CN105315169B - A kind of preparation method for the treatment of cardiovascular disease drug - Google Patents
A kind of preparation method for the treatment of cardiovascular disease drug Download PDFInfo
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Abstract
The present invention provides a kind of preparation methods for the treatment of cardiovascular disease drug, and specifically, the present invention provides a kind of such as following formula (IV) compound represented, and the method for preparing tolvaptan by the formula (IV) compound.The method has the advantages that environmental-friendly, raw material is easy to get, and total recovery is high, is suitble to preparation of industrialization tolvaptan.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and specifically, the present invention provides a kind of systems for the treatment of cardiovascular disease drug
Preparation Method.
Background technique
Tolvaptan English name Tolvaptan, trade name: Samsca, entitled N- [the 4- [(7- chloro- 2,3,4,5- tetra- of chemistry
Hydrogen -5- hydroxyl -1H-1- benzo-aza- 1- base) carbonyl] -3- aminomethyl phenyl] -2- methyl benzamide.Support in 2009 is cut down general
The smooth oral type selectivity vasopressin antagonists for obtaining U.S. FDA approval treatment hyponatremia.Tolvaptan obtains national food within 2011
The official approval of product Drug Administration starts in domestic product and sells.The medicine is a kind of selective pitressin V2Receptor is short of money
Anti- medicine can prevent the V of AVP Yu kidney unit distal end2Receptor combines, and increases water excrement in urine, but do not change urine sodium potassium
Secretion and blood potassium value reduce urine osmotic pressure, increase blood sodium value, therefore clinically for treating because of cirrhosis, heart failure, anti-benefit
High capacity caused by urine hormone diacrisis syndrome (SIADH) and etc. hypovolemic hyponatremia.The medical instrument has good
Tolerance, and electrolyte balance is not destroyed, adverse reaction is lighter.Therefore, before such structure medicament has preferable development and application
Scape.
Shown in the structure of tolvaptan such as following formula (I).
Currently, the preparation process route of reported tolvaptan there are several types of:
Route one:
Patent WO 2007/026971, FR 2867187, JP 2009107972 and Bioorg.Med.Chem., 1999,
One kind is reported in 7:17432-1754, and totally 11 steps react to obtain the synthetic route of tolvaptan, which has the disadvantage that: 1)
The single line route of the reaction synthesizes, and greatly reduces overall yield；2) reduction instead uses price height and is a huge sum of money in reaction
The platinum oxide of category makees catalyst, is unsuitable for economical production and environmental protection；3) each portion's reaction all uses column chromatography method and purifies,
Increase production cost；4) some organic solvents for being unfavorable for safety in production are also largely used during, as chloroform extracts
Reagent etc..Therefore the route is not suitable for industrialized production.
Route two:
Alejandro Cordero-Vargas etc. is in Bioorg.Med.Chem., 2006,14 (18): in 6165-6173
Report the synthetic method of another tolvaptan, the preparation method using 4- chloroacetophenone base xanthate as starting material,
Through addition, cyclization, restore to obtain the chloro- 1,2,3,4- tetrahydro benzo azepine of 5- pivaloyl oxygroup -7- at oxime, rearrangement, two stepsAgain
Through obtaining target product with the acylation of 2- methyl -4- nitrobenzoyl chloride, reduction, with the acylation of 2- methyl benzoyl chloride, hydrolysis.The road
There is line starting material to be difficult to obtain, and first step reaction is unfavorable for environmental protection using a kind of solvent 1,2- dichloroethanes, reset
The disadvantages such as yield is low of reaction and the reduction of rear two step, therefore the route is unfavorable for industrial operation and economic industrialization production.
In conclusion this field still lacks, a kind of high income, reaction safety, being suitble to the N- of industrialized production, [[(7- is chloro- by 4-
2,3,4,5- tetrahydro -5- hydroxyl -1H-1- benzo-aza- 1- base) carbonyl] -3- aminomethyl phenyl] and -2- methyl benzamide system
Preparation Method.
Summary of the invention
This field still lacks a kind of high income, reaction safety, N- [4- [(the chloro- 2,3,4,5- of 7- for being suitble to industrialized production
Tetrahydro -5- hydroxyl -1H-1- benzo-aza- 1- base) carbonyl] -3- aminomethyl phenyl] and -2- methyl benzamide preparation method.
The first aspect of the present invention provides a kind of such as following formula (VI) compound represented:
The second aspect of the present invention provides a kind of preparation side of formula (VI) compound as described in the first aspect of the invention
Method, the method includes the steps:
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
In another preferred example, in the step (2), the reaction carries out in the presence of base catalyst；Preferably,
The base catalyst is selected from the group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, or combinations thereof；It is excellent
It is selected as triethylamine, diisopropylethylamine, or combinations thereof.
In another preferred example, in the step (2), it is slowly added to formula (V) compound at a suitable temperature.
In another preferred example, in the step (2), the atent solvent is selected from the group: methylene chloride, acetonitrile,
Tetrahydrofuran, 1,4- dioxane, ether, toluene, dimethylbenzene, or combinations thereof；It is preferred that methylene chloride, acetonitrile.
In another preferred example, in the step (2), the reaction temperature be 0~50 DEG C, preferably 10~40
℃。
In another preferred example, in the step (2), the compound (IV) and 2- methyl -4- nitrobenzene formyl
The molar ratio of chlorine (V) and alkali is 1:1~2:1~5；It is preferably in a proportion of 1:1.2:2.
The third aspect of the present invention provides a kind of such as following formula (IV) compound represented:
The fourth aspect of the present invention provides a kind of preparation side of formula as described in the third aspect of the present invention (IV) compound
Method, the method includes the steps:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III) compound, obtains formula (IV) compound；
In another preferred example, in the step (1), the reaction carries out in the presence of base catalyst；Preferably,
The base catalyst is selected from the group: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, or combinations thereof；It is preferred that sodium carbonate, carbonic acid
Potassium, or combinations thereof.
In another preferred example, in the step (1), the atent solvent is selected from the group: methylene chloride, acetonitrile,
Propionitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, or combinations thereof；It is preferred that propionitrile, acetonitrile, or combinations thereof.
In another preferred example, in the step (1), the reaction temperature be 30~120 DEG C, preferably 50~100
℃。
In another preferred example, in the step (1), the formula (II) compound and formula (III) compound and alkali
Molar ratio is 1:1~2:1~5；Preferably 1:1:2.
In another preferred example, in the step (1), the reaction time is 2-8h.
The fifth aspect of the present invention provides a kind of preparation method of formula (VII) compound, the method includes the steps:
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) change
Close object:
In another preferred example, in the step (3), the reaction carries out in the presence of base catalyst；Preferably,
The base catalyst is selected from the group: sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or combinations thereof；The preferably tert-butyl alcohol
Sodium, potassium tert-butoxide, or combinations thereof.
In another preferred example, in the step (3), the atent solvent is selected from the group: methylene chloride, tetrahydro furan
It mutters, Isosorbide-5-Nitrae-dioxane, ether, toluene, dimethylbenzene, or combinations thereof；It is preferred that toluene, dimethylbenzene, or combinations thereof.
In another preferred example, in the step (3), the reaction temperature be 80~150 DEG C, preferably 100~130
℃。
In another preferred example, in the step (3), the molar ratio of the formula (VI) compound and base catalyst is
1:1~5；Preferably 1:2.
In another preferred example, in the step (3), the reaction time is 0.5-2h.
In another preferred example, the method also includes steps:
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
In another preferred example, the method also includes steps:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III) compound, obtains formula (IV) compound；
The sixth aspect of the present invention provides a kind of formula (VI) compound or such as this hair as described in the first aspect of the invention
Formula described in the bright third aspect (IV) compound is used to prepare the purposes of formula (I) compound (tolvaptan).
In another preferred example, with formula (VI) compound prepare the formula (I) compound method comprising steps of
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) change
Close object:
With
With formula (VII) preparation of compounds of formula (I) compound.
In another preferred example, with formula (IV) compound prepare the formula (I) compound method comprising steps of
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) change
Close object:
With
With formula (VII) preparation of compounds of formula (I) compound.
The seventh aspect of the present invention provides a kind of preparation method of formula (I) compound, the method includes the steps:
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) change
Close object:
(4) it in atent solvent, in presence of an acid catalyst, is reacted with formula (VII) compound, obtains formula (VIII)
Compound；
(5) in atent solvent, hydro-reduction is carried out with formula (VIII) compound, obtains formula (IX) compound；
(6) it in atent solvent, is reacted with formula (IX) compound with o-methyl-benzene formyl chloride, obtains formula (X) compound；
(7) it in atent solvent, is reacted with formula (IX) compound with go back original reagent, obtains formula (I) compound；
In another preferred example, in the step (4), the atent solvent is selected from the group: methanol, ethyl alcohol, water, four
Hydrogen furans, 1,4- dioxane, isopropanol, or combinations thereof, preferred water.
In another preferred example, in the step (4), the acid catalyst is selected from the group: formic acid, acetic acid, hydrochloric acid,
Sulfuric acid, nitric acid, phosphoric acid, or combinations thereof；It is preferred that acetic acid, hydrochloric acid.
In another preferred example, in the step (4), the reaction temperature be 80~130 DEG C, preferably 80~110
℃。
In another preferred example, in the step (5), the atent solvent is selected from the group: methanol, ethyl alcohol, isopropyl
Alcohol, or combinations thereof；It is preferred that methanol, ethyl alcohol, or combinations thereof.
In another preferred example, in the step (5), the reaction carries out in the presence of acid reagent；Preferably, institute
The acid reagent stated is selected from the group: nitric acid, phosphoric acid, hydrochloric acid, sulfuric acid, or combinations thereof；It is preferred that hydrochloric acid.
In another preferred example, in the step (5), the hydro-reduction carries out in the presence of a catalyst；Preferably
Ground, the catalyst are selected from the group: sodium borohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, potassium borohydride, lithium borohydride, dichloro
Change tin, or combinations thereof；It is preferred that sodium borohydride, potassium borohydride, stannous chloride, or combinations thereof.
In another preferred example, in the step (5), the hydro-reduction divides at a suitable temperature in catalyst
It criticizes and is added in reaction system.
In another preferred example, in the step (5), the reaction temperature be 0~50 DEG C, preferably 10~30
℃。
In another preferred example, in the step (5), the molar ratio of the formula (VIII) compound and reducing catalyst
For 1:1~5；Preferably 1:3.
In another preferred example, in the step (6), the atent solvent is selected from the group: methylene chloride, acetonitrile,
Tetrahydrofuran, 1,4- dioxane, toluene, dimethylbenzene, or combinations thereof；It is preferred that methylene chloride, acetonitrile, or combinations thereof.
In another preferred example, in the step (6), the reaction carries out in the presence of base catalyst；Preferably,
The base catalyst is organic base and inorganic base；More preferably, the base catalyst is selected from the group: triethylamine, pyridine, two different
Ethylamine, N-methylmorpholine, DBU, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, or combinations thereof；It is preferred that triethylamine,
Diisopropylethylamine, or combinations thereof.
In another preferred example, in the step (6), the reaction temperature is 0~50 DEG C, preferably 10~40 DEG C.
In another preferred example, in the step (6), the formula (Ⅸ) compound, o-methyl-benzene formyl chloride and alkali
Molar ratio be 1:1~2:1~5；Preferably 1:1.2:2.
In another preferred example, in the step (7), the atent solvent is selected from the group: methanol, ethyl alcohol, isopropyl
Alcohol, or combinations thereof；It is preferred that methanol, ethyl alcohol, or combinations thereof.
In another preferred example, in the step (7), the reaction carries out in the presence of reducing catalyst；Preferably,
The reducing catalyst is selected from the group: sodium borohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, potassium borohydride, lithium borohydride, or
A combination thereof；It is preferred that sodium borohydride, potassium borohydride, or combinations thereof.
In another preferred example, in the step (7), the reducing catalyst is added portionwise instead at a suitable temperature
It answers in system.
In another preferred example, in the step (7), the reaction temperature is -10~30 DEG C, preferably -5~5 DEG C.
In another preferred example, in the step (7), the molar ratio of formula (Ⅹ) compound and reducing catalyst is
1:1~10, preferably 1:1.5.
In another preferred example, the method also includes steps:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III) compound, obtains formula (IV) compound；
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
It is intermediate to devise a kind of synthesis of the tolvaptan as shown in formula (IV) for the present inventor's in-depth study by long-term
Body, prepared by the intermediate convenient, and raw material is easy to get, and reaction condition is mild, is suitble to a large amount of preparations, and be used for work as intermediate
Industry prepares tolvaptan.Based on above-mentioned discovery, inventor completes the present invention.
Term
Herein, term " tolvaptan ", " Tolvaptan ", " Samsca " or " N- [4- [(7- chloro- 2,3,4,5- tetra-
Hydrogen -5- hydroxyl -1H-1- benzo-aza- 1- base) carbonyl] -3- aminomethyl phenyl] -2- methyl benzamide " it is used interchangeably,
Refer to such as following formula (I) compound represented:
Formula (VI) compound
The present invention provides a kind of such as following formula (VI) compound represented:
Formula (VI) compound can be used as intermediate, be used to prepare formula (I) compound (tolvaptan).
The preparation of formula (VI) compound
The present invention also provides the preparation method of formula (VI) compound described in one kind, the method includes the steps:
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
In a preferred embodiment of the invention, the reaction carries out in the presence of base catalyst；Preferably, the alkali
Catalyst is selected from the group: triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, or combinations thereof；Preferably three second
Amine, diisopropylethylamine, or combinations thereof.
In another preferred example, in the step (2), the base catalyst is slowly added to formula at a suitable temperature
(V) compound.
In another preferred example, in the step (2), the atent solvent is selected from the group: methylene chloride, acetonitrile,
Tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ether, toluene, dimethylbenzene, or combinations thereof；It is preferred that methylene chloride, acetonitrile；
In another preferred example, in the step (2), the reaction temperature be 0~50 DEG C, preferably 10~40
℃。
In another preferred example, in the step (2), the compound (IV) and 2- methyl -4- nitrobenzene formyl
The molar ratio of chlorine (V) and alkali is 1:1~2:1~5；It is preferably in a proportion of 1:1.2:2.
Formula (IV) compound
The present invention provides a kind of such as following formula (IV) compound represented:
Formula (IV) compound can be used as intermediate, be used to prepare formula (I) compound (tolvaptan).
The preparation of formula (IV) compound
The present invention also provides the preparation method of formula (IV) compound described in one kind, the method includes the steps:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III) compound, obtains formula (IV) compound；
In a preferred embodiment of the invention, in the step (1), the reaction in the presence of base catalyst into
Row；Preferably, the base catalyst is selected from the group: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, or combinations thereof；It is preferred that
Sodium carbonate, potassium carbonate, or combinations thereof.
In another preferred example, in the step (1), the atent solvent is selected from the group: methylene chloride, acetonitrile,
Propionitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, or combinations thereof；It is preferred that propionitrile, acetonitrile, or combinations thereof.
In another preferred example, in the step (1), the reaction temperature be 30~120 DEG C, preferably 50~100
℃。
In another preferred example, in the step (1), the formula (II) compound and formula (III) compound and alkali
Molar ratio is 1:1~2:1~5；Preferably 1:1:2.
The preparation method of formula (I) compound
The present invention also provides a kind of preparation method of formula (I) compound, the method includes the steps:
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) change
Close object:
With
With formula (VII) preparation of compounds of formula (I) compound, means known in the art progress is can be used in the preparation.
In another preferred example, with formula (IV) compound prepare the formula (I) compound method comprising steps of
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) change
Close object:
With
With formula (VII) preparation of compounds of formula (I) compound, means known in the art progress is can be used in the preparation.
In a preferred embodiment of the invention, the preparation method of the formula (I) compound, comprising steps of
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) change
Close object:
(4) it in atent solvent, in presence of an acid catalyst, is reacted with formula (VII) compound, obtains formula (VIII)
Compound；
(5) in atent solvent, hydro-reduction is carried out with formula (VIII) compound, obtains formula (IX) compound；
(6) it in atent solvent, is reacted with formula (IX) compound with o-methyl-benzene formyl chloride, obtains formula (X) compound；
(7) it in atent solvent, is reacted with formula (IX) compound with go back original reagent, obtains formula (I) compound；
In another preferred example, in the step (4), the atent solvent is selected from the group: methanol, ethyl alcohol, water, four
Hydrogen furans, 1,4- dioxane, isopropanol, or combinations thereof, preferred water.
In another preferred example, in the step (4), the acid catalyst is selected from the group: formic acid, acetic acid, hydrochloric acid,
Sulfuric acid, nitric acid, phosphoric acid, or combinations thereof；It is preferred that acetic acid, hydrochloric acid.
In another preferred example, in the step (4), the reaction temperature be 80~130 DEG C, preferably 80~110
℃。
In another preferred example, in the step (5), the atent solvent is selected from the group: methanol, ethyl alcohol, isopropyl
Alcohol, or combinations thereof；It is preferred that methanol, ethyl alcohol, or combinations thereof.
In another preferred example, in the step (5), the reaction carries out in the presence of acid reagent；Preferably, institute
The acid reagent stated is selected from the group: nitric acid, phosphoric acid, hydrochloric acid, sulfuric acid, or combinations thereof；It is preferred that hydrochloric acid.
In another preferred example, in the step (5), the hydro-reduction carries out in the presence of a catalyst；Preferably
Ground, the catalyst are selected from the group: sodium borohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, potassium borohydride, lithium borohydride, dichloro
Change tin, or combinations thereof；It is preferred that sodium borohydride, potassium borohydride, stannous chloride, or combinations thereof.
In another preferred example, in the step (5), the hydro-reduction divides at a suitable temperature in catalyst
It criticizes and is added in reaction system.
In another preferred example, in the step (5), the reaction temperature be 0~50 DEG C, preferably 10~30
℃。
In another preferred example, in the step (5), the molar ratio of the formula (VIII) compound and reducing catalyst
For 1:1~5；Preferably 1:3.
In another preferred example, in the step (6), the atent solvent is selected from the group: methylene chloride, acetonitrile,
Tetrahydrofuran, 1,4- dioxane, toluene, dimethylbenzene, or combinations thereof；It is preferred that methylene chloride, acetonitrile, or combinations thereof.
In another preferred example, in the step (6), the reaction carries out in the presence of base catalyst；Preferably,
The base catalyst is organic base and inorganic base；More preferably, the base catalyst is selected from the group: triethylamine, pyridine, two different
Ethylamine, N-methylmorpholine, DBU, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, or combinations thereof；It is preferred that triethylamine,
Diisopropylethylamine, or combinations thereof.
In another preferred example, in the step (6), the reaction temperature is 0~50 DEG C, preferably 10~40 DEG C.
In another preferred example, in the step (6), the formula (Ⅸ) compound, o-methyl-benzene formyl chloride and alkali
Molar ratio be 1:1~2:1~5；Preferably 1:1.2:2.
In another preferred example, in the step (7), the atent solvent is selected from the group: methanol, ethyl alcohol, isopropyl
Alcohol, or combinations thereof；It is preferred that methanol, ethyl alcohol, or combinations thereof.
In another preferred example, in the step (7), the reaction carries out in the presence of reducing catalyst；Preferably,
The reducing catalyst is selected from the group: sodium borohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, potassium borohydride, lithium borohydride, or
A combination thereof；It is preferred that sodium borohydride, potassium borohydride, or combinations thereof.
In another preferred example, in the step (7), the reducing catalyst is added portionwise instead at a suitable temperature
It answers in system.
In another preferred example, in the step (7), the reaction temperature is -10~30 DEG C, preferably -5~5 DEG C.
In another preferred example, in the step (7), the molar ratio of formula (Ⅹ) compound and reducing catalyst is
1:1~10, preferably 1:1.5.
In another preferred embodiment of the invention, it is described the preparation method is as follows:
The present invention provides following technical scheme, a kind of to prepare N- [4- [(chloro- 2,3,4,5- tetrahydro -5- hydroxyl -1H-1- of 7-
Benzo-aza- 1- base) carbonyl] -3- aminomethyl phenyl] and -2- methyl benzamide new method.The reaction the following steps are included:
(1) preparation of compound (IV):
2- amino -5- chloro benzoic ether (II) and 4- bromo butyric acid methyl ester (III) will be distributed in suitable solvent, and
Suitable base catalyst is added, at a suitable temperature fully reacting, compound (IV) can be obtained through post-processing appropriate.
Wherein: suitable solvent is methylene chloride, acetonitrile, propionitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane etc., preferably propionitrile,
Acetonitrile；Suitable base catalyst can be divided into sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate etc., preferably sodium carbonate, potassium carbonate.Temperature
Degree is 30~120 DEG C, preferably 50~100 DEG C；Suitable 2- amino -5- chloro benzoic ether (II) and 4- bromo butyric acid methyl ester (III)
And the ratio of alkali is 1:1~2:1~5；It is preferably in a proportion of 1:1:2.
(2) preparation of compound (VI):
Compound (IV) is distributed in suitable solvent, sequentially adds suitable base catalyst, at a suitable temperature
It is slowly added to 2- methyl -4- nitrobenzoyl chloride (V), obtains compound (VI) through processing appropriate after the reaction was completed.
Wherein: suitable solvent is methylene chloride, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ether, toluene, dimethylbenzene
Deng, preferred methylene chloride, acetonitrile；Suitable base catalyst is triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine,
DBU etc., preferably triethylamine, diisopropylethylamine.Temperature is 0~50 DEG C, preferably 10~40 DEG C；Suitable compound (IV) and 2-
The ratio of methyl -4- nitrobenzoyl chloride (V) and alkali is 1:1~2:1~5；It is preferably in a proportion of 1:1.2:2.
(3) preparation of compound (VII):
Compound (VI) is dissolved in suitable solvent, catalyst appropriate is added, carries out cyclization at a suitable temperature,
Compound (VII) is obtained through processing appropriate.
Wherein: suitable solvent is methylene chloride, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ether, toluene, and dimethylbenzene etc. is excellent
Select toluene, dimethylbenzene；Suitable base catalyst sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide etc., preferably sodium tert-butoxide, uncle
Butanol potassium.Temperature is 80~150 DEG C, preferably 100~130 DEG C；The ratio of suitable compound (VI) and alkali is 1:1~5；It is preferred that compare
Example is 1:2.
(4) preparation of compound (VIII):
Compound (VII) is dispersed in suitable acid mixed solution, is reacted at a proper temperature, obtains chemical combination
Object (VIII).
Wherein: suitable solvent is methanol, ethyl alcohol, water, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, isopropanol etc., preferably water；
Suitable acid catalyst is formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., preferably acetic acid, hydrochloric acid；Suitable temperature is 80
~130 DEG C, preferably 80~110 DEG C.
(5) preparation of compound (Ⅸ):
By compound (VIII) dispersion in a suitable solvent, suitable reducing catalyst is added, at a proper temperature into
Compound (Ⅸ) can be obtained through processing appropriate in row hydro-reduction.
Wherein: suitable solvent is methanol, ethyl alcohol, isopropanol, preferably methanol, ethyl alcohol；Suitable acid reagent is nitric acid, phosphorus
Acid, hydrochloric acid, sulfuric acid etc., preferably hydrochloric acid；Suitable reducing catalyst is sodium borohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, boron hydrogen
Change potassium, lithium borohydride, stannous chloride etc., preferably sodium borohydride, potassium borohydride, stannous chloride；Suitable temperature is added portionwise, temperature
Degree is 0~50 DEG C, preferably 10~30 DEG C；Suitable compound (VIII) and reducing catalyst ratio are 1:1~5, are preferably in a proportion of
1:3。
(6) preparation of compound (Ⅹ):
In a suitable solvent, suitable catalyst is added in compound (Ⅸ) dispersion, then adds suitable adjacent first
Base chlorobenzoyl chloride carries out amidation process at a proper temperature, and compound can be obtained through processing appropriate after the reaction was completed
(Ⅹ)。
Wherein: suitable solvent is methylene chloride, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, and dimethylbenzene etc. is excellent
Select methylene chloride, acetonitrile；Suitable base catalyst can be divided into organic base and inorganic base, and organic base is triethylamine, pyridine, diisopropyl
Base ethylamine, N-methylmorpholine, DBU etc.；Inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate etc., preferably triethylamine,
Diisopropylethylamine.Temperature is 0~50 DEG C, preferably 10~40 DEG C；Suitable compound (Ⅸ) and o-methyl-benzene formyl chloride and alkali
Ratio be 1:1~2:1~5；It is preferably in a proportion of 1:1.2:2.
(7) N- [4- [(the chloro- 2,3,4,5- tetrahydro of 7- -- 5- hydroxyl -1H-1- benzo-aza- 1- base) carbonyl] -3- methyl
Phenyl] -2- methyl benzamide (I) preparation:
In a suitable solvent by compound (Ⅹ) dispersion, suitable go back original reagent is added at a suitable temperature and carries out hydrogen
Change reaction, N- [4- [(7- chloro- 2,3,4,5- tetrahydros -- 5- hydroxyl -1H-1- benzo-aza can be obtained- 1- base) carbonyl] -3-
Aminomethyl phenyl] -2- methyl benzamide (I).
Wherein: suitable solvent is methanol, ethyl alcohol, isopropanol, preferably methanol, ethyl alcohol；Suitable reducing catalyst is boron
Sodium hydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, potassium borohydride, stannous chloride and lithium borohydride etc., preferably sodium borohydride, boron
Hydrofining；Suitable temperature is added portionwise, and temperature is -10~30 DEG C, preferably -5~5 DEG C；Suitable compound (Ⅹ) with also
Raw catalyst ratio is 1:1~10, is preferably in a proportion of 1:1.5.
Compared with prior art, main advantages of the present invention include:
N- [4- [(the chloro- 2,3,4,5- tetrahydro of 7- -- 5- hydroxyl -1H-1- benzo is prepared the object of the present invention is to provide a kind of
Azepine- 1- base) carbonyl] -3- aminomethyl phenyl] and -2- methyl benzamide new method, the synthetic route not only high income is pure
It spends, the chloro- 5- hydroxyl -2,3 of the 7- for avoiding traditional price high, 4,5- tetrahydro -1H-1- benzo-azasFor raw material, reaction is reduced
Step shortens process cycle, substantially reduces production cost, and raw material 2- amino -5- chloro benzoic ether is completely easy to get, and operates
It is more simple, the advantages that safety is more preferable.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1:
(1) synthesis of compound (IV)
By 2- amino -5- chloro benzoic ether (30.0g, 161.63mmol) and with 4- bromo butyric acid methyl ester (III) (29.26g,
It 161.63mmol) is dissolved in acetonitrile (600mL), is added sodium carbonate (34.26g, 323.26mmol), is then heated with stirring to 80
DEG C, 5h, TLC detection are reacted, reaction is completed.It is cooled to room temperature, reaction solution is poured into water in (300mL), take organic phase, water phase is used
Ethyl acetate extracts twice of (200mL x 2), merges organic phase, and be washed with water twice (200mL x 2), and anhydrous sodium sulfate is dry
Dry, rotation goes solvent to obtain compound (IV) 43.41g, yield 94.0%.
1H-NMR(400MHz,DMSO):δ7.69(s,1H),7.50(s,1H),6.75(s,1H),6.61(s,1H),3.85
(s,3H),3.65(s,3H),3.33(m,2H),2.50(m,2H),2.03(m,2H)。C13H16ClNO4(M+H)+Calcd:
285.0768,found:285.0771。
(2) synthesis of compound (VI)
Compound (IV) (40.0g, 140.00mmol) is dissolved in methylene chloride (600mL), triethylamine is added with stirring
(39.03mL, 280.00mmol), at room temperature, be slowly added to 2- methyl -4- nitrobenzoyl chloride (V) (33.53g,
168.00mmol), 4h, TLC detection are reacted, reaction is completed.Reaction solution is poured into water (300mL), organic phase washed with water
(200mL) and saturated salt solution (200mL) are washed, and anhydrous sodium sulfate is dry, are spin-dried for, are obtained compound (VI) 54.04g, are received
Rate is 86.0%.
1H-NMR(400MHz,DMSO):δ8.31(s,1H),8.24(s,1H),8.17(s,1H),7.88(s1H),7.75
(s, 1H), 7.65 (s, 1H), 4.22 (m, 2H), 3.85 (s, 3H), 3.66 (s, 3H), 2.43~2.48 (m, 5H), 2.09 (m,
2H)。C21H21ClN2O7(M+H)+Calcd:448.1037,found:448.1042。
(3) synthesis of compound (VII)
Compound (VI) (50.0g, 111.40mmol) is dissolved in toluene (500mL), addition potassium tert-butoxide (25.0g,
222.79mmol), 120 DEG C are warming up to, 1h, TLC detection are stirred, reaction is completed.It is cooled to room temperature.Successively with water (2x 200mL) and
Saturated salt solution (200mL) is washed, and anhydrous sodium sulfate dries, filters, and is spin-dried for, and obtains compound (VII) 39.93g, and yield is
86.0%.
(4) synthesis of compound (VIII)
Compound (VII) (30.0g, 71.98mmol) is dissolved in acetic acid (150mL), concentrated hydrochloric acid (75mL) and water (15mL) are mixed
It closes in solution, is heated to 100 DEG C, stir 6h, TLC detection, reaction is completed.It is cooled to room temperature, pours into ice water (150mL), stirs
15min, stirring is lower to use 4N sodium hydroxide solution by pH=7-8, methylene chloride (200mL x 3) extraction.Successively use water (200mL)
It is washed with saturated salt solution (200mL), anhydrous sodium sulfate is dried, filtered, is spin-dried for, and obtains product 22.88g, yield 88.6%.
(5) synthesis of compound (Ⅸ)
Into the concentrated hydrochloric acid (70mL) and ethyl alcohol (140mL) suspension of compound (VIII) (22.0g, 61.32mmol), in batches
SnCl is added2·2H2O (41.51g, 183.96mmol), in room temperature reaction 4h after finishing.TLC detects end of reaction, and decompression rotation is gone
Ethyl alcohol, residual reaction liquid are placed refrigerator freezing and are stayed overnight, and have a large amount of solids to be precipitated, and filter, after filter cake is washed with a small amount, then use
The dissolution of 150ml water, 20% sodium hydroxide solution is added dropwise while stirring and is adjusted to pH=9, filters, and filter cake is carried out weight with dehydrated alcohol
Crystallization, obtains light yellow solid, is compound (Ⅸ) (16.13g, 80.0%).
(6) synthesis of compound (Ⅹ)
Compound (Ⅸ) (16.0g, 48.66mmol) is dissolved in methylene chloride (400mL), triethylamine is added
(13.57mL, 97.33mmol) stirs 15min, o-methyl-benzene formyl chloride (9.03g, 58.40mmol) is then added portionwise again,
2h, TLC detection are reacted at room temperature, and reaction is completed.Reaction solution is poured into water in (200mL), organic phase is washed twice
(200ml x 2), anhydrous sodium sulfate is dry, and rotation goes methylene chloride to obtain product 2- methyl -4- (2- methyl benzamide base) benzoic acid
(19.21g, 88.3%).
(7) N- [4- [(the chloro- 2,3,4,5- tetrahydro of 7- -- 5- hydroxyl -1H-1- benzo-aza- 1- base) carbonyl] -3- methyl
Phenyl] -2- methyl benzamide (I) preparation
By the chloro- 5- hydroxyl -2,3,4,5- tetrahydro -1H-1- benzo-aza of 7-(19.0g, 42.51mmol) is dissolved in methanol
In (200ml) solvent, sodium borohydride (2.42g, 63.77mmol) is added portionwise under the conditions of 0 DEG C, continues to stir after charging
2h, TLC detection reaction are completed.Reaction solution is poured into water, methylene chloride extraction, anhydrous sodium sulfate is dry, filters and depressurizes
Distill to obtain crude product, utilize methanol: petroleum ether (2:1) recrystallization obtains white solid tolvaptan (18.33g, 96.0%).
Embodiment 2:
(1) synthesis of compound (IV)
By 2- amino -5- chloro benzoic ether (30.0g, 161.63mmol) and with 4- bromo butyric acid methyl ester (III) (29.26g,
It 161.63mmol) is dissolved in acetonitrile (600mL), is added potassium carbonate (44.68g, 323.26mmol), is then heated with stirring to 80
DEG C, 5h, TLC detection are reacted, reaction is completed.It is cooled to room temperature, reaction solution is poured into water in (300mL), take organic phase, water phase is used
Ethyl acetate extracts twice of (200mL x 2), merges organic phase, and be washed with water twice (200mL x 2), and anhydrous sodium sulfate is dry
Dry, rotation goes solvent to obtain compound (IV) 42.49g, yield 92.0%.
(2) synthesis of compound (VI)
Compound (IV) (40.0g, 140.00mmol) is dissolved in methylene chloride (600mL), diisopropyl is added with stirring
Base ethamine (36.19g, 280.00mmol), at room temperature, be slowly added to 2- methyl -4- nitrobenzoyl chloride (V) (33.53g,
168.00mmol), 4h, TLC detection are reacted, reaction is completed.Reaction solution is poured into water (300mL), organic phase washed with water
(200mL) and saturated salt solution (200mL) are washed, and anhydrous sodium sulfate is dry, are spin-dried for, are obtained compound (VI) 55.74g, are received
Rate is 88.7%.
(3) synthesis of compound (VII)
Compound (VI) (50.0g, 111.40mmol) is dissolved in toluene (500mL), addition potassium tert-butoxide (25.0g,
222.79mmol), 120 DEG C are warming up to, 1h, TLC detection are stirred, reaction is completed.It is cooled to room temperature.Successively with water (2x 200mL) and
Saturated salt solution (200mL) is washed, and anhydrous sodium sulfate dries, filters, and is spin-dried for, and obtains compound (VII) 39.0g, and yield is
84.0%.
(4) synthesis of compound (VIII)
Compound (VII) (30.0g, 71.98mmol) is dissolved in acetic acid (150mL), concentrated hydrochloric acid (75mL) and water (15mL) are mixed
It closes in solution, is heated to 100 DEG C, stir 5h, TLC detection, reaction is completed.It is cooled to room temperature, pours into ice water (150mL), stirs
15min, stirring is lower to use 4N sodium hydroxide solution by pH=7-8, methylene chloride (200mL x 3) extraction.Successively use water (200mL)
It is washed with saturated salt solution (200mL), anhydrous sodium sulfate is dried, filtered, is spin-dried for, and obtains product 21.95g, yield 85.0%.
(5) synthesis of compound (Ⅸ)
Into the concentrated hydrochloric acid (70mL) and ethyl alcohol (140mL) suspension of compound (VIII) (20.0g, 55.75mmol), in batches
SnCl is added2·2H2O (37.74g, 167.23mmol), in room temperature reaction 4h after finishing.TLC detects end of reaction, and decompression rotation is gone
Ethyl alcohol, residual reaction liquid are placed refrigerator freezing and are stayed overnight, and have a large amount of solids to be precipitated, and filter, after filter cake is washed with a small amount, then use
The dissolution of 150ml water, 20% sodium hydroxide solution is added dropwise while stirring and is adjusted to pH=9, filters, and filter cake is carried out weight with dehydrated alcohol
Crystallization, obtains light yellow solid, is compound (Ⅸ) (14.90g, 81.3%).
(6) synthesis of compound (Ⅹ)
Compound (Ⅸ) (14.0g, 42.58mmol) is dissolved in methylene chloride (350mL), diisopropylethylamine is added
(11.0g, 85.16mmol) stirs 15min, o-methyl-benzene formyl chloride (7.90g, 51.10mmol) is then added portionwise again,
2h, TLC detection are reacted under room temperature, and reaction is completed.Reaction solution is poured into water in (200mL), organic phase is washed twice
(200ml x 2), anhydrous sodium sulfate is dry, and rotation goes methylene chloride to obtain product 2- methyl -4- (2- methyl benzamide base) benzoic acid
(17.24g, 90.6%).
(7) N- [4- [(the chloro- 2,3,4,5- tetrahydro of 7- -- 5- hydroxyl -1H-1- benzo-aza- 1- base) carbonyl] -3- methyl
Phenyl] -2- methyl benzamide (I) preparation
By the chloro- 5- hydroxyl -2,3,4,5- tetrahydro -1H-1- benzo-aza of 7-(17.0g, 38.04mmol) is dissolved in methanol
In (200ml) solvent, sodium borohydride (2.16g, 57.06mmol) is added portionwise under the conditions of 0 DEG C, continues to stir after charging
2h, TLC detection reaction are completed.Reaction solution is poured into water, methylene chloride extraction, anhydrous sodium sulfate is dry, filters and depressurizes
Distill to obtain crude product, utilize methanol: petroleum ether (2:1) recrystallization obtains white solid tolvaptan (16.22g, 95.0%).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (12)
1. a kind of such as following formula (VI) compound represented:
2. the preparation method of formula (VI) compound as described in claim 1, which is characterized in that comprising steps of
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
3. preparation method as claimed in claim 2, which is characterized in that in the step (2), the reaction is in base catalysis
It is carried out in the presence of agent.
4. preparation method as claimed in claim 3, which is characterized in that the base catalyst is selected from the group: triethylamine, pyrrole
Pyridine, diisopropyl ethyl amine, N-methylmorpholine, DBU, or combinations thereof.
5. preparation method as claimed in claim 3, which is characterized in that the base catalyst is selected from the group: triethylamine, two different
Propylethylamine, or combinations thereof.
6. method according to claim 2, which is characterized in that the method also includes steps:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III) compound, obtains formula (IV) compound；
7. preparation method as claimed in claim 6, which is characterized in that in the step (1), the reaction is in base catalysis
It is carried out in the presence of agent.
8. preparation method as claimed in claim 7, which is characterized in that the base catalyst is selected from the group: sodium carbonate, carbonic acid
Hydrogen sodium, potassium carbonate, cesium carbonate, or combinations thereof.
9. preparation method as claimed in claim 7, which is characterized in that the base catalyst is selected from the group: sodium carbonate, carbonic acid
Potassium, or combinations thereof.
10. a kind of preparation method of formula (VII) compound, which is characterized in that comprising steps of
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) chemical combination
Object:
11. a kind of preparation method of formula (I) compound, which is characterized in that comprising steps of
(2) it in atent solvent, is reacted with formula (IV) compound with formula (V) compound, obtains formula (VI) compound；
(3) it in atent solvent, in the presence of base catalyst, is reacted with formula (VI) compound, obtains formula (VII) chemical combination
Object:
(4) it in atent solvent, in presence of an acid catalyst, is reacted with formula (VII) compound, obtains formula (VIII) chemical combination
Object；
(5) in atent solvent, hydro-reduction is carried out with formula (VIII) compound, obtains formula (IX) compound；
(6) it in atent solvent, is reacted with formula (IX) compound with o-methyl-benzene formyl chloride, obtains formula (X) compound；
(7) it in atent solvent, is reacted with formula (IX) compound with go back original reagent, obtains formula (I) compound；
12. preparation method as claimed in claim 11, which is characterized in that the method also includes steps:
(1) it in atent solvent, is reacted with formula (II) compound and formula (III) compound, obtains formula (IV) compound；
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| 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 |
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| WO2005085183A1 (en) * | 2004-03-02 | 2005-09-15 | Centre National De La Recherche Scientifique | Method of preparing benzazepines and derivatives thereof |
| 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 |
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| Title |
|---|
| "7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine(OPC-41061): A Potent, Orally Active Nonpeptide Arginine Vasopressin V2 Receptor Antagonist";Kazumi Kondo,et al.;《Bioorganic & Medicinal Chemistry》;19991231;第7卷;1743-1754 * |
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