CN103819402B - Dust is for drawing Wei intermediate and its preparation method and application - Google Patents
Dust is for drawing Wei intermediate and its preparation method and application Download PDFInfo
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- CN103819402B CN103819402B CN201210466109.5A CN201210466109A CN103819402B CN 103819402 B CN103819402 B CN 103819402B CN 201210466109 A CN201210466109 A CN 201210466109A CN 103819402 B CN103819402 B CN 103819402B
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- 239000000428 dust Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- 229910052763 palladium Inorganic materials 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 235000010755 mineral Nutrition 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 230000021736 acetylation Effects 0.000 claims description 7
- 238000006640 acetylation reaction Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940102001 zinc bromide Drugs 0.000 description 2
- ZVHBHGCJOIOWBI-UHFFFAOYSA-N 1-[bromo(chloro)methyl]-2-fluorobenzene Chemical compound FC1=CC=CC=C1C(Cl)Br ZVHBHGCJOIOWBI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 229960003586 elvitegravir Drugs 0.000 description 1
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses dust for drawing Wei intermediate and its preparation method and application.Described dust has chemical structure shown in formula II for drawing Wei intermediate:
x is wherein Cl, Br or I; And chemical structure shown in formula III:
Description
Technical field
The present invention relates to dust for drawing Wei intermediate and its preparation method and application, belonging to technical field of medicine synthesis.
Background technology
Dust is by Gilid Science Co. (GileadSciences for drawing Wei (Elvitegravir), Inc.) the new class integrase inhibitor developed, it is mainly used for stoping HIV virus by chromosomal integration to the medicine in host cell DNA, now be in pre-registration stage, its chemical structural formula is as follows:
At present, the following two kinds is mainly contained about dust for drawing the synthetic route of Wei:
1) following synthetic route disclosed in WO2004046115:
2) following synthetic route disclosed in US2009036684A1:
It is complicated all to there is reaction in above two kinds of routes, and yield is low, and reaction reagent is expensive or employ the defects such as the larger reagent of toxicity; Therefore, above-mentioned route is all not suitable for suitability for industrialized production.
Summary of the invention
For the above-mentioned defect existing for prior art and problem, the object of this invention is to provide and synthesizing dust for the application of drawing in Wei for the synthesis of dust for intermediate drawing Wei and preparation method thereof and this intermediate, to realize utilizing raw material cheap and easy to get, low cost synthesis of high purity dust for the object of drawing Wei, meet dust for the industrial 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:
x is wherein Cl, Br or I.
Another kind of dust, for drawing Wei intermediate, has chemical structure shown in formula III:
Dust shown in preparation formula II, for a method of drawing Wei intermediate, comprises following reaction:
that is: formula IV compound and acetylation reagent are reacted, obtained formula II intermediate; X is wherein Cl, Br or I.
As a kind of preferred version, formula IV compound and acetylation reagent react in the basic conditions.
Described alkaline condition is formed by organic bases or mineral alkali; Any one or a few in the preferred pyridine of described organic bases, triethylamine, DMA, N, 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, best with 1:1 ~ 1:3.
Prepare the dust shown in formula III for a method of drawing Wei intermediate, comprise following reaction:
that is: formula II intermediate and formula V compound are carried out linked reaction, obtained formula III intermediate; X is wherein Cl, Br or I.
As a kind of preferred version, formula II intermediate and formula V compound carry out linked reaction under the catalysis of palladium catalyst.
Preferably two (dibenzalacetones) close palladium to described palladium catalyst, dichloro two (triphenylphosphine) closes palladium, palladium or Palladous chloride.
Apply described intermediate synthesis dust for the method for drawing Wei, comprise step c ~ steps d in following synthetic route or step b ~ steps d or step a ~ steps d:
x is wherein Cl, Br or I.
As a kind of preferred version, step c) be hydrolyzed in the basic conditions by formula III intermediate to remove ethanoyl, obtained formula I intermediate.
Described alkaline condition is 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, best with 1:2 ~ 1:4.
Described steps d) be prior art, can operate according to method described in WO2004046115.
Compared with prior art; apply intermediate of the present invention synthesis dust 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; very be applicable to large-scale production, to realizing low cost, mass-producing prepares high purity dust for drawing the significant and practical value of Wei.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail and completely.
Formula IV compound in the present invention can refer to prior art preparation and obtains, and formula IV compound used in following embodiment obtains according to the preparation of method disclosed in WO2004046115.
Embodiment 1: preparation formula II intermediate
Formula IV compound (17.21g, 38.5mmol) and triethylamine (5.83g, 57.7mmol) are dissolved in 70mL methylene dichloride, are cooled to 5 ~ 10 DEG C, add Acetyl Chloride 98Min. (4.53g, 57.8mmol); Reinforced complete, at room temperature react 30min; Reaction terminates, and washed once with 2N aqueous hydrochloric acid successively by reaction solution, saturated aqueous common salt washes twice; Separatory, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, obtains glassy yellow oily matter (that is: formula II intermediate) 18.55g, and molar yield is 98.5%, HPLC purity is 95.0%.
1HNMR(DMSO-d
6300MHz)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
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 diacetyl oxide (12.24g, 0.12mol) again; Reinforced complete, under ice bath, react 30min; Reaction terminates, and adds 80mL water, separatory in reaction solution, and organic phase is successively with 80mL2N aqueous hydrochloric acid, the washing of 80mL saturated sodium bicarbonate aqueous solution; Separatory, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, obtains glassy yellow oily matter (that is: formula II intermediate) 39.34g, and molar yield is 89%, HPLC purity is 96.5%.
1HNMR(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
Under nitrogen protection, by zinc powder (160.0g, 2.46mol) be suspended in 380mL tetrahydrofuran (THF), 3-chloro-2-luorobenzyl iodine (604.8g is dripped under room temperature, 110mL tetrahydrofuran solution 2.24mol), dropwise, at room temperature stir 30min, the tetrahydrofuran solution of obtained 3-chloro-2-luorobenzyl zinc iodide;
By formula II intermediate (547.0g, 1.12mol) be dissolved in 130mL tetrahydrofuran (THF), palladium (3.82g is added under argon shield, the tetrahydrofuran solution of 3-chloro-2-luorobenzyl zinc iodide 0.017mol) obtained with upper step, dropwise, be heated to backflow, back flow reaction terminates (after about 1.5 hours), cooling reaction solution, filter, 100mL20% aqueous ammonium chloride solution is added in filtrate, separate organic phase, aqueous phase is extracted with ethyl acetate twice (300mL × 2 time), merge organic phase, once anhydrous magnesium sulfate drying is used afterwards 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%.
1HNMR(DMSO-d
6300MHz)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
Under nitrogen protection, by zinc powder (160.0g, 2.46mol) be suspended in 380mL tetrahydrofuran (THF), the chloro-2-fluoro benzyl bromide of 3-(499.5g is dripped under room temperature, 110mL tetrahydrofuran solution 2.24mol), dropwise, at room temperature stir 30min, the tetrahydrofuran solution of obtained 3-chloro-2-luorobenzyl zinc bromide;
By formula II intermediate (495.0g, 1.12mol) be dissolved in 130mL tetrahydrofuran (THF), under argon shield, add dichloro two (triphenylphosphine) close palladium (12.0g, the tetrahydrofuran solution of 3-chloro-2-luorobenzyl zinc bromide 0.017mol) obtained with upper step, dropwise, be heated to backflow, back flow reaction terminates (after about 1.5 hours), cooling reaction solution, filter, 100mL20% aqueous ammonium chloride solution is added in filtrate, separate organic phase, aqueous phase is extracted with ethyl acetate twice (300mL × 2 time), merge organic phase, once anhydrous magnesium sulfate drying is used afterwards 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%.
1HNMR(DMSO-d
6300MHz)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 above-mentioned intermediate to synthesize dust for drawing Wei
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 DEG C; 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 DEG C, cool to room temperature, solid collected by filtration, with 40mL washed with isopropyl alcohol solid and vacuum-drying, obtains formula I intermediate 37.9g, molar yield is 88%, HPLC purity is 98.6%.
Obtained formula I intermediate is obtained target product dust for drawing Wei 26.1g according to method disclosed in WO2004046115, and molar yield is 67%, HPLC purity is 98.1%.
Intermediate compound I:
1hNMR (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：
1HNMR(DMSO-d
6300MHz)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 only in order to illustrate technical scheme of the present invention and unrestricted the present invention, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
Claims (12)
1. dust is for drawing a Wei intermediate, it is characterized in that, has chemical structure shown in formula II:
x is wherein Cl, Br or I.
2. dust is for drawing a Wei intermediate, it is characterized in that, has chemical structure shown in formula III:
3. a preparation method for intermediate described in claim 1, is characterized in that, comprises following reaction:
that is: formula IV compound and acetylation reagent are reacted, obtained formula II intermediate; X is wherein Cl, Br or I.
4. preparation method according to claim 3, is characterized in that: formula IV compound and acetylation reagent react in the basic conditions.
5. preparation method according to claim 4, is characterized in that: described alkaline condition is formed by organic bases or mineral alkali; Described organic bases be selected from pyridine, triethylamine, DMA, N, N-Dimethylamino pyridine any one or a few; Described mineral alkali is selected from salt of wormwood or sodium carbonate.
6. the preparation method according to claim 3 or 4, 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:
that is: formula II intermediate and formula V compound are carried out linked reaction, obtained 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 carry out linked reaction under the catalysis of palladium catalyst.
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.
10. application rights requires that 1 or/and intermediate synthesis dust described in claim 2, for a method of drawing Wei, is characterized in that, comprises step c ~ steps d in following synthetic route or step b ~ steps d or step a ~ steps d:
x is wherein Cl, Br or I.
11. synthesis dusts according to claim 10, for the method for drawing Wei, is characterized in that: step c) be hydrolyzed in the basic conditions by formula III intermediate to remove ethanoyl, obtained formula I intermediate.
12. synthesis dusts according to claim 11, for the method for drawing Wei, is characterized in that: described alkaline condition is 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210466109.5A CN103819402B (en) | 2012-11-17 | 2012-11-17 | Dust is for drawing Wei intermediate and its preparation method and application |
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| MY134672A (en) * | 2004-05-20 | 2007-12-31 | Japan Tobacco Inc | Stable crystal of 4-oxoquinoline compound |
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