or the methylsulfonic acid.
5. according to the synthetic method of the ritonavir intermediate described in the claim 1, it is characterized in that: (2S among the step c, 3S, 5S)-2-(N, the N-dibenzyl amino)-and 3-hydroxyl-5-(tert.-butoxy formamido group)-1, the debenzylation of 6-phenylbenzene hexane is realized by one or more the catalyzed reaction in the palladium catalyst charcoal, Palladous chloride, rhodium carbon, platinum oxide.
6. according to the synthetic method of the ritonavir intermediate described in the claim 1, it is characterized in that: the temperature of reaction of nucleophilic substitution is 25 ℃～100 ℃ in the steps d.
7. according to the synthetic method of the ritonavir intermediate described in the claim 5, it is characterized in that: the temperature of reaction of nucleophilic substitution is 60 ℃～80 ℃ in the steps d.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102180812A (en) * | 2011-03-16 | 2011-09-14 | 济南爱思化工有限公司 | New method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane |
| CN102786494A (en) * | 2012-07-26 | 2012-11-21 | 合肥华方医药科技有限公司 | Synthesis research and control method of ritonavir isomer impurities |
| WO2013116715A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Methods and intermediates for preparing pharmaceutical agents |
| CN107602454A (en) * | 2017-09-19 | 2018-01-19 | 佛山科学技术学院 | Novel sulfonyl amine compound and its production and use |
| CN111454168A (en) * | 2020-04-14 | 2020-07-28 | 南通森萱药业有限公司 | Synthesis method of ritonavir intermediate BDH |
| CN112500367A (en) * | 2020-12-16 | 2021-03-16 | 盐城迪赛诺制药有限公司 | Refining method of ritonavir intermediate |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102180812A (en) * | 2011-03-16 | 2011-09-14 | 济南爱思化工有限公司 | New method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane |
| CN102180812B (en) * | 2011-03-16 | 2013-06-19 | 济南爱思化工有限公司 | New method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane |
| WO2013116715A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Methods and intermediates for preparing pharmaceutical agents |
| CN104093702A (en) * | 2012-02-03 | 2014-10-08 | 吉里德科学公司 | Methods and intermediates for preparing pharmaceutical agents |
| US9346796B2 (en) | 2012-02-03 | 2016-05-24 | Gilead Sciences, Inc. | Methods and intermediates for preparing pharmaceutical agents |
| CN102786494A (en) * | 2012-07-26 | 2012-11-21 | 合肥华方医药科技有限公司 | Synthesis research and control method of ritonavir isomer impurities |
| CN102786494B (en) * | 2012-07-26 | 2016-01-06 | 合肥华方医药科技有限公司 | The study on the synthesis of ritonavir isomer impurities and control method |
| CN107602454A (en) * | 2017-09-19 | 2018-01-19 | 佛山科学技术学院 | Novel sulfonyl amine compound and its production and use |
| CN107602454B (en) * | 2017-09-19 | 2020-12-01 | 佛山科学技术学院 | Sulfonamide compound and preparation method and application thereof |
| CN111454168A (en) * | 2020-04-14 | 2020-07-28 | 南通森萱药业有限公司 | Synthesis method of ritonavir intermediate BDH |
| CN111454168B (en) * | 2020-04-14 | 2022-04-05 | 南通森萱药业有限公司 | Synthesis method of ritonavir intermediate BDH |
| CN112500367A (en) * | 2020-12-16 | 2021-03-16 | 盐城迪赛诺制药有限公司 | Refining method of ritonavir intermediate |
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Effective date of registration: 20160721 Address after: Haicang District of Xiamen City, Fujian province 361000 Xinyang Street Weng Kok Road No. 289 Chong Building 523 unit Patentee after: XIAMEN CITY WEI JIA CHEMICAL TECHNOLOGY CO., LTD. Address before: Haicang District of Xiamen City, Fujian province 361000 Xinyang Street Weng Kok Road No. 289 branch 7 storey building No. 17, No. 18 unit Patentee before: Xiamen Henry Biological Chemistry Co., Ltd. |
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Effective date of registration: 20200727 Address after: Unit 03, 9 / F, building B1, Xiamen biomedical industrial park, 2050 wengjiao West Road, Haicang District, Xiamen City, Fujian Province Patentee after: Xiamen Weijia Pharmaceutical Co.,Ltd. Address before: Haicang District of Xiamen City, Fujian province 361000 Xinyang Street Weng Kok Road No. 289 Chong Building 523 unit Patentee before: XIAMEN CITY WEI JIA CHEMICAL TECHNOLOGY Co.,Ltd. |
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