CN103819402A - Elvitegravir intermediate and preparation method and application thereof - Google Patents

Elvitegravir intermediate and preparation method and application thereof Download PDF

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Publication number
CN103819402A
CN103819402A CN201210466109.5A CN201210466109A CN103819402A CN 103819402 A CN103819402 A CN 103819402A CN 201210466109 A CN201210466109 A CN 201210466109A CN 103819402 A CN103819402 A CN 103819402A
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formula
preparation
wei
dust
compound
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CN103819402B (en
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李金亮
赵楠
刘育
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SHANGHAI DISAINUO CHEMICAL PHARMACEUTICAL CO Ltd
Shanghai Desano Chemical Pharmaceutical Co Ltd
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SHANGHAI DISAINUO CHEMICAL PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Abstract

The invention discloses an elvitegravir intermediate and a preparation method and application thereof. The elvitegravir intermediate has a chemical structure shown as FORMULA II, in which X is Cl, Br or I, and a chemical structure shown as FORMULA III. Application of the elvitegravir intermediate to synthesis of elvitegravir has the advantages as follows: simple preparation process, mild reaction conditions, cheap and easily-available raw materials, high total molar yield, simple posttreatment, high product purity and the like, is very suitable for large-scale production and has a great significance and a practical value for low-cost and large-scale preparation of high-purity elvitegravir.

Description

Dust is for drawing Wei intermediate and its preparation method and application
Technical field
The present invention relates to dust for drawing Wei intermediate and its preparation method and application, belong to technical field of medicine synthesis.
Background technology
Dust is by (the Gilead Sciences of Gilid Science Co. for drawing Wei (Elvitegravir), Inc.) the new class integrase inhibitor of exploitation, its be mainly used for stoping HIV virus by chromosomal integration to the medicine in host cell DNA, now, in pre-registration stage, its chemical structural formula is as follows:
Figure BDA00002421769300011
At present, replace and draw the synthetic route of Wei to mainly contain following two kinds about dust:
1) disclosed following synthetic route in WO2004046115:
Figure BDA00002421769300012
2) disclosed following synthetic route in US2009036684A1:
Figure BDA00002421769300013
Above two kinds of routes all exist reaction complicated, and yield is low, and reaction reagent is expensive or used the defects such as reagent that toxicity is larger; Therefore, above-mentioned route is all not suitable for suitability for industrialized production.
Summary of the invention
For the existing above-mentioned defect of prior art and problem, the object of this invention is to provide for the synthesis of dust for drawing intermediate of Wei and preparation method thereof and this intermediate to replace the application of drawing in Wei at synthetic dust, utilize raw material cheap and easy to get, low cost synthesis of high purity dust for the object of drawing Wei to realize, meet dust for the suitability for industrialized production demand of drawing Wei.
For achieving the above object, the technical solution used in the present invention is as follows:
A kind of dust, for drawing Wei intermediate, has chemical structure shown in formula II:
Figure BDA00002421769300021
x is wherein Cl, Br or I.
Another kind of dust, for drawing Wei intermediate, has chemical structure shown in formula III:
Figure BDA00002421769300022
Dust shown in preparation formula II, for a method of drawing Wei intermediate, comprises following reaction:
Figure BDA00002421769300023
that is: formula IV compound is reacted with acetylation reagent, make formula II intermediate; X is wherein Cl, Br or I.
As a kind of preferred version, formula IV compound is to react under alkaline condition with acetylation reagent.
Described alkaline condition is to be formed by organic bases or mineral alkali; The preferred pyridine of described organic bases, triethylamine, DMA, N, any one or a few in N-Dimethylamino pyridine; The preferred salt of wormwood of described mineral alkali or sodium carbonate.
Described acetylation reagent is preferably diacetyl oxide or Acetyl Chloride 98Min..
The mol ratio of formula IV compound and acetylation reagent is preferably 1:1～1:5, with 1:1～1:3 the best.
Prepare the dust shown in formula III for a method of drawing Wei intermediate, comprise following reaction:
Figure BDA00002421769300031
that is: formula II intermediate and formula V compound are carried out to linked reaction, make formula III intermediate; X is wherein Cl, Br or I.
As a kind of preferred version, formula II intermediate and formula V compound are under the catalysis of palladium catalyst, to carry out linked reaction.
Preferably two (dibenzalacetones) close palladium to described palladium catalyst, dichloro two (triphenylphosphine) closes palladium, palladium or Palladous chloride.
Apply the synthetic dust of described intermediate for the method for drawing Wei, comprise step c～steps d or step b～steps d or step a～steps d in following synthetic route:
x is wherein Cl, Br or I.
As a kind of preferred version, step is c) to be hydrolyzed and to remove ethanoyl under alkaline condition by formula III intermediate, makes formula I intermediate.
Described alkaline condition is to be formed by organic bases or mineral alkali; The preferred triethylamine of described organic bases; The preferred sodium hydroxide of described mineral alkali, potassium hydroxide, sodium carbonate or salt of wormwood.
As further preferred version, the mol ratio of formula III intermediate and alkali is 1:1～1:10, with 1:2～1:4 the best.
Described steps d) be prior art, can operate according to method described in WO2004046115.
Compared with prior art; apply the synthetic dust of intermediate of the present invention for drawing Wei; have that preparation technology is simple, reaction conditions is gentle, raw material is cheap and easy to get, total molar yield is high, aftertreatment is simple, product purity advantages of higher; be applicable to very much large-scale production, prepare high purity dust for drawing the significant and practical value of Wei to realizing low cost, mass-producing.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail and completely.
Formula IV compound in the present invention can obtain with reference to prior art preparation, and in following embodiment, formula IV compound used is to obtain according to disclosed method preparation in WO2004046115.
Embodiment 1: preparation formula II intermediate
Figure BDA00002421769300041
Formula IV compound (17.21g, 38.5mmol) and triethylamine (5.83g, 57.7mmol) are dissolved in 70mL methylene dichloride, are cooled to 5～10 ℃, add Acetyl Chloride 98Min. (4.53g, 57.8mmol); Reinforced complete, at room temperature react 30min; Reaction finishes, and reaction solution is washed once successively to saturated aqueous common salt washed twice with 2N aqueous hydrochloric acid; Separatory, organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure filtrate, obtains glassy yellow oily matter (that is: formula II intermediate) 18.55g, and molar yield is that 98.5%, HPLC purity is 95.0%.
1H?NMR(DMSO-d 6?300MHz)δ0.72(3H,d,J=6.6Hz),1.10(3H,d,J=6.6Hz),1.28(3H,t,J=7.0Hz),2.21(3H,s),2.27(1H,br),3.77(1H,br),4.23(2H,q,J=7.0Hz),4.56(1H,br),5.12(1H,t,J=4.9Hz),8.09(1H,d,J=11.1Hz),8.62(1H,d,J=7.5Hz),8.68(1H,s)；
MS(ESI)m/z：(M +)=490.28。
Embodiment 2: preparation formula II intermediate
Figure BDA00002421769300042
Formula IV compound (40.0g, 0.1mol) is dissolved in 150mL chloroform, under room temperature, adds pyridine (16g, 0.2mol) and N, N-Dimethylamino pyridine (2.4g, 0.02mol), add again diacetyl oxide (12.24g, 0.12mol); Reinforced complete, under ice bath, react 30min; Reaction finishes, and in reaction solution, adds 80mL water, separatory, and organic phase is successively with 80mL 2N aqueous hydrochloric acid, the washing of 80mL saturated sodium bicarbonate aqueous solution; Separatory, organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure filtrate, obtains glassy yellow oily matter (that is: formula II intermediate) 39.34g, and molar yield is that 89%, HPLC purity is 96.5%.
1H?NMR(DMSO-d 6300MHz)δ0.75(3H,d,J=6.6Hz),1.13(3H,d,J=6.6Hz),1.27(3H,t,J=7.0Hz),2.21(3H,s),2.30(1H,br),3.87(1H,br),4.13(2H,q,J=7.0Hz),4.56(1H,br),5.12(1H,t,J=4.9Hz),7.95(1H,d,J=11.1Hz),8.56(1H,d,J=7.5Hz),8.70(1H,s)；
MS(ESI)m/z：(M +)=442.6。
Embodiment 3: prepare formula III intermediate
Figure BDA00002421769300051
Under nitrogen protection, by zinc powder (160.0g, 2.46mol) be suspended in 380mL tetrahydrofuran (THF), under room temperature, drip the chloro-2-luorobenzyl of 3-iodine (604.8g, 110mL tetrahydrofuran solution 2.24mol), dropwise, at room temperature stir 30min, make the tetrahydrofuran solution of the chloro-2-luorobenzyl of 3-zinc iodide;
By formula II intermediate (547.0g, 1.12mol) be dissolved in 130mL tetrahydrofuran (THF), under argon shield, add palladium (3.82g, 0.017mol) and the tetrahydrofuran solution of the chloro-2-luorobenzyl of the 3-zinc iodide that makes of upper step, dropwise, be heated to backflow, back flow reaction finishes (after approximately 1.5 hours), cooling reaction solution, filter, in filtrate, add 100mL20% aqueous ammonium chloride solution, separate organic phase, water is extracted with ethyl acetate (300mL × 2 time) twice, merge organic phase, once use afterwards anhydrous magnesium sulfate drying with the water washing of 150mL saturated common salt, filter, concentrating under reduced pressure filtrate, column chromatography for separation obtains formula III intermediate 498.65g, molar yield is 88%, HPLC purity is 97.8%.
1H?NMR(DMSO-d 6?300MHz)δ0.74(3H,d,J=6.6Hz),1.15(3H,d,J=6.6Hz),1.30(3H,t,J=7.0Hz),2.23(3H,s),2.35(1H,br),3.76(1H,br),4.13(2H,q,J=7.0Hz),4.25(2H,s),4.64(1H,br),5.16(1H,t,J=4.9Hz),7.20-7.23(1H,m),7.32-7.35(1H,m),7.85(1H,d,J=11.1Hz),8.24-8.28(1H,m),9.00(1H,s)；
MS(ESI)m/z：(M +)=506.25。
Embodiment 4: prepare formula III intermediate
Figure BDA00002421769300052
Under nitrogen protection, by zinc powder (160.0g, 2.46mol) be suspended in 380mL tetrahydrofuran (THF), under room temperature, drip the chloro-2-fluoro benzyl bromide of 3-(499.5g, 110mL tetrahydrofuran solution 2.24mol), dropwise, at room temperature stir 30min, make the tetrahydrofuran solution of the chloro-2-luorobenzyl of 3-bromination zinc;
By formula II intermediate (495.0g, 1.12mol) be dissolved in 130mL tetrahydrofuran (THF), under argon shield, add dichloro two (triphenylphosphine) to close palladium (12.0g, 0.017mol) and the tetrahydrofuran solution of the chloro-2-luorobenzyl of the 3-bromination zinc that makes of upper step, dropwise, be heated to backflow, back flow reaction finishes (after approximately 1.5 hours), cooling reaction solution, filter, in filtrate, add 100mL20% aqueous ammonium chloride solution, separate organic phase, water is extracted with ethyl acetate (300mL × 2 time) twice, merge organic phase, once use afterwards anhydrous magnesium sulfate drying with the water washing of 150mL saturated common salt, filter, concentrating under reduced pressure filtrate, column chromatography for separation obtains formula III intermediate 522.5g, molar yield is 92.5%, HPLC purity is 98.3%.
1H?NMR(DMSO-d 6?300MHz)δ0.74(3H,d,J=6.6Hz),1.15(3H,d,J=6.6Hz),1.30(3H,t,J=7.0Hz),2.23(3H,s),2.35(1H,br),3.76(1H,br),4.13(2H,q,J=7.0Hz),4.25(2H,s),4.64(1H,br),5.16(1H,t,J=4.9Hz),7.20-7.23(1H,m),7.32-7.35(1H,m),7.85(1H,d,J=11.1Hz),8.24-8.28(1H,m),9.00(1H,s)；
MS(ESI)m/z：(M +)=506.25。
Embodiment 5: utilize the synthetic dust of above-mentioned intermediate for drawing Wei
Figure BDA00002421769300061
Formula III intermediate (50g, 0.099mol) is dissolved in 50mL Virahol, adds 4N aqueous sodium hydroxide solution (50mL, 0.3mol), then stir 1.5 hours at 50 ℃; In reaction solution, add gac 37g, and at room temperature stir 30 minutes, pass through diatomite filtration, in filtrate, add 6N hydrochloric acid 40mL and ethyl acetate 150mL, stir separatory, concentrating under reduced pressure organic phase, and concentrated residue is suspended in 50mL Virahol, stir 1 hour at 60 ℃, cool to room temperature, solid collected by filtration, with 40mL washed with isopropyl alcohol solid vacuum-drying, obtains formula I intermediate 37.9g, molar yield is that 88%, HPLC purity is 98.6%.
It is that 67%, HPLC purity is 98.1% for drawing Wei 26.1g, molar yield that the formula I intermediate making is made to target product dust according to disclosed method in WO2004046115.
Intermediate compound I: 1h NMR (DMSO-d 6300MHz) δ 0.71 (3H, d, J=6.5Hz), 1.13 (3H, d, J=6.5Hz), 2.36 (1H, br), 3.77 (1H, br), 4.25 (2H, s), 4.64 (1H, br), 4.77 (1H, br), 5.16 (1H, t, J=4.9Hz), 7.20-7.23 (1H, m), 7.32-7.35 (1H, m), 7.85 (1H, d, J=11.1Hz), 8.24-8.28 (1H, m), 9.00 (1H, s), 15.00 (1H, s);
MS(ESI)m/z：(M +)=436.53；
Eltigravir： 1H?NMR(DMSO-d 6?300MHz)δ0.72(3H,d,J=6.6Hz),1.16(3H,d,J=6.6Hz),2.30-2.50(1H,m),3.70-3.90(1H,m),3.95-4.05(1H,m),4.03(3H,s),4.12(2H,s),4.83-4.90(1H,m),5.19(1H,t,J=4.9Hz),7.19-7.25(2H,m),7.46-7.51(2H,m),8.04(1H,s),8.88(1H,s),15.44(1H,s)；
MS(ESI)m/z：(M +)=448.12。
Finally should be noted that, above embodiment is unrestricted the present invention in order to technical scheme of the present invention to be described only, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement the technical scheme of invention, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed within the scope of claim of the present invention.

Claims (12)

1. dust, for drawing a Wei intermediate, is characterized in that having chemical structure shown in formula II:
Figure FDA00002421769200011
x is wherein Cl, Br or I.
2. dust, for drawing a Wei intermediate, is characterized in that having chemical structure shown in formula III:
3. a preparation method for intermediate described in claim 1, is characterized in that, comprises following reaction:
Figure FDA00002421769200013
that is: formula IV compound is reacted with acetylation reagent, make formula II intermediate; X is wherein Cl, Br or I.
4. preparation method according to claim 3, is characterized in that: formula IV compound is to react under alkaline condition with acetylation reagent.
5. preparation method according to claim 4, is characterized in that: described alkaline condition is to be formed by organic bases or mineral alkali; Described organic bases is selected from pyridine, triethylamine, DMA, N, any one or a few in N-Dimethylamino pyridine; Described mineral alkali is selected from salt of wormwood or sodium carbonate.
6. according to the preparation method described in claim 3 or 4, it is characterized in that: described acetylation reagent is diacetyl oxide or Acetyl Chloride 98Min..
7. a preparation method for intermediate described in claim 2, is characterized in that, comprises following reaction:
Figure FDA00002421769200014
that is: formula II intermediate and formula V compound are carried out to linked reaction, make formula III intermediate; X is wherein Cl, Br or I.
8. preparation method according to claim 7, is characterized in that: formula II intermediate and formula V compound are under the catalysis of palladium catalyst, to carry out linked reaction.
9. preparation method according to claim 8, is characterized in that: described palladium catalyst is selected from that two (dibenzalacetones) close palladium, dichloro two (triphenylphosphine) closes palladium, palladium or Palladous chloride.
Application rights require 1 or/and described in claim 2 the synthetic dust of intermediate for a method of drawing Wei, it is characterized in that, comprise step c～steps d or step b～steps d or step a～steps d in following synthetic route:
x is wherein Cl, Br or I.
11. synthetic dusts according to claim 10, for the method for drawing Wei, is characterized in that: step is c) to be hydrolyzed and to remove ethanoyl under alkaline condition by formula III intermediate, makes formula I intermediate.
12. synthetic dusts according to claim 11, for the method for drawing Wei, is characterized in that: described alkaline condition is to be formed by organic bases or mineral alkali; Described organic bases is selected from triethylamine; Described mineral alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113509A1 (en) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor
CN1956961A (en) * 2004-05-20 2007-05-02 日本烟草产业株式会社 Stable crystal form of 4-oxoquinoline compound
WO2009035662A1 (en) * 2007-09-12 2009-03-19 Concert Pharmaceuticals, Inc. Deuterated 4 -oxoquinoline derivatives for the treatment of hiv infection
CN101437785A (en) * 2006-03-06 2009-05-20 日本烟草产业株式会社 Method for producing 4-oxoquinoline compound
WO2011004389A2 (en) * 2009-06-18 2011-01-13 Matrix Laboratories Ltd An improved process for the preparation of elvitegravir

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113509A1 (en) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor
CN1956961A (en) * 2004-05-20 2007-05-02 日本烟草产业株式会社 Stable crystal form of 4-oxoquinoline compound
CN101437785A (en) * 2006-03-06 2009-05-20 日本烟草产业株式会社 Method for producing 4-oxoquinoline compound
WO2009035662A1 (en) * 2007-09-12 2009-03-19 Concert Pharmaceuticals, Inc. Deuterated 4 -oxoquinoline derivatives for the treatment of hiv infection
WO2011004389A2 (en) * 2009-06-18 2011-01-13 Matrix Laboratories Ltd An improved process for the preparation of elvitegravir

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