CN106317060A - Preparation method of conivaptan hydrochloride - Google Patents
Preparation method of conivaptan hydrochloride Download PDFInfo
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- CN106317060A CN106317060A CN201610697235.XA CN201610697235A CN106317060A CN 106317060 A CN106317060 A CN 106317060A CN 201610697235 A CN201610697235 A CN 201610697235A CN 106317060 A CN106317060 A CN 106317060A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a preparation method of conivaptan hydrochloride. The preparation method includes: taking aniline (compound I) as a raw material which is subjected to amidation, alkylation, friedel-crafts acylation, nitro reduction, amidation, alpha-chloro, cyclization and salt-forming reaction to obtain the conivaptan hydrochloride. With the method, the aniline is taken as the raw material easy to obtain, and toxic substances of acyl chloride and the like are avoided during amidation. The entire synthesis process is small in pollution and easy to process with the brand new synthesis theory, and reaction conditions of procedures are moderate; the preparation method is moderate in reaction condition of each procedure, simple in operation, high in yield and purity, environment friendly, low in production cost and suitable in industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, be specifically related to the preparation method of a kind of hydrochloric acid conivaptan.
Background technology
Hydrochloric acid conivaptan, chemical entitled N-[4-(2-methyl-4,5-dihydro-3H-imidazo [4,5-d] [1] benzo nitrogen
Miscellaneous Zhuo-6-formoxyl) phenyl]-2-phenyl benzoyl amine hydrochlorate, Astellas Pharma company produce, be that arginine adds
The one non-peptides double inhibitor of pressure element (AVP) V1a and V2 receptor.It is mainly used in the normal hyponatremia of blood volume, mental and physical efforts
Exhaustion is treated.The injection of this medicine obtains in U.S. food Drug Administration (FDA) approval in December in 2005 on the 29th
City.Its chemical structural formula is as follows:
Several synthetic methods reported about the preparation of hydrochloric acid conivaptan at present are as follows:
Route one: the synthetic route (patent JP1995505056) of Yamanouchi pharmaceutical factory of Japan exploitation discloses as follows
Synthetic route:
In this route, second step acyl chlorides reagent carries out amidation process, although yield is higher, but acyl chlorides price is held high
Expensive, toxicity greatly and has corrosivity to equipment, produces and transports the safety issue that existence is bigger, be easily generated bigger spent acidic
Gas.When 3rd step introduces 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 greatly and has corrosivity to equipment, raw
Produce and transport exists bigger safety issue, be easily generated bigger acid waste gas.When benzazepine alpha-position introduces bromine,
The bromating agent that bromating agent uses is copper bromide, hydrogen bromide, N-bromo-succinimide (NBS), bromination dimethyl bromo sulfur
(DMBS), sodium bromide, potassium bromide, ammonium bromide, bromine chloride, generally have that expensive, toxicity is big, equipment is had corrosivity,
Produce and transport exists bigger safety issue, easily pollute environment.
Route three: Zheng Dengyu, Gao Wenlei, Zhao Jun et al. are at Chinese Journal of Pharmaceuticals 2015, and 46 (9) " hydrochloric acid is examined Buddhist nun and cut down
Smooth synthesis " document discloses following synthetic route:
In this route, there is N-alkylation, intramolecular condensation cyclization, acid through sulfonylation and 4-chlorobutyronitrile in artificial neroli oil
Under the conditions of property, decyanation and bromo obtain bromo-2,3,4, the 5-tetrahydrochysene-5-oxo-1H-benzo nitrogen of 1-p-toluenesulfonyl-4-, then
Form imidazole ring with ethenylamidine hydrochloride condensation cyclization, de-sulfonyl obtains 2-methyl isophthalic acid, 4,5,6-imidazolidine [4,5-d] [1]
Benzo nitrogen, prepares conivaptan finally by amidatioon.This route has the disadvantage in that (1) initiation material is expensive；(2)
The potassium iodide reagents that N-alkylated reaction uses is expensive, and the response time is up to 46 hours, and yield is 87.6%, needs to be carried further
High；(3) amidation process uses acyl chlorides reagent, expensive, toxicity greatly and equipment to be had corrosivity, produce and transport existence
Bigger safety issue, is easily generated bigger acid waste gas.
Summarize above-mentioned route, during preparing hydrochloric acid conivaptan, have following defects that initiation material and reagent valency
Lattice are expensive；Amidation process uses acyl chlorides reagent, expensive, toxicity greatly and equipment to be had corrosivity, produce and transport is deposited
In bigger safety issue；Response time is long, severe reaction conditions, and complex operation is not suitable for industrialized production.
Summary of the invention
For solving the above-mentioned technical problem that prior art exists, the invention provides the preparation side of a kind of hydrochloric acid conivaptan
Method, it is gentle that it respectively walks reaction condition, and synthetic method is simple to operate, and yield and purity are high, and production cost is low, is suitable for industry metaplasia
Produce.
Technical scheme is as follows:
The preparation method of a kind of hydrochloric acid conivaptan, it is characterised in that comprise the steps:
1) with aniline (compound 1) as raw material, send out under conditions of condensing agent and alkali with Nitrodracylic acid (compound 2)
Raw amidation process obtains compound 3；
2) there is alkylation in compound 3 and 4-chlorobutanoate (compound 4) under the conditions of phase transfer catalyst and alkalescence
React, then acidifying obtains compound 5；
3) compound 5 obtains compound 6 through friedel-crafts acylation under the action of an acid；
4) compound 6 reduces under the effect of reducing agent and obtains compound 7；
5) there is amidation process in compound 7 and 2-Phenylbenzoic acid (compound 8) under the effect of condensing agent
Compound 9；
6) compound 9 occurs α chlorination to obtain compound 10 under the effect of α chlorination system；
7) compound 10 is with ethenylamidine hydrochloride is cyclized, salt-forming reaction obtains hydrochloric acid conivaptan (compound 11)；It closes
Become route as follows:
As preferably, step 1) in, described condensing agent is NSC 6513-iodine system, and reaction dissolvent is dichloromethane
One or more in alkane, chloroform, acetonitrile, oxolane；NSC 6513, iodine, compound 1, compound 2 and alkali
Mol ratio is 1-1.5:1-1.5:1-1.5:1:1-1.2:1-3, described alkali be triethylamine, DIPEA, pyridine,
One or more in DMAP.
As preferably, step 2) in, described phase transfer catalyst is tetrabutyl ammonium bromide or PEG-4000, described
Alkali is for entering mixed base (NaOH+Na2CO3) or (KOH+K2CO3), reaction temperature is 40-50 DEG C；Described tetrabutyl ammonium bromide and change
The amount ratio of compound 4 is 1g:1mol, and described PEG-4000 is 20ml:1mol with the amount ratio of compound 4.
As preferably, step 2) in, compound 3, compound 4, NaOH, Na2CO3Mol ratio be 3:3-3.5:2.5:1
Or compound 3, compound 4, KOH, K2CO3Mol ratio be 3:3-3.5:2.5:1.
As preferably, step 3) in, described acid is polyphosphoric acids, and reaction dissolvent is sym.-tetrachloroethane；Chemical combination
Thing 5 is 0.8:0.8-1.2 with the mol ratio of polyphosphoric acids.
As preferably, it is characterised in that: step 4) in, described reducing agent is palladium charcoal/ammonium formate, palladium charcoal/formic acid or palladium
Charcoal/ammonium formate/formic acid, described palladium charcoal is 10% palladium charcoal, the 4%-6% that weight is compound 6 weight of described 10% palladium charcoal, instead
Answer solvent from methyl formate, Ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetic acid
One in isobutyl ester.
As preferably, in step 4) in be additionally added anhydrous sodium sulfate.
As preferably, step 5) in, described condensing agent is NSC 6513-iodine system, and reaction dissolvent is dichloromethane
One or more in alkane, chloroform, acetonitrile, oxolane；NSC 6513, iodine, compound 1, compound 2 and alkali
Mol ratio is 1-1.5:1-1.5:1:1-1.2:1-3, and described alkali is triethylamine, DIPEA, pyridine, 4-diformazan
One or more in aminopyridine, room temperature reaction 1-3 hour.
As preferably, step 6) in, described alpha-chloro reaction system is DCDMH-p-methyl benzenesulfonic acid-acetonitrile system.
As preferably, step 6) in, compound 9, DCDMH, the mol ratio of p-methyl benzenesulfonic acid are 1:0.44-0.66:
0.4-0.6。
Relative to prior art, the present invention has a following beneficial effect:
1) providing a kind of new synthetic route, using aniline cheap and easy to get is initiation material, and amidation process is avoided
The noxious substances such as use acyl chlorides.It is little that whole synthetic route makes whole building-up process not only pollute, disposable, and each step is anti-
Answering mild condition, simple to operate, yield and purity are high, and environmentally friendly, production cost is substantially reduced, and are suitable for industrialized production.
2) amidation process process uses NSC 6513-iodine system as condensing agent, and reagent is cheap, be 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 gentle,
Solving amidation process in prior art uses acyl chlorides reagent, expensive, toxicity greatly and equipment to be had corrosivity, produce
The problem poor with Transport Safety, yield is up to 99%；
3) N-alkylated reaction occurs under the conditions of phase transfer catalyst and mixed base, and yield is high (more than 90%), operation
Simply, solving the potassium iodide reagents used in prior art expensive, the response time is long, the problem of complex operation.
4) in nitro-reduction reaction, with palladium charcoal/ammonium formate, palladium charcoal/formic acid or palladium charcoal/ammonium formate/formic acid as reducing agent,
Solve in prior art by palladium charcoal/hydrogen reducing severe reaction conditions, operation complexity, be unfavorable for the defect of industrialized production,
Yield more than 90%.
5), when introducing chlorine on benzazepine alpha-position, DCDMH-p-methyl benzenesulfonic acid-acetonitrile alpha-chloro reaction system is used,
With traditional halogenating agent such as bromine, copper bromide, hydrogen bromide, N-bromo-succinimide (NBS), bromination dimethyl bromo sulfur
Etc. (DMBS) compare, have low price, efficiently, low toxicity, corrosion-free to equipment, free from environmental pollution, by-product can reclaim again
The advantages such as utilization, meet the trend of green chemistry.
Detailed description of the invention
In order to be better understood from present disclosure, it is described further below in conjunction with specific embodiment, but specifically
Embodiment be not the restriction that present disclosure is done.
Embodiment 1-1: the synthesis of compound 3
76.2g I2(0.3mol) 1.5L CH it is dissolved in2C12In, after iodine is completely dissolved, it is placed on the cryosel bath of-10 DEG C
In.Subsequently, in system, 53.1mL P (OMe) is dripped by syringe3(0.45mol), adding after ten minutes, 50.1g is to nitre
Yl benzoic acid (compound 2,0.3mol), then after ten minutes, add the DIPEA (0.6mol) of 104.5mL, work as body
After system reacts about 10min at such a temperature, then dropping 27.3mL aniline (0.3mol) wherein.After continuing reaction 10min, remove
Deicing salt bath.Room temperature reaction is to TLC detection raw material reaction completely (about 3h).The dilution of 30mL water, CH is added to reaction system2C12Instead
Multiple extraction, merges organic facies, and successively with water and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and column chromatography for separation obtains 69.5gization
Compound 3, productivity 96%.
Embodiment 1-2: the synthesis of compound 3
114.3g I2(0.45mol) 1.5L CHC1 it is dissolved in3In, after iodine is completely dissolved, it is placed on the cryosel of-10 DEG C
In bath.Subsequently, in system, 46.0mL P (OMe) is dripped by syringe3(0.39mol), add after ten minutes, 60.2g pair
Nitrobenzoic acid (compound 2,0.36mol), then after ten minutes, add the Et of 41.6mL3N (0.3mol), when system is in this temperature
After lower reaction about 10min, then dropping 27.3mL aniline (0.3mol) wherein.After continuing reaction 10min, remove cryosel bath.
Room temperature reaction is to TLC detection raw material reaction completely (about 3h).The dilution of 30mL water, CHC1 is added to reaction system3Repeatedly extract, close
And organic facies, successively with water and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, 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) it is dissolved in 1.5L THF, after iodine is completely dissolved, is placed on the cryosel bath of-10 DEG C
In.Subsequently, in system, 35.4mL P (OMe) is dripped by syringe3(0.3mol), adding after ten minutes, 55.1g is to nitro
Benzoic acid (compound 2,0.33mol), then add the pyridine (0.9mol) of 72.5mL after ten minutes, when system is the most anti-
Should be after about 10min, then dropping 27.3mL aniline (0.3mol) wherein.After continuing reaction 10min, remove cryosel bath.Room temperature
React to TLC detection raw material reaction completely (about 2h).Adding the dilution of 30mL water to reaction system, THF extracts repeatedly, merges organic
Phase, successively with water and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and column chromatography for separation obtains 71.6g compound 3, productivity 99%.
Embodiment 2-1: the synthesis of compound 5
In 500m1 there-necked flask, add 32.8g4-chlorobutanoate (compound 4,0.24mo1) and 57.9g compound 3
(0.24mol) (40%) aqueous solution, adds 0.2g tetrabutyl ammonium bromide, is slowly added into mixed base under the cooling of ice-water bath
(0.2molNaOH+0.08molNa2CO3), quickly stir 2 hours at 40 DEG C, place after having reacted, make reactant liquor cool down,
Extract with ether, be slowly added dropwise 1mol/L salt acid for adjusting pH to 5-6, gradually separate out solid, drip and stir 2h under Bi Jixu cooling, take out
Filter, filter cake water (3*30ml) is washed, and is dried, obtains 78.9g compound 5, productivity 90%.
Embodiment 2-2: the synthesis of compound 5
In 500m1 there-necked flask, add 36.1g4-chlorobutanoate (compound 4,0.26mo1) and 57.9g compound 3
(0.24mol) (40%) aqueous solution, adds 0.16g tetrabutyl ammonium bromide, is slowly added into mixed base under the cooling of ice-water bath
(0.2molKOH+0.08molK2CO3), quickly stir 2 hours at 50 DEG C, place after having reacted, make reactant liquor cool down, use
Ether extracts, and is slowly added dropwise 1mol/L salt acid for adjusting pH to 5-6, gradually separates out solid, drips and stirs 2h under Bi Jixu cooling, takes out
Filter, filter cake water (3*30ml) is washed, and is dried, obtains 76.7g compound 5, productivity 88%.
Embodiment 2-3: the synthesis of compound 5
In 500m1 there-necked flask, add 38.2g4-chlorobutanoate (compound 4,0.28mo1) and 57.9g compound 3
(0.24mol) (40%) aqueous solution, adds 3.2ml PEG-4000, is slowly added into mixed base under the cooling of ice-water bath
(0.2molKOH+0.08molK2CO3), quickly stir 2 hours at 50 DEG C, place after having reacted, make reactant liquor cool down, use
Ether extracts, and is slowly added dropwise 1mol/L salt acid for adjusting pH to 5-6, gradually separates out solid, drips and stirs 2h under Bi Jixu cooling, takes out
Filter, filter cake water (3*30ml) is washed, and is dried, obtains 82.4g compound 5, productivity 94%.
Embodiment 2-4: the synthesis of compound 5
In 500m1 there-necked flask, add 36.1g4-chlorobutanoate (compound 4,0.26mo1) and 57.9g compound 3
(0.24mol) (40%) aqueous solution, adds 2.4ml PEG-4000, is slowly added into mixed base under the cooling of ice-water bath
(0.2molNaOH+0.08mol Na2CO3), quickly stir 2 hours at 40 DEG C, place after having reacted, make reactant liquor cool down,
Extract with ether, be slowly added dropwise 1mol/L salt acid for adjusting pH to 5-6, gradually separate out solid, drip and stir 2h under Bi Jixu cooling, take out
Filter, filter cake water (3*30ml) is washed, and is dried, obtains 79.8g compound 5, productivity 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-sym-tetrachloroethane
(250ml) add in 1000ml three-neck flask, be warming up to 120 DEG C of reaction 2h.It is cooled to room temperature, adds 85g frozen water and decompose residue
Polyphosphoric acids, remove water layer, organic layer is washed with saturated sodium bicarbonate solution (120ml), saturated aqueous common salt (120ml) successively
Washing, anhydrous sodium sulfate is dried, and 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-
Ethyl chloride (250ml) adds in 1000ml three-neck flask, is warming up to 120 DEG C of reaction 2h.It is cooled to room temperature, adds 85g frozen water and divide
Solving remaining polyphosphoric acids, remove water layer, organic layer is successively with saturated sodium bicarbonate solution (120ml), saturated aqueous common salt
(120ml) washing, anhydrous sodium sulfate is dried, and filters, and fraction is collected in distillation, obtains 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-sym-tetrachloroethane
(250ml) add in 1000ml three-neck flask, be warming up to 120 DEG C of reaction 2h.It is cooled to room temperature, adds 85g frozen water and decompose residue
Polyphosphoric acids, remove water layer, organic layer is washed with saturated sodium bicarbonate solution (120ml), saturated aqueous common salt (120ml) successively
Washing, anhydrous sodium sulfate is dried, and 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 joined in 1000ml four-hole boiling flask, adds the 10%Pd/C of 1.9g, add
Entering 850ml ethyl acetate, stirring is lower adds 17.7g ammonium formate (0.28mol) and 25.6g anhydrous sodium sulfate (0.18mol), heats up
To backflow, reflux 2 hours.TLC follows the tracks of reaction (developing solvent is toluene: acetone=6:4, volume ratio), after reaction completely, is cooled to
Room temperature, is recovered by filtration palladium charcoal.With water (400ml × 2) wash filtrate, anhydrous sodium sulfate is dried, and filters, and filtrate is concentrated to dryness, and uses
The mixed solvent (1: 1, volume ratio) of 600ml ethyl acetate and normal hexane is recrystallized to give 39.9g compound 7, yield 95%,
HPLC detection purity is 99.8%.
Embodiment 4-2: the synthesis of compound 7
46.5g compound 6 (0.15mol) is joined in 1000ml four-hole boiling flask, adds the 10%Pd/C of 2.3g, add
Entering 850ml ethyl acetate, stirring is lower adds 17.7g ammonium formate (0.28mol) and 25.6g anhydrous sodium sulfate (0.18mol), heats up
To backflow, reflux 2 hours.TLC follows the tracks of reaction (developing solvent is toluene: acetone=6:4, volume ratio), after reaction completely, is cooled to
Room temperature, is recovered by filtration palladium charcoal.With water (400ml × 2) wash filtrate, anhydrous sodium sulfate is dried, and filters, and filtrate is concentrated to dryness, and uses
The mixed solvent (1: 1, volume ratio) of 600ml ethyl acetate and normal hexane is recrystallized to give 40.8g compound 7, yield 97%,
HPLC detection purity is 99.8%.
Embodiment 4-3: the synthesis of compound 7
46.5g compound 6 (0.15mol) is joined in 1000ml four-hole boiling flask, adds the 10%Pd/C of 2.8g, add
Entering 850ml ethyl acetate, stirring is lower adds 17.7g ammonium formate (0.28mol) and 25.6g anhydrous sodium sulfate (0.18mol), heats up
To backflow, reflux 2 hours.TLC follows the tracks of reaction (developing solvent is toluene: acetone=6:4, volume ratio), after reaction completely, is cooled to
Room temperature, is recovered by filtration palladium charcoal.With water (400ml × 2) wash filtrate, anhydrous sodium sulfate is dried, and filters, and filtrate is concentrated to dryness, and uses
The mixed solvent (1: 1, volume ratio) of 600ml ethyl acetate and normal hexane is recrystallized to give 39.5g compound 7, yield 94%,
HPLC detection purity is 99.8%.
Embodiment 5-1: the synthesis of compound 9
25.4g I2(0.1mol) 300mL CH it is dissolved in2C12In, after iodine is completely dissolved, it is placed on the cryosel of-10 DEG C
In bath.Subsequently, in system, 17.7mL P (OMe) is dripped by syringe3(0.15mol), add after ten minutes, 19.8gization
Compound 8 (0.1mol), then add the DIPEA (0.2mol) of 34.8mL after ten minutes, when system at such a temperature
After reacting about 10min, then dropping 22.1mL compound 7 (0.1mol) wherein.After continuing reaction 10min, remove cryosel bath.
Room temperature reaction is to TLC detection raw material reaction completely (about 3h).The dilution of 30mL water, CH is added to reaction system2C12Repeatedly extract, close
And organic facies, successively with water and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, 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) 400mL CHC1 it is dissolved in3In, after iodine is completely dissolved, it is placed on the cryosel of-10 DEG C
In bath.Subsequently, in system, 15.3mL P (OMe) is dripped by syringe3(0.13mol), add after ten minutes, 23.8gization
Compound 8 (0.12mol), then add the DIPEA (0.1mol) of 17.4mL after ten minutes, when system is in this temperature
After lower reaction about 10min, then dropping 22.1mL compound 7 (0.1mol) wherein.After continuing reaction 10min, remove cryosel
Bath.Room temperature reaction is to TLC detection raw material reaction completely (about 2h).The dilution of 30mL water, CHC1 is added to reaction system3Repeatedly extract
Taking, merge organic facies, successively with water and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and column chromatography for separation obtains 45.6g compound
9, productivity 99%.
Embodiment 5-3: the synthesis of compound 9
33.0g I2(0.13mol) it is dissolved in 300mL THF, after iodine is completely dissolved, is placed on the cryosel bath of-10 DEG C
In.Subsequently, in system, 11.8mL P (OMe) is dripped by syringe3(0.1mol), add after ten minutes, 21.8g compound
8 (0.11mol), then add the DIPEA (0.3mol) of 52.3mL after ten minutes, when system is the most anti-
Should be after about 10min, then dropping 22.1mL compound 7 (0.1mol) wherein.After continuing reaction 10min, remove cryosel bath.Room
Temperature reaction is to TLC detection raw material reaction completely (about 2h).Adding the dilution of 30mL water to reaction system, THF extracts repeatedly, is associated with
Machine phase, successively with water and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and column chromatography for separation obtains 44.7g compound 9, productivity
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) with 6.2g p-methyl benzenesulfonic acid (0.036mol), it is dissolved in 70mL acetonitrile, homoiothermic to 25 DEG C, drips 7.8g1,3-bis-
The acetonitrile saturated solution of chloro-5,5-dimethyl hydantion (DCDMH, 0.0396mol).Stopped reaction after 6h, rotation is except acetonitrile, in remnants
Adding 180mL dichloromethane in thing to dissolve, then wash for twice with 230mL moisture, organic facies anhydrous magnesium sulfate is dried, and rotation obtains 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) with 7.7g p-methyl benzenesulfonic acid (0.045mol), it is dissolved in 70mL acetonitrile, homoiothermic to 25 DEG C, drips 9.7g1,3-bis-
The acetonitrile saturated solution of chloro-5,5-dimethyl hydantion (DCDMH, 0.0495mol).Stopped reaction after 6h, rotation is except acetonitrile, in remnants
Adding 180mL dichloromethane in thing to dissolve, then wash for twice with 230mL moisture, organic facies anhydrous magnesium sulfate is dried, and rotation obtains 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) with 9.3g p-methyl benzenesulfonic acid (0.054mol), it is dissolved in 70mL acetonitrile, homoiothermic to 25 DEG C, drips 11.7g1,3-bis-
The acetonitrile saturated solution of chloro-5,5-dimethyl hydantion (DCDMH, 0.0594mol).Stopped reaction after 6h, rotation is except acetonitrile, in remnants
Adding 180mL dichloromethane in thing to dissolve, then wash for twice with 230mL moisture, organic facies anhydrous magnesium sulfate is dried, and rotation obtains 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), it is dissolved in 300ml chloroform.Back flow reaction 20h, TLC follows the tracks of
Monitoring, stopped reaction after raw material reaction is complete, it is cooled to room temperature.With (300ml × 3) distilled water wash three times, take organic facies,
Anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure is done, and obtains crude product.Dissolve crude product with ethanol, add appropriate concentrated hydrochloric acid, freezing precipitation
Solid, sucking filtration, vacuum drying, obtain solid, solid is soluble in water, extract with (200ml × 3) dichloromethane, concentrating under reduced pressure
Being dried to obtain 15.4g compound 11, yield is 72%.
Comparative example 1: the synthesis of compound 5
In 500m1 there-necked flask, add 38.2g4-chlorobutanoate (compound 4,0.28mo1) and 57.9g compound 3
(0.24mol) (40%) aqueous solution, adds 3.2ml PEG-4000, 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, make reactant liquor cool down, extract with ether after having reacted
Take, be slowly added dropwise 1mol/L hydrochloric acid regulation PH to 5-6, gradually separate out solid, drip and stir 2h, sucking filtration, filter cake under Bi Jixu cooling
Wash with water (3*30ml), be dried, obtain 71.9g compound 5, productivity 82%.
Claims (10)
1. the preparation method of a hydrochloric acid conivaptan, it is characterised in that comprise the steps:
1) with aniline (compound 1) as raw material, under conditions of condensing agent and alkali, there is acyl with Nitrodracylic acid (compound 2)
Aminating reaction obtains compound 3；
2) there is alkylated reaction in compound 3 and 4-chlorobutanoate (compound 4) under the conditions of phase transfer catalyst and alkalescence,
Acidifying obtains compound 5 again；
3) compound 5 obtains compound 6 through friedel-crafts acylation under the action of an acid；
4) compound 6 reduces under the effect of reducing agent and obtains compound 7；
5) compound 7 and 2-Phenylbenzoic acid (compound 8) occur amidation process to obtain compound 9 under the effect of condensing agent；
6) compound 9 occurs alpha-chloro reaction to obtain compound 10 under the effect of α chlorination system；
7) compound 10 is with ethenylamidine hydrochloride is cyclized, salt-forming reaction obtains hydrochloric acid conivaptan (compound 11)；It synthesizes road
Line is as follows:
2. preparation method as claimed in claim 1, it is characterised in that: step 1) in, described condensing agent be NSC 6513-
Iodine system, reaction dissolvent is one or more in dichloromethane, chloroform, acetonitrile, oxolane；NSC 6513,
The mol ratio of iodine, compound 1, compound 2 and alkali is 1-1.5:1-1.5:1:1-1.2:1-3, and described alkali is triethylamine, N, N-
One or more in diisopropylethylamine, pyridine, DMAP.
3. preparation method as claimed in claim 1, it is characterised in that: step 2) in, described phase transfer catalyst is the tetrabutyl
Ammonium bromide or PEG-4000, described alkali is for entering mixed base (NaOH+Na2CO3) or (KOH+K2CO3), reaction temperature is 40-
50℃；Described tetrabutyl ammonium bromide is 1g:1mol with the amount ratio of compound 4, described PEG-4000 and the use of compound 4
Amount ratio is 20ml:1mol.
4. preparation method as claimed in claim 3, it is characterised in that: step 2) in, compound 3, compound 4, NaOH,
Na2CO3Mol ratio be 3:3-3.5:2.5:1 or compound 3, compound 4, KOH, K2CO3Mol ratio be 3:3-3.5:2.5:
1。
5. preparation method as claimed in claim 1, it is characterised in that: step 3) in, described acid is polyphosphoric acids, reaction dissolvent
For 1,1,2,2-sym-tetrachloroethane；Compound 5 is 0.8:0.8-1.2 with the mol ratio of polyphosphoric acids.
6. preparation method as claimed in claim 1, it is characterised in that: step 4) in, described reducing agent be palladium charcoal/ammonium formate,
Palladium charcoal/formic acid or palladium charcoal/ammonium formate/formic acid, described palladium charcoal is 10% palladium charcoal, and the weight of described 10% palladium charcoal is compound 6 weight
The 4%-6% of amount, reaction dissolvent is from methyl formate, Ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate
One in ester, butyl acetate, isobutyl acetate.
Method the most according to claim 1, it is characterised in that in step 4) in be additionally added anhydrous sodium sulfate.
8. preparation method as claimed in claim 1, it is characterised in that: step 5) in, described condensing agent be NSC 6513-
Iodine system, reaction dissolvent is one or more in dichloromethane, chloroform, acetonitrile, oxolane；NSC 6513,
The mol ratio of iodine, compound 1, compound 2 and alkali is 1-1.5:1-1.5:1-1.5:1:1-1.2:1-3, and described alkali is three second
One or more in amine, DIPEA, pyridine, DMAP, room temperature reaction 1-3 hour.
9. preparation method as claimed in claim 1, it is characterised in that: step 6) in, described alpha-chloro reaction system is
DCDMH-p-methyl benzenesulfonic acid-acetonitrile system.
10. preparation method as claimed in claim 9, it is characterised in that: step 6) in, compound 9, DCDMH, p-methyl benzenesulfonic acid
Mol ratio be 1:0.44-0.66:0.4-0.6.
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| CN107325003A (en) * | 2017-08-01 | 2017-11-07 | 安徽东至广信农化有限公司 | A kind of method that Liquid-phase Hydrogenation Process synthesizes o-chloraniline |
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