CN104193643B - For the synthesis of the intermediate of anti-AIDS drug toughener cobicistat - Google Patents
For the synthesis of the intermediate of anti-AIDS drug toughener cobicistat Download PDFInfo
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Abstract
One aspect of the present invention discloses the synthetic method of a kind of new intermediate compound I for the synthesis of anti-AIDS drug toughener cobicistat, disclose with this Compound I synthesis (2R on the other hand, the method of 5R)-1,6-phenylbenzene-2,5-hexanediamine.This new intermediate compound I synthesizes (2R, the method route of 5R)-1,6-phenylbenzene-2,5-hexanediamine has the advantages such as step is short, working condition is simple to operation, production cost is low, and product purity is high, can the high quality requirement of fulfilling medicinal product.
Description
Technical field
The present invention relates to the new intermediate compound of a kind of anti-AIDS drug toughener cobicistat, and the application of its preparation and synthesis cobicistat key intermediate (2R, 5R)-1,6-phenylbenzene-2,5 hexanediamine.
Background technology
Cobicistat is one of composition of the anti-AIDS drug Stribild gone on the market, and it a kind ofly novel can improve inverase pharmacokinetic parameters thus improve the synergistic agent of drug effect.This medicine itself is without HIV (human immunodeficiency virus)-resistant activity, but the Plasma Concentration by suppressing the Major Enzymes-CYP3A of human body metabolism's medicine to improve inverase.
(2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine be one of key intermediate of Cobicistat.
Desai etc. disclose a kind of synthesis (2R at patent WO2008010921 in 2008; 5R)-1; 6-phenylbenzene-2; the method of 5-hexanediamine: this method with L-(-)-phenylalaninol for raw material; by amido protecting, prepare aldehyde compound and sulfone-based compound, then carry out coupling with butyllithium-78 DEG C; sodium amalgam carries out eliminating, sodium liquefied ammonia deprotection, last hydrogenating reduction obtain product, total recovery 33%.
HongtaoLiu etc. delivered another kind of synthesis (2R in 2008 in magazine TetrahedronLetters50 (2009) 552-554; 5R)-1; 6-phenylbenzene-2; the method of 5-hexanediamine: this method is also for raw material with L-(-)-phenylalaninol; 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. disclosed a kind of synthesis (2R in patent WO2010115000 in 2010; 5R)-1; 6-phenylbenzene-2; the method of 5-hexanediamine: this method is also for raw material with L-(-)-phenylalaninol; first prepare ring third nitrogen heterocyclic compounds; protect again, then carry out coupling with butyllithium, obtain the finished product finally by deprotection, reduction.
These three routes are all with L-(-)-phenylalaninol for starting raw material, first carry out protecting 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 also exist distinct disadvantage, limit its suitability for industrialized production:
(1) raw material L-(-)-phenylalaninol price, reaction reagent is special, not easily obtains;
(2) reactions steps is many;
(3) need to protect deprotection, Atom economy is poor;
(4) severe reaction conditions, energy consumption is huge.
Summary of the invention
Technical problem to be solved by this invention there is provided the new intermediate of a kind of anti-AIDS drug toughener cobicistat, and provides and synthesize (2R, 5R)-1,6-method of phenylbenzene-2,5-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, can the high quality requirement of 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, disclose the new intermediate compound I of a kind of anti-AIDS drug toughener cobicistat, 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) make Compound II per and activating reagent deposit at amide condensed dose to react in case, obtain carboxylic acid halides or activated ester intermediate;
2) this carboxylic acid halides or activated 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 be selected from thionyl chloride, phosphorus oxychloride, methyl-chloroformate, Vinyl chloroformate, dicarbapentaborane imidazoles, HOBt any one.
The present invention also discloses (the R of new intermediate compound I, R) preparation method of type Compound I-1, namely (R is utilized, R) type Compound II per-1 synthesis (R, R) type Compound I-1, the method comprises: Compound II per-1 and activating reagent are deposited at amide condensed dose and reacts in case, then with ammonia react, obtain described Compound I-1.
Reaction formula is as follows:
Wherein, described amide condensed dose be selected from thionyl chloride, phosphorus oxychloride, methyl-chloroformate, Vinyl chloroformate, dicarbapentaborane imidazoles, HOBt any one.
Another aspect of the present invention, provides the method with new intermediate compound I synthesis (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine.
The present invention, by the method for new intermediate compound I preparation (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine, comprises the steps:
1) Compound I and halogenating agent react, 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 be selected from sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium methylate, sodium ethylate any one; Described acid chiral resolving agent be selected from tartrate, amygdalic acid, camphorsulfonic acid, DTTA, DBTA any one.
Another aspect again of the present invention, provides and prepares (2R by (R, R) type Compound I-1,5R)-1, the method of 6-phenylbenzene-2,5-hexanediamine, the method comprises the steps: that Compound I-1 and halogenating agent react, 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 be selected from sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium methylate, sodium ethylate any one.
In sum, the present invention to (2R, 5R)-1,6-the synthesis technique of phenylbenzene-2,5-hexanediamine carried out the research of novelty.Propose the variation route utilizing new intermediate compound I of the present invention synthesis (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine, as shown in Scheme 4:
Or, utilize Compound I-1 synthesis (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 proposes with this new intermediate compound I preparation (2R, 5R)-1 innovatively, the synthetic route of 6-phenylbenzene-2,5-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, can the high quality requirement of fulfilling medicinal product.
Accompanying drawing explanation
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 content of the present invention better, be described further below in conjunction with specific embodiments and the drawings.Should be understood that these embodiments only for the present invention is further described, and be not used in and limit the scope of the invention.In addition should be understood that, after having read 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 II per 60g, thionyl chloride 200ml, back flow reaction 2h, reaction solution dissolves clarification, detects with HPLC sampling, complete to raw material primitive reaction, stopped reaction.By reaction solution in less than 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 1000ml four-hole bottle, add the ammoniacal liquor 250ml that concentration is 15%, stir, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solid 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
1hNMR (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).
13cNMR (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 about 9.5%) 100ml, stirs, is cooled to about 10 DEG C, start a point several Compound I 52.5g is added, temperature rising 2-5 DEG C, removes cooling, is naturally warmed up to room temperature, and be incubated 1.5h, sampling, detects with TLC, 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 about 1h, drip and finish, then continue insulation reaction 3-4h in 75-78 DEG C, then stop heating, be down to room temperature, use dichloromethane extraction product, be concentrated into dry, 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 is clarified, and adds d-camphorsulfonic acid 29.5g under room temperature, and reaction solution is heated to dissolve clarification, then cool, 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
Gained white solid 15.7g is walked, methylene dichloride 72ml, water 36ml on dropping in a 200ml four-hole bottle, stirring and dissolving, to clear, with about aqueous sodium hydroxide solution adjust pH to 10, continues to stir 10min, stratification, water layer uses 20ml*2 dichloromethane extraction again, merges organic layer, with 20ml water washing one time, organic over anhydrous dried over mgso 30min, filter, concentrated, obtain oily matter 6.4g.Nuclear-magnetism:
1hNMR (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).
13cNMR (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 II per-15g, thionyl chloride 15ml, back flow reaction 2h, reaction solution dissolves clarification, detects with HPLC sampling, complete to raw material primitive reaction, stopped reaction.By reaction solution in less than 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 100ml four-hole bottle, add the ammoniacal liquor 20ml that concentration is 15%, stir, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solid 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
1hNMR (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).
13cNMR (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 about 9.5%) 9ml, stir, be cooled to about 10 DEG C, start a point several and Compound I-14.5g is added, remove cooling, naturally be warmed up to room temperature, and be incubated 1.5h, sampling, detect with TLC, 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 about 1h, drip and finish, then continue insulation reaction 3h in 75-78 DEG C, then stop heating, be down to room temperature, use dichloromethane extraction product, be concentrated into dry, obtain 3.0 grams of oily matter.Nuclear-magnetism
1hNMR (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).
13cNMR (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 II per-21g, thionyl chloride 10ml, back flow reaction 2h, reaction solution dissolves clarification, detects with HPLC sampling, complete to raw material primitive reaction, stopped reaction.By reaction solution in less than 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 100ml four-hole bottle, add the ammoniacal liquor 10ml that concentration is 15%, stir, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solid 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
1hNMR (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).
13cNMR (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 II per-21g, thionyl chloride 10ml, back flow reaction 2h, reaction solution dissolves clarification, detects with HPLC sampling, complete to raw material primitive reaction, stopped reaction.By reaction solution in less than 50 DEG C, underpressure distillation goes out excessive sulfur oxychloride, and residue is stand-by.In another 100ml four-hole bottle, add the ammoniacal liquor 10ml that concentration is 15%, stir, be cooled to 10-15 DEG C, drip above-mentioned concentrating residues thing, about 1h dropwises, have a large amount of white solid 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
1hNMR (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).
13cNMR (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:
Or:
Or:
Or:
2. a preparation method for new intermediate as claimed in claim 1, the method comprises: Compound II per and activating reagent are deposited at amide condensed dose and reacts in case, then with ammonia react, obtain described Compound I:
3. a preparation method for new intermediate as claimed in claim 1, the method comprises: Compound II per-1 and activating reagent are deposited at amide condensed dose and reacts in case, then with ammonia react, obtain described Compound I-1:
4. the preparation method of as claimed in claim 2 or claim 3 new intermediate, 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.
5. as claimed in claim 1 new intermediate for the preparation of the purposes in intermediate compound III-1 (2R, 5R)-1,6-phenylbenzene-2, the 5-hexanediamine of anti-AIDS drug toughener cobicistat:
6. according to claim 1 new intermediate at intermediate compound III-1 (2R for the preparation of anti-AIDS drug toughener cobicistat, 5R)-1,6-phenylbenzene-2, purposes in 5-hexanediamine, is characterized in that, wherein, comprise and prepare compound III-1 (2R by Compound I-1, the method of 5R)-1,6-phenylbenzene-2,5-hexanediamine:
7. as claimed in claim 1 new intermediate at intermediate compound III-1 (2R for the preparation of anti-AIDS drug toughener cobicistat, 5R)-1, purposes in 6-phenylbenzene-2,5-hexanediamine, is characterized in that: Compound I and halogenating agent react, 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 Compound I-1 and halogenating agent react, then with alkali reaction, directly obtain compound III-1 (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine.
8. purposes as claimed in claim 7, is characterized in that: described halogenating agent be selected from clorox, bromine, chlorine, C5H6Br2N2O2, NBS any one; Described alkali be selected from sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium methylate, sodium ethylate any one; Described acid chiral resolving agent be selected from tartrate, amygdalic acid, camphorsulfonic acid, DTTA, DBTA any one.
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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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| CN105017082B (en) * | 2015-07-31 | 2017-09-19 | 上海皓元医药股份有限公司 | A kind of preparation method of heart failure medicine Entresto key intermediates (R) tert-butyl group (base of 1 ([1,1` biphenyl] 4 bases) 3 hydroxy propane 2) carbamate |
| CN109912426B (en) * | 2017-12-13 | 2023-01-13 | 上海奥博生物医药股份有限公司 | Intermediate for synthesizing anti-AIDS medicine intensifier cobicistat |
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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 |
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| 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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Non-Patent Citations (2)
| Title |
|---|
| A novel and efficient synthesis of chiral C2-symmetric 1,4-diamines;Lianhong Xu,et al.;《Tetrahedron Lett.》;20081124;第50卷(第5期);552-554 * |
| Cobicistat(GS-9350):A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer;Lianhong Xu,et al.;《ACS Medicinal Chemistry Letters》;20100517;第1卷(第5期);209-213 * |
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| WO2016037588A3 (en) | 2016-05-26 |
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