CN103342707B - For the preparation of the preparation method of A Sainaping intermediate - Google Patents
For the preparation of the preparation method of A Sainaping intermediate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 239000000543 intermediate Substances 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 230000001035 methylating effect Effects 0.000 claims abstract description 13
- 229940125904 compound 1 Drugs 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 238000003756 stirring Methods 0.000 description 34
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N (S,S)-asenapine Chemical compound O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229960005245 asenapine Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical group CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical group CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- KPUNOVLMCQQCSK-UHFFFAOYSA-N diazomethane;ethoxyethane Chemical compound C=[N+]=[N-].CCOCC KPUNOVLMCQQCSK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- MXIRPJHGXWFUAE-UHFFFAOYSA-N lithium;propan-1-olate Chemical compound [Li+].CCC[O-] MXIRPJHGXWFUAE-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- IHRQBJYWHVRTCP-UHFFFAOYSA-N CN(CC1c(cc(cc2)Cl)c2Oc2ccccc2C11)C1=O Chemical compound CN(CC1c(cc(cc2)Cl)c2Oc2ccccc2C11)C1=O IHRQBJYWHVRTCP-UHFFFAOYSA-N 0.000 description 1
- OOUVAHYYJVOIIB-XJKSGUPXSA-N CN(C[C@H]([C@H]1c2c3)c4ccccc4Oc2ccc3Cl)C1=O Chemical compound CN(C[C@H]([C@H]1c2c3)c4ccccc4Oc2ccc3Cl)C1=O OOUVAHYYJVOIIB-XJKSGUPXSA-N 0.000 description 1
- GLXCXYZWVRLFFY-UHFFFAOYSA-N CO.[Li] Chemical compound CO.[Li] GLXCXYZWVRLFFY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical group CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- 125000005911 methyl carbonate group Chemical group 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000005527 methyl sulfate group Chemical group 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229940042084 saphris Drugs 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a kind of preparation method of A Sainaping key intermediate.This intermediate structure is such as formula the compound 1 in 1, or the compound V in formula 2.This preparation method is shown in formula 1 or formula 2 respectively, namely first then the trans of arbitrary proportion and cis mixture I and II or V and VI open loop under excessive strong base solution effect are obtained by reacting trans intermediates III or VII with methylating reagent cancellation, then cyclisation obtains trans-compound I or V in the basic conditions.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, be Specifically a kind of for the preparation of can as the preparation method of the intermediate of schizophrenia medicine A Sainaping (Asenapine), its structure enters the compound shown in following formula 1
ior
v,
。
Background technology
A Sainaping (Asenapine), commodity are called Saphris, are researched and developed by Organon BioSciences, and Schering Plough company produces.On August 14th, 2009, FDA ratified this medicine for grownup's schizophrenia, manic disorder or mix with the two-way affective disorder of I type the emergency treatment shown effect.
The English language Chemical title of A Sainaping is: trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz [2,3:6,7] oxepino [4,5-c] pyrrole; Chinese chemical name: chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo also [4, the 5-c] pyrroles of trans-5-; Molecular formula: C17H16ClNO; Relative molecular weight: 285.77; CAS registration number: 65576-45-6.A Sainaping, since appearance, has had a lot of patents and bibliographical information its preparation method both at home and abroad.Wherein, EP1710241 has reported for work the trans of arbitrary proportion and cis mixture
iwith
iI(1:4) trans and cis mixture is obtained with 1,5-diazabicyclo [4,3,0]-5-nonene (DBN) moiety isomerization
iwith
iI(1:2), after purification by silica gel column chromatography, cis-isomeride
iIagain obtain trans and cis mixture through 1,5-diazabicyclo [4,3,0]-5-nonene (DBN) isomerization
iwith
iI(1:2), aforesaid operations is repeated, the trans intermediates three column chromatographies obtained
iafter merging, recrystallization obtains trans intermediates
i, as shown in Equation 2:
Above-mentioned route is adopted to synthesize A Sainaping intermediate
iwaste time and energy, and finally trans intermediate
iyield lower.
This patent adopts starting raw material subsequently
iwith
iImixture be hydrolyzed in highly basic alcoholic solution and obtain key intermediate amino acid derivative
Ⅸwith
Ⅹ, wherein
Ⅸwith
Ⅹratio be 10:1, with after obtain trans-isomer(ide) through recrystallization
Ⅸtrans intermediates is obtained through cyclisation
i.Route See Figure formula 3:
Equally, this patent with
vwith
vImixture be starting raw material, obtain trans intermediates through similar method
v.Route See Figure formula 4:
above-mentioned route is adopted to synthesize key intermediate
ior
vtime, exist due to compound
Ⅸor
Ⅺhave certain water-soluble, lose comparatively large in last handling process, the yield obtaining compound Ⅸ or Ⅺ is lower.
Summary of the invention
The invention provides a kind of overcome prior art deficiency, for preparation schizophrenia medicine A Sainaping (Asenapine) intermediate as shown in Equation 1
ior
vpreparation method.
Preparation method of the present invention reacts as shown in Equation 5, namely with transization of the arbitrary proportion in formula 5
Compound
iand/or, its preparation method as shown in Equation 6, trans namely with arbitrary proportion in formula 6
Compound
vand/or cis-compound
vImixture be raw material, be hydrolyzed under strongly alkaline conditions, be then obtained by reacting trans intermediates with methylating reagent cancellation
vII, then in the basic conditions
vIIcyclisation obtains A Sainaping key intermediate trans-compound
v.
In above-described preparation method, highly basic can be lithium hydroxide or sodium hydroxide or potassium hydroxide, methylating reagent be methyl-sulfate or methyl iodide or or monobromethane or methyl chloride or methylcarbonate or diazomethane, cyclization alkaline condition reagent used is the carbonate of potassium or sodium or lithium, or the acetate of potassium or sodium or lithium, or carbonatoms is less than the potassium of the alcohol equaling 4 carbon atoms or sodium or lithium compound, solvent is toluene or dimethylbenzene or tetrahydrofuran (THF) or glycol dimethyl ether.
Not only yield is high for method of the present invention, route brief, and product is easy to purifying, and quality product is better.
Embodiment
embodiment one: in synthetic route as shown in Equation 5, wherein highly basic is potassium hydroxide, and methylating reagent is methyl-sulfate, and cyclisation conditions is sodium-acetate and dimethylbenzene.
Compound
iIIpreparation:
Trans and the cis mixture of 30g is added in 500mL there-necked flask
iwith
iI(wherein
i: II=1:3), dissolved with 300mL ethanol, added 84g potassium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours, concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL acetone, drips methyl-sulfate 38g, back flow reaction more than 36 hours.Reacting liquor while hot is filtered, filter cake washing with acetone.Merging filtrate, is evaporated to about 200mL, cooling crystallization, filters to obtain 28.9g compound
iII, yield 87%.
Compound
ipreparation:
In 500mL tri-mouthfuls of round-bottomed flasks, add 28g compounds Ⅳ, add 280mL dimethylbenzene and 14g sodium acetate, anhydrous successively, constantly stir lower reflux, react after about six hours.Filtered while hot, filter cake dimethylbenzene washs.Merging filtrate, adds 200mL water, stirs a moment, separates dimethylbenzene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 23g with methyl tertiary butyl ether, yield 91%.
embodiment two: in synthetic route as shown in Equation 5, wherein highly basic is sodium hydroxide, and methylating reagent is methyl iodide, and cyclisation conditions is sodium methylate and toluene.
Compound
iIIpreparation:
30g cis-compound is added in 500mL there-necked flask
iI, dissolved with 300mL ethanol, added 60g sodium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours.Concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL acetone, and drip methyl iodide 42.6g, stirring at room temperature reacts more than 24 hours.By reacting liquid filtering, filter cake washing with acetone.Merging filtrate, is evaporated to about 200mL, cooling crystallization, filters to obtain 30g compound
iII, yield 90%.
Compound
ipreparation:
In 500mL tri-mouthfuls of round-bottomed flasks, add 30g compounds Ⅳ, add 300mL toluene and 9.8g solid sodium methylate successively, constantly stir lower reflux, react after about 8 hours.Filtered while hot, filter cake toluene wash.Merging filtrate, adds 200mL water, stirs a moment, separates toluene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 24g with methyl tertiary butyl ether, yield 89%.
embodiment three: in synthetic route as shown in Equation 6, wherein highly basic is potassium hydroxide, and methylating reagent is methylcarbonate, and cyclisation conditions is potassium tert.-butoxide and tetrahydrofuran (THF).
Compound
vIIpreparation:
Trans and the cis mixture of 30g is added in 500mL there-necked flask
vwith
vI(wherein
v:
vI=1:4), dissolved with 300mL ethanol, added 84g potassium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours.Concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL methylcarbonate, and return stirring reacts more than 24 hours.Reclaim under reduced pressure methylcarbonate, adds 200mL methylene dichloride and 100mL water in resistates, stir a moment, separate organic phase.Dry concentrating to obtain solid crude product, pulls an oar, filter to obtain 31g compound with methyl tertiary butyl ether
vII, yield 91%.
Compound
vpreparation:
30g compound is added in 500mL tri-mouthfuls of round-bottomed flasks
vII, the tetrahydrofuran (THF) adding 300mL drying is dissolved, and adds 20g solid potassium tert-butoxide subsequently, constantly stirs lower reflux, reacts after about 6 hours.Filtered while hot, filter cake toluene wash.Merging filtrate, adds 200mL water, stirs a moment, separates toluene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 23g with methyl tertiary butyl ether, yield 85%.
embodiment four: in synthetic route as shown in Equation 6, wherein highly basic is lithium hydroxide, and methylating reagent is diazomethane, and cyclisation conditions is potassium ethylate and glycol dimethyl ether.
Compound
vIIpreparation:
Trans and the cis mixture of 30g is added in 500mL there-necked flask
vwith
vI(wherein V: VI=1:2.8), is dissolved with 300mL ethanol, adds 63g lithium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours.Concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL acetone, and add 10mL diazomethane diethyl ether solution, stirring at room temperature reacts more than 12 hours.Reclaim under reduced pressure acetone, adds 200mL methylene dichloride and 100mL water in resistates, stir a moment, separate organic phase.Dry concentrating to obtain solid crude product, pulls an oar, filter to obtain 30g compound with methyl tertiary butyl ether
vII, yield 90%.
Compound
vpreparation:
30g compound is added in 500mL tri-mouthfuls of round-bottomed flasks
vII, add 300mL glycol dimethyl ether, add 14g solid alcohol potassium subsequently, constantly stir lower reflux, react after about 8 hours.Filtered while hot, filter cake toluene wash.Merging filtrate, adds 200mL water, stirs a moment, separates toluene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 23g with methyl tertiary butyl ether, yield 86%.
embodiment five: in synthetic route as shown in Equation 5, wherein highly basic is sodium hydroxide, and methylating reagent is monochloroethane, and cyclisation conditions is lithium methoxide and toluene.
Compound
iIIpreparation:
30g cis-compound is added in 500mL there-necked flask
iI, dissolved with 300mL ethanol, added 60g sodium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours.Concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL acetone, and drip monochloroethane 23g, stirring at room temperature reacts more than 24 hours.By reacting liquid filtering, filter cake washing with acetone.Merging filtrate, is evaporated to about 200mL, cooling crystallization, filters to obtain 30g compound
iII, yield 90%.
Compound
ipreparation:
30g compound is added in 500mL tri-mouthfuls of round-bottomed flasks
iII, add 300mL toluene and 9.8g solid methanol lithium successively, constantly stir lower reflux, react after about 8 hours.Filtered while hot, filter cake toluene wash.Merging filtrate, adds 200mL water, stirs a moment, separates toluene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 24g with methyl tertiary butyl ether, yield 89%.
embodiment six: in synthetic route as shown in Equation 6, wherein highly basic is potassium hydroxide, and methylating reagent is diethyl carbonate, and cyclisation conditions is potassium tert.-butoxide and glycol dimethyl ether.
Compound
vIIpreparation:
Trans and the cis mixture of 30g is added in 500mL there-necked flask
vwith
vI(wherein
v:
vI=1:4), dissolved with 300mL ethanol, added 84g potassium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours.Concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL diethyl carbonate, and return stirring reacts more than 24 hours.Reclaim under reduced pressure methylcarbonate, adds 200mL methylene dichloride and 100mL water in resistates, stir a moment, separate organic phase.Dry concentrating to obtain solid crude product, pulls an oar, filter to obtain 31g compound with methyl tertiary butyl ether
vII, yield 91%.
Compound
vpreparation:
30g compound is added in 500mL tri-mouthfuls of round-bottomed flasks
vII, the glycol dimethyl ether adding 300mL drying is dissolved, and adds 20g solid potassium tert-butoxide subsequently, constantly stirs lower reflux, reacts after about 6 hours.Filtered while hot, filter cake toluene wash.Merging filtrate, adds 200mL water, stirs a moment, separates toluene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 23g with methyl tertiary butyl ether, yield 85%.
embodiment seven: in synthetic route as shown in Equation 5, wherein highly basic is potassium hydroxide, and methylating reagent is ethyl sulfate, and cyclisation conditions is salt of wormwood and dimethylbenzene.
Compound
iIIpreparation:
Trans and the cis mixture of 30g is added in 500mL there-necked flask
iwith
iI(wherein
i:
iI=1:3), dissolved with 300mL ethanol, added 84g potassium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours.Concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL acetone, drips methyl-sulfate 38g, back flow reaction more than 36 hours.Reacting liquor while hot is filtered, filter cake washing with acetone.Merging filtrate, is evaporated to about 200mL, cooling crystallization, filters to obtain 28.9g compound
iII, yield 87%.
Compound
ipreparation:
28g compound is added in 500mL tri-mouthfuls of round-bottomed flasks
iII, add 280mL dimethylbenzene and 14g Anhydrous potassium carbonate successively, constantly stir lower reflux, react after about six hours.Filtered while hot, filter cake dimethylbenzene washs.Merging filtrate, adds 200mL water, stirs a moment, separates dimethylbenzene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 23g with methyl tertiary butyl ether, yield 91%.
embodiment eight: in synthetic route as shown in Equation 6, wherein highly basic is lithium hydroxide, and methylating reagent is diazomethane, and cyclisation conditions is lithium propoxide and toluene.
Compound
vIIpreparation:
Trans and the cis mixture of 30g is added in 500mL there-necked flask
vwith
vI(wherein
v:
vI=1:2.8), dissolved with 300mL ethanol, added 63g lithium hydroxide.Reaction mixture is warming up to backflow under constantly stirring, reacts 18 hours.Concentrating under reduced pressure reclaims ethanol, and resistates is dissolved in 300mL acetone, and add 10mL diazomethane diethyl ether solution, stirring at room temperature reacts more than 12 hours.Reclaim under reduced pressure acetone, adds 200mL methylene dichloride and 100mL water in resistates, stir a moment, separate organic phase.Dry concentrating to obtain solid crude product, pulls an oar, filter to obtain 30g compound with methyl tertiary butyl ether
vII, yield 90%.
Compound
vpreparation:
30g compound is added in 500mL tri-mouthfuls of round-bottomed flasks
vII, add 300mL toluene, add 11.5g solid lithium propoxide subsequently, constantly stir lower reflux, react after about 8 hours.Filtered while hot, filter cake toluene wash.Merging filtrate, adds 200mL water, stirs a moment, separates toluene phase, dry concentrated to obtain solid crude product, to pull an oar to obtain product 23g with methyl tertiary butyl ether, yield 86%.
Claims (2)
1., for the preparation of the method such as formula the compound 1 shown in I, it is characterized in that reaction formula is formula II, namely with the trans-compound of the arbitrary proportion in formula II
1and/or cis-compound
2mixture be raw material, be hydrolyzed under strongly alkaline conditions and use methylating reagent cancellation to be obtained by reacting trans intermediates
3, then cyclisation obtains A Sainaping key intermediate trans-compound in the basic conditions
1
。
2. for the preparation of the compound such as shown in formula III
5method, it is characterized in that reaction formula is formula IV, namely with the trans-compound of arbitrary proportion in formula IV
5and/or cis-compound
6mixture be raw material, be hydrolyzed under strongly alkaline conditions and use methylating reagent cancellation to be obtained by reacting trans intermediates
7, then cyclisation obtains A Sainaping key intermediate trans-compound in the basic conditions
5
。
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| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12138353B2 (en) | 2016-12-20 | 2024-11-12 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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