CN104974168B - The preparation method of asenapine and the intermediate for being used to prepare asenapine - Google Patents
The preparation method of asenapine and the intermediate for being used to prepare asenapine Download PDFInfo
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- CN104974168B CN104974168B CN201410131959.9A CN201410131959A CN104974168B CN 104974168 B CN104974168 B CN 104974168B CN 201410131959 A CN201410131959 A CN 201410131959A CN 104974168 B CN104974168 B CN 104974168B
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Abstract
The present invention relates to the intermediates that asenapine is prepared shown in the method for preparing asenapine shown in general formula (11) and general formula (8).Described method includes following steps: obtaining general formula (9) compound represented by ring-closure reaction by general formula (8) compound represented；General formula (10) compound represented is obtained by reduction reaction by general formula (9) compound represented；And asenapine shown in general formula (11) is obtained by substitution reaction as general formula (10) compound represented.In general formula (8), R1Represent halogen, preferably chlorine or bromine.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of preparation method and preparation of asenapine (asenapine)
The intermediate of asenapine.
Background technique
Asenapine refers to trans- -5- chloro-2-methyl -233a12b- tetrahydro -1H- dibenzo [23:67]-oxa-And
[4,5-c] pyrroles (Trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz [2,3:6,7]
Oxepino [4,5-c] pyrrole), it is a kind of with central nervous system impression activity and with antihistamine and medmain
Active compound.Asenapine is the racemic modification for including following two optical isomer:
For convenience, the racemic for covering two kinds of enantiomers is indicated with the structural formula of individual isomer herein
Body.It has been confirmed that the maleate of asenapine is a kind of wide spectrum, dynamical serotonin, norepinephrine and DOPA
Amine antagonist is widely used in treatment schizophreniac.
The synthetic method of different asenapines is had reported in the prior art.But the side disclosed in the prior art
Method is there are still many problems, such as yield are low, and reactant is difficult to obtain, severe reaction conditions, post-processing complexity etc., therefore still
Need to be more suitable for the preparation method of industrial new asenapine.
Summary of the invention
The purpose of the present invention is to provide a kind of new method for preparing asenapine, the method, which is capable of providing, to be had well
The trans intermediates of selectivity have in high yield, and reaction condition is mild, and post-processing is simple, thus raw particularly suitable for industry
It produces.
To achieve the goals above, on the one hand, prepare asenapine shown in general formula (11) the present invention provides a kind of
Method:
It is characterized in that, described method includes following steps:
General formula (9) compound represented is obtained by ring-closure reaction by general formula (8) compound represented
Wherein, R1Halogen, preferably chlorine or bromine are represented,
General formula (10) compound represented is obtained by reduction reaction by general formula (9) compound represented
And
Asenapine shown in general formula (11) is obtained by substitution reaction as general formula (10) compound represented.
An embodiment according to the present invention, general formula (8) compound represented is:
An embodiment according to the present invention, general formula (8) compound represented is the chemical combination as shown in general formula (7)
Object is prepared by eliminating hydroxide protecting group:
Wherein, R1As defined above,
R2It represents and C is optionally selected from by one or more1-6Alkoxy, C1-6Alkanoyl and C6-10The substituent group of aryl replaces
C1-6Alkyl, the C6-10Aryl is optionally selected from C by one or more1-6Alkoxy, C1-6Alkanoyl and C6-10Aryl takes
Replace for base；The C preferably optionally replaced by one or more substituent groups selected from methoxyl group, acetyl group and phenyl1-6Alkane
Base, the phenyl are optionally replaced by one or more substituent groups selected from methoxyl group, acetyl group and phenyl；More preferably first
Base, benzyl, to methoxy-benzyl, 3,4- dimethoxy-benzyl, to acetyl group benzyl or to phenylbenzyl；Most preferably methyl or
Benzyl.
An embodiment according to the present invention, general formula (7) compound represented is the chemical combination as shown in general formula (6)
Object is prepared by reduction reaction:
Wherein, R1And R2It is as defined above respectively.
An embodiment according to the present invention, general formula (6) compound represented is the chemical combination as shown in general formula (5)
Object is prepared by methylation reaction:
Wherein, R1And R2It is as defined above respectively.
An embodiment according to the present invention, general formula (5) compound represented is the chemical combination as shown in general formula (4)
Object is prepared by cyclization:
Wherein, R1And R2It is as defined above respectively.
An embodiment according to the present invention, general formula (4) compound represented is the chemical combination as shown in general formula (3)
Object is prepared by cyanogenation:
Wherein, R1And R2It is as defined above respectively.
An embodiment according to the present invention, general formula (3) compound represented is chemical combination shown by the general formula (1)
Object and general formula (2) compound represented are prepared by condensation reaction:
Wherein, R1As defined above,
Wherein, R2As defined above.
It on the other hand, is to be used to prepare in asenapine the present invention provides a kind of general formula (8) compound represented
Mesosome:
Wherein, R1Represent halogen, preferably chlorine or bromine.
An embodiment according to the present invention, general formula (8) compound represented is:
On the other hand, the present invention provides the purposes that a kind of general formula (8) compound represented is used to prepare asenapine:
Wherein, R1Represent halogen, preferably chlorine or bromine.
An embodiment according to the present invention, general formula (8) compound represented is:
Specific embodiment
Definition
The term as used herein " halogen " refers to fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
The term as used herein " C1-6Alkyl " refers to the linear or branched alkyl group group with 1-6 carbon atom, such as first
Base, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,
Isohesyl etc., preferably methyl.
The term as used herein " C1-6Alkoxy " refers to the straight or branched alkoxyl group with 1-6 carbon atom, example
As methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy,
Positive hexyloxy etc., preferably methoxyl group.
The term as used herein " C1-6Alkanoyl " refers to the linear chain or branched chain alkanoyl groups with 1-6 carbon atom, example
Such as formoxyl, acetyl group, propiono, iso-propionyl, positive bytyry, positive valeryl, positive caproyl, preferably acetyl group.
The term as used herein " C6-10Aryl " refers to the list of armaticity or partial aromatic with 6-10 carbon atom
Ring or bicyclic hydrocarbon ring, such as the ring (" C with 6 carbon atoms6Aryl ") such as phenyl, or the ring (" C with 9 carbon atoms9-
Aryl ") such as indanyl or indenyl, or the ring (" C with 10 carbon atoms10Aryl ") such as tetrahydro naphthyl, dihydronaphthalene
Base or naphthalene, preferably phenyl.
The term as used herein " C1-6Monohydric alcohol ", which refers in the molecule, only has 1-6 carbon atom containing hydroxyl
Straight chain, branch or cyclic alcohol, such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol,
Isoamyl alcohol, sec-amyl alcohol, tert-pentyl alcohol, cyclopentanol, 1- hexanol, 2- hexanol, 3- hexanol, 2- methyl-1-pentene alcohol, 3,3- dimethyl -1-
Butanol, cyclohexanol etc., preferably methanol and ethyl alcohol.
As described above, for convenience, herein, asenapine shown in general formula (11) and general formula (5) to (10)
Shown in midbody compound be the racemic modification indicated in the form of individual isomer, actually cover two kinds of enantiomers.Example
Such as, it is the racemic modification for covering following two enantiomer that asenapine shown in general formula (11) is practical:
Midbody compound shown in general formula (5) to (10) is also such.
In structural formula provided in this article, with runic wedge key and hash wedge key to indicating relative stereochemistry structure
Type.
DBU used herein refers to 11 carbon -7- alkene of 1,8- diazabicylo [5.4.0].
TEA used herein refers to triethylamine.
TMSCN used herein refers to trimethylsilyl cyanide.
DMF used herein refers to N,N-dimethylformamide.
DMAc used herein refers to DMAC N,N' dimethyl acetamide.
NMP used herein refers to N-Methyl pyrrolidone.
DCM used herein refers to methylene chloride.
THF used herein refers to tetrahydrofuran.
Me used herein refers to methyl.
Et used herein refers to ethyl.
Bn used herein refers to benzyl.
AcOH used herein refers to acetic acid.
Dense HCl used herein refers to concentrated hydrochloric acid.
Reaction route
The synthetic method of asenapine provided by the invention is as shown in following route:
Wherein, R1Halogen, preferably chlorine or bromine are represented,
R2It represents and C is optionally selected from by one or more1-6Alkoxy, C1-6Alkanoyl and C6-10The substituent group of aryl replaces
C1-6Alkyl, the C6-10Aryl is optionally selected from C by one or more1-6Alkoxy, C1-6Alkanoyl and C6-10Aryl takes
Replace for base；The C preferably optionally replaced by one or more substituent groups selected from methoxyl group, acetyl group and phenyl1-6Alkane
Base, the phenyl are optionally replaced by one or more substituent groups selected from methoxyl group, acetyl group and phenyl；More preferably first
Base, benzyl, to methoxy-benzyl, 3,4- dimethoxy-benzyl, to acetyl group benzyl or to phenylbenzyl；Most preferably methyl or
Benzyl.
According to the method for the present invention, asenapine can be prepared by above-mentioned reaction route.Each step is illustrated below.
Step a: dehydration condensation
At a suitable temperature, the compound as shown in general formula (1) passes through dehydration condensation with compound shown in general formula (2)
Obtain compound shown in general formula (3).Wherein:
Preferred 10-80 DEG C of the temperature, more preferable 15-60 DEG C, particularly preferred 20-40 DEG C, for example, room temperature.
The molar ratio of compound shown in compound shown in the general formula (1) and general formula (2) is preferably 1:3-3:1, more preferably
For 1:2.5-2.5:1, even more preferably 1:2-2:1, particularly preferred 1:1.5-1.5:1, such as 1:1.3.
The dehydration condensation preferably carries out in the presence of acids and bases.The acid is such as, but not limited to toluene sulphur
Acid, sulfuric acid and lewis acid.The alkali is such as, but not limited to sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, DBU and TEA.Using acid or alkali, the molar ratio of the acid or alkali and compound shown in general formula (1) is preferred
For 1:20-1:1, more preferably 1:10-1:2, particularly preferred 1:5-1:3, such as 3:10.
The dehydration condensation preferably carries out in a suitable solvent, and the solvent is preferably polar aprotic solvent, excellent
It is selected as C1-6Monohydric alcohol, such as, but not limited to methanol and ethyl alcohol.
The reaction time of the dehydration condensation is preferably 1-24h, more preferably 3-10h, particularly preferably 5-7h.
In the dehydration condensation, compound shown in mutual-through type (1), compound shown in general formula (2) and optionally deposit
Acid or the addition sequence of alkali be not particularly limited.
In a preferred embodiment of the invention, the dehydration condensation of step a are as follows:
Compound shown in compound shown in general formula (1) and general formula (2) is added in the ethanol solution of sodium ethoxide, and in room
Temperature is lower to react 5-7h until the reaction is complete, to obtain compound shown in general formula (3).Compound, general formula shown in its formula of (1)
(2) molar ratio of compound and sodium ethoxide shown in is 1:1.3:0.3.
Wherein the sodium ethoxide can be obtained according to conventional method in that art, such as can be by the way that metallic sodium is added to anhydrous second
Sodium ethoxide is prepared in alcohol.
Product generated can be directly used in subsequent step by simple separation without isolation or only without purification.
Step b: cyanogenation
At a suitable temperature, the compound as shown in general formula (3) is led to suitable cyanating reagent by cyanogenation
Compound shown in formula (4).
Preferred 25-80 DEG C of the temperature, more preferable 35-60 DEG C, such as 40 DEG C.
The cyanating reagent be such as, but not limited to alkali metal cyanide (such as Cymag, potassium cyanide), cuprous cyanide and
TMSCN, preferably TMSCN.
The molar ratio of compound shown in the general formula (3) and the cyanating reagent is preferably 1:4-1:1, more preferably 1:3-
1:1, particularly preferred 1:2-1:1, such as 1:1.5.
The cyanogenation preferably carries out in the presence of fluorine reagent.The fluorine reagent is such as, but not limited to alkali metal fluorination
Object (such as sodium fluoride, potassium fluoride), ammonium fluoride and quaternary ammonium fluoride salt, preferred fluorinated quaternary ammonium salt.The quaternary ammonium fluoride salt is for example but not
It is limited to tetrabutyl ammonium fluoride and Methanaminium, N,N,N-trimethyl-, fluoride, preferably tetrabutyl ammonium fluoride.Using fluorine reagent, the fluorine examination
The molar ratio of compound shown in agent and general formula (3) is preferably 1:20-1:1, more preferably 1:10-1:2, particularly preferred 1:5-1:3,
Such as 3:10.
The cyanogenation preferably carries out in a suitable solvent, and the solvent is such as, but not limited to acetonitrile, DMF, DMAc
And NMP.
The reaction time of the cyanogenation is preferably 10min-12h, more preferably 20min-4h, particularly preferably 30-
40min。
In the cyanogenation, compound shown in mutual-through type (3), the cyanating reagent and the fluorine reagent being optionally present
Addition sequence be not particularly limited.
In a preferred embodiment of the invention, the cyanogenation of step b are as follows:
Compound shown in general formula (3), TMSCN and tetrabutyl ammonium fluoride are added in acetonitrile, react 30- at 40 DEG C
40min until the reaction is complete, to obtain compound shown in general formula (4).Compound, TMSCN and four fourths shown in its formula of (3)
The molar ratio of base ammonium fluoride is 1:1.5:0.3.
Product generated can be directly used in subsequent step by simple separation without isolation or only without purification.
Step c: cyclization
At a suitable temperature, in the presence of acid and water, the compound as shown in general formula (4) is led to by cyclization
Compound shown in formula (5).
Preferred 60-200 DEG C of the temperature, more preferable 80-150 DEG C, particularly preferred 100-120 DEG C, such as 110 DEG C.
The acid is preferably 98% sulfuric acid, more preferably -98% sulfuric acid system of acetic acid.In -98% sulfuric acid system of acetic acid
In, the molar ratio of acetic acid and 98% sulfuric acid is 6:1-1:1, preferably 4:1-2:1, such as 2.8:1；Wherein it is anti-to play dilution for acetic acid
It answers liquid and increases deliquescent effect.
The reaction time of the cyclization is preferably 30min-12h, more preferably 1-5h, particularly preferably 1.5-2h.
In the cyclization, the addition sequence of compound shown in mutual-through type (4), the acid and water has no special limit
It is fixed.
In a preferred embodiment of the invention, the cyclization of step c are as follows:
Compound shown in general formula (4), acetic acid, 98% sulfuric acid and water are mixed, mixture is warming up to 110 DEG C, reacts 1.5-
2h until the reaction is complete, to obtain compound shown in general formula (5).Compound shown in its formula of (4), acetic acid, 98% sulfuric acid and
The molar ratio of water is 359.6:2756:993:595.
Product generated can be directly used in subsequent step by simple separation without isolation or only without purification.
By step c, method of the invention generated with high yield (80-90%) have good selectivity it is trans- in
Compound shown in mesosome --- general formula (5).The highly-solid selectively reacted in the step is for the high yield of entire method
Provide great benefit.Also, as containing nitro in reactant (i.e. compound shown in formula (4)), enable cyclization
It enough goes on smoothly, to increase reaction yield.
Step d: methylation reaction
At a suitable temperature, the compound as shown in general formula (5) is obtained with suitable methylating reagent by methylation reaction
To compound shown in general formula (6).
Preferred 30-110 DEG C of the temperature, more preferable 40-90 DEG C, even more preferably 50-80 DEG C, particularly preferred 60-70 DEG C.
The methylating reagent is such as, but not limited to halomethane (such as iodomethane, bromomethane, chloromethanes etc.), dimethyl sulfate
Ester, Methyl triflate, p-methyl benzenesulfonic acid methyl esters and dimethyl carbonate, preferably iodomethane.
The molar ratio of compound shown in the general formula (5) and the methylating reagent is preferably 1:4-1:1, and more preferably 1:
3-1:1, particularly preferred 1:2-1:1, such as 1:1.5.
The methylation reaction preferably carries out in the presence of base.The alkali is such as, but not limited to alkali carbonate and carbon
Sour hydrogen salt, such as potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate.Using alkali, shown in the alkali and general formula (5)
The molar ratio of compound is preferably 4:1-1:2, more preferably 3:1-1:1, such as 2:1.
The methylation reaction preferably carries out in a suitable solvent.The solvent includes polar aprotic solvent and nonpolarity
Aprotic solvent.The polar aprotic solvent is such as, but not limited to acetonitrile, DMF, DMAc and NMP；The nonpolar aprotic is molten
Agent is such as, but not limited to THF, dioxane and glycol dimethyl ether.
The reaction time of the methylation reaction is preferably 10min-8h, more preferably 20min-5h, particularly preferably 30-
40min。
In the methylation reaction, compound shown in mutual-through type (5), the methylating reagent and the alkali being optionally present
Addition sequence be not particularly limited.
In a preferred embodiment of the invention, the methylation reaction of step d are as follows:
Compound, potassium carbonate and iodomethane shown in general formula (5) are mixed in THF, react 40min at 70 DEG C until anti-
Should be complete, to obtain compound shown in general formula (6).The molar ratio of compound shown in its formula of (5), potassium carbonate and iodomethane
For 1:2:1.5.
Product generated can be directly used in subsequent step by simple separation without isolation or only without purification.
Step e: lactam reduction reaction
According to the restoring method of well known lactams, the compound as shown in general formula (6) and suitable reducing agent pass through reduction
Reaction obtains compound shown in general formula (7).
The reducing agent is such as, but not limited to: sodium borohydride and lewis acid (such as BF3·Et2O etc.) combination, hydrogenation
Aluminium lithium, borine (BH3) and lithium aluminium hydride reduction and alchlor combination.
The reducing agent is preferably the combination of lithium aluminium hydride reduction and alchlor.In the combination, lithium aluminium hydride reduction and trichlorine
The molar ratio for changing aluminium is preferably 3:1-1:3, more preferably 2.5:1-1:2, particularly preferred 2:1-1:1, such as 8:5.Using hydrogen
In the case where changing the combination of aluminium lithium and alchlor as reducing agent, compound shown in the general formula (6) and lithium aluminium hydride reduction rub
You are than being preferably 1:10-1:1, more preferably 1:6-1:2, particularly preferred 1:5-1:3, such as 1:4.
It is described reaction preferably -30-50 DEG C at a temperature of carry out, more preferably -20-30 DEG C at a temperature of carry out, especially
It is preferred that -10-10 DEG C at a temperature of carry out, such as 0 DEG C at a temperature of carry out.
The reduction reaction preferably carries out in a suitable solvent, the solvent be such as, but not limited to THF, dioxane,
Glycol dimethyl ether and toluene.
The reduction reaction preferably carries out under the protection of nitrogen.
The reaction time of the reduction reaction is preferably 10min-12h, more preferably 30min-4h, particularly preferably 40-
120min, such as 60-70min.
In a preferred embodiment of the invention, the reduction reaction of step e are as follows:
At 0 DEG C of temperature and nitrogen protection, by LiAlH4It is added in THF, AlCl is added dropwise3Toluene solution, through 45min
It is added dropwise.Stir 15min.Then the THF solution of compound shown in general formula (6) is added dropwise in above-mentioned reaction solution anti-to carry out
It answers, is added dropwise through 1h, 10min is reacted until the reaction is complete, to obtain compound shown in general formula (7).Its formula of (6) institute
Show compound, LiAlH4And AlCl3Molar ratio be 2:8:5.
Product generated can be only directly used in subsequent step by simple separation without purification.
Step f: the removing of hydroxyl protection base
According to the method for well known deprotection base, the compound as shown in general formula (7) is obtained by eliminating hydroxide protecting group
Compound shown in general formula (8).
The method of the deprotection base includes but is not limited to:
I. it using hydrogen bromide as deprotection reagent, reacts under reflux conditions；
Ii. it is with the combination (in the combination, the molar ratio of hydrogen bromide and acetic acid is preferably 1:3) of hydrogen bromide and acetic acid
Deprotection reagent is reacted under reflux conditions；
Iii. it is reacted using Boron tribromide or boron chloride as deprotection reagent；
Iv. deprotection reagent is combined into the group of acetic acid and concentrated hydrochloric acid to be reacted；
V. it in the presence of Pd/carbon catalyst, is reacted by deprotection reagent of hydrogen.
R in the compound shown in general formula (7)2When for methyl (such as the compound shown in general formula (7) is as described below
When compound shown in general formula (7A)), it is preferable to use method iii, is more preferably reacted by deprotection reagent of Boron tribromide.
In the case where using Boron tribromide as deprotection reagent:
The molar ratio of compound shown in the general formula (7) and Boron tribromide is preferably 1:10-1:1, more preferably 1:8-1:
2, particularly preferred 1:6-1:3, such as 1:5；
It is described reaction preferably -30-50 DEG C at a temperature of carry out, more preferably -10-20 DEG C at a temperature of carry out, especially
It is preferred that -5-10 DEG C at a temperature of carry out, such as 0 DEG C at a temperature of carry out；
The reaction preferably carries out in a suitable solvent, the solvent be such as, but not limited to methylene chloride, tetrahydrofuran,
Dioxane and glycol dimethyl ether；
The reaction preferably carries out under the protection of nitrogen；
The reaction time of the deprotection reaction is preferably 1min-8h, more preferably 5-120min, particularly preferably
10-30min。
In a preferred embodiment of the invention, the deprotection reaction of step f are as follows:
Under 0 DEG C and nitrogen protection, compound shown in general formula (7) is added in methylene chloride, Boron tribromide, reaction is added
10min until the reaction is complete, to obtain compound shown in general formula (8).Compound shown in its formula of (7) and Boron tribromide
Molar ratio 1:5.
R in the compound shown in general formula (7)2When for benzyl (such as the compound shown in general formula (7) is as described below
When compound shown in general formula (7B)), it is preferable to use method iv.Use the combination of acetic acid and concentrated hydrochloric acid as deprotection reagent
In the case where:
The volume ratio of acetic acid and concentrated hydrochloric acid is preferably 1:2-2:1, more preferably 1:1.5-1.5:1 in the combination, such as
1:1；
It is described reaction preferably 50-150 DEG C at a temperature of carry out, more preferably 80-120 DEG C at a temperature of carry out, especially
It is preferred that 90-100 DEG C at a temperature of carry out；
The reaction time of the deprotection reaction is preferably 30min-12h, more preferably 1-8h, particularly preferably 2-
6h, such as 3-4h.
In another preferred embodiment of the present invention, the deprotection reaction of step f are as follows:
General formula (7) compound represented is added in acetic acid/concentrated hydrochloric acid (v/v=1:1), is reacted at 100 DEG C, flow back 3-
4h until the reaction is complete, to obtain compound shown in general formula (8).
Product generated can be directly used in subsequent step by simple separation without isolation or only without purification.
Step g: ring-closure reaction (Intramolecular substitution reaction)
In the presence of suitable temperature and alkali, general formula (9) are obtained by ring-closure reaction by general formula (8) compound represented
Shown compound.
The temperature is preferably 20-150 DEG C, more preferably 40-120 DEG C, particularly preferably 60-100 DEG C, such as 80 DEG C.
The alkali is such as, but not limited to alkali carbonate or bicarbonate (such as potassium carbonate, sodium carbonate, sodium bicarbonate, carbon
Sour caesium etc.), TEA and DBU.
General formula (8) compound represented and the molar ratio of the alkali are preferably 1:5-3:1, more preferably 1:4-2:1,
Particularly preferably 1:3-1:1, such as 1:2.
The ring-closure reaction preferably carries out in a suitable solvent, and the solvent is such as, but not limited to DMF, DMAc and NMP.
The reaction time of the ring-closure reaction is preferably 30min-12h, more preferably 1-8h, particularly preferably 3-4h.
In the methylation reaction, the addition sequence of compound shown in mutual-through type (8) and the alkali is not particularly limited.
In a preferred embodiment of the invention, the ring-closure reaction of step g are as follows:
In the presence of potassium carbonate, in DMF, general formula (8) compound represented is made to react 3-4h at 80 DEG C until anti-
Should be complete, to obtain compound shown in general formula (9).Its formula of (8) compound represented and the molar ratio of potassium carbonate are 1:2.
Product generated can be directly used in subsequent step by simple separation without isolation or only without purification.
Step h: the reduction reaction of nitro
According to the restoring method of well known nitro, the compound as shown in general formula (9) and suitable reducing agent are anti-by reduction
It should obtain compound shown in general formula (10).
The restoring method of the nitro includes but is not limited to:
A. it in the presence of Pd/carbon catalyst, is reacted by reducing agent of hydrogen；
B. it in the presence of Raney's nickel (Rany Ni) catalyst, is reacted by reducing agent of hydrogen；
C. it in the presence of Raney's nickel catalyst, is reacted by reducing agent of hydrazine hydrate；
D. it is reacted by reducing agent of iron；
E. with SnCl2It is reacted for reducing agent；
F. in FeCl3·6H2In the presence of O/ activated-carbon catalyst, reacted by reducing agent of hydrazine hydrate.
Present invention preferably uses method f.In the case where application method f, FeCl3·6H2The molar ratio of O and active carbon is excellent
It is selected as 1:30-1:1, more preferably 1:20-1:2, particularly preferred 1:15-1:5, such as 1:10；Compound shown in the general formula (9)
Molar ratio with hydrazine hydrate is preferably 1:30-1:1, more preferably 1:20-1:2, particularly preferred 1:15-1:5, such as 1:10；Institute
State FeCl3·6H2The molar ratio of O and hydrazine hydrate is preferably 1:300-1:10, more preferably 1:200-1:20, particularly preferred 1:
150-1:50, such as 1:100.
It is described reaction preferably 0-120 DEG C at a temperature of carry out, more preferably 20-100 DEG C at a temperature of carry out, it is especially excellent
It is carried out at a temperature of being selected in 40-80 DEG C.
The reduction reaction preferably carries out in a suitable solvent, and the solvent is such as, but not limited to C1-6Monohydric alcohol, such as
But it is not limited to methanol and ethyl alcohol.
The reaction time of the reduction reaction is preferably 0.5-12h, more preferably 1-8h, particularly preferably 2-5h, such as
3-4h。
In a preferred embodiment of the invention, the reduction reaction of step h are as follows:
Compound shown in general formula (9) is dissolved in ethyl alcohol, FeCl is added3·6H2O and active carbon are warming up to reflux, are added dropwise
80% hydrazine hydrate was added dropwise through 50-60 minutes, the reaction was continued 2-3h until the reaction is complete, to obtain shown in general formula (10)
Compound.Compound, hydrazine hydrate, FeCl shown in its formula of (9)3·6H2The molar ratio of O and active carbon is 10:100:1:10.
Product generated can be only directly used in subsequent step by simple separation without purification.
Step i: substitution reaction (sandmeyer reaction)
In the presence of suitable temperature and nitrite, passed through by general formula (10) compound represented and suitable chlorine source
Sandmeyer reaction obtains asenapine shown in general formula (11).
The temperature is preferably -20-120 DEG C, more preferably -10-100 DEG C, particularly preferably 0-80 DEG C, such as 0-75 DEG C.
The nitrite is such as, but not limited to sodium nitrite.
Chlorine source is such as, but not limited to CuCl and n-butyl chloride.
The molar ratio of general formula (10) compound represented and chlorine source is preferably 1:4-3:1, more preferably 1:3-
2:1, particularly preferably 1:2-1:1, such as 1:1.15.
General formula (10) compound represented and the molar ratio of the nitrite are preferably 1:4-3:1, more preferably
1:3-2:1, particularly preferably 1:2-1:1, such as 1:1.15.
The sandmeyer reaction preferably carries out in the presence of acid, it is described acid be such as, but not limited to fluoboric acid, hydrochloric acid and
Sulfuric acid.
The sandmeyer reaction preferably carries out in a suitable solvent, and the solvent is such as, but not limited to water.
The reaction time of the sandmeyer reaction is preferably 0.5-24h, more preferably 1.5-12h, particularly preferably 4-
10h。
In a preferred embodiment of the invention, the substitution reaction of step i are as follows:
Compound shown in general formula (10) is dissolved in water and concentrated hydrochloric acid at 0 DEG C, sodium nitrite in aqueous solution is added dropwise to
It states in reaction solution, was added dropwise through 40 minutes, then proceed to reaction 1.5-2 hours until end of reaction.It is stripped at 0 DEG C
It takes, and retains water phase.Stannous chloride is soluble in water, and concentrated hydrochloric acid is added, it is warming up to 75 DEG C.Above-mentioned water phase is poured into the chlorination
In cuprous solution, the reaction was continued 5-6 hours until the reaction is complete, to obtain asenapine shown in general formula (11).Wherein lead to
Formula (10) compound represented, sodium nitrite and CuCl molar ratio are 1:1.15:1.15.
Product generated only needs simple separation to purify the asenapine that can be obtained high-purity.
It can be seen from the foregoing description that method of the invention is in addition to providing the completely new new road for preparing asenapine
Except line, also have the advantage that
First, each step of the method for the present invention carries out under normal pressure, reaction temperature is also without departing from popular response temperature model
It encloses, reaction condition is more mild；
Second, raw materials and reagents used in the method for the present invention are the cheap raw material that can be obtained by conventional route
And reagent, there is lower cost；
Third, the intermediate obtained in each step of the method for the present invention is not necessarily to purify, it can without isolation or only pass through letter
List is separated and is directly used in subsequent step, is post-processed relatively simple；
Fourth, the method for the present invention is capable of providing the trans intermediates with good selectivity --- chemical combination shown in general formula (5)
Object enables the method for the present invention easily to obtain the asenapine of high-purity in high yield；And
Fifth, in the methods of the invention, the introducing of nitro enables cyclization to go on smoothly, to increase reaction
Yield.
In conclusion above due to having the advantages that, process of this invention is particularly practical for industrial productions.
Embodiment
To keep the present invention easier to understand, below in conjunction with specific embodiment, the present invention is further explained.It should be understood that these
Examples are only for illustrating the present invention and not for limiting the scope of the present invention.Also, it is unmentioned specific in the following example
Experimental method is carried out according to routine experiment method.
Raw materials and reagents used in following embodiment are purchased from Shanghai Kai Sai Chemical Co., Ltd..
As shown below is to work as R1For chlorine and R2When for methyl, a preferred embodiment of the method for the present invention:
Embodiment 1A
The synthesis of compound shown in general formula (3A)
At room temperature, dehydrated alcohol (300ml) is added in 500ml eggplant-shape bottle, stirring, and gold is added under nitrogen protection
Belong to sodium (1.9g, 84mmol), obtains sodium ethoxide after sodium is completely dissolved.
Then general formula (1A) compound represented (52g, 280mmol) and general formula (2A) compound represented are sequentially added
(53.6g, 364mmol).5-7 hours are reacted at room temperature until the reaction is complete.It filters, with methanol (100ml) filter wash cake, does
It is dry, to obtain light yellow solid (49.3g, yield: 56%).
1H NMR(400Hz,CDCl3): δ 8.54 (s, 1H);7.98(s,1H);7.83-7.88(d,1H);7.57-7.61
(d,1H);7.04-7.10(m,2H);7.16-7.25(t,1H);7.38-7.44(d,1H);3.92(s,3H)。
MS:315 (M+1).
Embodiment 2A
The synthesis of compound shown in general formula (4A)
Acetonitrile (250ml) is added in 500ml eggplant-shape bottle.Chemical combination shown in general formula (3A) is sequentially added under stirring at room temperature
Object (45g, 143mmol), tetrabutyl ammonium fluoride (11.2g, 42.9mmol) and trimethylsilyl cyanide (26.8ml, 214.5mmol),
40 DEG C are warming up to, reacts 30-40 minutes until the reaction is complete.It is cooling, reaction solution is poured into the beaker for filling water (200ml),
Side bevelling is stirred so that solid is precipitated.Stirring filters after 30 minutes, and filter cake is stirred with methanol (30ml) and washed, and filters, by filtration cakes torrefaction, from
And obtain white solid (30.8g, yield: 63%).
1H NMR(400Hz,DMSO-d6):δ:8.08(s,1H);7.82-7.89(d,1H);7.63-7.68(d,1H);
7.17-7.22(d,1H);6.91-6.98(m,3H);4.38(s,1H);4.32(s,1H);3.74(s,3H)。
MS:342(M+1)。
Embodiment 3A
The synthesis of compound shown in general formula (5A)
Under stirring at room temperature, sequentially added in 250ml eggplant-shape bottle general formula (4A) compound represented (12.28g,
35.96mmol), glacial acetic acid (15.77ml, 275.6mmol), water (1.07ml, 59.5mmol) and 98% sulfuric acid (5.39ml,
99.3mmol), 110 DEG C are then heated to, reaction 1.5-2h is until the reaction is complete.It is cooling, it is poured slowly into water under stiring
In (50ml), solid is precipitated, suction filtration obtains white solid (10.49g, yield: 81%).
1H NMR(400Hz,CDCl3):δ:8.28(s,1H);7.93-7.99(d,1H);7.57-7.63(d,1H);7.42-
7.47;(d,1H);6.88-6.96(m,3H);4.39(s,1H);4.34(s,1H);3.79(s,3H)。
MS:361(M+1)。
Embodiment 4A
The synthesis of compound shown in general formula (6A)
Under stirring at room temperature, sequentially add THF(180ml in 250ml eggplant-shape bottle), general formula (5A) compound represented
(20.0g, 55.5mmol), Anhydrous potassium carbonate (15.3g, 111mmol) and iodomethane (5.2ml, 83.25mmol), addition finishes
After be warming up to 70 DEG C, reaction 40 minutes is until the reaction is complete.Reaction solution is slowly poured into the burning for filling water (60ml) under stiring
In cup, solid is precipitated, stirring is filtered after 30 minutes, is washed with methanol (20ml), is filtered, and it is dry, to obtain white solid
(13.1g, yield: 63%).
1H NMR(400Hz,CDCl3):δ:8.32(s,1H);7.98-8.03(d,1H);7.68-7.74(d,1H);7.37-
7.44(d,1H);6.90-6.98(m,3H);4.19(s,1H);4.25(s,1H);3.92(s,3H);3.26(s,3H)。
MS:375(M+1)。
Embodiment 5A
The synthesis of compound shown in general formula (7A)
At 0 DEG C, THF(100ml is added in dry there-necked flask), stirring.In N2LiAlH is slowly added under protection4
(15.2g, 400mmol).By AlCl3(33.3g, 250mmol) is added in the beaker for filling toluene (100ml), then by it
It is added drop-wise in above-mentioned there-necked flask, is added dropwise through 45min.The reaction was continued 15 minutes after being added dropwise.Then by general formula (6A) institute
The compound (37.5g, 100mmol) shown is dissolved in THF(100ml) in, it is added dropwise in above-mentioned reaction solution, continues 1h.It is added dropwise
Afterwards, 10min is reacted until the reaction is complete.Water (50ml), which is added, quenches reaction, adjusts pH to 8-9 with ammonium hydroxide, filters, use acetic acid
Ethyl ester (80ml) filter wash cake retains filtrate, and is extracted 2 times with ethyl acetate (80ml × 2).It is dry with anhydrous sodium sulfate, it is evaporated
Obtain orange red grease (23.2g, yield: 67%).
1H NMR(400Hz,CDCl3):δ:8.19(s,1H);7.83-7.89(d,1H);7.58-7.63(d,1H);7.47-
7.54(d,1H);7.19-7.33(m,2H);6.88-6.94(d,1H);3.90(s,3H);3.07-3.27(m,2H);2.65-
2.79(m,4H);2.48(s,3H)。
MS:347(M+1)。
Embodiment 6A
The synthesis of compound shown in general formula (8A)
At 0 DEG C and N2Under protection, methylene chloride (200ml) is added in there-necked flask (500ml), and general formula (7A) institute is added
The compound (20.1g, 58mmol) shown, is sufficiently stirred, and is slowly added to Boron tribromide (30ml, 290mmol), and reaction 10min is straight
To fully reacting.Add water (10ml) to quench reaction, be evaporated methylene chloride, is extracted 3 times with ethyl acetate (100ml × 3), use ammonia
Water adjusts pH to 8-9, and organic layer is evaporated to obtain orange red grease (18g, yield: 93%) by separation.
1H NMR(400Hz,CDCl3):δ:8.26(s,1H);7.87-7.92(d,1H);7.65-7.73(d,1H);7.31-
7.36(d,1H);7.14-7.27(m,2H);6.98-7.02(d,1H);3.01-3.13(m,2H);2.68-2.83(m,4H);
2.63(s,3H)。
MS:333(M+1)。
Embodiment 7A
The synthesis of compound shown in general formula (9)
Under stirring at room temperature, sequentially add DMF(150ml in 250ml eggplant-shape bottle), general formula (8A) compound represented
(18g, 54mmol) and Anhydrous potassium carbonate (14.9g, 108mmol).80 DEG C are warming up to, reacts 3-4 hours until the reaction is complete.Add
Enter water (100ml), is extracted 3 times with ethyl acetate (100ml × 3), wash organic layer with clear water (50ml), dry, filter and dense
Contracting.It is impregnated with ether (200ml), impurity is precipitated, filtered, filtrate is evaporated to obtain orange red grease (15g, yield: 94%).
1HNMR(400Hz,CDCl3):δ:8.23(s,1H);7.98-8.02(d,1H);7.20-7.37(m,4H);7.45-
7.52(d,1H);3.27-3.35(m,2H);2.98-3.07(m,4H);2.56(s,3H)。
MS:MS:297(M+1)。
Embodiment 8A
The synthesis of compound shown in general formula (10)
At room temperature, general formula (9) compound represented (14.8g, 50mmol) is dissolved in 95% ethyl alcohol in there-necked flask
In (120ml).Sequentially add FeCl3·6H2O(1.4g, 5mmol) and active carbon (0.6g, 50mmol), it is warming up to reflux.Then
80% hydrazine hydrate (31.3g, 500mmol) is added dropwise, was added dropwise through 50-60 minutes, the reaction was continued 2-3 hours until end of reaction.
It filters, is evaporated while hot, add water (100ml), extracted 3 times with ethyl acetate (80ml × 3), merge organic phase, dry, filter and dense
Contracting.Acetone (10ml) and acidic alcohol (11ml) is added, solid is precipitated, sufficient standing filters, to obtain pale solid
(10.4g, yield: 78%).
1HNMR(400Hz,CDCl3):δ:7.93-7.98(d,1H);7.31-7.39(m,2H);7.19-7.23(d,1H);
7.06(s,1H);6.93-7.01(m,2H);5.46(s,2H);3.57-3.65(m,2H);3.02-3.13(m,4H);2.45(s,
3H)。
MS:MS:267(M+1)。
Embodiment 9A
The synthesis of compound shown in general formula (11)
At 0 DEG C, general formula (10) compound represented (9.9g, 37mmol) is dissolved in into water (50ml) and concentrated hydrochloric acid (50ml)
In, then water (30ml) solution of sodium nitrite (2.94g, 42.55mmol) is added dropwise in above-mentioned reaction solution, it was added dropwise through 40 minutes
It finishes.The reaction was continued after being added dropwise 1.5-2 hours until end of reaction.It is removed at 0 DEG C with ethyl acetate (20ml) back extraction
Decontamination, low temperature retain water phase.Stannous chloride (4.2g, 42.55mmol) is dissolved in water (20ml), concentrated hydrochloric acid is added
(20ml) is warming up to 75 DEG C.Above-mentioned water phase is poured into rapidly in the cuprous chloride solution, the reaction was continued 5-6 hours until reaction
It finishes.It is cooling, it is extracted 3 times with ethyl acetate (60ml × 3), organic layer is washed with weak aqua ammonia to alkalinity, is washed with clear water (30ml)
It washs, dry, concentration, to obtain orange red grease (3.92g, yield: 37%, purity > 98%).
1HNMR(400Hz,CDCl3):δ:7.73-7.79(d,1H);7.10-7.17(m,3H);7.03-7.08(m,3H);
3.53-3.56(m,2H);3.09-3.12(m,4H);2.38(s,3H)。
MS:286(M+1)。
As shown below is to work as R1For chlorine and R2When for benzyl, a preferred embodiment of the method for the present invention:
Embodiment 1B
The synthesis of compound shown in general formula (3B)
At room temperature, dehydrated alcohol (300ml) is added in 500ml eggplant-shape bottle, stirring, and gold is added under nitrogen protection
Belong to sodium (1.9g, 84mmol), obtains sodium ethoxide after sodium is completely dissolved.
Then general formula (1B) compound represented (52g, 280mmol) and general formula (2B) compound represented are sequentially added
(81.3g, 364mmol).5-7 hours are reacted at room temperature until the reaction is complete.It filters, with methanol (100ml) filter wash cake, does
It is dry, to obtain light yellow solid (65.7g, yield: 60%).
1H NMR(400Hz,CDCl3):δ:8.54(s,1H);7.98(s,1H);7.83-7.88(d,1H);7.57-7.61
(d,1H);7.35-7.49(m,5H);7.04-7.10(m,2H);7.16-7.25(t,1H);7.38-7.44(d,1H);5.20
(s,2H)。
MS:391 (M+1).
Embodiment 2B
The synthesis of compound shown in general formula (4B)
Acetonitrile (250ml) is added in 500ml eggplant-shape bottle.Chemical combination shown in general formula (3B) is sequentially added under stirring at room temperature
Object (55.9g, 143mmol), tetrabutyl ammonium fluoride (11.2g, 42.9mmol) and trimethylsilyl cyanide (26.8ml,
214.5mmol), 40 DEG C are warming up to, is reacted for 30-40 minutes until the reaction is complete.It is cooling, reaction solution is poured into and fills water
In the beaker of (200ml), side bevelling is stirred so that solid is precipitated.Stirring filters after 30 minutes, and filter cake is stirred with methanol (30ml) and washed, and takes out
Filter, by filtration cakes torrefaction, to obtain white solid (35.3g, yield: 59%).
1H NMR(400Hz,DMSO-d6):δ:8.08(s,1H);7.82-7.89(d,1H);7.63-7.68(d,1H);
7.35-7.49(m,5H);7.17-7.22(d,1H);6.91-6.98(m,3H);5.20(s,2H);4.38(s,1H);4.32(s,
1H)。
MS:418(M+1)。
Embodiment 3B
The synthesis of compound shown in general formula (5B)
Under stirring at room temperature, sequentially added in 250ml eggplant-shape bottle general formula (4B) compound represented (15g,
35.96mmol), glacial acetic acid (15.77ml, 275.6mmol), water (1.07ml, 59.5mmol) and 98% sulfuric acid (5.39ml,
99.3mmol), 110 DEG C are then heated to, reaction 1.5-2h is until the reaction is complete.It is cooling, it is poured slowly into water under stiring
In (50ml), solid is precipitated, suction filtration obtains white solid (13.3g, yield: 85%).
1H NMR(400Hz,CDCl3):δ:8.28(s,1H);7.93-7.99(d,1H);7.57-7.63(d,1H);7.42-
7.47(m,7H);6.88-6.96(m,3H);5.20(s,2H);4.39(s,1H);4.34(s,1H)。
MS:437(M+1)。
Embodiment 4B
The synthesis of compound shown in general formula (6B)
Under stirring at room temperature, sequentially add THF(180ml in 250ml eggplant-shape bottle), general formula (5B) compound represented
(24.2g, 55.5mmol), Anhydrous potassium carbonate (15.3g, 111mmol) and iodomethane (5.2ml, 83.25mmol), addition finishes
After be warming up to 70 DEG C, reaction 40 minutes is until the reaction is complete.Reaction solution is slowly poured into the burning for filling water (60ml) under stiring
In cup, solid is precipitated, stirring is filtered after 30 minutes, is washed with methanol (20ml), is filtered, and it is dry, to obtain white solid
(25g, yield: 60%).
1H NMR(400Hz,CDCl3):δ:8.32(s,1H);7.98-8.03(d,1H);7.68-7.74(d,1H);7.37-
7.44(m,6H);6.90-6.98(m,3H);5.20(s,2H);4.25(s,1H);4.19(s,1H);3.80(s,3H)。
MS:451(M+1)。
Embodiment 5B
The synthesis of compound shown in general formula (7B)
At 0 DEG C, THF(100ml is added in dry there-necked flask), stirring.In N2LiAlH is slowly added under protection4
(15.2g, 400mmol).By AlCl3(33.3g, 250mmol) is added in the beaker for filling toluene (100ml), then by it
It is added drop-wise in above-mentioned there-necked flask, is added dropwise through 45min.The reaction was continued 15 minutes after being added dropwise.Then by general formula (6B) institute
The compound (45.1g, 100mmol) shown is dissolved in THF(100ml) in, it is added dropwise in above-mentioned reaction solution, continues 1h.It is added dropwise
Afterwards, 10min is reacted until the reaction is complete.Water (50ml), which is added, quenches reaction, adjusts pH to 8-9 with ammonium hydroxide, filters, use acetic acid
Ethyl ester (80ml) filter wash cake retains filtrate, and is extracted 2 times with ethyl acetate (80ml × 2).It is dry with anhydrous sodium sulfate, it is evaporated
Obtain orange red grease (25.4g, yield: 60%).
1H NMR(400Hz,CDCl3):δ:8.19(s,1H);7.83-7.89(d,1H);7.58-7.63(d,1H);7.47-
7.54(d,1H);7.35-7.49(m,5H);7.19-7.33(m,2H);6.88-6.94(d,1H);5.20(s,2H);3.07-
3.27(m,2H);2.65-2.79(m,4H);2.30(s,3H)。
MS:423(M+1)。
Embodiment 6B
The synthesis of compound shown in general formula (8B)
The dense HCl(100ml/100ml of AcOH/ is added in general formula (7B) compound represented (14.8g, 35mmol)) in, add
Heat reacts 3-4h until the reaction is complete under reflux conditions to 100 DEG C.Concentration, obtain orange red grease (10.2g, yield:
90%).
1H NMR(400Hz,CDCl3):δ:8.26(s,1H);7.87-7.92(d,1H);7.65-7.73(d,1H);7.31-
7.36(d,1H);7.14-7.27(m,2H);6.98-7.02(d,1H);3.01-3.13(m,2H);2.68-2.83(m,4H);
2.63(s,3H)。
MS:333(M+1)。
Embodiment 7B
The synthesis of compound shown in general formula (9)
Under stirring at room temperature, sequentially add DMF(150ml in 250ml eggplant-shape bottle), general formula (8B) compound represented
(18g, 54mmol), Anhydrous potassium carbonate (14.9g, 108mmol).80 DEG C are warming up to, reacts 3-4 hours until the reaction is complete.Add
Enter water (100ml), is extracted 3 times with ethyl acetate (100ml × 3), wash organic layer with clear water (50ml), dry, filter and dense
Contracting.It is impregnated with ether (200ml), impurity is precipitated, filtered, filtrate is evaporated to obtain orange red grease (15g, yield: 94%).
1HNMR(400Hz,CDCl3):δ:8.23(s,1H);7.98-8.02(d,1H);7.20-7.37(m,4H);7.45-
7.52(d,1H);3.27-3.35(m,2H);2.98-3.07(m,4H);2.56(s,3H)。
MS:297(M+1)。
Embodiment 8B
The synthesis of compound shown in general formula (10)
At room temperature, general formula (9) compound represented (14.8g, 50mmol) is dissolved in 95% ethyl alcohol in there-necked flask
In (120ml).Sequentially add FeCl3·6H2O(1.4g, 5mmol) and active carbon (0.6g, 50mmol), it is warming up to reflux.Then
80% hydrazine hydrate (31.3g, 500mmol) is added dropwise, was added dropwise through 50-60 minutes, the reaction was continued 2-3 hours until end of reaction.
It filters, is evaporated while hot, add water (100ml), extracted 3 times with ethyl acetate (80ml × 3), merge organic phase, dry, filter and dense
Contracting.Acetone (10ml) and acidic alcohol (11ml) is added, solid is precipitated, sufficient standing filters, to obtain pale solid
(10.4g, yield: 78%).
1HNMR(400Hz;CDCl3):δ:7.93-7.98(d,1H);7.31-7.39(m,2H);7.19-7.23(d,1H);
7.06(s,1H);6.93-7.01(m,2H);5.46(s,2H);3.57-3.65(m,2H);3.02-3.13(m,4H);2.45(s,
3H)。
MS:267(M+1)。
Embodiment 9B
The synthesis of compound shown in general formula (11)
At 0 DEG C, general formula (10) compound represented (9.9g, 37mmol) is dissolved in into water (50ml) and concentrated hydrochloric acid (50ml)
In, then water (30ml) solution of sodium nitrite (2.94g, 42.55mmol) is added dropwise in above-mentioned reaction solution, it was added dropwise through 40 minutes
It finishes.The reaction was continued after being added dropwise 1.5-2 hours until end of reaction.It is removed at 0 DEG C with ethyl acetate (20ml) back extraction
Decontamination, low temperature retain water phase.Stannous chloride (4.2g, 42.55mmol) is dissolved in water (20ml), concentrated hydrochloric acid is added
(20ml) is warming up to 75 DEG C.Above-mentioned water phase is poured into rapidly in the cuprous chloride solution, the reaction was continued 5-6 hours until reaction
It finishes.It is cooling, it is extracted 3 times with ethyl acetate (60ml × 3), organic layer is washed with weak aqua ammonia to alkalinity, is washed with clear water (30ml)
It washs, dry, concentration, to obtain orange red grease (3.92g, yield: 37%, purity > 98%).
1HNMR(400Hz,CDCl3)δ:7.73-7.79(d,1H);7.10-7.17(m,3H);7.03-7.08(m,3H);
3.53-3.56(m,2H);3.09-3.12(m,4H);2.38(s,3H)。
MS:286(M+1)。
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
Protect the limitation of range.Although being made that detailed description, the ordinary skill people of this field to the present invention referring to preferred embodiment
Member it should be appreciated that can in the case where not departing from the spirit and scope of technical solution of the present invention to technical solution of the present invention into
Row modification or equivalent replacement.
Claims (10)
1. a kind of method for preparing asenapine shown in general formula (11):
It is characterized in that, described method includes following steps:
General formula (6) compound represented is prepared by methylation reaction by general formula (5) compound represented:
Wherein, R1Represent halogen；And
R2It represents and C is optionally selected from by one or more1-6Alkoxy, C1-6Alkanoyl and C6-10The C that the substituent group of aryl replaces1-6
Alkyl, the C6-10Aryl is optionally selected from C by one or more1-6Alkoxy, C1-6Alkanoyl and C6-10The substituent group of aryl takes
Generation；
General formula (7) compound represented is prepared by reduction reaction by general formula (6) compound represented:
General formula (8) compound represented is prepared by eliminating hydroxide protecting group by general formula (7) compound represented:
General formula (9) compound represented is obtained by ring-closure reaction by general formula (8) compound represented
General formula (10) compound represented is obtained by reduction reaction by general formula (9) compound represented
And
Asenapine shown in general formula (11) is obtained by substitution reaction as general formula (10) compound represented.
2. preparation method according to claim 1, wherein R1For chlorine or bromine.
3. preparation method according to claim 1, wherein R2To be optionally selected from methoxyl group, acetyl group by one or more
The C replaced with the substituent group of phenyl1-6Alkyl, the phenyl are optionally selected from methoxyl group, acetyl group and phenyl by one or more
Substituent group replace.
4. preparation method according to claim 3, wherein R2For methyl, benzyl, to methoxy-benzyl, 3,4- dimethoxy
Benzyl, to acetyl group benzyl or to phenylbenzyl.
5. the preparation method according to claim 4, wherein R2For methyl or benzyl.
6. preparation method according to claim 1, which is characterized in that general formula (8) compound represented is:
7. preparation method according to claim 1 to 6, which is characterized in that chemical combination shown in the general formula (5)
Object is to be prepared by general formula (4) compound represented by cyclization:
Wherein, R1If any one of claim 1-6 is defined,
R2As any one of claim 1-6 is defined.
8. preparation method according to claim 7, which is characterized in that general formula (4) compound represented is by general formula
(3) compound represented is prepared by cyanogenation:
Wherein, R1If any one of claim 1-6 is defined,
R2As any one of claim 1-6 is defined.
9. preparation method according to claim 8, which is characterized in that general formula (3) compound represented is by general formula
(1) compound represented and general formula (2) compound represented are prepared by condensation reaction:
Wherein, R1If any one of claim 1-6 is defined,
Wherein, R2As any one of claim 1-6 is defined.
10. preparation method according to claim 1 to 6, which is characterized in that the method includes such as reacting road
Step described in line 1:
Reaction route 1
Wherein, R1If any one of claim 1-6 is defined,
R2As any one of claim 1-6 is defined.
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| US20180193283A1 (en) | 2016-12-20 | 2018-07-12 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| EP3644973B1 (en) | 2017-06-26 | 2021-03-24 | LTS LOHMANN Therapie-Systeme AG | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| JP2021529737A (en) | 2018-06-20 | 2021-11-04 | エルテーエス ローマン テラピー−ジステーメ アーゲー | Percutaneous treatment system containing asenapine |
| CN110606852B (en) * | 2019-08-13 | 2021-02-05 | 浙江奥翔药业股份有限公司 | Process for the preparation of asenapine |
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| WO2012040845A1 (en) * | 2010-09-27 | 2012-04-05 | Alphora Research Inc. | Process for the preparation of tetracyclic derivatives and intermediate products used in the process |
| WO2013061247A1 (en) * | 2011-10-24 | 2013-05-02 | Alembic Pharmaceuticals Limited | Novel process for the preparation of asenapine |
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| WO2012040845A1 (en) * | 2010-09-27 | 2012-04-05 | Alphora Research Inc. | Process for the preparation of tetracyclic derivatives and intermediate products used in the process |
| WO2013061247A1 (en) * | 2011-10-24 | 2013-05-02 | Alembic Pharmaceuticals Limited | Novel process for the preparation of asenapine |
Non-Patent Citations (1)
| Title |
|---|
| Convenient Methods for the Reduction of Amides, Nitriles, Carboxylic Esters, Acids and Hydroboration of Alkenes Using NaBH4/I2 System;A.S. Bhanu Prasad et al.;《Tetrahedron》;19921231;第48卷(第22期);4623-4628 * |
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