CN101570511B - Method for preparing mozavaptan - Google Patents
Method for preparing 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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- 0 CN(*)C1c(cccc2)c2NCCC1 Chemical compound CN(*)C1c(cccc2)c2NCCC1 0.000 description 2
- RPQCNCIFKALLIW-UHFFFAOYSA-N Cc1ccccc1C(Nc(cc1)ccc1C(Cl)=O)=O Chemical compound Cc1ccccc1C(Nc(cc1)ccc1C(Cl)=O)=O RPQCNCIFKALLIW-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a method for preparing mozavaptan, which comprises the following steps: dissolving reactants of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzodiazepine and 4-(ortho-methyl-benzamido) benzoyl chloride in an alkylogen solvent; adding an anhydrous aprotic solvent dissolved with a silver salt to the mixture; and reacting the mixture at a temperature of between 10 and 30 DEG C. Theinvention also discloses another method which comprises the following steps: reacting the 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzodiazepine with paranitrobenzoyl chloride under the action of a sol uble silver salt; and after deoxidizing nitro groups, reacting the mixture with ortho-methyl benzoyl chloride under the action of the soluble silver salt. The methods have short reaction time without column chromatography purification on a product, the product can be purified through recrystallization after the solvent is reclaimed, the post-treatment is simple, the reaction yield is high, and theyield after the recrystallization can reach more than 70 percent.
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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| 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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