CN101570511B - Preparation method of mozavaptan - Google Patents
Preparation method of mozavaptan Download PDFInfo
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- CN101570511B CN101570511B CN2009100330814A CN200910033081A CN101570511B CN 101570511 B CN101570511 B CN 101570511B CN 2009100330814 A CN2009100330814 A CN 2009100330814A CN 200910033081 A CN200910033081 A CN 200910033081A CN 101570511 B CN101570511 B CN 101570511B
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- WRNXUQJJCIZICJ-UHFFFAOYSA-N mozavaptan Chemical compound C12=CC=CC=C2C(N(C)C)CCCN1C(=O)C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1C WRNXUQJJCIZICJ-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229950000546 mozavaptan Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 36
- 150000001350 alkyl halides Chemical class 0.000 claims abstract description 33
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 22
- 239000000376 reactant Substances 0.000 claims abstract description 13
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- OKHSVCZDYHBEKX-UHFFFAOYSA-N formyl chloride toluene Chemical compound C(=O)Cl.CC1=CC=CC=C1 OKHSVCZDYHBEKX-UHFFFAOYSA-N 0.000 claims description 8
- WCGIGOVLOFXAMG-UHFFFAOYSA-N silver;trifluoromethanesulfonic acid Chemical group [Ag].OS(=O)(=O)C(F)(F)F WCGIGOVLOFXAMG-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- ZYXPMOIHQRKWGT-UHFFFAOYSA-N silver;2,2,2-trifluoroacetic acid Chemical compound [Ag].OC(=O)C(F)(F)F ZYXPMOIHQRKWGT-UHFFFAOYSA-N 0.000 claims description 5
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- 238000011084 recovery Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 15
- 238000001953 recrystallisation Methods 0.000 abstract description 11
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- RPQCNCIFKALLIW-UHFFFAOYSA-N 4-[(2-methylbenzoyl)amino]benzoyl chloride Chemical compound CC1=CC=CC=C1C(=O)NC1=CC=C(C(Cl)=O)C=C1 RPQCNCIFKALLIW-UHFFFAOYSA-N 0.000 abstract description 2
- DHRGKPZGOKPOJJ-UHFFFAOYSA-N n,n-dimethyl-2,3,4,5-tetrahydro-1h-1-benzazepin-5-amine Chemical compound CN(C)C1CCCNC2=CC=CC=C12 DHRGKPZGOKPOJJ-UHFFFAOYSA-N 0.000 abstract 2
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- 210000003608 fece Anatomy 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 0 CN(*)C1c(cccc2)c2NCCC1 Chemical compound CN(*)C1c(cccc2)c2NCCC1 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 241000370738 Chlorion Species 0.000 description 1
- 206010021036 Hyponatraemia Diseases 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 102000004136 Vasopressin Receptors Human genes 0.000 description 1
- 108090000643 Vasopressin Receptors Proteins 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- IRFCWUHTGYXRNR-UHFFFAOYSA-N bis(4-nitrophenyl)methanone Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=C([N+]([O-])=O)C=C1 IRFCWUHTGYXRNR-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of mozavaptan, which comprises the steps of dissolving reactants of 5-dimethylamino-2, 3, 4, 5-tetrahydro-1H-benzazepine and 4- (o-methylbenzamido) benzoyl chloride in an alkyl halide solvent, adding an anhydrous aprotic solvent in which silver salt is dissolved, and reacting at 10-30 ℃. The invention also discloses another method, which comprises the steps of firstly reacting 5-dimethylamino-2, 3, 4, 5-tetrahydro-1H-benzazepine and p-nitrobenzoyl chloride under the action of soluble silver salt, reducing nitro and then reacting with o-methylbenzoyl chloride under the action of soluble silver salt. The method has the advantages of short reaction time, no need of column chromatography purification of the product, simple post-treatment, high reaction yield and high yield of over 70 percent after recrystallization, and the product can be purified by recrystallization after the solvent is recovered.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to the preparation method of mozavaptan.
Background technology
Mozavaptan is non-peptide class V2 receptor antagonist, the rare disease of hyponatremia when being mainly used in the relevant antidiuretic hormone hyposecretion syndrome of malignant tumour.Preparation method's main method of mozavaptan has two kinds.
Method one: 5-dimethylin-2,3,4,5-tetrahydrochysene-1H-benzazepine drip 4-(o-methyl-benzene formamido group) Benzoyl chloride solution in solvent, use alkali (salt of wormwood, yellow soda ash, triethylamine etc.) catalysis, obtain mozavaptan.
Method two: 5-dimethylin-2,3,4,5-tetrahydrochysene-1H-benzazepine uses alkali (triethylamine, pyridine etc.) catalysis and 4-nitrobenzoyl chloride to generate acid amides in solvent, through palladium charcoal hydrogenating reduction nitro, under alkali (triethylamine, pyridine etc.) catalysis, obtain mozavaptan with the o-methyl-benzene formyl chloride.
These two kinds of methods all are that benzheterocycle and chloride compounds react under the effect of basic cpd, and the effect of basic cpd in this reaction is to eliminate hydrogen ion, and driving a reaction develops to the product direction.But the above this synthetic method yield that is recorded among the CN1027505C is not high, is example with method one, and after reaction finished, ethyl alcohol recrystallization obtained product behind column chromatography purification, and yield only has 54%.
Summary of the invention
The objective of the invention is to overcome the low problem of yield in the existing mozavaptan synthetic method, provide a kind of employing can be in non-proton polarity the dissolved silver salt, eliminate the chlorion in the reaction system, promote the reaction of benzheterocycle and chloride compounds, prepare the method for mozavaptan.
Purpose of the present invention can reach by following measure:
The preparation method of a kind of mozavaptan (TM), contain single step reaction, with reactant 5-dimethylin-2,3,4,5-tetrahydrochysene-1H-benzazepine and 4-(o-methyl-benzene formamido group) Benzoyl chloride is dissolved in the haloalkane solvent, add the anhydrous aprotic solvent that has dissolved silver salt, in 0～40 ℃ (preferred 10～30 ℃) reaction down, its reaction equation is as follows again
The process that in the haloalkane that contains reactant, adds the anhydrous aprotic solvent that has dissolved silver salt, can be (as 1 below haloalkane solvent boiling point temperature, the 2-ethylene dichloride is below 84 ℃) carry out, in order to reduce the generation of side reaction, preferably haloalkane is cooled to below 0 ℃ more preferably 0～-10 ℃.
The haloalkane solvent is preferably methylene dichloride or 1 in the method, the 2-ethylene dichloride; The present invention selects to dissolve in the silver salt of anhydrous aprotic solvent, is preferably Silver Nitrate, trifluoro-methane sulfonic acid silver, silver perchlorate or trifluoroacetic acid silver; Aprotic solvent is preferably tetrahydrofuran (THF), ether, acetonitrile or dioxane; The consumption of silver salt is 1～1.5 times of formula I compound molar weight.
The mole dosage ratio of formula I compound and 4-(o-methyl-benzene formamido group) Benzoyl chloride is 1: 1～1.5, is preferably 1: 1.2.Consumption to the haloalkane solvent in this method does not have particular requirement, and the consumption that reaches solvent in the general reaction gets final product, and in the haloalkane solvent that adds reactant, the content of formula I compound is preferably 0.0001～0.1mol/mL.Add in the haloalkane solvent that contains reactant when having dissolved the aprotic solvent of silver salt, preferred slowly the adding in the haloalkane is such as modes such as employing droppings.Finish reaction behind the silver salt preferably 10～30 ℃ of reactions down, the reaction times was generally 20～40 minutes.
Reaction can obtain the pure product of mozavaptan through simple aftertreatment after finishing, and is specially: add carbonate solution after reacting in reaction solution, filter, separate organic layer, behind organic layer washing drying, recovery solvent, recrystallization obtains mozavaptan.Described carbonate can be yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc.
The preparation method of another kind of mozavaptan contains three-step reaction, specifically comprises the steps:
A, with reactant 5-dimethylin-2,3,4,5-tetrahydrochysene-1H-benzazepine and paranitrobenzoyl chloride are dissolved in the haloalkane, add the anhydrous aprotic solvent dissolved silver salt, in 10～30 ℃ of reactions down, obtain formula II compound again;
B, formula II compound reduction nitro is obtained the formula III compound;
C, formula III compound and o-methyl-benzene formyl chloride are dissolved in the haloalkane, add the anhydrous aprotic solvent that has dissolved silver salt, again in 10～30 ℃ of reactions down;
Its reaction equation is as follows,
In the steps A, the process that in the haloalkane that contains reactant, adds the anhydrous aprotic solvent that has dissolved silver salt, can be (as 1 below haloalkane solvent boiling point temperature, the 2-ethylene dichloride is below 84 ℃) carry out, in order to reduce the generation of side reaction, preferably haloalkane is cooled to below 0 ℃ more preferably 0～-10 ℃.Among the step C, in the haloalkane solvent that contains formula III compound and o-methyl-benzene formyl chloride, the process that adds the anhydrous aprotic solvent that has dissolved silver salt, can be (as 1 below haloalkane solvent boiling point temperature, the 2-ethylene dichloride is below 84 ℃) carry out, in order to reduce the generation of side reaction, preferably haloalkane is cooled to below 0 ℃ more preferably 0～-10 ℃.
Wherein the haloalkane described in steps A and the C is methylene dichloride or 1, the 2-ethylene dichloride; Select to dissolve in the silver salt of anhydrous aprotic solvent among steps A and the C, be preferably Silver Nitrate, trifluoro-methane sulfonic acid silver, silver perchlorate or trifluoroacetic acid silver; Described aprotic solvent is tetrahydrofuran (THF), ether, acetonitrile or dioxane.The consumption of silver salt is 1～1.5 times of formula I compound molar weight in the steps A; The consumption of silver salt is 1～1.5 times of formula III compound molar weight among the step C.
In the steps A, formula I compound is 1: 1～1.5 with the mole dosage ratio of paranitrobenzoyl chloride.Consumption to the haloalkane solvent in this step does not have particular requirement, and the consumption that reaches solvent in the general reaction gets final product, and in the haloalkane solvent that adds reactant, the content of formula I compound is preferably 0.0001～0.1mol/mL.Add in the haloalkane solvent that contains reactant when having dissolved the aprotic solvent of silver salt, preferred slowly the adding in the haloalkane is such as modes such as employing droppings.Finish reaction behind the silver salt preferably 10～30 ℃ of reactions down, the reaction times was generally 20～40 minutes.The reaction of steps A adds carbonate solution (carbonate can be yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc.) after finishing in reaction solution, filter, and separates organic layer, and organic layer is washed drying, reclaims solvent, can obtain formula II compound.
Nitro-reduction reaction among the step B is a popular response, can adopt hydrogenating reduction, metal to add method of reducing such as hydrochloric acid reduction, lithium aluminium hydride.Concrete as with formula II compound (5-dimethylamino-2,3,4,5-tetrahydrochysene-benzazepine-1-yl)-and (4-nitrophenyl)-ketone is dissolved in (methyl alcohol or ethanol) in the alcoholic solution, adds the palladium charcoal, and normal pressure or pressurization feed hydrogen, reaction finishes and obtains (5-dimethylamino-2,3,4,5-tetrahydrochysene-benzazepine-1-yl)-(4-aminophenyl)-ketone (formula III).
Among the step C, the formula III compound is 1: 1～1.5 with the mole dosage ratio of o-methyl-benzene formyl chloride, and the reaction times that finishes behind the silver salt was generally 20～40 minutes.Add in the haloalkane solvent that contains formula III compound and o-methyl-benzene formyl chloride when having dissolved the aprotic solvent of silver salt, preferred slowly the adding in the haloalkane is such as modes such as employing droppings.The reaction of step C adds carbonate solution (carbonate can be yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc.) after finishing in reaction solution, filter, separate organic layer, the organic layer washing is dry, recovery solvent, recrystallization obtains the pure product of mozavaptan.
The method reaction times of the present invention is short, and product does not need column chromatography purification, and recrystallization is with regard to the energy purifying behind the recovery solvent, and aftertreatment is simple, the reaction yield height, and yield reaches more than 70% behind the recrystallization.
Embodiment
Embodiment 1:
5-dimethylin-2,3,4,5-tetrahydrochysene-1H-benzazepine (formula 1) 1.9 grams are dissolved in 20 milliliters of methylene dichloride with 3 gram 4-(o-methyl-benzene formamido-)-Benzoyl chlorides, under 0～-5 ℃, the tetrahydrofuran solution 5ml of 2.3 gram trifluoro-methane sulfonic acid silvers has been dissolved in dropping, dropwises room temperature reaction 30 minutes.Add the 10ml saturated solution of sodium bicarbonate and stirred 10 minutes, filter, a small amount of washed with dichloromethane of filter cake merges organic phase, washes 2 times for 10 milliliters, with anhydrous sodium sulphate 5g dried overnight.After reclaiming solvent, solid obtains 3.4 gram mozavaptans, yield 79.6% with ethyl alcohol recrystallization.
Embodiment 2:
5-dimethylin-2,3,4,5-tetrahydrochysene-1H-benzazepine (formula 1) 1.9 grams are dissolved in 20 milliliter 1 with 3 gram 4-(o-methyl-benzene formamido-)-Benzoyl chlorides, in the 2-ethylene dichloride, under 0～-5 ℃, drip the dioxane solution 10ml that has dissolved 2.1 gram trifluoroacetic acid silver, dropwise room temperature reaction 30 minutes.Add 10ml saleratus saturated solution and stirred 10 minutes, filter, filter cake is with a small amount of 1, and the washing of 2-ethylene dichloride merges organic phase, and anhydrous sodium sulphate 5g dried overnight is used in 10 milliliters of washings 2 times.After reclaiming solvent, solid obtains 3.3 gram mozavaptans, yield 77.3% with ethyl alcohol recrystallization.
Embodiment 3:
5-dimethylin-2,3,4,5-tetrahydrochysene-1H-benzazepine (formula 1) 1.9 grams are dissolved in 20 milliliter 1 with 1.6 gram paranitrobenzoyl chlorides, in the 2-ethylene dichloride, under 0～-5 ℃, drip the tetrahydrofuran solution 5ml that has dissolved 2.3 gram trifluoro-methane sulfonic acid silvers, dropwise room temperature reaction 30 minutes.Add the 10ml saturated solution of sodium bicarbonate and stirred 10 minutes, filter, a small amount of washed with dichloromethane of filter cake merges organic phase, washes 2 times for 10 milliliters, with anhydrous sodium sulphate 5g dried overnight.After reclaiming solvent, solid obtains 2.7 gram formula II with ethyl alcohol recrystallization, and formula II reduces with 5% palladium charcoal 0.2g hydrogenation normal pressure in the 30ml dehydrated alcohol.After reclaiming solvent, be dissolved in the 20ml methylene dichloride, add o-methyl-benzene formyl chloride 1.3 grams, under 0～5 ℃, drip the tetrahydrofuran solution 5ml that has dissolved 2 gram trifluoro-methane sulfonic acid silvers, dropwise room temperature reaction 30 minutes.Filter, a small amount of washed with dichloromethane of filter cake merges organic phase, washes 2 times for 10 milliliters, with anhydrous sodium sulphate 5g dried overnight.After reclaiming solvent, solid obtains 3 gram mozavaptans, yield 70.2% with ethyl alcohol recrystallization.
Claims (10)
1. the preparation method of a mozavaptan, it is characterized in that dimethylamino-2 with reactant 5-, 3,4,5-tetrahydrochysene-1H-benzazepine and 4-(o-methyl-benzene formamido group) Benzoyl chloride is dissolved in the haloalkane solvent, adds the anhydrous aprotic solvent that has dissolved silver salt, again in 10～30 ℃ of reactions down, its reaction equation is as follows
Wherein said silver salt is trifluoro-methane sulfonic acid silver, silver perchlorate or trifluoroacetic acid silver.
2. preparation method according to claim 1 when it is characterized in that adding the anhydrous aprotic solvent that has dissolved silver salt, is cooled to the haloalkane solvent that has dissolved reactant below 0 ℃.
3. preparation method according to claim 1 and 2 is characterized in that described haloalkane solvent is methylene dichloride or 1, the 2-ethylene dichloride.
4. preparation method according to claim 1 and 2 is characterized in that described aprotic solvent is tetrahydrofuran (THF), ether, acetonitrile or dioxane.
5. preparation method according to claim 1 after it is characterized in that reacting end, adds carbonate solution in reaction solution, filter, and separates organic layer, behind organic layer washing drying, recovery solvent, obtains mozavaptan.
6. the preparation method of a mozavaptan is characterized in that comprising the steps:
A, with reactant 5-dimethylamino-2,3,4,5-tetrahydrochysene-1H-benzazepine and paranitrobenzoyl chloride are dissolved in the haloalkane, add the anhydrous aprotic solvent dissolved silver salt, in 10～30 ℃ of reactions down, obtain formula II compound again;
B, formula II compound reduction nitro is obtained the formula III compound;
C, formula III compound and o-methyl-benzene formyl chloride are dissolved in the haloalkane, add the anhydrous aprotic solvent that has dissolved silver salt, again in 10～30 ℃ of reactions down;
Its reaction equation is as follows,
Wherein said silver salt is trifluoro-methane sulfonic acid silver, silver perchlorate or trifluoroacetic acid silver.
7. preparation method according to claim 6 is characterized in that in the steps A, when adding the anhydrous aprotic solvent dissolved silver salt, the haloalkane solvent that has dissolved reactant is cooled to below 0 ℃; Among the step C, when adding the anhydrous aprotic solvent dissolved silver salt, the haloalkane solvent that has dissolved formula III compound and o-methyl-benzene formyl chloride is cooled to below 0 ℃.
8. according to claim 6 or 7 described preparation methods, it is characterized in that the haloalkane described in steps A and the C is methylene dichloride or 1, the 2-ethylene dichloride; Described aprotic solvent is tetrahydrofuran (THF), ether, acetonitrile or dioxane.
9. preparation method according to claim 6 after the reaction that it is characterized in that steps A finishes, adds carbonate solution in reaction solution, filter, and separates organic layer, and is the organic layer washing is dry, reclaim solvent, obtains formula II compound.
10. preparation method according to claim 6 after the reaction that it is characterized in that step C finishes, adds carbonate solution in reaction solution, filter, and separates organic layer, and is the organic layer washing is dry, reclaim solvent, obtains mozavaptan.
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| CN2009100330814A CN101570511B (en) | 2009-06-11 | 2009-06-11 | Preparation method of mozavaptan |
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| CN2009100330814A CN101570511B (en) | 2009-06-11 | 2009-06-11 | Preparation method of mozavaptan |
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| CN101570511B true CN101570511B (en) | 2011-01-12 |
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| CN2009100330814A Expired - Fee Related CN101570511B (en) | 2009-06-11 | 2009-06-11 | Preparation method of mozavaptan |
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| CN101817783B (en) * | 2010-05-12 | 2012-02-22 | 天津泰普药品科技发展有限公司 | Method for preparing tolvaptan intermediate |
| CN102093247B (en) * | 2010-12-15 | 2014-03-12 | 天津药物研究院 | Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid |
| CN108101906B (en) * | 2017-12-19 | 2020-03-20 | 太原理工大学 | Preparation method of cyclopentyl [ f ] pyrrolo [2,1,5-cd ] indolizine derivative |
| CN112121051B (en) * | 2020-09-30 | 2021-06-18 | 郑州大学 | Application of mozavatan in preparation of anti-digestive tract tumor medicine |
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