CN104193643A - Novel midbody for synthesizing anti-AIDS medicine reinforcing agent cobicistat - Google Patents
Novel midbody for synthesizing anti-AIDS medicine reinforcing agent cobicistat Download PDFInfo
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- CN104193643A CN104193643A CN201410466139.5A CN201410466139A CN104193643A CN 104193643 A CN104193643 A CN 104193643A CN 201410466139 A CN201410466139 A CN 201410466139A CN 104193643 A CN104193643 A CN 104193643A
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- HPOOEJLMMHYFMU-UHFFFAOYSA-N C=C1C=CC(CC(CCC(CC(C=CC2)=CC2=C)C(O)=O)CC(O)=O)=CC1 Chemical compound C=C1C=CC(CC(CCC(CC(C=CC2)=CC2=C)C(O)=O)CC(O)=O)=CC1 HPOOEJLMMHYFMU-UHFFFAOYSA-N 0.000 description 1
- ASZMUABEZZBJNV-UHFFFAOYSA-N CNC(C(CCC(Cc1ccccc1)C(N)=O)Cc1ccccc1)Cl Chemical compound CNC(C(CCC(Cc1ccccc1)C(N)=O)Cc1ccccc1)Cl ASZMUABEZZBJNV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a method for synthesizing a novel midbody compound I for synthesizing an anti-AIDS medicine reinforcing agent cobicistat and further discloses a method for synthesizing (2R,5R)-1,6-diphenyl-2,5-hexamethylendiamine by using the compound I. The method for synthesizing (2R,5R)-1,6-diphenyl-2,5-hexamethylendiamine by using the compound I has the advantages that a relatively small amount of steps are needed, the production condition is simple, the operation is easy, the production cost is low, and the like, the product purity is high, and the high-quality requirements on medical products are met.
Description
Technical field
The present invention relates to the new intermediate compound of a kind of anti-AIDS drug toughener cobicistat, with and preparation and synthetic cobicistat key intermediate (2R, 5R)-1,6-phenylbenzene-2, the application of 5 hexanediamines.
Background technology
Cobicistat is one of composition of the anti-AIDS drug Stribild that gone on the market, thereby it is a kind of novel synergistic agent that can improve inverase pharmacokinetic parameters and improve drug effect.This medicine itself is without HIV (human immunodeficiency virus)-resistant activity, but can improve by suppressing the Major Enzymes-CYP3A of human body metabolism's medicine the Plasma Concentration of inverase.
(2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine is one of key intermediate of Cobicistat.
Desai etc. disclose a kind of synthetic (2R at patent WO2008010921 in 2008; 5R)-1; 6-phenylbenzene-2; the method of 5-hexanediamine: this method is taking L-(-)-phenylalaninol as raw material; by amido protecting, prepare aldehyde compound and sulfuryl compound, then carry out coupling with butyllithium-78 DEG C; sodium amalgam is eliminated, sodium liquefied ammonia deprotection, last hydrogenating reduction obtain product, total recovery 33%.
Hongtao Liu etc. has delivered another kind of synthetic (2R in magazine Tetrahedron Letters 50 (2009) 552-554 in 2008; 5R)-1; 6-phenylbenzene-2; the method of 5-hexanediamine: this method is also taking L-(-)-phenylalaninol as raw material; first amino with Cbz protection; become aldehyde with SO3-oxidation of methylpyridine again, then carry out catalytic coupling with vanadium trichloride and obtain tetramethyl ethylene ketone, then obtain product by steps such as high temperature elimination, reduction, deprotections.
Polniaszek etc. disclose a kind of synthetic (2R in patent WO2010115000 in 2010; 5R)-1; 6-phenylbenzene-2; the method of 5-hexanediamine: this method is also taking L-(-)-phenylalaninol as raw material; first preparation ring the third nitrogen heterocyclic compounds; protect again, then carry out coupling with butyllithium, finally obtain the finished product by deprotection, reduction.
These three routes are all taking L-(-)-phenylalaninol as starting raw material, first protect and derivatize, then carry out coupling through diverse ways, and finally by deprotection, the steps such as reduction obtain the finished product.But these methods exist distinct disadvantage, limit its suitability for industrialized production:
(1) raw material L-(-)-phenylalaninol price, reaction reagent is special, is difficult for obtaining;
(2) reactions steps is many;
(3) deprotection that needs protection, Atom economy is poor;
(4) severe reaction conditions, energy consumption is huge.
Summary of the invention
Technical problem to be solved by this invention has been to provide the new intermediate of a kind of anti-AIDS drug toughener cobicistat, and provides and synthesize (2R, 5R)-1,6-phenylbenzene-2, the method for 5-hexanediamine with this new intermediate.The method route has the advantages such as step is short, working condition is simple to operation, production cost is low, and product purity is high, high quality requirement that can fulfilling medicinal product.
The present invention solves the problems of the technologies described above adopted technical scheme:
An aspect of of the present present invention, discloses the new intermediate compound I of a kind of anti-AIDS drug toughener cobicistat, and the structural formula of this Compound I is as follows:
Wherein, this Compound I comprises following three kinds of chiral configurations:
Another aspect of the present invention, discloses the preparation method of this new intermediate compound I, comprises the steps:
1) Compound I I and activating reagent are reacted the in the situation that of amide condensed dose of existence, obtain carboxylic acid halides or active ester intermediate;
2) this carboxylic acid halides or active ester intermediate and ammonia react, obtain Compound I, i.e. the new intermediate compound I of anti-AIDS drug toughener cobicistat of the present invention.
Reaction formula is as follows:
Wherein, described amide condensed dose is selected from any one in thionyl chloride, phosphorus oxychloride, methyl-chloroformate, Vinyl chloroformate, dicarbapentaborane imidazoles, HOBt.
The present invention also discloses (the R of new intermediate compound I, R) preparation method of type Compound I-1, utilize (R, R) synthetic (R of type Compound I I-1, R) type Compound I-1, the method comprises: Compound I I-1 and activating reagent are reacted the in the situation that of amide condensed dose of existence, then with ammonia react, obtain described Compound I-1.
Reaction formula is as follows:
Wherein, described amide condensed dose is selected from any one in thionyl chloride, phosphorus oxychloride, methyl-chloroformate, Vinyl chloroformate, dicarbapentaborane imidazoles, HOBt.
Another aspect of the present invention, provides synthetic (2R, 5R)-1 with new intermediate compound I, 6-phenylbenzene-2, the method for 5-hexanediamine.
The present invention prepares (2R, 5R)-1 by new intermediate compound I, 6-phenylbenzene-2, and the method for 5-hexanediamine, comprises the steps:
1) Compound I is reacted with halogenating agent, and then and alkali reaction, complete rearrangement reaction, obtain racemoid III.
2) racemoid III, splits with acid chiral resolving agent, obtains (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine.
Reaction formula is as follows:
Wherein, described halogenating agent is selected from any one in clorox, bromine, chlorine, C5H6Br2N2O2, NBS; Described alkali is selected from any one in sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium methylate, sodium ethylate; Described acid chiral resolving agent is selected from any one in tartrate, amygdalic acid, camphorsulfonic acid, DTTA, DBTA.
Of the present invention again on the other hand, provide by (R, R) type Compound I-1 preparation (2R, 5R)-1,6-phenylbenzene-2, the method for 5-hexanediamine, the method comprises the steps: that Compound I-1 reacts with halogenating agent, and then and alkali reaction, complete rearrangement reaction, directly obtain (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine.
Reaction formula is as follows:
Wherein, described halogenating agent is selected from any one in clorox, bromine, chlorine, C5H6Br2N2O2, NBS; Described alkali is selected from any one in sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium methylate, sodium ethylate.
In sum, the present invention is to (2R, 5R)-1,6-phenylbenzene-2, and the synthesis technique of 5-hexanediamine has carried out the research of novelty.Propose to utilize new intermediate compound I of the present invention to synthesize (2R, 5R)-1,6-phenylbenzene-2, the variation route of 5-hexanediamine, as shown in Scheme 4:
Or, utilize Compound I-1 to synthesize (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine, as shown in Scheme 5:
The present invention compared with prior art, tool has the following advantages: new intermediate compound I disclosed by the invention has no report, and the present invention has proposed innovatively with this new intermediate compound I preparation (2R, 5R)-1,6-phenylbenzene-2, the synthetic route of 5-hexanediamine.The method route has the advantages such as step is short, working condition is simple to operation, production cost is low, and product purity is high, high quality requirement that can fulfilling medicinal product.
Brief description of the drawings
Fig. 1 is the structural formula of the present invention for the synthesis of the new intermediate compound I of anti-AIDS drug toughener cobicistat.
Fig. 2 is the nucleus magnetic resonance C spectrogram of Compound I-1.
Fig. 3 is the nucleus magnetic resonance H spectrogram of Compound I-1.
Fig. 4 is the nucleus magnetic resonance C spectrogram of Compound I-2.
Fig. 5 is the nucleus magnetic resonance H spectrogram of Compound I-2.
Fig. 6 is the nucleus magnetic resonance C spectrogram of Compound I-3.
Fig. 7 is the nucleus magnetic resonance H spectrogram of Compound I-3.
Fig. 8 is the nucleus magnetic resonance C spectrogram of Compound I.
Fig. 9 is the nucleus magnetic resonance H spectrogram of Compound I.
Figure 10 is the nucleus magnetic resonance C spectrogram of compound III-1.
Figure 11 is the nucleus magnetic resonance H spectrogram of compound III-1.
Embodiment
In order to understand better content of the present invention, be described further below in conjunction with specific embodiments and the drawings.Should be understood that these embodiment, only for the present invention is further described, limit the scope of the invention and be not used in.In addition should be understood that and reading after content of the present invention, person skilled in art makes some nonessential change or adjustment to the present invention, still belongs to protection scope of the present invention.,
Embodiment 1, preparation Compound I
In a 500ml four-hole bottle, drop into Compound I I 60g, thionyl chloride 200ml, back flow reaction 2h, reaction solution dissolves clarification, with HPLC sampling detection, complete to raw material primitive reaction, stopped reaction.By reaction solution, in below 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 1000ml four-hole bottle, adding concentration is 15% ammoniacal liquor 250ml, stirs, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solids to generate, reaction solution is warming up to 15-20 DEG C and continues reaction 2h, filters, filter cake 200ml water washing, 70 DEG C of oven dry, obtain white solid 52.5g, yield 87.5%, fusing point, 204.8-211.8 DEG C, nuclear-magnetism
1h NMR (400MHz, DMSO): δ 7.19-7.25 (m, 10H), 6.70-7.15 (br, 4H), 2.72-2.79 (m, 2H), 2.39-2.53 (m, 4H), 1.33-1.51 (m, 4H).
13c NMR (400MHz, DMSO): δ 176.6,175.9,140.1,128.7,128.01,128.0,125.7,47.17,47.1,38.24,38.1,30.08,30.04.
Embodiment 2, preparation compound III
In a 500ml four-hole bottle, drop into sodium hydroxide 20g, water 150ml, technical grade chlorine bleach liquor (available chlorine content approximately 9.5%) 100ml, stirs, and is cooled to 10 DEG C of left and right, starting a point several adds Compound I 52.5g, temperature rise 2-5 DEG C, removes coolingly, is naturally warmed up to room temperature, and be incubated 1.5h, sampling, with TLC detection, complete to raw material reaction.In another 1000ml four-hole bottle, add water 150ml, be heated to 75-78 DEG C, above-mentioned reaction solution is dripped in 1h left and right, drip and finish, then in 75-78 DEG C of continuation insulation reaction 3-4h, then stop heating, be down to room temperature, use dichloromethane extraction product, be concentrated into dryly, obtain 34 grams of oily matter.
Embodiment 3, preparation compound III-1
In a 500ml reaction flask, add step gained condenses 34g, methyl alcohol 150ml, stirring and dissolving clarification adds d-camphorsulfonic acid 29.5g under room temperature, and reaction solution is heated to dissolve clarification, then cooling, adularescent solid is constantly separated out, and after 4h, Slow cooling reaction solution is to room temperature, continue stirring and crystallizing 2h, filter, obtain white solid 15.7g
On dropping into, walk gained white solid 15.7g, methylene dichloride 72ml, water 36ml in a 200ml four-hole bottle, stirring and dissolving, to clear, with aqueous sodium hydroxide solution adjust pH to 10 left and right, continues to stir 10min, stratification, water layer is used 20ml*2 dichloromethane extraction again, merges organic layer, with 20ml water washing one time, organic layer anhydrous magnesium sulfate drying 30min, filter, concentrated, obtain oily matter 6.4g.Nuclear-magnetism:
1h NMR (500MHz, DMSO): δ 8.3 (br, 4H), 7.24-7.33 (m, 10H), 3.3 (m, 2H), 2.97-3.0 (dd, 2H), 2.77-2.81 (dd, 2H), 1.57-1.76 (m, 4H).
13c NMR (400MHz, DMSO): δ 136.4,129.3,128.5,126.7,51.7,37.8,26.8.
Embodiment 4, preparation Compound I-1
In a 50ml four-hole bottle, drop into Compound I I-15g, thionyl chloride 15ml, back flow reaction 2h, reaction solution dissolves clarification, with HPLC sampling detection, complete to raw material primitive reaction, stopped reaction.By reaction solution, in below 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 100ml four-hole bottle, adding concentration is 15% ammoniacal liquor 20ml, stirs, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solids to generate, reaction solution is warming up to 15-20 DEG C and continues reaction 2h, filters, filter cake 20ml water washing, 70 DEG C of oven dry, obtain white solid 4.5g, yield 90.2%, fusing point, 208.9-209.1 DEG C, nuclear-magnetism
1h NMR (400MHz, DMSO): δ 7.19-7.25 (m, 10H), 6.70-7.16 (br, 4H), 2.72-2.79 (m, 2H), 2.40-2.54 (m, 4H), 1.27-1.51 (m, 4H).
13c NMR (400MHz, DMSO): δ 175.9,140.1,128.7,127.9,125.7,47.1,38.2,30.0.
Embodiment 5, preparation compound III-1
In a 50ml four-hole bottle, drop into sodium hydroxide 2g, water 15ml, technical grade chlorine bleach liquor (available chlorine content approximately 9.5%) 9ml, stir, be cooled to 10 DEG C of left and right, start a point several Compound I-14.5g is added, remove cooling, naturally be warmed up to room temperature, and be incubated 1.5h, sampling, with TLC detection, complete to raw material reaction.In another 100ml four-hole bottle, add water 15ml, be heated to 75-78 DEG C, above-mentioned reaction solution is dripped in 1h left and right, drip and finish, then in 75-78 DEG C of continuation insulation reaction 3h, then stop heating, be down to room temperature, use dichloromethane extraction product, be concentrated into dryly, obtain 3.0 grams of oily matter.Nuclear-magnetism
1h NMR (500MHz, DMSO): δ 8.3 (br, 4H), 7.24-7.33 (m, 10H), 3.3 (m, 2H), 2.97-3.0 (dd, 2H), 2.77-2.81 (dd, 2H), 1.57-1.76 (m, 4H).
13c NMR (400MHz, DMSO): δ 136.4,129.3,128.5,126.7,51.7,37.8,26.8
Embodiment 6, preparation Compound I-2
In a 50ml four-hole bottle, drop into Compound I I-21g, thionyl chloride 10ml, back flow reaction 2h, reaction solution dissolves clarification, with HPLC sampling detection, complete to raw material primitive reaction, stopped reaction.By reaction solution, in below 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 100ml four-hole bottle, adding concentration is 15% ammoniacal liquor 10ml, stirs, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solids to generate, reaction solution is warming up to 15-20 DEG C and continues reaction 2h, filters, filter cake 10ml water washing, 70 DEG C of oven dry, obtain white solid 0.85g, yield 85%, fusing point, 208.8-209.1 DEG C of nuclear-magnetism
1h NMR (400MHz, DMSO): δ 7.13-7.24 (m, 10H), 6.70-7.16 (br, 4H), 2.76-2.80 (m, 2H), 2.43-2.55 (m, 4H), 1.30-1.53 (m, 4H).
13c NMR (500MHz, DMSO): δ 176.0,140.1,128.7,127.9,125.7,47.1,38.2,30.1.
Embodiment 7, preparation Compound I-3
In a 50ml four-hole bottle, drop into Compound I I-21g, thionyl chloride 10ml, back flow reaction 2h, reaction solution dissolves clarification, with HPLC sampling detection, complete to raw material primitive reaction, stopped reaction.By reaction solution, in below 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 100ml four-hole bottle, adding concentration is 15% ammoniacal liquor 10ml, stirs, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solids to generate, reaction solution is warming up to 15-20 DEG C and continues reaction 2h, filters, filter cake 10ml water washing, 70 DEG C of oven dry, obtain white solid 0.75g, yield 75%, fusing point, 246.3-246.7 DEG C of nuclear-magnetism
1h NMR (400MHz, DMSO): δ 7.13-7.25 (m, 10H), 6.70-7.16 (br, 4H), 2.73-2.78 (m, 2H), 2.38-2.53 (m, 4H), 1.34-1.46 (m, 4H).
13c NMR (400MHz, DMSO): δ 176.1,140.1,128.7,127.9,125.8,47.2,38.1,30.0.
Claims (8)
1. for the synthesis of a new intermediate of anti-AIDS drug toughener cobicistat, shown in structural formula as I:
Wherein, comprise following three kinds of chiral configurations:
2. a preparation method for new intermediate as claimed in claim 1, the method comprises: Compound I I and activating reagent are reacted the in the situation that of amide condensed dose of existence, then with ammonia react, obtain described Compound I:
3. a preparation method for new intermediate as claimed in claim 1, the method comprises: Compound I I-1 and activating reagent are reacted the in the situation that of amide condensed dose of existence, then with ammonia react, obtain described Compound I-1:
4. the preparation method of new intermediate as claimed in claim 2 or claim 3, is characterized in that, described amide condensed dose is selected from any one of thionyl chloride, phosphorus oxychloride, methyl-chloroformate, Vinyl chloroformate, dicarbapentaborane imidazoles and HOBt.
As claimed in claim 1 new intermediate in intermediate compound III-1 (2R, 5R)-1 for the preparation of anti-AIDS drug toughener cobicistat, 6-phenylbenzene-2, the purposes in 5-hexanediamine:
6. purposes according to claim 5, is characterized in that, wherein, comprise by preparation compound III-1, Compound I-1 (2R, 5R)-1, and 6-phenylbenzene-2, the method for 5-hexanediamine:
7. the preparation method of compound III-1 as shown in claim 5, it is characterized in that: Compound I is reacted with halogenating agent, again with alkali reaction, obtain racemoid III, use acid chiral resolving agent to split and obtain compound III-1 (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine; Or react with halogenating agent Compound I-1, then with alkali reaction, directly obtain compound III-1 (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine.
8. the preparation method of compound III-1 as claimed in claim 7, is characterized in that: described halogenating agent is selected from any one in clorox, bromine, chlorine, C5H6Br2N2O2, NBS; Described alkali is selected from any one in sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium methylate, sodium ethylate; Described acid chiral resolving agent is selected from any one in tartrate, amygdalic acid, camphorsulfonic acid, DTTA, DBTA.
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CN201410466139.5A CN104193643B (en) | 2014-09-12 | 2014-09-12 | For the synthesis of the intermediate of anti-AIDS drug toughener cobicistat |
PCT/CN2015/089406 WO2016037588A2 (en) | 2014-09-12 | 2015-09-11 | New intermediate for synthesis of anti-aids drug enhancer cobicistat |
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Cited By (3)
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CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
WO2016037588A3 (en) * | 2014-09-12 | 2016-05-26 | 宁波九胜创新医药科技有限公司 | Intermediate for synthesis of anti-aids drug enhancer cobicistat |
CN109912426A (en) * | 2017-12-13 | 2019-06-21 | 上海奥博生物医药技术有限公司 | For synthesizing anti-AIDS pharmaceutical reinforcing agent than the new intermediate for taking charge of his (cobicistant) |
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WO2010115000A2 (en) * | 2009-04-03 | 2010-10-07 | Gilead Sciences, Inc. | Methods and intermediates for preparing pharmaceutical agents |
WO2013116715A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Methods and intermediates for preparing pharmaceutical agents |
US20140051888A1 (en) * | 2012-08-20 | 2014-02-20 | Ampac Fine Chemicals Llc | Novel stereoisomeric mixtures, synthesis and uses thereof |
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WO2012045007A1 (en) * | 2010-10-01 | 2012-04-05 | Gilead Sciences, Inc. | Method of preparation of (4 - {4 -acetylamino- 2 - [3- ( 2 - isopropyl - thiazol - 4 - ylmethyl) - 3 -methyl - ureido] - butyryl amino} -1 -benzyl- 5 -phenyl- pentyl) -carbamic acid thiazol - 5 - ylmethyl ester |
CN104193643B (en) * | 2014-09-12 | 2016-02-10 | 宁波九胜创新医药科技有限公司 | For the synthesis of the intermediate of anti-AIDS drug toughener cobicistat |
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WO2010115000A2 (en) * | 2009-04-03 | 2010-10-07 | Gilead Sciences, Inc. | Methods and intermediates for preparing pharmaceutical agents |
WO2013116715A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Methods and intermediates for preparing pharmaceutical agents |
US20140051888A1 (en) * | 2012-08-20 | 2014-02-20 | Ampac Fine Chemicals Llc | Novel stereoisomeric mixtures, synthesis and uses thereof |
Non-Patent Citations (2)
Title |
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LIANHONG XU,ET AL.: "A novel and efficient synthesis of chiral C2-symmetric 1,4-diamines", 《TETRAHEDRON LETT.》, vol. 50, no. 5, 24 November 2008 (2008-11-24), pages 552 - 554, XP025799917, DOI: doi:10.1016/j.tetlet.2008.11.071 * |
LIANHONG XU,ET AL.: "Cobicistat(GS-9350):A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer", 《ACS MEDICINAL CHEMISTRY LETTERS》, vol. 1, no. 5, 17 May 2010 (2010-05-17), pages 209 - 213, XP009156835, DOI: doi:10.1021/ml1000257 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016037588A3 (en) * | 2014-09-12 | 2016-05-26 | 宁波九胜创新医药科技有限公司 | Intermediate for synthesis of anti-aids drug enhancer cobicistat |
CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
CN109912426A (en) * | 2017-12-13 | 2019-06-21 | 上海奥博生物医药技术有限公司 | For synthesizing anti-AIDS pharmaceutical reinforcing agent than the new intermediate for taking charge of his (cobicistant) |
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WO2016037588A3 (en) | 2016-05-26 |
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