CN106317060B - A kind of preparation method of hydrochloric acid conivaptan - Google Patents
A kind of preparation method of hydrochloric acid conivaptan Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of hydrochloric acid conivaptan to obtain hydrochloric acid conivaptan through amidation, alkylation, friedel-crafts acylation, nitro reduction, amidation, alpha-chloro, cyclisation, salt-forming reaction with aniline (compound 1) for raw material；The present invention uses aniline cheap and easy to get for starting material, and amidation process is avoided using noxious materials such as acyl chlorides.It is small that completely new synthetic route pollutes entire synthesis process not only, easy to handle, and the reaction condition respectively walked is mild, easy to operate, and yield and purity is high, environmentally friendly, production cost substantially reduces, and is suitble to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method of hydrochloric acid conivaptan.
Background technique
Hydrochloric acid conivaptan, entitled N- [4- (2- methyl -4,5- dihydro -3H- imidazo [4,5-d] [1] the benzo nitrogen of chemistry
Miscellaneous Zhuo -6- formoxyl) phenyl] -2- phenyl benzoyl amine hydrochlorate, it is produced by Astellas Pharma company, is that arginine adds
Press a kind of non-peptides double inhibitor of plain (AVP) V1a and V2 receptor.It is mainly used for the normal hyponatremia of blood volume, mental and physical efforts
Failure treatment.The injection of the drug is in acquisition on December 29th, 2005 U.S. Food and Drug Administration (FDA) approval
City.Its chemical structural formula is as follows:
It is as follows at present about the reported several synthetic methods that prepare of hydrochloric acid conivaptan:
Route one: the synthetic route (patent JP1995505056) of Japanese Yamanouchi pharmaceutical factory exploitation discloses as follows
Synthetic route:
In this route, second step carries out amidation process with acyl chlorides reagent, although yield is higher, acyl chlorides price is high
Expensive, toxicity has corrosivity greatly and to equipment, and there are biggish safety issues for production and transportation, are also easy to produce biggish spent acidic
Gas.For third step when introducing bromine on benzazepine alpha-position, bromating agent uses bromination ketone, expensive, needs higher reaction
Temperature.
Route two: Chinese patent CN105153168A discloses following synthetic route:
In this route, amidation process uses acyl chlorides reagent, and expensive, toxicity has corrosivity greatly and to equipment, raw
There are biggish safety issues for production and transport, are also easy to produce biggish acid waste gas.When introducing bromine on benzazepine alpha-position,
The bromating agent that bromating agent uses is copper bromide, hydrogen bromide, N- bromo-succinimide (NBS), bromination dimethyl bromo sulphur
(DMBS), sodium bromide, potassium bromide, ammonium bromide, bromine chloride, generally existing expensive, toxicity have corrosivity greatly, to equipment,
There are biggish safety issue, environment easy to pollute for production and transportation.
Route three: Zheng Dengyu, " hydrochloric acid is examined Buddhist nun and is cut down in Chinese Journal of Pharmaceuticals 2015,46 (9) by Gao Wenlei, Zhao Jun et al.
Smooth synthesis " following synthetic route is disclosed in document:
In this route, N- alkylation, intramolecular condensation cyclization, acid occur through sulfonylation, with 4- chlorobutyronitrile for artificial neroli oil
Decyanation and bromo obtain 1- p-toluenesulfonyl -4- bromo- 2 under the conditions of property, 3,4,5- tetrahydro -5- oxo -1H- benzo nitrogen, then
With ethenylamidine hydrochloride condensation and cyclization forms imidazole ring, de- sulfonyl obtains 2- methyl-1,4,5,6- imidazolidine [4,5-d] [1]
Conivaptan is made finally by amidation in benzo nitrogen.This route has the disadvantage in that (1) starting material is expensive；(2)
The potassium iodide reagents that N- alkylated reaction uses are expensive, and the reaction time is up to 46 hours, and yield 87.6% needs further to be mentioned
It is high；(3) amidation process uses acyl chlorides reagent, and expensive, toxicity has corrosivity greatly and to equipment, and production and transportation exist
Biggish safety issue is also easy to produce biggish acid waste gas.
Above-mentioned route is summarized, starting material and reagent valence are had following defects that during preparing hydrochloric acid conivaptan
Lattice are expensive；Amidation process uses acyl chlorides reagent, and expensive, toxicity has corrosivity greatly and to equipment, and production and transportation are deposited
In biggish safety issue；Reaction time is long, severe reaction conditions, cumbersome, is not suitable for industrialized production.
Summary of the invention
To solve above-mentioned technical problem of the existing technology, the present invention provides a kind of preparation sides of hydrochloric acid conivaptan
Method, respectively step reaction condition is mild, and synthetic method is easy to operate, and yield and purity is high, production cost is low, is suitble to industry metaplasia
It produces.
Technical scheme is as follows:
A kind of preparation method of hydrochloric acid conivaptan, it is characterised in that include the following steps:
1) it is sent out under conditions of condensing agent and alkali for raw material with paranitrobenzoic acid (compound 2) with aniline (compound 1)
Raw amidation process obtains compound 3；
2) compound 3 and 4- chlorobutanoate (compound 4) is alkylated under phase transfer catalyst and alkaline condition
Reaction, then be acidified to obtain compound 5；
3) compound 5 obtains compound 6 through friedel-crafts acylation under the action of an acid；
4) compound 6 restores under the action of reducing agent and obtains compound 7；
5) amidation process occurs under the action of condensing agent for compound 7 and 2- Phenylbenzoic acid (compound 8)
Close object 9；
6) compound 9 α-chlorination occurs under the action of α-chlorination system obtains compound 10；
7) cyclisation occurs for compound 10 and ethenylamidine hydrochloride, salt-forming reaction obtains hydrochloric acid conivaptan (compound 11)；It is closed
It is as follows at route:
Preferably, the condensing agent is Trimethyl phosphite-iodine system, and reaction dissolvent is dichloromethane in step 1)
One or more of alkane, chloroform, acetonitrile, tetrahydrofuran；Trimethyl phosphite, iodine, compound 1, compound 2 and alkali
Molar ratio is 1-1.5:1-1.5:1-1.5:1:1-1.2:1-3, the alkali be triethylamine, n,N-diisopropylethylamine, pyridine,
One or more of 4-dimethylaminopyridine.
Preferably, in step 2), the phase transfer catalyst is tetrabutylammonium bromide or polyethylene glycol-400, described
Alkali is into mixed base (NaOH+Na2CO3) or (KOH+K2CO3), reaction temperature is 40-50 DEG C；The tetrabutylammonium bromide and change
The amount ratio of object 4 is closed as 1g:1mol, the amount ratio of the polyethylene glycol-400 and compound 4 is 20ml:1mol.
Preferably, in step 2), compound 3, compound 4, NaOH, Na2CO3Molar ratio be 3:3-3.5:2.5:1
Or compound 3, compound 4, KOH, K2CO3Molar ratio be 3:3-3.5:2.5:1.
Preferably, the acid is polyphosphoric acids, 1,1,2,2- tetrachloroethanes of reaction dissolvent in step 3)；Chemical combination
The molar ratio of object 5 and polyphosphoric acids is 0.8:0.8-1.2.
Preferably, it is characterized by: the reducing agent is palladium charcoal/ammonium formate, palladium charcoal/formic acid or palladium in step 4)
Charcoal/ammonium formate/formic acid, the palladium charcoal are 10% palladium charcoal, and the weight of the 10% palladium charcoal is the 4%-6% of 6 weight of compound, instead
Answer solvent from methyl formate, Ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetic acid
One of isobutyl ester.
Preferably, being additionally added anhydrous sodium sulfate in step 4).
Preferably, the condensing agent is Trimethyl phosphite-iodine system, and reaction dissolvent is dichloromethane in step 5)
One or more of alkane, chloroform, acetonitrile, tetrahydrofuran；Trimethyl phosphite, iodine, compound 1, compound 2 and alkali
Molar ratio is 1-1.5:1-1.5:1:1-1.2:1-3, and the alkali is triethylamine, n,N-diisopropylethylamine, pyridine, 4- diformazan
One or more of aminopyridine reacts at room temperature 1-3 hours.
Preferably, the alpha-chloro reaction system is DCDMH- p-methyl benzenesulfonic acid-acetonitrile system in step 6).
Preferably, in step 6), compound 9, DCDMH, p-methyl benzenesulfonic acid molar ratio be 1:0.44-0.66:
0.4-0.6。
Compared with the existing technology, the present invention has the following beneficial effects:
1) a kind of new synthetic route is provided, uses aniline cheap and easy to get for starting material, amidation process avoids
Use the noxious materials such as acyl chlorides.It is small that entire synthetic route pollutes entire synthesis process not only, easy to handle, and respectively walks anti-
Mild condition is answered, easy to operate, yield and purity is high, environmentally friendly, production cost substantially reduces, and is suitble to industrialized production.
2) for amidation process process using Trimethyl phosphite-iodine system as condensing agent, reagent is cheap, is easy to get, different
In many common condensing agents, P (OMe)3And I2More stable to water, storage is easier to；Purification process is simple, and reaction condition is mild,
It solves amidation process in the prior art and uses acyl chlorides reagent, expensive, toxicity has corrosivity, production greatly and to equipment
With the problem of Transport Safety difference, yield is up to 99%；
3) N- alkylated reaction occurs under the conditions of phase transfer catalyst and mixed base, high income (90% or more), operation
Simply, the potassium iodide reagents valuableness used in the prior art is solved, the reaction time is long, cumbersome problem.
4) in nitro-reduction reaction, using palladium charcoal/ammonium formate, palladium charcoal/formic acid or palladium charcoal/ammonium formate/formic acid as reducing agent,
It solves in the prior art with palladium charcoal/hydrogen reducing severe reaction conditions, it is complicated for operation, it is unfavorable for the defect of industrialized production,
90% or more yield.
5) when introducing chlorine on benzazepine alpha-position, using DCDMH- p-methyl benzenesulfonic acid-acetonitrile alpha-chloro reaction system,
With traditional halogenating agent such as bromine, copper bromide, hydrogen bromide, N- bromo-succinimide (NBS), bromination dimethyl bromo sulphur
(DMBS) etc. it compares, there is cheap, efficient, less toxic, corrosion-free to equipment, free from environmental pollution, by-product can recycle again
The advantages that utilization, meets the trend of green chemistry.
Specific embodiment
Content in order to better understand the present invention is described further combined with specific embodiments below, but specific
Embodiment be not the limitation that the contents of the present invention are done.
Embodiment 1-1: the synthesis of compound 3
76.2g I2(0.3mol) is dissolved in 1.5L CH2C12In, after iodine is completely dissolved, place it in -10 DEG C of ice salt bath
In.Then, it is added dropwise by syringe into system 53.1mL P (OMe)3(0.45mol), is added ten minutes later, and 50.1g is to nitre
Yl benzoic acid (compound 2,0.3mol), then the n,N-diisopropylethylamine (0.6mol) of 104.5mL is added ten minutes later, work as body
It ties up to after reacting about 10min at this temperature, then 27.3mL aniline (0.3mol) is added dropwise thereto.After the reaction was continued 10min, remove
Deicing salt bath.It reacts at room temperature to TLC and detects raw material fully reacting (about 3h).The dilution of 30mL water, CH is added to reaction system2C12Instead
Multiple extraction, merges organic phase, successively uses water and saturated common salt water washing, and anhydrous sodium sulfate is dry, and column chromatography for separation obtains 69.5gization
Close object 3, yield 96%.
Embodiment 1-2: the synthesis of compound 3
114.3g I2(0.45mol) is dissolved in 1.5L CHC13In, after iodine is completely dissolved, place it in -10 DEG C of cryosel
In bath.Then, it is added dropwise by syringe into system 46.0mL P (OMe)3(0.39mol), is added ten minutes later, and 60.2g pairs
Nitrobenzoic acid (compound 2,0.36mol), then the Et of 41.6mL is added ten minutes later3N (0.3mol), when system is in the temperature
After lower reaction about 10min, then 27.3mL aniline (0.3mol) is added dropwise thereto.After the reaction was continued 10min, ice salt bath is removed.
It reacts at room temperature to TLC and detects raw material fully reacting (about 3h).The dilution of 30mL water, CHC1 is added to reaction system3It extracts, closes repeatedly
And organic phase, water and saturated common salt water washing are successively used, anhydrous sodium sulfate is dry, and column chromatography for separation obtains 70.9g compound 3, produces
Rate 98%.
Embodiment 1-3: the synthesis of compound 3
99.1g I2(0.39mol) is dissolved in 1.5L THF, after iodine is completely dissolved, places it in -10 DEG C of ice salt bath
In.Then, it is added dropwise by syringe into system 35.4mL P (OMe)3(0.3mol), is added ten minutes later, and 55.1g is to nitro
Benzoic acid (compound 2,0.33mol), then the pyridine (0.9mol) of 72.5mL is added ten minutes later, when system is anti-at such a temperature
Should be after about 10min, then 27.3mL aniline (0.3mol) is added dropwise thereto.After the reaction was continued 10min, ice salt bath is removed.Room temperature
It reacts to TLC and detects raw material fully reacting (about 2h).The dilution of 30mL water is added to reaction system, THF is extracted repeatedly, is merged organic
Phase successively uses water and saturated common salt water washing, and anhydrous sodium sulfate is dry, and column chromatography for separation obtains 71.6g compound 3, yield 99%.
Embodiment 2-1: the synthesis of compound 5
In 500m1 there-necked flask, 32.8g4- chlorobutanoate (compound 4,0.24mo1) and 57.9g compound 3 is added
(0.24mol) (40%) aqueous solution, adds 0.2g tetrabutylammonium bromide, is slowly added into mixed base under the cooling of ice-water bath
(0.2molNaOH+0.08molNa2CO3), it quickly stirs at 40 DEG C 2 hours, places after the reaction was completed, keep reaction solution cooling,
It is extracted with ether, 1mol/L salt acid for adjusting pH is slowly added dropwise to 5-6, solid is gradually precipitated, drop Bi Jixu cooling is lower to stir 2h, takes out
Filter, filter cake are washed with water (3*30ml), dry, obtain 78.9g compound 5, yield 90%.
Embodiment 2-2: the synthesis of compound 5
In 500m1 there-necked flask, 36.1g4- chlorobutanoate (compound 4,0.26mo1) and 57.9g compound 3 is added
(0.24mol) (40%) aqueous solution, adds 0.16g tetrabutylammonium bromide, is slowly added into mixed base under the cooling of ice-water bath
(0.2molKOH+0.08molK2CO3), it quickly stirs at 50 DEG C 2 hours, places after the reaction was completed, keep reaction solution cooling, use
Ether extraction is slowly added dropwise 1mol/L salt acid for adjusting pH to 5-6, solid is gradually precipitated, drop Bi Jixu cooling is lower to stir 2h, takes out
Filter, filter cake are washed with water (3*30ml), dry, obtain 76.7g compound 5, yield 88%.
Embodiment 2-3: the synthesis of compound 5
In 500m1 there-necked flask, 38.2g4- chlorobutanoate (compound 4,0.28mo1) and 57.9g compound 3 is added
(0.24mol) (40%) aqueous solution, adds 3.2ml polyethylene glycol-400, is slowly added into mixed base under the cooling of ice-water bath
(0.2molKOH+0.08molK2CO3), it quickly stirs at 50 DEG C 2 hours, places after the reaction was completed, keep reaction solution cooling, use
Ether extraction is slowly added dropwise 1mol/L salt acid for adjusting pH to 5-6, solid is gradually precipitated, drop Bi Jixu cooling is lower to stir 2h, takes out
Filter, filter cake are washed with water (3*30ml), dry, obtain 82.4g compound 5, yield 94%.
Embodiment 2-4: the synthesis of compound 5
In 500m1 there-necked flask, 36.1g4- chlorobutanoate (compound 4,0.26mo1) and 57.9g compound 3 is added
(0.24mol) (40%) aqueous solution, adds 2.4ml polyethylene glycol-400, is slowly added into mixed base under the cooling of ice-water bath
(0.2molNaOH+0.08mol Na2CO3), it quickly stirs at 40 DEG C 2 hours, places after the reaction was completed, keep reaction solution cooling,
It is extracted with ether, 1mol/L salt acid for adjusting pH is slowly added dropwise to 5-6, solid is gradually precipitated, drop Bi Jixu cooling is lower to stir 2h, takes out
Filter, filter cake are washed with water (3*30ml), dry, obtain 79.8g compound 5, yield 91%.
Embodiment 3-1: the synthesis of compound 6
By 73.1g compound 5 (0.20mol), 67.5g polyphosphoric acids (0.20mol) and 1,1,2,2- tetrachloroethanes
(250ml) is added in 1000ml three-neck flask, is warming up to 120 DEG C of reaction 2h.It is cooled to room temperature, 85g ice water is added and decomposes residue
Polyphosphoric acids, remove water layer, organic layer successively washed with saturated sodium bicarbonate solution (120ml), saturated salt solution (120ml)
It washs, anhydrous sodium sulfate dries, filters, and fraction is collected in distillation, obtains 56.5g compound 6, yield 91%.
Embodiment 3-2: the synthesis of compound 6
By 73.1g compound 5 (365.395,0.20mol), 84.4g polyphosphoric acids (0.25mol) and 1,1,2,2- tetra-
Chloroethanes (250ml) adds in 1000ml three-neck flask, is warming up to 120 DEG C of reaction 2h.It is cooled to room temperature, 85g ice water point is added
Remaining polyphosphoric acids is solved, water layer is removed, organic layer successively uses saturated sodium bicarbonate solution (120ml), saturated salt solution
(120ml) washing, anhydrous sodium sulfate dry, filter, and fraction is collected in distillation, obtain 58.3g compound 6, yield 94%.
Embodiment 3-3: the synthesis of compound 6
By 73.1g compound 5 (0.20mol), 101.2g polyphosphoric acids (0.3mol) and 1,1,2,2- tetrachloroethanes
(250ml) is added in 1000ml three-neck flask, is warming up to 120 DEG C of reaction 2h.It is cooled to room temperature, 85g ice water is added and decomposes residue
Polyphosphoric acids, remove water layer, organic layer successively washed with saturated sodium bicarbonate solution (120ml), saturated salt solution (120ml)
It washs, anhydrous sodium sulfate dries, filters, and fraction is collected in distillation, obtains 55.8g compound 6, yield 90%.
Embodiment 4-1: the synthesis of compound 7
46.5g compound 6 (0.15mol) is added in 1000ml four-hole boiling flask, the 10%Pd/C of 1.9g is added, adds
Enter 850ml ethyl acetate, be added with stirring 17.7g ammonium formate (0.28mol) and 25.6g anhydrous sodium sulfate (0.18mol), heats up
To reflux, flow back 2 hours.TLC tracking reaction (solvent is toluene: acetone=6:4, volume ratio), after fully reacting, is cooled to
Palladium charcoal is recovered by filtration in room temperature.Filtrate is washed with water (400ml × 2), anhydrous sodium sulfate dries, filters, and filtrate is concentrated to dryness, and uses
The mixed solvent (1: 1, volume ratio) of 600ml ethyl acetate and n-hexane is recrystallized to give 39.9g compound 7, yield 95%,
It is 99.8% that HPLC, which detects purity,.
Embodiment 4-2: the synthesis of compound 7
46.5g compound 6 (0.15mol) is added in 1000ml four-hole boiling flask, the 10%Pd/C of 2.3g is added, adds
Enter 850ml ethyl acetate, be added with stirring 17.7g ammonium formate (0.28mol) and 25.6g anhydrous sodium sulfate (0.18mol), heats up
To reflux, flow back 2 hours.TLC tracking reaction (solvent is toluene: acetone=6:4, volume ratio), after fully reacting, is cooled to
Palladium charcoal is recovered by filtration in room temperature.Filtrate is washed with water (400ml × 2), anhydrous sodium sulfate dries, filters, and filtrate is concentrated to dryness, and uses
The mixed solvent (1: 1, volume ratio) of 600ml ethyl acetate and n-hexane is recrystallized to give 40.8g compound 7, yield 97%,
It is 99.8% that HPLC, which detects purity,.
Embodiment 4-3: the synthesis of compound 7
46.5g compound 6 (0.15mol) is added in 1000ml four-hole boiling flask, the 10%Pd/C of 2.8g is added, adds
Enter 850ml ethyl acetate, be added with stirring 17.7g ammonium formate (0.28mol) and 25.6g anhydrous sodium sulfate (0.18mol), heats up
To reflux, flow back 2 hours.TLC tracking reaction (solvent is toluene: acetone=6:4, volume ratio), after fully reacting, is cooled to
Palladium charcoal is recovered by filtration in room temperature.Filtrate is washed with water (400ml × 2), anhydrous sodium sulfate dries, filters, and filtrate is concentrated to dryness, and uses
The mixed solvent (1: 1, volume ratio) of 600ml ethyl acetate and n-hexane is recrystallized to give 39.5g compound 7, yield 94%,
It is 99.8% that HPLC, which detects purity,.
Embodiment 5-1: the synthesis of compound 9
25.4g I2(0.1mol) is dissolved in 300mL CH2C12In, after iodine is completely dissolved, place it in -10 DEG C of cryosel
In bath.Then, it is added dropwise by syringe into system 17.7mL P (OMe)3(0.15mol), is added, 19.8gization ten minutes later
Close object 8 (0.1mol), then ten minutes later be added 34.8mL n,N-diisopropylethylamine (0.2mol), when system at such a temperature
After reacting about 10min, then 22.1mL compound 7 (0.1mol) is added dropwise thereto.After the reaction was continued 10min, ice salt bath is removed.
It reacts at room temperature to TLC and detects raw material fully reacting (about 3h).The dilution of 30mL water, CH is added to reaction system2C12It extracts, closes repeatedly
And organic phase, water and saturated common salt water washing are successively used, anhydrous sodium sulfate is dry, and column chromatography for separation obtains 43.3g compound 9, produces
Rate 94%.
Embodiment 5-2: the synthesis of compound 9
38.1g I2(0.15mol) is dissolved in 400mL CHC13In, after iodine is completely dissolved, place it in -10 DEG C of cryosel
In bath.Then, it is added dropwise by syringe into system 15.3mL P (OMe)3(0.13mol), is added, 23.8gization ten minutes later
It closes object 8 (0.12mol), then the n,N-diisopropylethylamine (0.1mol) of 17.4mL is added ten minutes later, when system is in the temperature
After lower reaction about 10min, then 22.1mL compound 7 (0.1mol) is added dropwise thereto.After the reaction was continued 10min, cryosel is removed
Bath.It reacts at room temperature to TLC and detects raw material fully reacting (about 2h).The dilution of 30mL water, CHC1 is added to reaction system3Extract repeatedly
It takes, merges organic phase, successively use water and saturated common salt water washing, anhydrous sodium sulfate is dry, and column chromatography for separation obtains 45.6g compound
9, yield 99%.
Embodiment 5-3: the synthesis of compound 9
33.0g I2(0.13mol) is dissolved in 300mL THF, after iodine is completely dissolved, places it in -10 DEG C of ice salt bath
In.Then, it is added dropwise by syringe into system 11.8mL P (OMe)3(0.1mol), is added ten minutes later, 21.8g compound
8 (0.11mol), then the n,N-diisopropylethylamine (0.3mol) of 52.3mL is added ten minutes later, when system is anti-at such a temperature
Should be after about 10min, then 22.1mL compound 7 (0.1mol) is added dropwise thereto.After the reaction was continued 10min, ice salt bath is removed.Room
Temperature, which is reacted to TLC, detects raw material fully reacting (about 2h).The dilution of 30mL water is added to reaction system, THF is extracted repeatedly, is associated with
Machine phase successively uses water and saturated common salt water washing, and anhydrous sodium sulfate is dry, and column chromatography for separation obtains 44.7g compound 9, yield
97%.
Embodiment 6-1: the synthesis of compound 10
41.4g compound 9 is added in the three-necked bottle equipped with magnetic stir bar, reflux condensing tube and constant pressure funnel
(0.09mol) and 6.2g p-methyl benzenesulfonic acid (0.036mol), is dissolved in 70mL acetonitrile, and 7.8g1,3- bis- is added dropwise to 25 DEG C in temperature adjustment
The acetonitrile saturated solution of chloro- 5,5- Dimethyl Hydan (DCDMH, 0.0396mol).Stop reaction after 6h, rotation removes acetonitrile, in remnants
In object plus 180mL methylene chloride dissolves, then is washed twice with 230mL moisture, and organic phase is dry with anhydrous magnesium sulfate, and rotation is obtained except solvent
41.1g compound 10, yield 92%.
Embodiment 6-2: the synthesis of compound 10
41.4g compound 9 is added in the three-necked bottle equipped with magnetic stir bar, reflux condensing tube and constant pressure funnel
(0.09mol) and 7.7g p-methyl benzenesulfonic acid (0.045mol), is dissolved in 70mL acetonitrile, and 9.7g1,3- bis- is added dropwise to 25 DEG C in temperature adjustment
The acetonitrile saturated solution of chloro- 5,5- Dimethyl Hydan (DCDMH, 0.0495mol).Stop reaction after 6h, rotation removes acetonitrile, in remnants
In object plus 180mL methylene chloride dissolves, then is washed twice with 230mL moisture, and organic phase is dry with anhydrous magnesium sulfate, and rotation is obtained except solvent
42.0g compound 10, yield 94%.
Embodiment 6-3: the synthesis of compound 10
41.4g compound 9 is added in the three-necked bottle equipped with magnetic stir bar, reflux condensing tube and constant pressure funnel
(0.09mol) and 9.3g p-methyl benzenesulfonic acid (0.054mol), is dissolved in 70mL acetonitrile, and 11.7g1,3- bis- is added dropwise to 25 DEG C in temperature adjustment
The acetonitrile saturated solution of chloro- 5,5- Dimethyl Hydan (DCDMH, 0.0594mol).Stop reaction after 6h, rotation removes acetonitrile, in remnants
In object plus 180mL methylene chloride dissolves, then is washed twice with 230mL moisture, and organic phase is dry with anhydrous magnesium sulfate, and rotation is obtained except solvent
40.2g compound 10, yield 90%.
Embodiment 7: the synthesis of hydrochloric acid conivaptan
In 500mL three-necked bottle, successively by 39.7g compound 10 (0.08mol), 3.8g ethenylamidine hydrochloride (0.04mol),
5.5g potassium carbonate (0.04mol), 0.54g distilled water (0.03mol), is dissolved in 300ml chloroform.Back flow reaction 20h, TLC tracking
Monitoring stops reaction after raw material fully reacting, is cooled to room temperature.Three times with (300ml × 3) distillation water washing, organic phase is taken,
Anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure and does, obtains crude product.Crude product is dissolved with ethyl alcohol, appropriate concentrated hydrochloric acid is added, freezing is precipitated
Solid filters, and vacuum drying obtains solid, and solid is soluble in water, is extracted, is concentrated under reduced pressure with (200ml × 3) methylene chloride
Dry 15.4g compound 11, yield 72%.
Comparative example 1: the synthesis of compound 5
In 500m1 there-necked flask, 38.2g4- chlorobutanoate (compound 4,0.28mo1) and 57.9g compound 3 is added
(0.24mol) (40%) aqueous solution, adds 3.2ml polyethylene glycol-400, is slowly added into 0.2mol under the cooling of ice-water bath
Caustic alkali (NaOH or KOH), quickly stirs 2 hours at 50 DEG C, places after the reaction was completed, keeps reaction solution cooling, is extracted with ether
It takes, 1mol/L hydrochloric acid is slowly added dropwise and adjusts PH to 5-6, solid is gradually precipitated, drop Bi Jixu cooling is lower to stir 2h, filters, filter cake
It is washed with water (3*30ml), it is dry, obtain 71.9g compound 5, yield 82%.
Claims (9)
1. a kind of preparation method of hydrochloric acid conivaptan, it is characterised in that include the following steps:
1) it is raw material with aniline compound 1, amidation occurs under conditions of condensing agent and alkali with paranitrobenzoic acid compound 2
Reaction obtains compound 3；
2) compound 3 and 4- chlorobutanoate compound 4 in phase transfer catalyst tetrabutylammonium bromide or polyethylene glycol-400 and
Alkylated reaction occurs under the conditions of mixed base, then is acidified to obtain compound 5, the mixed base is NaOH+Na2CO3Or mixed base is
KOH+K2CO3；
3) compound 5 obtains compound 6 through friedel-crafts acylation under the action of an acid；
4) compound 6 restores under the action of reducing agent and obtains compound 7；
5) compound 7 and 2- Phenylbenzoic acid compound 8 amidation process occur under the action of condensing agent obtain compound 9；
6) compound 9 alpha-chloro occurs under the action of α-chlorination system reacts to obtain compound 10；
7) cyclisation occurs for compound 10 and ethenylamidine hydrochloride, salt-forming reaction obtains hydrochloric acid conivaptan compound 11；Its synthetic route
It is as follows:
2. preparation method as described in claim 1, it is characterised in that: in step 1), the condensing agent is Trimethyl phosphite-
Iodine system, reaction dissolvent are one or more of methylene chloride, chloroform, acetonitrile, tetrahydrofuran；Trimethyl phosphite,
Iodine, compound 1, compound 2 and alkali molar ratio be 1-1.5:1-1.5:1:1-1.2:1-3, the alkali is triethylamine, N, N-
One or more of diisopropylethylamine, pyridine, 4-dimethylaminopyridine.
3. preparation method as described in claim 1, it is characterised in that: in step 2), reaction temperature is 40-50 DEG C；Described four
The amount ratio of butylammonium bromide and compound 4 is 1g:1mol or the polyethylene glycol-400 and the amount ratio of compound 4 are
20ml:1mol。
4. preparation method as claimed in claim 3, it is characterised in that: in step 2), compound 3, compound 4, NaOH,
Na2CO3Molar ratio be 3:3-3.5:2.5:1 or compound 3, compound 4, KOH, K2CO3Molar ratio be 3:3-3.5:2.5:
1。
5. preparation method as described in claim 1, it is characterised in that: in step 3), the acid is polyphosphoric acids, reaction dissolvent
For 1,1,2,2- tetrachloroethanes；The molar ratio of compound 5 and polyphosphoric acids is 0.8:0.8-1.2.
6. preparation method as described in claim 1, it is characterised in that: in step 4), the reducing agent be palladium charcoal/ammonium formate,
Palladium charcoal/formic acid or palladium charcoal/ammonium formate/formic acid, the palladium charcoal are 10% palladium charcoal, and the weight of the 10% palladium charcoal is 6 weight of compound
The 4%-6% of amount, reaction dissolvent are methyl formate, Ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate
One of ester, butyl acetate, isobutyl acetate.
7. the method according to claim 1, wherein being additionally added anhydrous sodium sulfate in step 4).
8. preparation method as described in claim 1, it is characterised in that: in step 6), the alpha-chloro reaction system is
DCDMH- p-methyl benzenesulfonic acid-acetonitrile system.
9. preparation method as claimed in claim 8, it is characterised in that: in step 6), compound 9, DCDMH, p-methyl benzenesulfonic acid
Molar ratio be 1:0.44-0.66:0.4-0.6.
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| CN1127508A (en) * | 1993-07-21 | 1996-07-24 | 山之内制药株式会社 | Fused benzazepine derivative and pharmaceutical composition containing the same |
| CN105153168A (en) * | 2015-09-29 | 2015-12-16 | 上海天慈国际药业有限公司 | Preparation method of N-[4-(2-methyl-4,5-dihydro-3H-imidazo [4,5-d] [1] benzazepin-6-formyl) phenyl]-2-phenylbenzamide hydrochloride |
| CN105753735A (en) * | 2014-12-16 | 2016-07-13 | 上海天慈国际药业有限公司 | Preparation method of high-efficiency low-toxicity pitressin antagonist |
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| CN1127508A (en) * | 1993-07-21 | 1996-07-24 | 山之内制药株式会社 | Fused benzazepine derivative and pharmaceutical composition containing the same |
| CN105753735A (en) * | 2014-12-16 | 2016-07-13 | 上海天慈国际药业有限公司 | Preparation method of high-efficiency low-toxicity pitressin antagonist |
| CN105153168A (en) * | 2015-09-29 | 2015-12-16 | 上海天慈国际药业有限公司 | Preparation method of N-[4-(2-methyl-4,5-dihydro-3H-imidazo [4,5-d] [1] benzazepin-6-formyl) phenyl]-2-phenylbenzamide hydrochloride |
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