CN109503482A - A kind of preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate - Google Patents
A kind of preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate Download PDFInfo
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- CN109503482A CN109503482A CN201710827097.7A CN201710827097A CN109503482A CN 109503482 A CN109503482 A CN 109503482A CN 201710827097 A CN201710827097 A CN 201710827097A CN 109503482 A CN109503482 A CN 109503482A
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Abstract
The invention discloses a kind of preparation methods of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate, and using indone as raw material, process is halogenated, cyaniding, hydrolysis, ring-closure reaction, and reduction and hydrochloric acid salt six-step process obtain target compound.Using preparation method of the invention, raw material is easy to get, and reaction condition is mild, and simple process, high income, cost is relatively low, and environmental pollution is small, there is good utility value in the industrial production.
Description
Technical field
The present invention relates to a kind of preparation methods of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate, belong to field of fine chemical.
Background technique
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is by Pfizer Inc.'s research and development for treating the drug of nicotine addiction, successively with 2005 5
The moon and August are by U.S. FDA and Europe EMEA approval listing.
Currently, most importantly its key intermediate compound 6 (benzazepine) is prepared in 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, synthesis
There are mainly two types of for method:
One, using o-fluorobenzyl bromide as starting material, grignard reaction is first passed through, then bishydroxy is obtained by catalytic osmium tetroxide
Object is closed, then periodic acid scission of link obtains aldehyde compound, then obtains target compound by multistep reactions such as reduction, hydrogenations again
6(benzazepine)。
Two, it using the bromo- benzene acetonitrile of 2- as starting material, by multistep reactions such as condensation, closed loop, hydrogenation, ammonolysis, reduction, obtains
To target compound (benzazepine).
The more expensive and toxicity big noble metal reagent of existing technical application and some strong oxidizing properties and deep-etching
The acid compound of property, this is all very unfavorable for industrialized production and environmental protection and cost control.
Summary of the invention
A kind of it is an object of the invention to overcome the deficiencies of the prior art and provide productions easy, at low cost, environmental pollution
The preparation method of small, high income 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate.
To achieve the above object, the invention adopts the following technical scheme: successively being carried out using formula (1) indone as starting material
Halogenating reaction, cyanogenation, hydrolysis, ring-closure reaction, reduction reaction and hydrochloric acid salt obtain target product 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h pass
Key intermediate.
Specifically, the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate provided by the invention, reaction process such as route (1) institute
Show:
Wherein, X halogen atom, including fluorine, chlorine, bromine, iodine.
Specifically includes the following steps:
(a) in a solvent, using formula (1) indone as starting material, halogenating reaction, production (2) halogen are carried out with halide reagent
For object.
(b) formula (2) halide is added in solvent appropriate, and cyanating reagent is added and carries out cyanogenation, obtains formula (3) change
Close object.
(c) formula (3) compound is added in organic solvent/aqueous slkali appropriate, heats and reaction is hydrolyzed, end of reaction,
Hydrochloric acid acidification, obtains formula (4) diacid compounds.
(d) formula (4) compound heats reaction in acetic anhydride, and acetic anhydride, obtained solid and Ammonium Acetate is recovered under reduced pressure and is closing
Ring-closure reaction is carried out in suitable solvent, obtains formula (5) compound.
(e) formula (5) compound, is dissolved in organic solvent, is restored with reducing agent, obtains formula (6) compound.
(f) formula (6) compound, is dissolved in organic solvent appropriate, is passed through hydrochloric acid salt under the conditions of hydrogen chloride gas, obtains formula
(7) compound.
In step (a), the solvent is selected from one of formic acid, acetic acid, propionic acid etc. or a variety of；Preferably acetic acid.
In step (a), the halide reagent is selected from NBS, NCS, NIS, Br2Deng, it is therefore preferable to Br2；X can be F, Cl,
Br, I, it is therefore preferable to Br.
In step (a), the molar ratio of the indone and halide reagent is (1:2)~(1:5)；Preferably (1:2)~(1:
3)。
In step (a), the temperature of the halogenating reaction is -25 DEG C~50 DEG C；Preferably -10 DEG C~30 DEG C；Further
It preferably, is 25 DEG C.
In step (a), the time of the halogenating reaction is 1~48h；Preferably 1~6h；It is further preferred that being 2h.
In step (b), the solvent is selected from one of methanol, ethyl alcohol, propyl alcohol, water etc. or a variety of；Preferably ethyl alcohol,
The mixed solution of water or both；It is further preferred that the mixed solution mixed for second alcohol and water with volume ratio 7:1.
In step (b), the cyanating reagent is selected from KCN, NaCN etc.；Preferably KCN.
In step (b), the molar ratio of formula (2) halide and cyanating reagent is (1:2)~(1:8)；Preferably (1:
2)~(1:3).
In step (b), the temperature of the cyanogenation is 10 DEG C~80 DEG C；Preferably 25 DEG C of room temperature.
In step (b), the time of the cyanogenation is 5~30h；Preferably 5~10h；It is further preferred that being
5h。
It further include adding water stratification, water layer oxidation processes, organic layer is by washing after the completion of the cyanogenation in step (b)
After washing, the step of organic solvent is recovered under reduced pressure, formula (3) compound purified.Preferably, the washing are as follows: organic layer according to
It is secondary to pass through saturated sodium carbonate solution washing, the washing of saturated sodium thiosulfate solution and water-washing step.
In step (c), the organic solvent is selected from one of alcohols solvents such as methanol, ethyl alcohol, propyl alcohol or a variety of；It is preferred that
Ground is ethyl alcohol.
In step (c), the alkali is inorganic base, is selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, hydroxide
One of potassium, sodium hydroxide etc. are a variety of；Preferably potassium hydroxide.
In step (c), formula (3) compound and organic solvent weight ratio are (1:6)~(1:20), it is therefore preferable to (1:
6)~(1:10)；The molar ratio of formula (3) compound and alkali is (1:1.2)~(1:3)；Preferably (1:1.2)~(1:
1.6)。
In step (c), the temperature of the hydrolysis is 50 DEG C~150 DEG C；Preferably 50 DEG C~80 DEG C；It is further excellent
Selection of land is 75 DEG C.
In step (c), the time of the hydrolysis is 3~20h；Preferably 3~8h；It is further preferred that being 4h.
In step (c), hydrochloric acid acidification purpose be that product is dissolved in water phase under alkaline system at salt, acidification meeting so that
Product separate out.
In step (d), the acetic anhydride is selected from acetic anhydride, propionic andydride, butyric anhydride etc.；Preferably acetic anhydride.
In step (d), weight ratio (1:5)~(1:15) of formula (4) compound, acetic anhydride；Preferably (1:5)~
(1:8)；Molar ratio (1:1.2)~(1:4) of formula (4) compound, Ammonium Acetate；Preferably (1:1.2)~(1:1.6).
In step (d), the temperature of the heating reaction is 60 DEG C~180 DEG C；Preferably 90 DEG C~110 DEG C；Further
It preferably, is 110 DEG C.
In step (d), the time of the heating reaction is 3~50h；Preferably 3~10h；It is further preferred that being
5h。
In step (d), the solvent is selected from one of alcohols solvents such as methanol, ethyl alcohol, propyl alcohol or a variety of；Preferably
Methanol.
In step (d), the temperature of the ring-closure reaction is 50 DEG C~120 DEG C；Preferably 50 DEG C~80 DEG C；It is further excellent
Selection of land is 75 DEG C.
In step (d), the time of the ring-closure reaction is 3~40h；Preferably 3~10h；It is further preferred that being
3h。
In step (e), the organic solvent is selected from one of methanol, ethyl alcohol, tetrahydrofuran (THF) etc. or a variety of；It is excellent
Selection of land is THF；It is further preferred that being dry THF.
In step (e), the reducing agent is selected from one of lithium aluminium hydride reduction, borane complex, sodium borohydride etc. or a variety of；
Preferably sodium borohydride.
In step (e), formula (5) compound, reducing agent molar ratio be (1:0.3)~(1:3)；Preferably (1:
0.3)~(1:1.2).
In step (e), the temperature of the reduction reaction is 0 DEG C~50 DEG C；Preferably 0 DEG C~25 DEG C.
In step (e), the time of the reduction reaction is 1~20h；Preferably 1~6h.
In step (f), the organic solvent is selected from one of alcohols solvents such as methanol, ethyl alcohol, propyl alcohol or a variety of；It is preferred that
Ground is methanol.
In step (f), formula (6) compound and organic solvent volume ratio are (1:8)~(1:20), it is therefore preferable to (1:
9)~(1:12)；
In step (f), the molar ratio of formula (6) compound and hydrogen chloride gas is (1:0.5)~(1:5)；Preferably, it is 1:
2。
In step (f), the temperature of the hydrochloric acid reactant salt is -10 DEG C~30 DEG C；Preferably 0 DEG C~5 DEG C.
In step (f), the time of the hydrochloric acid reactant salt is 2~20h；Preferably 8~10h.
Compared with prior art, the beneficial effects of the present invention are: pass through halogenated, cyaniding, hydrolysis, closed loop, reduction reaction
And hydrochloric acid salt, target product 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate is obtained, which is easy to get, avoids and be not easy using valuableness
The dangerous material such as the raw material and high-valency metal oxidant that obtain；For reaction intermediate without isolating and purifying, reaction condition is mild, post-processing letter
Just, reaction time is short, and for six step total recoverys up to 62%, cost is relatively low, small pollution of the environment, has in the industrial production very
Good utility value.
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail.Implement process of the invention, condition,
Experimental method etc. is among the general principles and common general knowledge in the art in addition to what is specifically mentioned below, and the present invention does not have
Especially limitation content.If the raw material that the present invention uses can be bought on the market without specified otherwise.
Embodiment 1
Indone (132g, 1mol) is dissolved in 1100ml acetic acid, bromine (320g, 2mol) is added dropwise under ice-water bath, at 2 hours
Reaction is inside set to be gradually increased to 25 DEG C of room temperature, then after fully reacting in 2 hours, ice-water bath is cooling, and 2L water quenching reaction is added dropwise, and is precipitated
A large amount of solids, after stirring 3 hours, the solid was filtered, and washing is drained, and 260g compound 2, yield 90% are dried to obtain in 50 DEG C of air blast.
Embodiment 2
Indone (132g, 1mol) is dissolved in 1100ml acetic acid, bromine (480g, 3mol) is added dropwise under ice-water bath, at 2 hours
Reaction is inside set to be gradually increased to 25 DEG C of room temperature, then after fully reacting in 3 hours, ice-water bath is cooling, and 2L water quenching reaction is added dropwise, and is precipitated
A large amount of solids, after stirring 3 hours, the solid was filtered, and washing is drained, and 254g compound 2, yield 88% are dried to obtain in 50 DEG C of air blast.
Embodiment 3
Compound 2 (144.5g, 0.5mol) is dissolved in 1400ml ethyl alcohol and 200ml water, be added potassium cyanide (71.5g,
1.1mol), fully reacting in 5 hours is reacted at room temperature, reaction is stopped.Ethyl alcohol is recovered under reduced pressure, be spin-dried for being added after ethyl alcohol 500ml water,
1.4L ethyl acetate extracts three times, and aqueous phase oxidation processing, organic phase dries to obtain 92g compound 3, yield 90%.
Embodiment 4
Compound 2 (144.5g, 0.5mol) is dissolved in 1400ml methanol and 200ml water, be added potassium cyanide (71.5g,
1.1mol), fully reacting in 5 hours is reacted at room temperature, reaction is stopped.Ethyl alcohol is recovered under reduced pressure, be spin-dried for being added after methanol 500ml water,
1.4L ethyl acetate extracts three times, and aqueous phase oxidation processing, organic phase dries to obtain 87g compound 3, yield 85%.
Embodiment 5
Compound 2 (144.5g, 0.5mol) is dissolved in 1400ml ethyl alcohol and 200ml water, be added potassium cyanide (84.5g,
1.3mol), fully reacting in 6 hours is reacted at room temperature, reaction is stopped.Ethyl alcohol is recovered under reduced pressure, be spin-dried for being added after ethyl alcohol 500ml water,
1.4L ethyl acetate extracts three times, and aqueous phase oxidation processing, organic phase dries to obtain 91g compound 3, yield 89%.
Embodiment 6
By compound 3 (73g, 0.4mol) be dissolved in 400ml dehydrated alcohol and aqueous slkali (potassium hydroxide (66g, 1.2mol) with
400ml water is made into) fully reacting after 75 DEG C of reflux 4 hours is heated, stop reaction.Cooled and filtered falls inorganic salts, ethanol rinse,
Ethyl alcohol is spun off, 6mol hydrochloric acid tune pH value is then added dropwise under ice-water bath to acidity, a large amount of solids are precipitated, filter out solid, it is water washed
Filter is drained, and 84g compound 4, yield 95% are dried to obtain in 50 DEG C of air blast.
Embodiment 7
By compound 3 (73g, 0.4mol) be dissolved in 400ml anhydrous methanol and aqueous slkali (potassium hydroxide (66g, 1.2mol) with
400ml water is made into) fully reacting after 65 DEG C of reflux 4 hours is heated, stop reaction.Cooled and filtered falls inorganic salts, ethanol rinse,
Methanol is spun off, 6mol hydrochloric acid tune pH value is then added dropwise under ice-water bath to acidity, a large amount of solids are precipitated, filter out solid, it is water washed
Filter is drained, and 82g compound 4, yield 93% are dried to obtain in 50 DEG C of air blast.
Embodiment 8
By compound 3 (73g, 0.4mol) be dissolved in 400ml dehydrated alcohol and aqueous slkali (potassium hydroxide (66g, 1.2mol) with
400ml water is made into) fully reacting after 75 DEG C of reflux 8 hours is heated, stop reaction.Cooled and filtered falls inorganic salts, ethanol rinse,
Ethyl alcohol is spun off, 6mol hydrochloric acid tune pH value is then added dropwise under ice-water bath to acidity, a large amount of solids are precipitated, filter out solid, it is water washed
Filter is drained, and 84g compound 4, yield 95% are dried to obtain in 50 DEG C of air blast.
Embodiment 9
By compound 3 (73g, 0.4mol) be dissolved in 400ml dehydrated alcohol and aqueous slkali (potassium hydroxide (110g, 2mol) with
400ml water is made into) fully reacting after 75 DEG C of reflux 8 hours is heated, stop reaction.Cooled and filtered falls inorganic salts, ethanol rinse,
Ethyl alcohol is spun off, 6mol hydrochloric acid tune pH value is then added dropwise under ice-water bath to acidity, a large amount of solids are precipitated, filter out solid, it is water washed
Filter is drained, and 82g compound 4, yield 93% are dried to obtain in 50 DEG C of air blast.
Embodiment 10
By compound 3 (73g, 0.4mol) be dissolved in 400ml dehydrated alcohol and aqueous slkali (sodium hydroxide (48g, 1.2mol) with
400ml water is made into) fully reacting after 75 DEG C of reflux 4 hours is heated, stop reaction.Cooled and filtered falls inorganic salts, ethanol rinse,
Ethyl alcohol is spun off, 6mol hydrochloric acid tune pH value is then added dropwise under ice-water bath to acidity, a large amount of solids are precipitated, filter out solid, it is water washed
Filter is drained, and 83g compound 4, yield 94% are dried to obtain in 50 DEG C of air blast.
Embodiment 11
Compound 4 (66g, 0.3mol) is dissolved in 660ml acetic anhydride, fully reacting after 100 DEG C of reactions 5 hours is heated,
Stop reaction and most of acetic anhydride is recovered under reduced pressure, intermediate is directly dissolved in methanol, is added Ammonium Acetate (46.2g, 0.6mol), is risen
Solvent is recovered under reduced pressure after progresss ring-closure reaction 3 hours in 75 DEG C of temperature, and 400ml water is added and 600ml ethyl acetate extracts three times, has
Machine mutually dries to obtain 51.2g compound 5, yield 85%.
Embodiment 12
Compound 4 (66g, 0.3mol) is dissolved in 400ml acetic anhydride, fully reacting after 100 DEG C of reactions 5 hours is heated,
Stopping reaction and most of acetic anhydride is recovered under reduced pressure, intermediate is directly dissolved in methanol, it is added Ammonium Acetate (27.7g, 0.36mol),
It heats up 75 DEG C after carrying out ring-closure reaction 3 hours, solvent is recovered under reduced pressure, 400ml water and the extraction of 600ml ethyl acetate is added three times,
Organic phase dries to obtain 45g compound 5, yield 75%.
Embodiment 13
Compound 4 (66g, 0.3mol) is dissolved in 660ml acetic anhydride, fully reacting after 100 DEG C of reactions 5 hours is heated,
Stop reaction and most of acetic anhydride is recovered under reduced pressure, intermediate is directly dissolved in ethyl alcohol, is added Ammonium Acetate (46.2g, 0.6mol), is risen
Solvent is recovered under reduced pressure after progresss ring-closure reaction 9 hours in 75 DEG C of temperature, and 400ml water is added and 600ml ethyl acetate extracts three times, has
Machine mutually dries to obtain 48g compound 5, yield 80%.
Embodiment 14
Compound 4 (66g, 0.3mol) is dissolved in 660ml acetic anhydride, fully reacting after 100 DEG C of reactions 5 hours is heated,
Stopping reaction and most of acetic anhydride is recovered under reduced pressure, intermediate is directly dissolved in methanol, it is added Ammonium Acetate (27.7g, 0.36mol),
It heats up 75 DEG C after carrying out ring-closure reaction 6 hours, solvent is recovered under reduced pressure, 400ml water and the extraction of 600ml ethyl acetate is added three times,
Organic phase dries to obtain 45g compound 5, yield 75%.
Embodiment 15
Compound 5 (40.2g, 0.2mol) is dissolved in dry 400ml tetrahydrofuran, boron hydrogen is added portionwise under ice-water bath
Change sodium (11.4g, 0.3mol), reaction 6h is warmed to room temperature after adding, dilute hydrochloric acid quenching reaction is added dropwise after fully reacting, recycles tetrahydro
Furans, remaining water phase are extracted with ethyl acetate three times, and organic phase drying is spin-dried for, and obtain 33g compound 6, yield 95%, compound 6
:1HNMR (400MHz, CD3OD) δ 7.69 (d, J=7.9Hz, 2H), 7.43-7.32 (m, 4H), 7.23 (d, J=7.9Hz, 2H),
3.37 (d, J=11.2Hz, 4H), 3.30 (bs, 2H), 3.15 (d, J=12.4Hz, 2H), 2.36 (s, 3H), 2.40-2.35 (m,
1H), 2.08 (d, J=11.2Hz, 1H)；13C NMR(100MHz,CD3OD)δ140.8,140.5,139.1,127.2,127.2,
124.3,122.3,45.1,39.7,37.3,18.7；IR(KBr,cm-1)3438,3021,2958,2822,2758,2719,
2683,2611,2424,1925,1606,1497,1473,1428,1339,1302,1259,1228,1219,1176,1160,
1137,1122,1087,1078,945,914,876,847,829,818,801,710,492.Anal.Calcd for
C18H21NO3S:C,65.23；H,6.39；N,4.23；Found:C,65.05；H,6.48；N,4.26.
Embodiment 16
Compound 5 (40.2g, 0.2mol) is dissolved in dry 400ml tetrahydrofuran, boron hydrogen is added portionwise under ice-water bath
Change sodium (22.8g, 0.6mol), reaction 6h is warmed to room temperature after adding, dilute hydrochloric acid quenching reaction is added dropwise after fully reacting, recycles tetrahydro
Furans, remaining water phase are extracted with ethyl acetate three times, and organic phase drying is spin-dried for, and obtain 32g compound 6, yield 92%.Wherein, it produces
The characterize data of object is the same as embodiment 15.
Embodiment 17
Compound 5 (40.2g, 0.2mol) is dissolved in dry 400ml tetrahydrofuran, LiAlH is added dropwise under ice-water bath4
(1M, 0.4mmol, 400mL) is warmed to room temperature reaction 6h, dilute hydrochloric acid quenching reaction is added dropwise after fully reacting, recycle tetrahydro after adding
Furans, remaining water phase are extracted with ethyl acetate three times, and organic phase drying is spin-dried for, and obtain 30g compound 6, yield 86%.Wherein, it produces
The characterize data of object is the same as embodiment 15.
Embodiment 18
Compound 5 (40.2g, 0.2mol) is dissolved in dry 400ml methanol, sodium borohydride is added portionwise under ice-water bath
(11.4g, 0.3mol) is warmed to room temperature reaction 6h, dilute hydrochloric acid quenching reaction is added dropwise after fully reacting, recycle methanol after adding, remaining
Lower water phase is extracted with ethyl acetate three times, and organic phase drying is spin-dried for, and obtains 30g compound 6, yield 86%.Wherein, the characterization of product
Data consistent with Example 15.
Embodiment 19
Compound 5 (40.2g, 0.2mol) is dissolved in dry 400ml ethyl alcohol, sodium borohydride is added portionwise under ice-water bath
(11.4g, 0.3mol) is warmed to room temperature reaction 6h, dilute hydrochloric acid quenching reaction is added dropwise after fully reacting, recycle ethyl alcohol after adding, remaining
Lower water phase is extracted with ethyl acetate three times, and organic phase drying is spin-dried for, and obtains 29g compound 6, yield 84%.Wherein, the characterization of product
Data consistent with Example 15.
Embodiment 20
Compound 6 (17.3g, 0.1mol) is dissolved in 173ml methanol, at 0 DEG C~5 DEG C of ice-water bath, it is anti-to be passed through hydrogen chloride gas
8-10h is answered, hydrogen chloride gas is not reabsorbed, a large amount of solids are precipitated in system, and solid is directly obtained by filtration, and 50 DEG C of reduced vacuum drying obtain
To 20g compound 7, yield 96%, product qualification.Wherein, the characterize data of product is the same as embodiment 15.
Embodiment 21
Compound 6 (17.3g, 0.1mol) is dissolved in 173ml ethyl alcohol, at 0 DEG C~5 DEG C of ice-water bath, it is anti-to be passed through hydrogen chloride gas
8-10h is answered, hydrogen chloride gas is not reabsorbed, a large amount of solids are precipitated in system, and solid is directly obtained by filtration, and 50 DEG C of reduced vacuum drying obtain
To 18.7g compound 7, yield 90%, product qualification.Wherein, the characterize data of product is the same as embodiment 15.
Embodiment 22
Compound 6 (17.3g, 0.1mol) is dissolved in 346ml methanol, at 0 DEG C~5 DEG C of ice-water bath, it is anti-to be passed through hydrogen chloride gas
8-10h is answered, hydrogen chloride gas is not reabsorbed, a large amount of solids are precipitated in system, and solid is directly obtained by filtration, and 50 DEG C of reduced vacuum drying obtain
To 16.6g compound 7, yield 80%, product qualification.Wherein, the characterize data of product is the same as embodiment 15.
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally
Field technical staff it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protect
Protect range.
Claims (10)
1. a kind of preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h key intermediate, which is characterized in that using formula (1) indone as starting material, successively
Halogenating reaction, cyanogenation, hydrolysis, ring-closure reaction, reduction reaction and hydrochloric acid salt are carried out, the 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is obtained and closes
Key intermediate.
2. preparation method as described in claim 1, which is characterized in that the reaction process of the preparation method such as route (1) institute
Show:
Wherein, X halogen atom；
Specifically includes the following steps:
(a) in a solvent, using formula (1) indone as raw material, halogenating reaction, production (2) halides are carried out with halide reagent；
(b) in a solvent, formula (2) halide and cyanating reagent carry out cyanogenation, obtain formula (3) compound；
(c) for formula (3) compound in organic solvent/aqueous slkali, reaction is hydrolyzed in heating, obtains formula (4) diacid compounds；
(d) formula (4) compound carries out heating reaction in acetic anhydride, and then products therefrom and Ammonium Acetate carry out closed loop in a solvent
Reaction, obtains formula (5) compound；
(e) formula (5) compound, is dissolved in organic solvent, and reduction reaction is carried out under the action of reducing agent, obtains formula (6) change
Close object.
(f) formula (6) compound, is dissolved in organic solvent, is passed through hydrochloric acid salt under the conditions of hydrogen chloride gas, obtains formula (7) compound.
3. preparation method as claimed in claim 2, which is characterized in that in step (a), the solvent is selected from formic acid, acetic acid, third
One of acid is a variety of；And/or the halide reagent is selected from NBS, NCS, NIS, Br2, X is F, Cl, Br, I；And/or institute
The molar ratio for stating indone and halide reagent is (1:2)~(1:5)；And/or the temperature of the halogenating reaction is -25 DEG C~50 DEG C；
And/or the time of the halogenating reaction is 1~48h.
4. preparation method as claimed in claim 2, which is characterized in that in step (b), the organic solvent is selected from methanol, second
One of alcohol, propyl alcohol, water are a variety of；And/or the cyanating reagent is selected from KCN, NaCN；And/or formula (2) halide
Molar ratio with cyanating reagent is (1:2)~(1:8)；And/or the temperature of the cyanogenation is 10 DEG C~80 DEG C；And/or
The time of the cyanogenation is 5~30h.
5. preparation method as claimed in claim 2, which is characterized in that in step (c), the organic solvent is selected from methanol, second
One of alcohol, propyl alcohol are a variety of；And/or the alkali is inorganic base, is selected from potassium carbonate, saleratus, sodium carbonate, bicarbonate
One of sodium, potassium hydroxide, sodium hydroxide are a variety of.
6. preparation method as claimed in claim 2, which is characterized in that in step (c), formula (3) compound with it is organic molten
Agent weight ratio is (1:6)~(1:20), and the molar ratio of formula (3) compound and alkali is (1:1.2)~(1:3)；And/or institute
The temperature for stating hydrolysis is 50 DEG C~150 DEG C；And/or the time of the hydrolysis is 3~20h.
7. preparation method as claimed in claim 2, which is characterized in that in step (d), the acetic anhydride is selected from acetic anhydride, third
Acid anhydrides, butyric anhydride；And/or formula (4) compound and acetic anhydride weight ratio (1:5)~(1:15), formula (4) compound
With molar ratio (1:1.2)~(1:4) with Ammonium Acetate；And/or the temperature of the heating reaction is 60 DEG C~180 DEG C；And/or
The time of the heating reaction is 3~50h.
8. preparation method as claimed in claim 2, which is characterized in that in step (d), the solvent is selected from methanol, ethyl alcohol, third
One of alcohol is a variety of；And/or the temperature of the ring-closure reaction is 50 DEG C~120 DEG C；The time 3 of the ring-closure reaction~
40h。
9. preparation method as claimed in claim 2, which is characterized in that in step (e), the organic solvent is selected from methanol, second
One of alcohol, tetrahydrofuran are a variety of；And/or the reducing agent is in lithium aluminium hydride reduction, borane complex, sodium borohydride
It is one or more；Molar ratio (1:0.3)~(1:3) of formula (5) compound, reducing agent；And/or the reduction reaction
Temperature be 0 DEG C~50 DEG C.
10. preparation method as claimed in claim 2, which is characterized in that in step (f), the organic solvent is selected from methanol, second
One of alcohol, propyl alcohol are a variety of；And/or formula (6) compound and organic solvent volume ratio are (1:8)~(1:20)；
And/or the molar ratio of formula (6) compound and hydrogen chloride gas is (1:0.5)~(1:5)；And/or in step (f), it is described at
The temperature of hydrochloric acid reactant salt is -10 DEG C~30 DEG C, and the reaction time is 2~20h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101693712A (en) * | 2009-10-13 | 2010-04-14 | 上海立科化学科技有限公司 | Method for synthesizing Varenicline intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine |
| WO2011051957A2 (en) * | 2009-10-30 | 2011-05-05 | Neuland Laboratories Ltd. | A process for the preparation of donepezil hydrochloride |
| CN102827079A (en) * | 2011-06-14 | 2012-12-19 | 上海科胜药物研发有限公司 | Method of synthesizing varenicline intermediate 2,3,4,5-tetrahydro-1,5-methano-1H-3-benzo azepine hydrochloride |
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|---|---|---|---|---|
| CN101693712A (en) * | 2009-10-13 | 2010-04-14 | 上海立科化学科技有限公司 | Method for synthesizing Varenicline intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine |
| WO2011051957A2 (en) * | 2009-10-30 | 2011-05-05 | Neuland Laboratories Ltd. | A process for the preparation of donepezil hydrochloride |
| CN102827079A (en) * | 2011-06-14 | 2012-12-19 | 上海科胜药物研发有限公司 | Method of synthesizing varenicline intermediate 2,3,4,5-tetrahydro-1,5-methano-1H-3-benzo azepine hydrochloride |
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