CN102093293A - Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone - Google Patents
Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone Download PDFInfo
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Abstract
The invention relates to a preparation method of benzazepine compounds, particularly a preparation method of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone. The 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone can be used as an intermediate for preparing a pitressin antagonist medicament Tolvaptan. The method comprises the following steps: by using parachloroaniline as a raw material, reacting with paratoluensulfonyl chloride in a condensation mode under the alkaline condition to firstly protect amino groups; under the alkaline condition, coupling with ethyl 4-bromobutyrate to obtain a compound; in the presence of alkali, hydrolyzing the obtained compound, and acidifying; in dichloromethane, preparing acyl chloride from the acidified compound under the action of thionyl chloride; under the action of Lewis acid, carrying out Friedel-Crafts acylation reaction to perform intramolecular cyclization; and finally, removing tosyl groups to obtain the target product. The invention has the advantages of simple technique and low cost, and is convenient for industrial large-scale production.
Description
Technical field
The present invention relates to the preparation method of benzazepine compounds, specifically a kind of preparation 7-chloro-2,3,4, the novel method of 5-tetrahydrochysene-1H-1-benzazepine-5-ketone; This compound is the important intermediate of preparation vasopressin antagonists medicine tolvaptan (Tolvaptan).
Background technology
Tolvaptan is a kind of arginine vasopressin (AVP) antagonist of high-efficiency low-toxicity, by Otsuka drugmaker research and develop successfully and in 2009 the listing.The Samsca (Tolvap tan) that its English commodity are by name; chemistry N-[4-[(5R by name)-7-chloro-5-hydroxyl-2; 3; 4; 5-tetrahydrochysene-1-benzazepine-1-formyl radical]-the 3-aminomethyl phenyl]-the 2-methyl benzamide, English chemistry N-[4-[(5R by name)-7-Chloro-5-hydroxy-2,3; 4,5-tetra hydro-1-benzazepine-1-carbonyl]-3-methylphenyl]-2-methylbenz amide.Molecular structural formula is as follows:
Tolvaptan is antagonism arginine vasopressin (AVP) efficiently.Systemic vasoconstriction and dilutional hyponatremia appear in congestive heart failure (CHF) patient, and very major part is because due to the rising of circulation A VP horizontal abnormality.Tolvaptan can reduce the concentration level of the arginine vasopressin (AVP) in the blood circulation system, therefore can be used for treating heavy body/wait the capacity hyponatremia, comprise patient with heart failure, sclerosis, syndrome of inapropriate ADH (SIADH).This medicine is unique oral type selectivity vasopressin antagonists of getting permission to treat this disease.
The synthetic method of tolvaptan can realize according to following reaction scheme, referring to Drugs of the Future 2002,27 (4): 350-357):
This route makes up integral part in the chemical structure of tolvaptan by carrying out the diekmann ester condensation under the alkaline condition, but when method shown in above-mentioned is applied to industrialized production, need the 5-chloro-2-Methyl anthranilate of raw material to cost an arm and a leg, synthetic route is also long, and the cycle and the cost of production are higher.
Can find that from said synthesis route 7-chloro--2,3,4,5-tetrahydrochysene-1H-1-benzazepine-5-ketone (hereinafter to be referred as compound 1) are the important intermediate of synthetic tolvaptan, its molecular structural formula is as follows:
The important intermediate of tolvaptan, promptly the synthetic method of compound 1 can be prepared by following route, referring to Bioorg.Med.Chem.7 (1999) 1743-1754):
The analogue of compound 1 can also be prepared by following route, referring to Bioorg.Med.Chem.14 (2006) 6165-6173):
This route then is to make up the azatropylidene ring by Beckmann rearrangement, and innovation is arranged very much, but method shown in above-mentioned can not be advantageously applied to industrialized production owing to hanging down yield and expensive restriction.
Summary of the invention
Technical problem to be solved by this invention is the present situation at prior art, and providing a kind of can prepare 7-chloro-2,3,4, the novel method of 5-tetrahydrochysene-1H-1-benzazepine-5-ketone at low cost industrial easy reaching.
The present invention solves the problems of the technologies described above the technical scheme that is adopted:
The present invention prepares 7-chloro-2,3,4, the method for 5-tetrahydrochysene-1H-1-benzazepine-5-ketone, and its preparation process is:
That is: the first step is a raw material with p-Chlorobenzoic acid amide (compound 2), react in solvent with Tosyl chloride under the condition that alkali exists and carries out the N protection, generation N-(4-chloro-phenyl-)-4-methyl benzenesulfonamide (compound 4); In second step, in solvent, compound 4 obtains 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) ethyl butyrate (compound 5) with the coupling of 4-bromo-butyric acid ethyl ester under the alkali effect; The 3rd the step, compound 5 in the presence of alkali after the hydrolysis again acidifying obtain 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) butyric acid (compound 6); The 4th step, make solvent with methylene dichloride, compound 6 generates acyl chlorides under the thionyl chloride effect, i.e. 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) butyryl chloride (compound 7); In the 5th step, compound 7 carries out Fu-Ke reaction cyclization and gets 7-chloro-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-5-ketone (compound 8) under the Lewis acid effect in solvent; In the 6th step, compound 8 takes off the N protection and promptly obtains target product 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-5-ketone (compound 1) in solvent and reaction reagent.
Alkali in the described the first step is selected from pyridine, triethylamine, salt of wormwood and yellow soda ash, wherein is preferably pyridine; Solvent in the described the first step is selected from ethyl acetate, methylene dichloride, toluene, acetone, 2-butanone and pyridine, and wherein methylene dichloride is preferred.The mole dosage of alkali is 1-1.5 with the ratio of the molar weight of p-Chlorobenzoic acid amide in the first step; The mole dosage of Tosyl chloride is 1-1.2 with the ratio of the molar weight of p-Chlorobenzoic acid amide; Temperature of reaction arrives the solvent refluxing temperature at 0 ℃, preferably in room temperature; Reaction time range is 1-24 hour, finishes at 5-7 hour internal reaction usually.
Alkali in described second step is selected from pyridine, triethylamine, salt of wormwood and yellow soda ash, and wherein salt of wormwood is preferred; The solvent in described second step is selected from tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, acetone and 2-butanone, and wherein acetone is preferred.The mole dosage of alkali is 1.2-2.5 with the ratio of the molar weight of p-Chlorobenzoic acid amide in second step; The mole dosage of 4-bromo-butyric acid ethyl ester is 1-1.1 with the ratio of the molar weight of p-Chlorobenzoic acid amide; Temperature of reaction in room temperature to the solvent refluxing temperature, preferably in room temperature to 50 ℃; Reaction time range is 3-20 hour, finishes at 7-10 hour internal reaction usually.
Alkali in described the 3rd step is selected from sodium hydroxide, potassium hydroxide and salt of wormwood; The mole dosage of alkali be compound 5 molar weight 1.1-1.5 doubly; Solvent is mixed solvent or the water and the ethanol mixed solvent of water, water and methyl alcohol.
Lewis acid in described the 5th step is selected from aluminum chloride, iron trichloride, zinc chloride and Trichlorobismuthine, aluminum chloride wherein, and iron trichloride is preferred; The 5th step, described solvent was selected from toluene, methylene dichloride, trichloromethane, tetracol phenixin and 1, the 2-ethylene dichloride, and methylene dichloride wherein, 1, the 2-ethylene dichloride is preferred; Range of reaction temperature arrives the solvent for use reflux temperature at 0 ℃, preferably in room temperature; Reaction time range is 1-24 hour, finishes at 5-10 hour internal reaction usually.Compound 7 is 1 with the ratio of described lewis acidic material molar weight in described the 5th step: 1.0-2.5 is preferably 1: 1.2.
Solvent in described the 6th step is selected from toluene, methylene dichloride, 1,2-ethylene dichloride, polyphosphoric acid PPA and glacial acetic acid, wherein preferred polyphosphoric acid (PPA) and glacial acetic acid; Described reaction reagent is selected from polyphosphoric acid PPA, the vitriol oil, Hydrogen bromide, tosic acid and methylsulfonic acid, wherein preferred polyphosphoric acid (PPA); Temperature of reaction determines according to solvent, usually between room temperature to 100 ℃; Reaction times is determined according to solvent and reaction reagent, finishes at 1-5 hour internal reaction usually.The volumetric usage of solvent described in the 6th step is in mL, and the quality consumption of described compound 8 is in g, then the volumetric usage of solvent be compound 8 the quality consumption 3-8 doubly; The mole dosage of described reaction reagent except that polyphosphoric acid be compound 8 mole dosage 0.1-2 doubly, be preferably 0.5-1.2 doubly; During as reaction reagent, its quality consumption is 0.5-1.5 with the ratio of the quality consumption of compound 8 with polyphosphoric acid.
Technical solution of the present invention is specified as:
Utilize p-Chlorobenzoic acid amide as raw material, under alkaline condition with the Tosyl chloride condensation, earlier with amido protecting, then under alkaline condition with the coupling of 4-bromo-butyric acid ethyl ester.Resulting compound 5 in the presence of alkali after hydrolysis acidifying get compound 6.In methylene dichloride, compound 6 generates acyl chlorides under the thionyl chloride effect, and then under the Lewis acid effect, friedel-crafts acylation reaction takes place, and molecule inner ring condensation gets compound 8.Slough p-toluenesulfonyl at last and can obtain target product compound 1.
Utilizing Tosyl chloride is a step very important among the present invention to the amino protection on the phenyl ring, carry out smoothly often will adding suitable alkali for making reaction, and comprising mineral alkali and organic bases, as pyridine, triethylamine, salt of wormwood, yellow soda ash.Pyridine is preferred in this invention.Used solvent comprises ethyl acetate, methylene dichloride, toluene when using organic bases.When using mineral alkali,, can select polar solvent, as acetone, 2-butanone for increasing the solubleness of mineral alkali in the reactionization system.Also can directly make solvent with pyridine, it both as alkali also as solvent.Be most preferred reaction solvent with methylene dichloride among the present invention.The mole dosage of used alkali is 1-1.5 with the ratio of the molar weight of compound 2; The mole dosage of Tosyl chloride is 1-1.2 with the ratio of the molar weight of compound 2; Temperature of reaction arrives the solvent refluxing temperature at 0 ℃, preferably in room temperature; Reaction time range is 1-24 hour, finishes at 5-7 hour internal reaction usually.The power of alkali and concentration are slightly influential to reaction.
Alkali comprises pyridine, triethylamine, salt of wormwood, yellow soda ash in the second described reaction of step.Wherein, salt of wormwood is preferred.The mole dosage of alkali is 1.2-2.5 with the ratio of the molar weight of compound 2, and solvent comprises tetrahydrofuran (THF), N, and dinethylformamide, methyl-sulphoxide, acetone, 2-butanone, wherein acetone is preferred.The mole dosage of 4-bromo-butyric acid ethyl ester is 1-1.1 with the ratio of the molar weight of compound 2; Temperature of reaction in room temperature to the solvent refluxing temperature, preferably in room temperature to 50 ℃; General temperature of reaction raises, corresponding shortening of reaction times, and reaction time range is 3-20 hour, finishes at 7-10 hour internal reaction usually.
The 3rd the step be the hydrolysis of ester, used alkali comprise mainly be can be water-soluble mineral alkali, as sodium hydroxide, potassium hydroxide, salt of wormwood.The mole dosage of alkali be compound 5 molar weight 1.1-1.5 doubly.Solvent is a water, and for increasing the solubleness of reaction substrate, the mixed solvent of optional water and methyl alcohol or water and ethanol mixed solvent are to shorten the reaction times.
The 4th step was to make solvent with methylene dichloride, compound 6 chloride and obtain compound 7 under the thionyl chloride effect.
Described Fu-Ke the reaction of the 5th step is that the key step of synthetic route of the present invention is poly-.The generation of Fu-Ke reaction needs lewis acidic catalysis, and used Lewis acid comprises aluminum chloride, iron trichloride, zinc chloride, Trichlorobismuthine.Wherein, aluminum chloride, iron trichloride are preferred.The 5th step, described solvent comprised toluene, methylene dichloride, and trichloromethane, tetracol phenixin, 1, the 2-ethylene dichloride, methylene dichloride wherein, 1, the 2-ethylene dichloride be that preferably Lewis acid can carry out complexing with substrate or product in the reaction process.So require the material molar weight of compound 7 to lack than Lewis acid, the ratio of both material molar weights is 1: 1.0-2.5, wherein 1: 1.2 for most preferably.This complex compound is in methylene dichloride or 1, and solvability is than strong relatively in toluene in the 2-ethylene dichloride, and reaction system easily becomes homogeneous reaction.Range of reaction temperature arrives the solvent for use reflux temperature at 0 ℃, preferably in room temperature; Reaction time range is 1-24 hour, finishes at 5-10 hour internal reaction usually.
In taking off the six-step process of p-toluenesulfonyl, used solvent comprises toluene, methylene dichloride, 1,2-ethylene dichloride, polyphosphoric acid (PPA), glacial acetic acid.Polyphosphoric acid (PPA) wherein, glacial acetic acid is preferred.The volumetric usage of solvent be compound 8 the quality consumption 3-8 (mL/g) doubly; Described reaction reagent comprises polyphosphoric acid (PPA), the vitriol oil, and Hydrogen bromide, tosic acid, methylsulfonic acid, wherein polyphosphoric acid (PPA) is preferred.The mole dosage of reaction reagent except that polyphosphoric acid be compound 8 mole dosage 0.1-2 doubly, preferable range is at 0.5-1.2 doubly; During as reaction reagent, its quality consumption is 0.5-1.5 with the ratio of the quality consumption of compound 8 with polyphosphoric acid.Temperature of reaction determines according to solvent, and scope is usually between room temperature to 100 ℃.Reaction times is determined according to solvent and reaction reagent, is generally 1-5 hour internal reaction and finishes.
Compared with prior art; the invention has the advantages that: the present invention is by a brand-new synthetic route; with p-Chlorobenzoic acid amide cheap and easy to get is raw material; amino through the sulfonylation protection; the coupling of 4-bromo-butyric acid ethyl ester, be hydrolyzed into acid after, make acyl chlorides again; make up benzazepine ketone by Fu-Ke acylation reaction, last amino takes off the N protection and obtains desired compound 1.Can further produce vasopressin antagonists medicine tolvaptan according to this at the industrial compound 1 of producing requirement easily by method of the present invention, reduce industrial cost.
Embodiment
By the following examples the present invention is done illustrating in greater detail, but the invention is not restricted to these embodiment itself.
One, the preparation of compound 4:
Embodiment 1
P-Chlorobenzoic acid amide (89.3g 0.70mol) puts in the 2L reaction flask with methylene dichloride (250mL), and the adding pyridine (60.9g, 62.3mL, 0.77mol).Ice-water bath is chilled to 0～5 ℃ with reaction solution, stirs to drip Tosyl chloride down (139.2g, 0.73mol) with the solution of methylene dichloride (250mL), 1h drips off.Drip and finish, stirring at room reaction 10h.In reaction solution, add entry (500mL), stir 10min, standing demix.Water layer adds methylene chloride (100mL) extraction once.Merge organic layer, saturated aqueous common salt (400mL) washing, anhydrous sodium sulfate drying.Methylene dichloride evaporated under reduced pressure, gained solid adding methyl alcohol (400mL) are warming up to molten clear, are chilled to 0～5 ℃, slowly add water (400mL), and 0～5 ℃ of insulated and stirred 30min filters, a little cold 50% (V/V) methanol in water washing.50 ℃ of forced air dryings of gained off-white color solid, compound 4 (189.7g, 0.674mol), yield 96.3%.
Embodiment 2
P-Chlorobenzoic acid amide (89.3g 0.70mol) puts in the 2L reaction flask with methylene dichloride (250mL), and the adding pyridine (55.4g, 56.6mL, 0.70mol).Ice-water bath is chilled to 0～5 ℃ with reaction solution, stirs to drip Tosyl chloride down (160.2g, 0.84mol) with the solution of methylene dichloride (250mL), 1h drips off.Drip and finish, be warming up to methylene chloride reflux, stirring reaction 7h.In reaction solution, add entry (500mL), stir 10min, standing demix.Water layer adds methylene chloride (100mL) extraction once.Merge organic layer, saturated aqueous common salt (400mL) washing, anhydrous sodium sulfate drying.Methylene dichloride evaporated under reduced pressure, gained solid adding methyl alcohol (400mL) are warming up to molten clear, are chilled to 0～5 ℃, slowly add water (400mL), and 0～5 ℃ of insulated and stirred 30min filters, a little cold 50% (V/V) methanol in water washing.50 ℃ of forced air dryings of gained off-white color solid, compound 4 (187.7g, 0.667mol), yield 95.2%.
Embodiment 3
P-Chlorobenzoic acid amide (89.3g 0.70mol) puts in the 2L reaction flask with methylene dichloride (250mL), and the adding pyridine (83.0g, 85.0mL, 1.05mol).Ice-water bath is chilled to 0～5 ℃ with reaction solution, stirs to drip Tosyl chloride down (152.5g, 0.80mol) with the solution of methylene dichloride (250mL), 1h drips off.Drip and finish, be warming up to methylene chloride reflux, stirring reaction 5h.In reaction solution, add entry (500mL), stir 10min, standing demix.Water layer adds methylene chloride (100mL) extraction once.Merge organic layer, saturated aqueous common salt (400mL) washing, anhydrous sodium sulfate drying.Methylene dichloride evaporated under reduced pressure, gained solid adding methyl alcohol (400mL) are warming up to molten clear, are chilled to 0～5 ℃, slowly add water (400mL), and 0～5 ℃ of insulated and stirred 30min filters, a little cold 50% (V/V) methanol in water washing.50 ℃ of forced air dryings of gained off-white color solid, compound 4 (189.3g, 0.672mol), yield 96.0%.
Embodiment 4
P-Chlorobenzoic acid amide (89.3g 0.70mol) puts in the 2L reaction flask with ethyl acetate (250mL), and the adding triethylamine (77.9g, 0.77mol).Ice-water bath is chilled to 0～5 ℃ with reaction solution, stirs to drip Tosyl chloride down (139.2g, 0.73mol) with the solution of ethyl acetate (250mL), 1h drips off.Drip and finish, be warming up to room temperature, stirring reaction 7h.In reaction solution, add entry (500mL), stir 10min, standing demix.Water layer adds ethyl acetate (100mL) extraction once.Merge organic layer, saturated aqueous common salt (400mL) washing, anhydrous sodium sulfate drying.Ethyl acetate evaporated under reduced pressure, gained solid adding methyl alcohol (400mL) are warming up to molten clear, are chilled to 0～5 ℃, slowly add water (400mL), and 0～5 ℃ of insulated and stirred 30min filters, a little cold 50% (V/V) methanol in water washing.50 ℃ of forced air dryings of gained off-white color solid, compound 4 (186.6g, 0.662mol), yield 94.6%.
Embodiment 5
P-Chlorobenzoic acid amide (89.3g 0.70mol) puts in the 2L reaction flask with acetone (250mL), and the adding anhydrous sodium carbonate (81.6g, 0.77mol).Ice-water bath is chilled to 0～5 ℃ with reaction solution, stirs to drip Tosyl chloride down (139.2g, 0.73mol) with the solution of acetone (250mL), 1h drips off.Drip and finish, at 0～5 ℃ of stirring reaction 24h.Reacting liquid filtering, a little washing with acetone filter cake.Filtrate decompression is steamed and is removed acetone, and gained solid adding methyl alcohol (400mL) is warming up to molten clear, is chilled to 0～5 ℃, slowly adds water (400mL), and 0～5 ℃ of insulated and stirred 30min filters, a little cold 50% (V/V) methanol in water washing.50 ℃ of forced air dryings of gained off-white color solid, compound 4 (180.7g, 0.641mol), yield 91.6%.
Embodiment 6
P-Chlorobenzoic acid amide (89.3g 0.70mol) puts in the 2L reaction flask with toluene (250mL), and the adding Anhydrous potassium carbonate (106.4g, 0.77mol).Ice-water bath is chilled to 0～5 ℃ with reaction solution, stirs to drip Tosyl chloride down (139.2g, 0.73mol) with the solution of toluene (250mL), 1h drips off.Drip and finish, be warming up to refluxing toluene, stirring reaction 7h.Reacting liquor while hot is filtered, a little hot toluene washing leaching cake.Filtrate decompression is steamed and is removed toluene, and gained solid adding methyl alcohol (400mL) is warming up to molten clear, is chilled to 0～5 ℃, slowly adds water (400mL), and 0～5 ℃ of insulated and stirred 30min filters, a little cold 50% (V/V) methanol in water washing.50 ℃ of forced air dryings of gained off-white color solid, compound 4 (182.6g, 0.648mol), yield 92.6%.
Embodiment 7
P-Chlorobenzoic acid amide (89.3g 0.70mol) puts in the 2L reaction flask with 2-butanone (250mL), and the adding pyridine (60.9g, 62.3mL, 0.77mol).Ice-water bath is chilled to 0～5 ℃ with reaction solution, stirs to drip Tosyl chloride down (139.2g, 0.73mol) with the solution of 2-butanone (250mL), 1h drips off.Drip and finish, be warming up to room temperature, stirring reaction 12h.Reacting liquid filtering, a little 2-butanone washing leaching cake.The filtrate decompression evaporate to dryness adds entry (500mL), and concentrated hydrochloric acid is transferred pH=4～5.Stir 30min under the room temperature, filter, filter cake washes with water to neutrality, drains.Gained solid adding methyl alcohol (400mL) is warming up to molten clear, is chilled to 0～5 ℃, slowly adds water (400mL), and 0～5 ℃ of insulated and stirred 30min filters, a little cold 50% (V/V) methanol in water washing.50 ℃ of forced air dryings of gained off-white color solid, compound 4 (179.8g, 0.638mol), yield 91.2%.
Two, the preparation of compound 5:
Embodiment 1
Compound 4 (56.3g 0.20mol) puts in the 500mL reaction flask with acetone (250mL), add 4-bromo-butyric acid ethyl ester (41.0g, 0.21mol), (33.2g 0.24mol), is heated with stirring to back flow reaction 8h to salt of wormwood.Reaction solution is chilled to room temperature, filters a little washing with acetone of filter cake.Merging filtrate, evaporated under reduced pressure gets light brown oily liquid, and promptly the crude product of compound 5 without refining, directly carries out next step reaction.
Embodiment 2
Compound 4 (56.3g 0.20mol) puts in the 500mL reaction flask with tetrahydrofuran (THF) (250mL), add 4-bromo-butyric acid ethyl ester (43.0g, 0.22mol), (53.0g 0.50mol), is heated with stirring to back flow reaction 10h to anhydrous sodium carbonate.Reaction solution is chilled to room temperature, filters a little tetrahydrofuran (THF) washing of filter cake.Merging filtrate, evaporated under reduced pressure gets light brown oily liquid, and promptly the crude product of compound 5 without refining, directly carries out next step reaction.
Embodiment 3
(56.3g 0.20mol) puts in the 500mL reaction flask with methyl-sulphoxide (250mL) compound 4, and (39.0g 0.20mol), triethylamine (0.40mol), stirs, and reacts 20h under the room temperature to add 4-bromo-butyric acid ethyl ester.Reaction solution is poured in the frozen water (1000mL), transfers pH=5～6 at 0～5 ℃ with concentrated hydrochloric acid, ethyl acetate (250mL * 3) extraction.The combined ethyl acetate layer, water (500mL * 2) washing, saturated aqueous common salt (400mL) washing.The ethyl acetate layer anhydrous sodium sulfate drying, evaporated under reduced pressure gets light brown oily liquid, and promptly the crude product of compound 5 without refining, directly carries out next step reaction.
Embodiment 4
(56.3g 0.20mol) puts in the 500mL reaction flask with 2-butanone (250mL) compound 4, and (41.0g 0.21mol), pyridine (0.30mol), is heated with stirring to backflow, reaction 10h to add 4-bromo-butyric acid ethyl ester.Remove 2-butanone under reduced pressure, add water (250mL), be chilled to 0～5 ℃ and transfer pH=5～6, ethyl acetate (250mL * 3) extraction with concentrated hydrochloric acid.The combined ethyl acetate layer, saturated aqueous common salt (400mL) washing, anhydrous sodium sulfate drying.Evaporated under reduced pressure gets light brown oily liquid, and promptly the crude product of compound 5 without refining, directly carries out next step reaction.
Embodiment 5
Compound 4 (56.3g 0.2mol) puts in the 500mL reaction flask with acetone (250mL), add 4-bromo-butyric acid ethyl ester (41.0g, 0.21mol), (33.2g 0.24mol), is heated with stirring to 50 ℃ to salt of wormwood, reaction 20h.Reaction solution is chilled to room temperature, filters a little washing with acetone of filter cake.Merging filtrate, evaporated under reduced pressure gets light brown oily liquid, and promptly the crude product of compound 5 without refining, directly carries out next step reaction.
Embodiment 6
Compound 4 (56.3g, 0.2mol) and N, dinethylformamide (250mL) is put in the 500mL reaction flask, add 4-bromo-butyric acid ethyl ester (41.0g, 0.21mol), (33.2g 0.24mol), is heated with stirring to 120 ℃ to salt of wormwood, reaction 7h.Reaction solution is chilled to room temperature, filters a little N of filter cake, dinethylformamide washing.Filtrate is poured in the frozen water (1000mL), transfers pH=5～6 at 0～5 ℃ with concentrated hydrochloric acid, ethyl acetate (250mL * 3) extraction.The combined ethyl acetate layer, water (500mL * 2) washing, saturated aqueous common salt (400mL) washing.The ethyl acetate layer anhydrous sodium sulfate drying, evaporated under reduced pressure gets light brown oily liquid, and promptly the crude product of compound 5 without refining, directly carries out next step reaction.
Three, the preparation of compound 6:
Embodiment 1
Gained compound 5 among the preparation embodiment 1 of compound 5 is put in the 250mL reaction flask, and (40g 0.3mol), methyl alcohol (50mL), is warming up to 50 ℃ of insulation 1h to add entry (100mL), 30% sodium hydroxide solution.Reaction solution is chilled to room temperature, drips concentrated hydrochloric acid and transfers system pH=3-4.Reaction solution is chilled to 5～10 ℃ and stirs 30min, filters, and filter cake washing twice, 50 ℃ of forced air dryings of gained solid, (66.3g, 0.18mol), in compound 4, two step total recoverys of previous step and this step reaction are 90% to get white solid compound 6.
Embodiment 2
Gained compound 5 among the preparation embodiment 2 of compound 5 is put in the 250mL reaction flask, and (56.1g 0.3mol), ethanol (50mL), is warming up to 50 ℃ of insulation 1h to add entry (100mL), 30% potassium hydroxide solution.Reaction solution is chilled to room temperature, drips concentrated hydrochloric acid and transfers system pH=3-4.Reaction solution is chilled to 5～10 ℃ and stirs 30min, filters, and filter cake washing twice, 50 ℃ of forced air dryings of gained solid, (67.8g, 0.184mol), in compound 4, two step total recoverys of previous step and this step reaction are 92% to get white solid compound 6.
Embodiment 3
Gained compound 5 among the preparation embodiment 3 of compound 5 is put in the 250mL reaction flask, added entry (150mL), (29.3g 0.22mol), is warming up to 50 ℃ of insulation 1h to 30% sodium hydroxide solution.Reaction solution is chilled to room temperature, drips concentrated hydrochloric acid and transfers system pH=3-4.Reaction solution is chilled to 5～10 ℃ and stirs 30min, filters, and filter cake washing twice, 50 ℃ of forced air dryings of gained solid, (63.4g, 0.172mol), in compound 4, two step total recoverys of previous step and this step reaction are 86% to get white solid compound 6.
Embodiment 4
Gained compound 5 among the preparation embodiment 4 of compound 5 is put in the 250mL reaction flask, and (33.2g 0.24mol), methyl alcohol (50mL), is warming up to 50 ℃ of insulation 1h to add entry (130mL), Anhydrous potassium carbonate.Reaction solution is chilled to room temperature, drips concentrated hydrochloric acid and transfers system pH=3-4.Reaction solution is chilled to 5～10 ℃ and stirs 30min, filters, and filter cake washing twice, 50 ℃ of forced air dryings of gained solid, (60.3g, 0.164mol), in compound 4, two step total recoverys of previous step and this step reaction are 82% to get white solid compound 6.
Embodiment 5
Gained compound 5 among the preparation embodiment 5 of compound 5 is put in the 250mL reaction flask, and (34.7g 0.26mol), methyl alcohol (50mL), is warming up to 50 ℃ of insulation 1h to add entry (100mL), 30% sodium hydroxide solution.Reaction solution is chilled to room temperature, drips concentrated hydrochloric acid and transfers system pH=3-4.Reaction solution is chilled to 5～10 ℃ and stirs 30min, filters, and filter cake washing twice, 50 ℃ of forced air dryings of gained solid, (64.7g, 0.176mol), in compound 4, two step total recoverys of previous step and this step reaction are 88% to get white solid compound 6.
Embodiment 6
Gained compound 5 among the preparation embodiment 6 of compound 5 is put in the 250mL reaction flask, and (37.3g 0.28mol), methyl alcohol (50mL), is warming up to 50 ℃ of insulation 1h to add entry (100mL), 30% sodium hydroxide solution.Reaction solution is chilled to room temperature, drips concentrated hydrochloric acid and transfers system pH=3-4.Reaction solution is chilled to 5～10 ℃ and stirs 30min, filters, and filter cake washing twice, 50 ℃ of forced air dryings of gained solid, (67.8g, 0.184mol), in compound 4, two step total recoverys of previous step and this step reaction are 92% to get white solid compound 6.
Four, the preparation of compound 7:
Embodiment 1
(14.7g 0.04mol) puts in the 250mL reaction flask with methylene dichloride (70ml) compound 6, and (5.3g, 0.044mol), 30min drips off to be chilled to 0～5 ℃ of dropping SOCl2.Drip to finish and be warming up to backflow 2h.Reaction solution is chilled to room temperature, removes methylene dichloride (DCM) under reduced pressure, light brown solid chemical compound (7) crude product (15.4g, 0.04mol), yield 99%.
Embodiment 2
(14.7g 0.04mol) puts in the 250mL reaction flask with methylene dichloride (70ml) compound 6, and (5.0g, 0.042mol), 30min drips off to be chilled to 0～5 ℃ of dropping SOCl2.Drip to finish and be warming up to back flow reaction 2h.Reaction solution is chilled to room temperature, removes methylene dichloride (DCM) under reduced pressure, light brown solid chemical compound (7) crude product (14.7g, 0.038mol), yield 95%.
Embodiment 3
(14.7g 0.04mol) puts in the 250mL reaction flask with methylene dichloride (100ml) compound 6, and (7.2g, 0.06mol), 30min drips off to be chilled to 0～5 ℃ of dropping SOCl2.Drip to finish and be warming up to room temperature reaction 8h.Remove methylene dichloride under reduced pressure, light brown solid chemical compound (7) crude product (14.7g, 0.038mol), yield 95%.
Five, the preparation of compound 8:
Embodiment 1
(38.6g 0.10mol) puts in the 250mL reaction flask with methylene dichloride (100mL) compound 7 crude products of previous step gained, and (15.8g 0.12mol), is warming up to back flow reaction 6h to add aluminum trichloride (anhydrous) under the room temperature.Reaction solution is chilled to room temperature, slowly pours in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water DCM (50mL) extraction once.Merge the DCM layer, anhydrous sodium sulfate drying removes DCM under reduced pressure.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (22.0g, 0.063mol), yield 63%.
Embodiment 2
(38.6g 0.10mol) puts in the 250mL reaction flask with methylene dichloride (100mL) compound 7 crude products of previous step gained, and (13.3g 0.10mol), reacts 10h under the room temperature to add aluminum trichloride (anhydrous) under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water with methylene dichloride (50mL) extraction once.The combined dichloromethane layer, anhydrous sodium sulfate drying removes methylene dichloride under reduced pressure.The gained residue adds anhydrous methanol (100mL), water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (16.4g, 0.047mol), yield 47%.
Embodiment 3
(38.6g 0.10mol) puts in the 250mL reaction flask with methylene dichloride (100mL) compound 7 crude products of previous step gained, and (33.3g 0.25mol), is warming up to back flow reaction 5h to add aluminum trichloride (anhydrous) under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water with methylene dichloride (50mL) extraction once.The combined dichloromethane layer, anhydrous sodium sulfate drying removes methylene dichloride under reduced pressure.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (21.0g, 0.060mol), yield 60%.
Embodiment 4
(38.6g 0.10mol) puts in the 250mL reaction flask with methylene dichloride (100mL) compound 7 crude products of previous step gained, and (20.0g 0.15mol), reacts 8h under the room temperature to add aluminum trichloride (anhydrous) under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water with methylene dichloride (50mL) extraction once.The combined dichloromethane layer, anhydrous sodium sulfate drying removes methylene dichloride under reduced pressure.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (21.7g, 0.062mol), yield 62%.
Embodiment 5
(38.6g 0.10mol) puts in the 250mL reaction flask with trichloromethane (100mL) compound 7 crude products of previous step gained, and (32.4g 0.20mol), is warming up to back flow reaction 8h to add FERRIC CHLORIDE ANHYDROUS under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water with trichloromethane (50mL) extraction once.Merge the trichloromethane layer, anhydrous sodium sulfate drying removes trichloromethane under reduced pressure.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (11.2g, 0.032mol), yield 32%.
Embodiment 6
(38.6g 0.10mol) puts in the 250mL reaction flask with toluene (100mL) compound 7 crude products of previous step gained, and (47.3g 0.15mol), is warming up to back flow reaction 8h to add anhydrous Trichlorobismuthine under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water with toluene (50mL) extraction once.The combining methylbenzene layer, anhydrous sodium sulfate drying removes toluene under reduced pressure.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (12.6g, 0.036mol), yield 36%.
Embodiment 7
(38.6g 0.10mol) puts in the 250mL reaction flask with tetracol phenixin (100mL) compound 7 crude products of previous step gained, and (16.3g 0.12mol), is warming up to back flow reaction 8h to add Zinc Chloride Anhydrous under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water with tetracol phenixin (50mL) extraction once.Merge carbon tetrachloride layer, anhydrous sodium sulfate drying removes tetracol phenixin under reduced pressure.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (9.5g, 0.027mol), yield 27%.
Embodiment 8
Compound 7 crude products of previous step gained (38.6g, 0.10mol) with 1,2-ethylene dichloride (100mL) is put in the 250mL reaction flask, and (15.8g 0.12mol), reacts 15h under the room temperature to add aluminum trichloride (anhydrous) under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water is with 1, and 2-ethylene dichloride (50mL) extracts once.Merge 1,2-ethylene dichloride layer, anhydrous sodium sulfate drying removes 1 under reduced pressure, the 2-ethylene dichloride.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (19.6g, 0.056mol), yield 56%.
Embodiment 9
Compound 7 crude products of previous step gained (38.6g, 0.10mol) with 1,2-ethylene dichloride (100mL) is put in the 250mL reaction flask, and (15.8g, 0.12mol), insulation is at 0～5 ℃ of reaction 24h to add aluminum trichloride (anhydrous) under the room temperature.Reaction solution is slowly poured in the frozen water (100mL), stirs 10min, leaves standstill separatory.Water is with 1, and 2-ethylene dichloride (50mL) extracts once.Merge 1,2-ethylene dichloride layer, anhydrous sodium sulfate drying removes 1 under reduced pressure, the 2-ethylene dichloride.The gained residue adds anhydrous methanol (100mL) water (25mL), is warming up to backflow, slowly cools to 0～5 ℃, filter, a little cold 80% (V/V) methanol aqueous solution washing of filter cake, light gray solid compound 8 (18.2g, 0.052mol), yield 52%.
Six, the preparation of compound 1:
Embodiment 1
Polyphosphoric acid (140g) is put in the 250mL reaction flask, is warming up to 90-100 ℃, and adding compound 8 (35.0g, 0.10mol) synthermal following, stirring reaction 2h.Reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, filters the filter cake washing.Gained solid wet product are recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (16.8g, 0.086mol).Yield 86%, HPLC purity＞99%.
Embodiment 2
Glacial acetic acid (105mL) is put in the 250mL reaction flask, slowly add again the vitriol oil (1.0g 0.01mol), is warming up to 90-100 ℃, add compound 8 (35.0g, 0.10mol), synthermal down, stirring reaction 1h.Remove most of acetate under reduced pressure, reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, filters the filter cake washing.Gained solid wet product are recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (15.8g, 0.081mol), yield 81%, HPLC purity＞99%.
Embodiment 3
Methylene dichloride (210mL) is put in the 500mL reaction flask, add 48% Hydrogen bromide (20.2g, 0.12mol), add again compound 8 (35.0g, 0.10mol), under the reflux conditions, stirring reaction 5h.Reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, leaves standstill separatory, and water with methylene dichloride (100mL) extraction once.The combined dichloromethane layer, anhydrous sodium sulfate drying, evaporated under reduced pressure.The gained solid is recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (4.5g, 0.023mol), yield 23%, HPLC purity＞99%.
Embodiment 4
Toluene (280mL) is put in the 500mL reaction flask, and (34.4g, 0.20mol), (35.0g 0.10mol), is warming up to 90-100 ℃, stirring reaction 5h to add compound 8 again to add tosic acid.Reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, leaves standstill separatory, and water with toluene (100mL) extraction once.The combining methylbenzene layer, anhydrous sodium sulfate drying, evaporated under reduced pressure.The gained solid is recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (14.7g, 0.075mol), yield 75%, HPLC purity＞99%.
Embodiment 5
Toluene (280mL) is put in the 500mL reaction flask, add tosic acid (13.8g 0.08mol), is warming up to 50-55 ℃, add again compound 8 (35.0g, 0.10mol), synthermal down, stirring reaction 8h.Reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, leaves standstill separatory, and water with toluene (100mL) extraction once.The combining methylbenzene layer, anhydrous sodium sulfate drying, evaporated under reduced pressure.The gained solid is recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (12.9g, 0.066mol), yield 66%, HPLC purity＞99%.
Embodiment 6
1,2-ethylene dichloride (200mL) is put in the 500mL reaction flask, the adding methylsulfonic acid (4.8g 0.05mol), is warming up to 70-80 ℃, and adding compound 8 (35.0g, 0.10mol) synthermal following, stirring reaction 3h.Reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, leaves standstill separatory, and water is with 1, and 2-ethylene dichloride (100mL) extracts once.Merge 1,2-ethylene dichloride layer, anhydrous sodium sulfate drying, evaporated under reduced pressure.The gained solid is recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (11.3g, 0.058mol), yield 58%, HPLC purity＞99%.
Embodiment 7
Glacial acetic acid (200mL) is put in the 500mL reaction flask, adds polyphosphoric acid 35.0 grams, is warming up to 90-100 ℃, and adding compound 8 (35.0g, 0.10mol) synthermal following, stirring reaction 2.5h.Reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, filters the filter cake washing.Gained solid wet product are recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (17.2g, 0.088mol), yield 88%, HPLC purity＞99%.
Embodiment 8
Glacial acetic acid (200mL) is put in the 500mL reaction flask, adds polyphosphoric acid 17.5 grams, is warming up to 90-100 ℃, and adding compound 8 (35.0g, 0.10mol) synthermal following, stirring reaction 5h.Reaction solution is slowly poured in the frozen water (400mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, filters the filter cake washing.Gained solid wet product are recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (16.0g, 0.082mol), yield 82%, HPLC purity＞99%.
Embodiment 9
Glacial acetic acid (200mL) is put in the 500mL reaction flask, adds polyphosphoric acid 52.5 grams, is warming up to 90-100 ℃, and adding compound 8 (35.0g, 0.10mol) synthermal following, stirring reaction 4h.Reaction solution is slowly poured in the frozen water (400 mL), stirs slowly to drip 30% liquid caustic soda accent pH=11 down, and insulation is stirred 10min at 0～5 ℃, filters the filter cake washing.Gained solid wet product are recrystallization in the methanol aqueous solution (150mL) of 50% (V/V), compound 1 (16.6g, 0.085mol), yield 85%, HPLC purity＞99%.
Claims (10)
1. one kind prepares 7-chloro-2,3,4, and the method for 5-tetrahydrochysene-1H-1-benzazepine-5-ketone is characterized in that preparation process is:
That is: the first step is raw material with the p-Chlorobenzoic acid amide, react in solvent with Tosyl chloride under the condition that alkali exists and carries out the N protection, generation N-(4-chloro-phenyl-)-4-methyl benzenesulfonamide; In second step, in solvent, N-under the alkali effect (4-chloro-phenyl-)-4-methyl benzenesulfonamide and the coupling of 4-bromo-butyric acid ethyl ester obtain 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) ethyl butyrate; The 3rd the step, 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) ethyl butyrate in the presence of alkali after the hydrolysis again acidifying obtain 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) butyric acid; The 4th step, make solvent with methylene dichloride, 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) butyric acid generates acyl chlorides under the thionyl chloride effect, i.e. 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) butyryl chloride; In the 5th step, 4-(N-(4-chloro-phenyl-)-4-Methyl benzenesulfonyl amido) butyryl chloride carries out Fu-Ke reaction cyclization and gets 7-chloro-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-5-ketone under the Lewis acid effect in solvent; In the 6th step, 7-chloro-1-(4-Methyl benzenesulfonyl base)-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-5-ketone take off the N protection and promptly obtain target product 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-5-ketone in solvent and reaction reagent.
2. method according to claim 1 is characterized in that the alkali in the described the first step is selected from pyridine, triethylamine, salt of wormwood and yellow soda ash; Solvent in the described the first step is selected from ethyl acetate, methylene dichloride, toluene, acetone, 2-butanone and pyridine.
3. method according to claim 2, the mole dosage that it is characterized in that described alkali is 1-1.5 with the ratio of the molar weight of p-Chlorobenzoic acid amide; The mole dosage of Tosyl chloride is 1-1.2 with the ratio of the molar weight of p-Chlorobenzoic acid amide; Temperature of reaction arrives the solvent refluxing temperature at 0 ℃; Reaction time range is 1-24 hour.
4. method according to claim 1 is characterized in that the alkali in described second step is selected from pyridine, triethylamine, salt of wormwood and yellow soda ash; The solvent in described second step is selected from tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, acetone and 2-butanone.
5. method according to claim 4, the mole dosage that it is characterized in that described alkali is 1.2-2.5 with the ratio of the molar weight of p-Chlorobenzoic acid amide; The mole dosage of 4-bromo-butyric acid ethyl ester is 1-1.1 with the ratio of the molar weight of p-Chlorobenzoic acid amide; Temperature of reaction arrives the solvent refluxing temperature in room temperature; Reaction time range is 3-20 hour.
6. method according to claim 1 is characterized in that the alkali in described the 3rd step is selected from sodium hydroxide, potassium hydroxide and salt of wormwood; The mole dosage of alkali be compound 5 molar weight 1.1-1.5 doubly; Solvent is mixed solvent or the water and the ethanol mixed solvent of water, water and methyl alcohol.
7. method according to claim 1 is characterized in that the Lewis acid in described the 5th step is selected from aluminum chloride, iron trichloride, zinc chloride and Trichlorobismuthine; The 5th step, described solvent was selected from toluene, methylene dichloride, trichloromethane, tetracol phenixin and 1,2-ethylene dichloride; Range of reaction temperature arrives the solvent for use reflux temperature at 0 ℃; Reaction time range is 1-24 hour.
8. method according to claim 7 is characterized in that the described compound 7 and the ratio of described lewis acidic material molar weight are 1: 1.0-2.5.
9. method according to claim 1 is characterized in that the solvent in described the 6th step is selected from toluene, methylene dichloride, 1,2-ethylene dichloride, polyphosphoric acid PPA and glacial acetic acid; Described reaction reagent is selected from polyphosphoric acid PPA, the vitriol oil, Hydrogen bromide, tosic acid and methylsulfonic acid; Temperature of reaction determines according to solvent, between room temperature to 100 ℃; Reaction times is determined according to solvent and reaction reagent, finishes at 1-5 hour internal reaction.
10. method according to claim 9, the volumetric usage that it is characterized in that described solvent be in mL, and the quality consumption of described compound 8 is in g, the volumetric usage of solvent be compound 8 the quality consumption 3-8 doubly; The mole dosage of described reaction reagent except that polyphosphoric acid be compound 8 mole dosage 0.1-2 doubly; During as reaction reagent, its quality consumption is 0.5-1.5 with the ratio of the quality consumption of compound 8 with polyphosphoric acid.
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| CN103012266A (en) * | 2012-11-23 | 2013-04-03 | 天津药物研究院 | Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine |
| CN103012265A (en) * | 2012-11-23 | 2013-04-03 | 天津药物研究院 | Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine |
| CN103012266B (en) * | 2012-11-23 | 2014-07-23 | 天津药物研究院 | Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine |
| 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 |
| CN105753735B (en) * | 2014-12-16 | 2020-01-17 | 上海天慈中商药业有限公司 | Preparation method of high-efficiency low-toxicity vasopressin antagonist |
| CN104829533A (en) * | 2015-05-19 | 2015-08-12 | 广安凯特医药化工有限公司 | Preparation method of tolvaptan key intermediate |
| CN109400533A (en) * | 2018-11-07 | 2019-03-01 | 亳州学院 | A kind of synthetic method of hydrochloric acid conivaptan key intermediate |
| CN112661759A (en) * | 2019-10-16 | 2021-04-16 | 浙江京新药业股份有限公司 | Benzodiazepine compound and preparation method thereof |
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