CN108358845A - A kind of new synthetic method of R-3- amino-hexahydro azepan hydrochloride - Google Patents
A kind of new synthetic method of R-3- amino-hexahydro azepan hydrochloride Download PDFInfo
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- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of new synthetic methods of 3 amino hexahydro azepan hydrochlorides of R, the yield of 3 amino hexahydro azepan hydrochlorides of R made from the preparation method of 3 amino hexahydro azepan hydrochlorides of R of the present invention is higher, post-processing is simple, its stereoselectivity is high, and racemization probability is small.In addition to starting material in reaction, agents useful for same (methanol, dichloromethane, paratoluensulfonyl chloride, ammonium hydroxide etc.) is common agents, simple and easy to get, cheap, meets economic benefit；Each step only needs low temperature or room temperature reaction, mild condition to reduce influence of the high temperature to its spatial configuration in reaction；Each step yield is higher in reaction, and post-processing can be carried out with means re-crystallization, substantially increases the efficiency of its purifying.
Description
Technical field
The present invention relates to a kind of preparation methods of compound, and in particular to R-3- amino-hexahydro azepan hydrochloride
A kind of new synthetic method.
Background technology
Besifloxacin (Besifloxacin) is a kind of fluoroquinolones of novel therapeutic bacterial conjunctivitis, is changed
Scientific name 7- [(3R) -3-aminoazepan-1-yl] -8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid, structural formula are：
Molecular formula is C19H2lClFN3O3, relative molecular mass 393.85.It is to causing the eye of bacterial conjunctivitis to cause
Germ has broad spectrum antibiotic activity.It is mainly present in the form of hydrochloride in the eye drops that drug concentration is 0.6%, for
Treat the conjunctivitis caused by sensitive bacteria.It shows superior bactericidal effect in clinic.
The main types part of besifloxacin is R-3- amino-hexahydro azepan, is the important centre of besifloxacin
Body, structure are：
As the important part of besifloxacin, the intermediate is about the specific document of synthesis and few.Therefore R-3- amino-
The synthesis of hexahydro azepan and its protection plays an important role to synthesis besifloxacin.
Related side chain R-3- amino-hexahydro azepan and its protection synthesis, there is following route：
CN104379575A obtains the side chain by two-step reaction, first passes around internal condensation cyclization, then by restoring
To R-3- amino-hexahydro azepan.CN101006051A, CN103073498A have carried out method to first step internal condensation and have changed
Into the method step is shorter.The disadvantage is that：First step cyclization needs high temperature in the route methods, in addition the reaction of internal condensation itself
Mechanism, the isomers for be easy to causeing the intermediate generates, therefore its stereochemical purity is not high, is caused to besifloxacin synthesis separation
Great obstruction.
CN103012264A reports the fractionation about side chain 3- amino-hexahydro azepan, but stereo-resolution tries
Costly, and three-dimensional effect of optimization also remains to be discussed for agent.
Invention content
R-3- amino-hexahydro azepine cycloheptyl is provided it is an object of the invention to overcome the shortcomings of the prior art place
A kind of new synthetic method of heptane hydrochloride salt.
To achieve the above object, the technical solution that the present invention takes is：R-3- amino-hexahydro azepan hydrochloride
Preparation method comprises the steps of：
(1), compound shown in formula I is subjected to esterification reaction of organic acid, then connects esterification reaction of organic acid product with benzyl chloroformate
It touches, obtains compound shown in formula II；
(2), compound shown in formula II is subjected to reduction reaction, obtains compound shown in formula III；
(3), sulfonylation is occurred into for compound shown in formula III and paratoluensulfonyl chloride, obtains compound shown in formula IV；
(4), compound shown in formula IV is subjected to cyclization, obtains compound shown in formula V；
(5), compound shown in formula V is subjected to removing benzyloxycarbonyl group reaction, obtains amino-hexahydro azepan hydrochloride；
Wherein, Cbz indicates that benzyloxycarbonyl group, Ts indicate p-toluenesulfonyl.
The preparation method of R-3- amino of the present invention-hexahydro azepan hydrochloride is R-3- amino-hexahydro azepine
A kind of new preparation method of cycloheptane hydrochloride, the receipts of R-3- amino-hexahydro azepan hydrochloride made from this method
Rate is higher, and post-processing is simple, and stereoselectivity is high, and racemization probability is small.In addition to starting material in reaction, agents useful for same (methanol,
Dichloromethane, paratoluensulfonyl chloride, ammonium hydroxide etc.) it is common agents, it is simple and easy to get, it is cheap, meet economic benefit.Reaction
In each step only need low temperature or room temperature reaction, mild condition reduces influence of the high temperature to its spatial configuration.It is each in reaction
It is higher to walk yield, post-processing can be carried out with means re-crystallization, substantially increase the efficiency of its purifying.
R-3- amino-hexahydro azepan hydrochloride that the present invention obtains is dissolved with organic solvent, organic solvent ratio
Such as methanol, sodium carbonate is then added, reacts 2 hours at normal temperatures, filters out inorganic salts, filtrate rotation solvent evaporated can be obtained R-
3- amino-hexahydro azepan.
Preferably, in step (1), in esterification reaction of organic acid, the first organic solvent is methanol, compound, methanol shown in formula I
It is heated to reflux with the concentrated sulfuric acid, the temperature being heated to reflux is 44~46 DEG C, and the time is 1.5~2.5h.
Preferably, in step (1), in esterification reaction of organic acid, the temperature being heated to reflux is 45 DEG C, time 2h.
Preferably, the volume ratio of compound, methanol and the concentrated sulfuric acid shown in the formula I is：Compound shown in formula I：Methanol：It is dense
Sulfuric acid=1:10:1.
Preferably, in step (1), the dry methanol of vacuum rotary steam after esterification reaction of organic acid obtains esterification reaction of organic acid product, is then added
Second organic solvent is cooled to -2~1 DEG C, and natrium carbonicum calcinatum and benzyl chloroformate is then added, water is added under stirring condition,
1.5~2.5h is reacted under the conditions of -2~1 DEG C.
It is highly preferred that in step (1), the temperature that esterification reaction of organic acid product is reacted with benzyl chloroformate is 0 DEG C, and the time is
2h。
Preferably, second organic solvent be dichloromethane, the esterification reaction of organic acid product, dichloromethane and water body
Accumulating ratio is：Esterification reaction of organic acid product：Dichloromethane：Water=1:10:10.
The reaction condition of step (1) is mild, and yield is higher.
Preferably, in step (2), reduction system used is tetrahydrochysene lithium aluminium, and the third organic solvent used is tetrahydrofuran；
Reaction temperature is -5~15 DEG C.
Following operation specifically may be used in step (2)：Compound adds tetrahydrofuran to dissolve shown in modus ponens II, is cooled to 0 DEG C,
Tetrahydrochysene lithium aluminium is added portionwise, 15 DEG C of reaction 2h are risen to after 20~40min is stirred at 0~15 DEG C.Step (2) is after reaction
Purification operations are：After reaction, add water, 20% sodium hydroxide solution and water quenching to go out into product, filter out inorganic salts, rotate
Dry solvent obtains crude product, is beaten with methyl tertiary butyl ether(MTBE), obtains white powdery solids, as compound shown in formula III, pure
Degree is more than 99%.The reaction condition of step (2) is mild, and yield is higher.
Preferably, in step (3), the 4th organic solvent of sulfonylation is dichloromethane, and reaction temperature is -2~1
DEG C, the reaction time is 1.5~2.5h.
It is highly preferred that in step (3), the reaction temperature of sulfonylation is 0 DEG C, reaction time 2h.
Following operation specifically may be used in step (3)：Compound shown in modus ponens III adds methylene chloride dissolving, and three second are added
Amine is cooled to -2~1 DEG C, stirs lower dropwise addition paratoluensulfonyl chloride, 1.5~2.5h is stirred at -2~1 DEG C.
The purification operations of step (3) after reaction are：After reaction, saturated sodium bicarbonate is added to be quenched, stands and divides
The organic phase that layer obtains is by washing, and after being dried with anhydrous sodium sulfate, concentrated by rotary evaporation obtains compound crude product shown in formula IV.It adopts
With ethyl alcohol recrystallization, white powdery solids are obtained, i.e. compound shown in IV, purity is more than 98%.
The reaction condition of step (3) is mild, and yield is higher.
Preferably, in step (4), the 5th organic solvent of the cyclization is acetonitrile.
Preferably, in step (4), reaction temperature is 20~28 DEG C, and the reaction time is 45~55h.
It is highly preferred that in step (4), the reaction temperature of the cyclization is 25 DEG C, reaction time 48h.
Following operation specifically may be used in step (4)：Compound shown in modus ponens IV adds the 5th organic solvent to dissolve, and 20~28
Ammonium hydroxide is added at DEG C, reacts 45~55h at being 20~28 DEG C in reaction temperature.
The purification operations of step (4) after reaction are：Revolving does the 5th organic solvent, remaining aqueous solution dichloromethane
Alkane extracts, and obtained organic phase is by washing, and after anhydrous sodium sulfate drying, concentrated by rotary evaporation obtains compound shown in formula V and slightly produces
Product.Ethyl alcohol recrystallization is added, obtains faint yellow solid, as compound shown in formula V, purity is more than 95%.
The ring-closure reaction mild condition of step (4), stereoselectivity is high, greatly reduces the generation of its isomers, significantly
The degree for reducing its racemization reduces the risk of its subsequent purification hardly possible, has obtained sterically purer R-3- amino-hexahydro azacyclo-
Heptane hydrochloride.
In step (5), the 6th solvent used is dichloromethane.Step (5) is that reaction, removing are protected in the removal to amino
Protection of the benzyloxycarbonyl group to amino.
Preferably, in step (5), compound is dissolved with dichloromethane shown in formula V, is then added dropwise under the conditions of -1~2 DEG C
Thionyl chloride is gone at 20~30 DEG C, reacts 10~15h.
Following operation specifically may be used in step (5)：After reaction, rotation solvent evaporated obtains R-3- amino-hexahydro nitrogen
R-3- amino-hexahydro azepan hydrochloride crude product is added ethyl alcohol recrystallization, obtained light by trioxepane hydrochloride crude product
Yellow crystalline solid, as R-3- amino-hexahydro azepan hydrochloride, purity are more than 97%.
The beneficial effects of the present invention are：The present invention provides one kind of R-3- amino-hexahydro azepan hydrochloride
New synthetic method, R-3- amino-made from the preparation method of R-3- amino of the present invention-hexahydro azepan hydrochloride
The yield of hexahydro azepan hydrochloride is higher, and post-processing is simple, and stereoselectivity is high, and racemization probability is small.It is removed in reaction
Starting material, agents useful for same (methanol, dichloromethane, paratoluensulfonyl chloride, ammonium hydroxide etc.) is common agents, simple and easy to get,
It is cheap, meet economic benefit；Each step only needs low temperature or room temperature reaction, mild condition to reduce high temperature pair in reaction
The influence of its spatial configuration；Each step yield is higher in reaction, and post-processing can be carried out with means re-crystallization, be substantially increased
Its efficiency purified.
Specific implementation mode
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
The synthetic route that R-3- amino-hexahydro azepan hydrochloride uses in the embodiment of the present invention is as follows：
Embodiment 1
A kind of embodiment of the preparation method of R-3- amino of the present invention-hexahydro azepan hydrochloride, this implementation
The preparation method of the example R-3- amino-hexahydro azepan hydrochloride includes the following steps：
(1), compound 20g (124mmol) shown in formula I is added in there-necked flask, 200mL methanol is added, is added with stirring
The 20mL concentrated sulfuric acids are heated to flowing back, and temperature is 45 DEG C, react 2h, and thin-layer chromatography (TLC) detection reaction terminates.It is cooled to room temperature,
The dry solvent of vacuum rotary steam, obtains colorless oil；The dissolving of 220mL dichloromethane is added in the grease, is cooled to 0 DEG C, successively
Natrium carbonicum calcinatum 26.31g and benzyl chloroformate 25.41g is added, is added with stirring 220mL water, 2h is stirred in continuation at 0 DEG C, thin
Layer chromatography (TLC) detection reaction terminates.After reaction was completed, stratification.Organic phase is by washing, anhydrous sodium sulfate drying, rotation
Steaming is concentrated to give compound crude product shown in formula II.
(2), the dissolving of 420mL tetrahydrofurans is added in compound crude product shown in modus ponens II, goes to three-necked flask, is cooled to -5
DEG C, tetrahydrochysene lithium aluminium 21g is added portionwise, temperature is kept to be no more than 0 DEG C, rising to 15 DEG C after stirring half an hour at 0 DEG C reacts 2h, thin
Layer chromatography (TLC) detection reaction terminates.Then water 40mL, 20% sodium hydroxide solution 40mL, water 120mL is added to be quenched successively, mistake
Inorganic salts are filtered, rotation solvent evaporated obtains compound crude product shown in formula III, and methyl tertiary butyl ether(MTBE) 80mL mashing is then added, obtains
To compound 29.3g shown in formula III, white powdery solids, purity is more than 99%.
(3), compound 20g shown in modus ponens III, is added in three-necked flask, and the dissolving of 200mL dichloromethane is added, is added three
Ethamine 31mL, 25 DEG C of stirring and dissolvings.Postcooling stirs lower dropwise addition paratoluensulfonyl chloride 18.85g to 0 DEG C, and continuation is stirred at 0 DEG C
2h is mixed, thin-layer chromatography (TLC) detection reaction terminates.After reaction, saturated sodium bicarbonate 40mL is added to be quenched, 160mL is added
Water, rear stratification.Obtained organic phase obtains compound shown in formula IV by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Crude product is added ethyl alcohol 40mL recrystallizations, obtains compound 26.5g, white powdery solids, purity shown in formula IV and be more than
98%.
(4), in compound 26.5g to three-necked flask shown in modus ponens IV, acetonitrile 50mL dissolvings is added, ammonium hydroxide is added at 25 DEG C
50mL, the reaction was continued at 25 DEG C about 48h, thin-layer chromatography (TLC) detection reaction terminate.After reaction, most of second is rotated
Dichloromethane extraction is added in nitrile, remaining aqueous solution, and obtained organic phase is by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Obtain compound crude product shown in formula V.30mL ethyl alcohol recrystallizations are added, obtain the azepan of amido protecting (shown in formula V
Compound) 11.5g, faint yellow solid, purity is more than 95%.
(5), in compound 10g to three-necked flask shown in modus ponens V, the dissolving of 100mL dichloromethane is added, two are added dropwise at 0 DEG C
Chlorine sulfoxide 20mL, goes to 25 DEG C of reaction about 12h, and thin-layer chromatography (TLC) detection reaction terminates.After reaction, solvent evaporated is revolved
Obtain R-3- amino-hexahydro azepan hydrochloride crude product.Crude product adds 10mL ethyl alcohol recrystallizations, obtains R-3- amino-
Hexahydro azepan hydrochloride (compound shown in formula VI) 5.1g, faint yellow crystalline solid, e.e. values>99%.
Analyzing data is：
1H NMR(400MHz,DMSO)δ2.73-2.63(m,2H),2.61-2.49(m,2H),2.43-2.38(m,1H),
2.21-2.16 (s, 2H), 2.05-2.02 (m, 1H), 2.0 (d, J=13.1Hz, 1H), 1.90 (d, J=13.8Hz, 1H),
1.79-1.71 (m, 1H), 1.68-1.55 (m, 1H), 1.55-1.43 (m, 1H), 1.20 (q, J=11.9Hz, 1H)
Embodiment 2
A kind of embodiment of the preparation method of R-3- amino of the present invention-hexahydro azepan hydrochloride, this implementation
The preparation method of the example R-3- amino-hexahydro azepan hydrochloride includes the following steps：
(1), compound 20g (124mmol) shown in formula I is added in there-necked flask, 200mL methanol is added, is added with stirring
The 20mL concentrated sulfuric acids are heated to flowing back, and temperature is 45 DEG C, react 2h, and thin-layer chromatography (TLC) detection reaction terminates.It is cooled to room temperature,
The dry solvent of vacuum rotary steam, obtains colorless oil；The dissolving of 220mL dichloromethane is added in the grease, is cooled to 0 DEG C, successively
Natrium carbonicum calcinatum 26.31g and benzyl chloroformate 25.41g is added, is added with stirring 220mL water, continues to stir 2h, thin layer at 0 DEG C
Chromatography (TLC) detection reaction terminates.After reaction was completed, stratification.Organic phase is by washing, anhydrous sodium sulfate drying, revolving
It is concentrated to give compound crude product shown in formula II.
(2), the dissolving of 400mL tetrahydrofurans is added in compound crude product shown in modus ponens II, goes to three-necked flask, is cooled to -5
DEG C, tetrahydrochysene lithium aluminium 19.5g is added portionwise, temperature is kept to be no more than 0 DEG C, 15 DEG C of reaction 2h are risen to after half an hour is stirred at 0 DEG C,
Thin-layer chromatography (TLC) detection reaction terminates.Then water 40mL, 20% sodium hydroxide solution 40mL, water 120mL is added to be quenched successively,
Inorganic salts are filtered out, rotation solvent evaporated obtains compound crude product shown in formula III, and methyl tertiary butyl ether(MTBE) 80mL mashing is then added,
Compound 27.8g shown in formula III, white powdery solids are obtained, purity is more than 99%.
(3), compound 20g shown in modus ponens III, is added in three-necked flask, and the dissolving of 200mL dichloromethane is added, is added three
Ethamine 31mL, 25 DEG C of stirring and dissolvings.Postcooling stirs lower dropwise addition paratoluensulfonyl chloride 18.85g, continues to stir at -2 DEG C to -2 DEG C
1.5h is mixed, thin-layer chromatography (TLC) detection reaction terminates.After reaction, saturated sodium bicarbonate 40mL is added to be quenched, is added
160mL water, rear stratification.Obtained organic phase obtains IV shownization of formula by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Object crude product is closed, ethyl alcohol 40mL recrystallizations are added, obtains compound 23.3g, white powdery solids, purity shown in formula IV and is more than
99%.
(4), in compound 23.3g to three-necked flask shown in modus ponens IV, acetonitrile 50mL dissolvings is added, ammonium hydroxide is added at 25 DEG C
50mL, the reaction was continued at 25 DEG C 45h, thin-layer chromatography (TLC) detection reaction terminate.After reaction, most of acetonitrile is rotated,
Dichloromethane extraction is added in remaining aqueous solution.Obtained organic phase is obtained by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Compound crude product shown in formula V.30mL ethyl alcohol recrystallizations are added, obtain the azepan (chemical combination shown in formula V of amido protecting
Object) 10.1g, faint yellow solid, purity is more than 97%.
(5), in compound 10g to three-necked flask shown in modus ponens V, the dissolving of 100mL dichloromethane is added, two are added dropwise at 0 DEG C
Chlorine sulfoxide 20mL, goes to room temperature reaction about 12h, and thin-layer chromatography (TLC) detection reaction terminates.After reaction, solvent evaporated is revolved
Obtain R-3- amino-hexahydro azepan hydrochloride crude product.Crude product adds 10mL ethyl alcohol recrystallizations, obtains R-3- amino-
Hexahydro azepan hydrochloride (compound shown in formula VI) 4.8g, faint yellow crystalline solid, e.e. values>99%.
Embodiment 3
A kind of embodiment of the preparation method of R-3- amino of the present invention-hexahydro azepan hydrochloride, this implementation
The preparation method of the example R-3- amino-hexahydro azepan hydrochloride includes the following steps：
(1), compound 20g (124mmol) shown in formula I is added in there-necked flask, 200mL methanol is added, is added with stirring
The 20mL concentrated sulfuric acids are heated to flowing back, and temperature is 44 DEG C, react 2.5h, and thin-layer chromatography (TLC) detection reaction terminates.It is cooled to room
Temperature, the dry solvent of vacuum rotary steam, obtains colorless oil；The dissolving of 220mL dichloromethane is added in the grease, is cooled to 1 DEG C, first
Natrium carbonicum calcinatum 26.31g and benzyl chloroformate 25.41g is added afterwards, is added with stirring 220mL water, continuation is stirred at 1 DEG C
1.5h, thin-layer chromatography (TLC) detection reaction terminate.After reaction was completed, stratification.Organic phase is by washing, anhydrous sodium sulfate
Dry, concentrated by rotary evaporation obtains compound crude product shown in formula II.
(2), the dissolving of 420mL tetrahydrofurans is added in compound crude product shown in modus ponens II, goes to three-necked flask, is cooled to -5
DEG C, tetrahydrochysene lithium aluminium 21g is added portionwise, temperature is kept to be no more than 0 DEG C, rising to 15 DEG C after stirring half an hour at 0 DEG C reacts 2h, thin
Layer chromatography (TLC) detection reaction terminates.Then water 40mL, 20% sodium hydroxide solution 40mL, water 120mL is added to be quenched successively, mistake
Inorganic salts are filtered, rotation solvent evaporated obtains compound crude product shown in formula III, and methyl tertiary butyl ether(MTBE) 80mL mashing is then added, obtains
To compound 29.8g shown in formula III, white powdery solids, purity is more than 99%.
(3), compound 20g shown in modus ponens III, is added in three-necked flask, and the dissolving of 200mL dichloromethane is added, is added three
Ethamine 31mL, stirring and dissolving at 25 DEG C.Postcooling stirs lower dropwise addition paratoluensulfonyl chloride 18.85g, continues to stir at 1 DEG C to 0 DEG C
1.5h is mixed, thin-layer chromatography (TLC) detection reaction terminates.After reaction, saturated sodium bicarbonate 40mL is added to be quenched, is added
160mL water, rear stratification.Obtained organic phase obtains IV shownization of formula by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Object crude product is closed, ethyl alcohol 40mL recrystallizations are added, obtains compound 25.8g, white powdery solids, purity shown in formula IV and is more than
98%.
(4), in compound 25.8g to three-necked flask shown in modus ponens IV, acetonitrile 50mL dissolvings is added, ammonium hydroxide is added at 28 DEG C
50mL, the reaction was continued at 28 DEG C 45h, thin-layer chromatography (TLC) detection reaction terminate.After reaction, most of acetonitrile is rotated,
Dichloromethane extraction is added in remaining aqueous solution, and obtained organic phase is obtained by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Compound crude product shown in formula V.30mL ethyl alcohol recrystallizations are added, obtain the azepan (chemical combination shown in formula V of amido protecting
Object) 12.1g, faint yellow solid, purity is more than 95%.
(5), in compound 10g to three-necked flask shown in modus ponens V, the dissolving of 100mL dichloromethane is added, is added dropwise at 0 DEG C
Thionyl chloride 20mL, goes to 28 DEG C of reaction about 10h, and thin-layer chromatography (TLC) detection reaction terminates.After reaction, revolving is dry molten
Agent obtains R-3- amino-hexahydro azepan hydrochloride crude product.Crude product adds 10mL ethyl alcohol recrystallizations, obtains R-3- ammonia
Base-hexahydro azepan hydrochloride (compound shown in formula VI) 4.7g, faint yellow crystalline solid, e.e. values>99%.
Embodiment 4
A kind of embodiment of the preparation method of R-3- amino of the present invention-hexahydro azepan hydrochloride, this implementation
The preparation method of the example R-3- amino-hexahydro azepan hydrochloride includes the following steps：
(1), compound 20g (124mmol) shown in formula I is added in there-necked flask, 200mL methanol is added, is added with stirring
The 20mL concentrated sulfuric acids are heated to flowing back, and temperature is 46 DEG C, react 1.5h, and thin-layer chromatography (TLC) detection reaction terminates.It is cooled to room
Temperature, the dry solvent of vacuum rotary steam, obtains colorless oil；The dissolving of 220mL dichloromethane is added in the grease, is cooled to -2 DEG C,
Natrium carbonicum calcinatum 26.31g and benzyl chloroformate 25.41g is successively added, is added with stirring 220mL water, continuation is stirred at -2 DEG C
2h, thin-layer chromatography (TLC) detection reaction terminate.After reaction was completed, stratification.For organic phase by washing, anhydrous sodium sulfate is dry
Dry, concentrated by rotary evaporation obtains compound crude product shown in formula II.
(2), the dissolving of 420mL tetrahydrofurans is added in compound crude product shown in modus ponens II, goes to three-necked flask, is cooled to -5
DEG C, tetrahydrochysene lithium aluminium 21g is added portionwise, temperature is kept to be no more than 0 DEG C, rising to 15 DEG C after stirring half an hour at 0 DEG C reacts 2h, thin
Layer chromatography (TLC) detection reaction terminates.Then water 40mL, 20% sodium hydroxide solution 40mL, water 120mL is added to be quenched successively, mistake
Inorganic salts are filtered, rotation solvent evaporated obtains compound crude product shown in formula III, and methyl tertiary butyl ether(MTBE) 80mL mashing is then added, obtains
To compound 28.3g shown in formula III, white powdery solids, purity is more than 99%.
(3), compound 20g shown in modus ponens III, is added in three-necked flask, and the dissolving of 200mL dichloromethane is added, is added three
Ethamine 31mL, stirring and dissolving at 25 DEG C.Postcooling stirs lower dropwise addition paratoluensulfonyl chloride 18.85g, continues to stir at -2 DEG C to 0 DEG C
2.5h is mixed, thin-layer chromatography (TLC) detection reaction terminates.After reaction, saturated sodium bicarbonate 40mL is added to be quenched, is added
160mL water, rear stratification.Obtained organic phase obtains IV shownization of formula by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Object crude product is closed, ethyl alcohol 40mL recrystallizations are added, obtains compound 25.1g, white powdery solids, purity shown in formula IV and is more than
98%.
(4), in compound 25.1g to three-necked flask shown in modus ponens IV, acetonitrile 50mL dissolvings is added, ammonium hydroxide is added at 20 DEG C
50mL, the reaction was continued at 20 DEG C 55h, thin-layer chromatography (TLC) detection reaction terminate.After reaction, most of acetonitrile is rotated,
Dichloromethane extraction is added in remaining aqueous solution, and obtained organic phase is obtained by washing, anhydrous sodium sulfate drying, concentrated by rotary evaporation
Compound crude product shown in formula V.30mL ethyl alcohol recrystallizations are added, obtain the azepan (chemical combination shown in formula V of amido protecting
Object) 10.4g, faint yellow solid, purity is more than 95%.
(5), in compound 10g to three-necked flask shown in modus ponens V, the dissolving of 100mL dichloromethane is added, is added dropwise at 0 DEG C
Thionyl chloride 20mL, goes to 20 DEG C of reaction about 15h, and thin-layer chromatography (TLC) detection reaction terminates.After reaction, revolving is dry molten
Agent obtains R-3- amino-hexahydro azepan hydrochloride crude product.Crude product adds 10mL ethyl alcohol recrystallizations, obtains R-3- ammonia
Base-hexahydro azepan hydrochloride (compound shown in formula VI) 4.1g, faint yellow crystalline solid, e.e. values>99%.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than is protected to the present invention
The limitation of range is protected, although being explained in detail to the present invention with reference to preferred embodiment, those skilled in the art should
Understand, technical scheme of the present invention can be modified or replaced equivalently, without departing from the essence of technical solution of the present invention
And range.
Claims (10)
- The preparation method of 1.R-3- amino-hexahydro azepan hydrochloride, which is characterized in that comprise the steps of：(1), compound shown in formula I is subjected to esterification reaction of organic acid, esterification reaction of organic acid product is contacted with benzyl chloroformate then, is obtained Compound shown in formula II；(2), compound shown in formula II is subjected to reduction reaction, obtains compound shown in formula III；(3), sulfonylation is occurred into for compound shown in formula III and paratoluensulfonyl chloride, obtains compound shown in formula IV；(4), compound shown in formula IV is subjected to cyclization, obtains compound shown in formula V；(5), compound shown in formula V is subjected to removing benzyloxycarbonyl group reaction, obtains R-3- amino-hexahydro azepan hydrochloride；Wherein, Cbz indicates that benzyloxycarbonyl group, Ts indicate p-toluenesulfonyl.
- 2. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that step (1) in, in esterification reaction of organic acid, the first organic solvent is methanol, and compound, methanol and the concentrated sulfuric acid shown in formula I are heated to reflux, add The temperature of heat reflux is 44~46 DEG C, and the time is 1.5~2.5h；Preferably, it in step (1), in esterification reaction of organic acid, is heated to reflux Temperature be 45 DEG C, time 2h.
- 3. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that described The volume ratio of compound, methanol and the concentrated sulfuric acid shown in formula I is：Compound shown in formula I：Methanol：The concentrated sulfuric acid=1:10:1.
- 4. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that step (1) in, the dry methanol of vacuum rotary steam after esterification reaction of organic acid obtains esterification reaction of organic acid product, and the second organic solvent is then added, cooling To -2~1 DEG C, natrium carbonicum calcinatum and benzyl chloroformate is then added, water is added under stirring condition, is reacted under the conditions of -2~1 DEG C 1.5~2.5h；Preferably, in step (1), temperature that esterification reaction of organic acid product is reacted with benzyl chloroformate is 0 DEG C, and the time is 2h。
- 5. the preparation method of R-3- amino as claimed in claim 4-hexahydro azepan hydrochloride, which is characterized in that described Second organic solvent is dichloromethane, and the volume ratio of the esterification reaction of organic acid product, dichloromethane and water is：Esterification reaction of organic acid produces Object：Dichloromethane：Water=1:10:10.
- 6. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that step (2) in, reduction system used is tetrahydrochysene lithium aluminium, and the third organic solvent used is tetrahydrofuran；Reaction temperature is -5~15 DEG C.
- 7. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that step (3) in, the 4th organic solvent of sulfonylation is dichloromethane, and reaction temperature is -2~1 DEG C, the reaction time is 1.5~ 2.5h；Preferably, in step (3), the reaction temperature of sulfonylation is 0 DEG C, reaction time 2h.
- 8. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that step (4) in, the 5th organic solvent of the cyclization is acetonitrile.
- 9. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that step (4) in, reaction temperature is 20~28 DEG C, and the reaction time is 45~55h；Preferably, in step (4), the cyclization it is anti- It is 25 DEG C to answer temperature, reaction time 48h.
- 10. the preparation method of R-3- amino as described in claim 1-hexahydro azepan hydrochloride, which is characterized in that step (5) in, compound is dissolved with dichloromethane shown in formula V, and thionyl chloride then is added dropwise under the conditions of -1~2 DEG C, goes to 20~30 At DEG C, 10~15h is reacted.
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