CN104974167B - 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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Abstract
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 -2,3,3a, 12b- tetrahydro -1H- dibenzo [2,3:6,7]-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 anti-5- hydroxyl
The active compound of tryptamines.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
There are still many problems, such as reactant to be difficult to obtain for method, severe reaction conditions, post-processing complexity etc., therefore there is still a need for more
Add the preparation method suitable for 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, and reaction condition is mild, and post-processing is simple, thus particularly suitable for industrial production.
To achieve the goals above, on the one hand, the present invention provides a kind of sides for preparing asenapine shown in general formula (9)
Method:
It is characterized in that, described method includes following steps:
Asenapine shown in general formula (9) is obtained by ring-closure reaction as general formula (8) compound represented
Wherein, X represents halogen, preferably Br.
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 R:
Wherein, X is as defined above,
R, which is represented, is optionally selected from C 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 are selected from:
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, X and R difference is as defined above.
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, X and R difference is as defined above.
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, X and R difference is as defined above.
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, X and R difference is as defined above.
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, R is as defined above,
Wherein, X is as defined above.
It on the other hand, is to be used to prepare in asenapine the present invention provides a kind of general formula (7) compound represented
Mesosome:
Wherein, X represents halogen, preferably Br,
R, which is represented, is optionally selected from C 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 are selected from:
On the other hand, the present invention provides the purposes that a kind of general formula (7) compound represented is used to prepare asenapine:
Wherein, X represents halogen, preferably Br,
R, which is represented, is optionally selected from C 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 are selected from:
Specific embodiment
Definition
The term as used herein " halogen " refers to fluorine, chlorine, bromine or iodine, preferably 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 (9) and general formula (5) to (8) institute
The midbody compound shown is the racemic modification indicated in the form of individual isomer, actually covers two kinds of enantiomers.For example,
Practical asenapine shown in general formula (9) is the racemic modification for covering following two enantiomer:
Midbody compound shown in general formula (5) to (8) 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.
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:
Reaction route 1
Wherein, X represents halogen, preferably Br,
R, which is represented, is optionally selected from C 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 20-60 DEG C, particularly preferred 30-40 DEG C, such as 35 DEG C.
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 1:1.25.
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 2-7h, particularly preferably 3-5h.
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 general formula (1) is added in the ethanol solution of sodium ethoxide, compound shown in general formula (2) is added, and
3-5h is reacted until the reaction is complete at 35 DEG C, to obtain compound shown in general formula (3).Compound shown in its formula of (1),
The molar ratio of compound shown in general formula (2) and sodium ethoxide is 1:1.25:0.3.
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 30-70 DEG C, particularly preferred 40-60 DEG C, such as 45 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 1:5-3:1, more preferably 1:4-2:1, particularly preferred 1:3-1:1, example
Such as 1:2.
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 30min-4h, particularly preferably 1-
2h。
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, it is straight that 1-2h is reacted at 45 DEG C
To fully reacting, to obtain compound shown in general formula (4).Compound shown in its formula of (3), TMSCN and the tetrabutyl are fluorinated
The molar ratio of ammonium is 2:3:1.
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 3:1；Wherein acetic acid plays diluting reaction
Liquid and the deliquescent effect of increase.
The reaction time of the cyclization is preferably 30min-12h, more preferably 1-4h, 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 168:1288:464:278.
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 (75-85%) 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.
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 30-100 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-12h, more preferably 30min-4h, particularly preferably 1-
1.5h。
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 1-1.5h under reflux conditions
Until the reaction is complete, to obtain compound shown in general formula (6).Compound shown in its formula of (5), potassium carbonate and iodomethane
Molar ratio is 1:2:1.5.
Product generated can be directly used in subsequent step by simple separation without isolation or only without purification.
Step e: 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 40:23.It is using
In the case that the combination of lithium aluminium hydride reduction and alchlor is as reducing agent, compound shown in the general formula (6) and lithium aluminium hydride reduction
Molar ratio is 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 60-
120min, such as 80-110min.
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, is added dropwise in the case where temperature control is lower than 0 DEG C
AlCl3Toluene solution, stir 15min.Then in the case where temperature control is lower than 10 DEG C by the THF of compound shown in general formula (6)
Solution is added dropwise in above-mentioned reaction solution to be reacted, and 1-1.5h is added dropwise, and reacts 20min until the reaction is complete, thus
To compound shown in general formula (7).Compound, LiAlH shown in its formula of (6)4And AlCl3Molar ratio be 10:40:23.
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.
When R in the compound shown in general formula (7) is 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 1:5-1:3, such as 1:4；
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 time of the deprotection reaction is preferably 1min-8h, more preferably 5-120min, particularly preferably
10-30min, such as 15min.
In a preferred embodiment of the invention, the deprotection reaction of step f are as follows:
Under ice bath, will compound shown in general formula (7) be added methylene chloride in, be added Boron tribromide, reaction 15min until
Fully reacting, to obtain compound shown in general formula (8).The molar ratio 1 of compound and Boron tribromide shown in its formula of (7):
4。
When R in the compound shown in general formula (7) is 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-
4h, such as 3h.
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 3h
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 in asenapine.
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 1.5-3h.
In the methylation reaction, the addition sequence of compound shown in mutual-through type (8) and the alkali has no special limit
It is fixed.
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, make general formula (8) compound represented reacted at 80 DEG C 1.5-3h until
Fully reacting, to obtain asenapine shown in general formula (9).Mole of its formula of (8) compound represented and potassium carbonate
Than for 1:2.
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.
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 one preferred embodiment of the method for the present invention when X is bromine and R is methyl:
Embodiment 1A
The synthesis of compound shown in general formula (3A)
At room temperature, dehydrated alcohol (300ml) is added in eggplant-shape bottle, stirring, and metallic sodium is added under nitrogen protection
(1.38g, 60mmol) obtains sodium ethoxide after sodium is completely dissolved.
In the ethanol solution for the sodium ethoxide that general formula (1A) compound represented (34.1g, 200mmol) is added to brand-new.
General formula (2) compound represented (49.4g, 252mmol) is added under stiring.3-5h is reacted until the reaction is complete at 35 DEG C.
It is cooling, it filters, with ethyl alcohol (10ml) filter wash cake, and it is dry, to obtain white solid (59.3g, yield: 85%).
1H NMR(400Hz,CDCl3): δ 3.841 (s, 3H);7.011-7.105(d,1H);7.150-7.234(m,2H);
7.240-7.411(m,3H);7.591-7.605(d,1H);8.511(s,1H)。
MS:M+1=348.
Embodiment 2A
The synthesis of compound shown in general formula (4A)
Acetonitrile (200ml) is added in eggplant-shape bottle.It is added at one time general formula (3A) compound represented under stiring
(55.8g, 160mmol), TMSCN(30.0ml, 240mmol) (using dioxygen water process using preceding) and tetrabutyl ammonium fluoride
(20.9g, 80mmol) reacts 1-2h until the reaction is complete at 45 DEG C, pours into the beaker for filling water (100ml), filter, so
It is impregnated, and filtered with methanol (50ml) afterwards, to obtain white solid (49.0g, yield: 82%).
1H NMR(400Hz,CDCl3): δ 3.841 (s, 3H);4.201(d,2H);7.011-7.105(d,1H);7.150-
7.234(m,2H);7.240-7.411(m,3H);7.591-7.605(d,1H)。
MS:M+1=373。
Embodiment 3A
The synthesis of compound shown in general formula (5A)
Under room temperature and stirring, general formula (4A) compound represented (6.28g, 16.8mmol), second are added in eggplant-shape bottle
Acid (7.37ml, 128.8mmol), 98% sulfuric acid (2.52ml, 46.4mmol), water (0.50ml, 27.8mmol), then heat to
110 DEG C, reaction 1.5-2h is until the reaction is complete.It is cooling, it is poured slowly into water (20ml) under stiring, solid is precipitated, filters
To white solid (5.37g, yield: 81%).
1H NMR (400Hz, CDCl3): δ 3.841 (s, 3H);4.392(d,2H);7.011-7.105(d,1H);7.150-
7.234(m,2H);7.240-7.411(m,3H);7.591-7.605(d,1H)。
MS:M+1=394。
Embodiment 4A
The synthesis of compound shown in general formula (6A)
THF(250ml is added in dry there-necked flask), under stiring be added general formula (5A) compound represented (30g,
76mmol), potassium carbonate (21.0g, 152mmol) and CH3I(7.1ml, 114mmol).1-1.5h flow back until the reaction is complete.It is cold
But, it pours into water (150ml), solid is precipitated, filter, impregnate filter cake with methanol (30ml), filter, to obtain white solid
(26.4g, yield: 85%).
1H NMR (400HZ, CDCl3): δ 3.741 (s, 3H);3.841(s,3H);4.392(d,2H);7.011-7.105
(d,1H);7.150-7.234(m,2H);7.240-7.411(m,3H);7.591-7.605(d,1H)。
MS:M+1=408。
Embodiment 5A
The synthesis of compound shown in general formula (7A)
Under ice bath, under nitrogen protection, THF(50ml is added in dry there-necked flask).It is then slowly added into
LiAlH4(7.59g, 200mmol), then AlCl is slowly added dropwise3(temperature control is lower than 0 to the toluene solution (50ml) of (15.3g, 115mmol)
DEG C).After being added dropwise, 15min is stirred.Then general formula (6A) compound represented (20.4g, 50mmol) is dissolved in THF
In (50ml) (temperature control is lower than 10 DEG C), it is added dropwise in above-mentioned reaction solution, continues 1-1.5h.After being added dropwise, reaction 20min until
Fully reacting.Ice water (50ml), which is slowly added dropwise, quenches reaction, is adjusted to alkalescent (pH=8-9) with 2N sodium hydroxide solution.It takes out
Filter retains filtrate with ethyl acetate (50ml) filter wash cake, and is extracted 3 times with ethyl acetate (50ml × 3).Merge organic phase simultaneously
It is concentrated to get white oil product (16.0g, yield: 84%).
1H NMR (400Hz, CDCl3): δ 2.272 (s, 3H);2.42-2.661(m,4H);4.392(m,2H);3.245(s,
3H);7.011-7.105(d,1H);7.150-7.234(m,2H);7.240-7.411(m,3H);7.591-7.605(d,1H)。
MS:M+1=380。
Embodiment 6A
The synthesis of compound shown in general formula (8)
Under ice bath, methylene chloride (150ml) is added in there-necked flask, and general formula (7A) compound represented is added
(15.2g, 40mmol), is sufficiently stirred, and is added Boron tribromide (15.4ml, 160mmol), and reaction 15min is until the reaction is complete.It is slow
Slow be added water (50ml) quenches reaction, is evaporated methylene chloride, is extracted 3 times with ethyl acetate (40ml × 3), be evaporated to obtain yellow
Grease (11.7g, yield: 80%).
1H NMR (400Mz, CDCl3): δ 2.272 (s, 3H);2.42-2.661(m,4H);4.392(m,2H);5.201(s,
1H);7.011-7.105(d,1H);7.150-7.234(m,2H);7.240-7.411(m,3H);7.591-7.605(d,1H)。
MS:M+1=366。
Embodiment 7A
The synthesis of compound shown in general formula (9)
At room temperature, DMF(150ml is added in eggplant-shape bottle).General formula (8) compound represented is added under stiring
(15.1g, 41mmol), is sufficiently stirred, and Anhydrous potassium carbonate (11.39g, 83mmol) is added.80 DEG C are warming up to, 1.5-3h is reacted
Until the reaction is complete.It is cooling, extracted with ethyl acetate (50ml × 3), be evaporated to obtain orange red grease (11.32g, yield:
96%).Impregnated with ether (200ml), Orange red solid be precipitated, filtered, by filtrate be evaporated to obtain orange red grease (11.08g,
Yield: 89%, purity > 98%).
1HNMR (400Mz, CDCl3): δ 2.272 (s, 3H);2.42-2.661(m,4H);4.392(m,2H);7.011-
7.105(d,1H);7.230-7.255(m,3H);7.371-7.411(m,1H);7.451-7.490(m,2H)。
MS:M+1=286。
As shown below is one preferred embodiment of the method for the present invention when X is bromine and R is benzyl:
Embodiment 1B
The synthesis of compound shown in general formula (3B)
At room temperature, dehydrated alcohol (300ml) is added in eggplant-shape bottle, stirring, and metallic sodium is added under nitrogen protection
(1.38g, 60mmol) obtains sodium ethoxide after sodium is completely dissolved.
In the ethanol solution for the sodium ethoxide that general formula (1B) compound represented (49.3g, 200mmol) is added to brand-new.
General formula (2) compound represented (50.9g, 260mmol) is added under stiring.3-5h is reacted until the reaction is complete at 35 DEG C.
It is cooling, it filters, with ethyl alcohol (10ml) filter wash cake, and it is dry, to obtain white solid (67.9g, yield: 80%).
1H NMR (400Hz, CDCl3): δ 5.20 (s, 2H);7.011-7.105(d,1H);7.150-7.234(m,2H);
7.240-7.411(m,8H);7.591-7.605(d,1H);8.511(s,1H)。
MS:M+1=424.
Embodiment 2B
The synthesis of compound shown in general formula (4B)
Acetonitrile (200ml) is added in eggplant-shape bottle.It is added at one time general formula (3B) compound represented under stiring
(67.95g, 160mmol), TMSCN(30.0ml, 240mmol) (using dioxygen water process using preceding) and tetrabutyl ammonium fluoride
(20.9g, 80mmol) reacts 1-2h until the reaction is complete at 45 DEG C, pours into the beaker for filling water (100ml), filter, so
It is impregnated, and filtered with methanol (50ml) afterwards, to obtain white solid (61.4g, yield: 85%).
1H NMR (400Hz, CDCl3): δ: 4.201 (d, 2H), 5.20 (s, 2H);7.011-7.105(d,1H);7.150-
7.234(m,2H);7.240-7.411(m,8H);7.591-7.605(d,1H)。
MS:M+1=451。
Embodiment 3B
The synthesis of compound shown in general formula (5B)
Under room temperature and stirring, general formula (4B) compound represented (7.58g, 16.8mmol), second are added in eggplant-shape bottle
Acid (7.37ml, 128.8mmol), 98% sulfuric acid (2.52ml, 46.4mmol), water (0.50ml, 27.8mmol), then heat to
110 DEG C, reaction 1.5-2h is until the reaction is complete.It is cooling, it is poured slowly into water (20ml) under stiring, solid is precipitated, filters
To white solid (5.9g, yield: 75%).
1H NMR (400Hz, CDCl3): δ 4.392 (d, 2H);5.20(s,2H);7.011-7.105(d,1H);7.150-
7.234(m,2H);7.240-7.411(m,8H);7.591-7.605(d,1H)。
MS:M+1=470。
Embodiment 4B
The synthesis of compound shown in general formula (6B)
THF(250ml is added in dry there-necked flask), general formula (5B) compound represented is added under stiring
(35.8g, 76mmol), potassium carbonate (21.0g, 152mmol) and CH3I(7.1ml, 114mmol).1-1.5h flow back until reaction
Completely.It is cooling, it pours into water (150ml), solid is precipitated, filter, impregnate filter cake with methanol (30ml), filter, to obtain white
Color solid (25.8g, yield: 70%).
1H NMR (400Hz, CDCl3): δ 3.741 (s, 3H);3.841(s,3H);4.392(d,2H);5.20(s,2H);
7.011-7.105(d,1H);7.150-7.234(m,2H);7.240-7.411(m,8H);7.591-7.605(d,1H).
MS:M+1=484
Embodiment 5B
The synthesis of compound shown in general formula (7B)
Under ice bath, under nitrogen protection, THF(50ml is added in dry there-necked flask).It is then slowly added into
LiAlH4(7.59g, 200mmol), then AlCl is slowly added dropwise3(temperature control is lower than 0 to the toluene solution (50ml) of (15.3g, 115mmol)
DEG C).After being added dropwise, 15min is stirred.Then general formula (6B) compound represented (24.2g, 50mmol) is dissolved in THF
In (50ml) (temperature control is lower than 10 DEG C), it is added dropwise in above-mentioned reaction solution, continues 1-1.5h.After being added dropwise, reaction 20min until
Fully reacting.Ice water (50ml), which is slowly added dropwise, quenches reaction, is adjusted to alkalescent (PH=8-9) with 2N sodium hydroxide solution.It takes out
Filter retains filtrate with ethyl acetate (50ml) filter wash cake, and is extracted 3 times with ethyl acetate (50ml × 3).Merge organic phase simultaneously
It is concentrated to get white oil product (19g, yield: 85%).
1H NMR (400Hz, CDCl3): δ 2.272 (s, 3H);2.42-2.661(m,4H);4.392(m,2H);3.245(s,
3H);5.20(2H,s);7.011-7.105(d,1H);7.150-7.234(m,2H);7.240-7.411(m,8H);7.591-
7.605(d,1H)。
MS:M+1=456。
Embodiment 6B
The synthesis of compound shown in general formula (8)
The dense HCl(150ml/150ml of AcOH/ is added in general formula (7B) compound represented (16g, 35mmol)) in, heating
To 100 DEG C, reflux 3h is until the reaction is complete.Concentration, obtains orange red grease (10.2g, yield: 90%).
1H NMR (400Mz, CDCl3): δ 2.272 (s, 3H);2.42-2.661(m,4H);4.392(m,2H);5.201(s,
1H);7.011-7.105(d,1H);7.150-7.234(m,2H);7.240-7.411(m,3H);7.591-7.605(d,1H)。
MS:M+1=366。
Embodiment 7B
The synthesis of compound shown in general formula (9)
At room temperature, DMF(150ml is added in eggplant-shape bottle).General formula (8) compound represented is added under stiring
(15g, 41mmol), is sufficiently stirred, and Anhydrous potassium carbonate (11.39g, 83mmol) is added.80 DEG C are warming up to, reaction 1.5-3h is straight
To fully reacting.It is cooling, extracted with ethyl acetate (50ml × 3), be evaporated to obtain orange red grease (11.32g, yield:
96%).Impregnated with ether (200ml), Orange red solid be precipitated, filtered, by filtrate be evaporated to obtain orange red grease (11.08g,
Yield: 89%, purity > 98%).
1HNMR (400Mz, CDCl3): δ 2.272 (s, 3H);2.42-2.661(m,4H);4.392(m,2H);7.011-
7.105(d,1H);7.230-7.255(m,3H);7.371-7.411(m,1H);7.451-7.490(m,2H)。
MS:M+1=286。
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 (9):
It is characterized in that, described method includes following steps:
Asenapine shown in general formula (9) is obtained by ring-closure reaction as general formula (8) compound represented:
Wherein, X represents halogen；
Wherein general formula (8) compound represented is to be prepared by general formula (7) compound represented by eliminating hydroxide protecting group R
It obtains:
Wherein, R, which is represented, is optionally selected from C 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；
Wherein general formula (7) compound represented is to be prepared by general formula (6) compound represented by reduction reaction:
Wherein general formula (6) compound represented is to be prepared by general formula (5) compound represented by methylation reaction
:
2. preparation method according to claim 1, wherein X is Br.
3. preparation method according to claim 1, wherein R is optionally to be 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 R is 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 R is methyl or benzyl.
6. preparation method according to claim 1, which is characterized in that general formula (7) compound represented is selected from:
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, any one of X such as claim 1-6 is defined,
Any one of R such as 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, any one of X such as claim 1-6 is defined,
Any one of R such as 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, any one of R such as claim 1-6 is defined,
Wherein, any one of X such as 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, any one of X such as claim 1-6 is defined,
Any one of R such as claim 1-6 is defined.
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