CN113004167A

CN113004167A - Tolvaptan related impurity, and synthesis method and application thereof

Info

Publication number: CN113004167A
Application number: CN201911321453.3A
Authority: CN
Inventors: 蔡华生; 黄祺; 陈洪; 黄浩喜; 苏忠海
Original assignee: Chengdu Beite Pharmaceutical Co ltd
Current assignee: Chengdu Beite Pharmaceutical Co ltd
Priority date: 2019-12-20
Filing date: 2019-12-20
Publication date: 2021-06-22

Abstract

The invention discloses a tolvaptan related impurity formula I and a synthetic method thereof, which can be used as a raw material for synthesizing tolvaptan impurity formulas VI and VII. The impurities disclosed by the invention provide a new reference substance for detecting the impurities in the tolvaptan bulk drug and the preparation thereof, and are more beneficial to quality research and quality control of the tolvaptan bulk drug and the preparation thereof. By adopting the inventionThe tolvaptan impurity prepared by the method has the characteristics of simple steps, low cost, small impurity amount and high yield.

Description

Tolvaptan related impurity, and synthesis method and application thereof

Technical Field

The invention relates to the field of medicines, in particular to tolvaptan related impurities, a synthetic method and application thereof.

Background

Tolvaptan (Tolvaptan, trade name: Samsca, Sumaica), chemical name: n- [4- [ (5R) -7-chloro-5-hydroxy-2, 3,4, 5-tetrahydro-1-benzazepine

1-formyl radical]-3-methylphenyl radical]-2-methylbenzamide. Is a non-peptide selective antagonist of the vasopressin V2 receptor, developed by tsukamur Pharmaceutical corporation of japan (Otsuka Pharmaceutical co., Ltd), which selectively blocks the tubular arginine vasopressin receptor, increases the concentration of sodium ions in the plasma, and helps to drain excess water from the urine. Tolvaptan can enhance the ability of the kidney to treat water, can obviously reduce the weight and edema of a patient, is not accompanied by the increase of electrolyte excretion, does not destroy the balance of blood electrolytes, and has the characteristics of no sodium discharge during water drainage. The Chinese medicinal preparation is sold on the market in 09 months in 2011, and is prepared from Tsukamur Zhejiang for treating clinically obvious hyponatremia with high and normal capacity (blood sodium concentration)<125mEq/L, hyponatremia is not obvious but symptomatic and fluid-limiting therapy is not effective), including patients with heart failure, cirrhosis of the liver and antidiuretic hormone secretion dysfunction Syndrome (SIADH).

In addition, tolvaptan was approved as a new indication by the European Medicines Agency (EMA) at month 05 2015: for slowing down the treatment of autosomal dominant hereditary polycystic kidney disease (ADPKD), under the trade name "Jinarc". The indication was approved by the U.S. drug administration (FDA) in 04 months in 2018 under the trade designation "jynarqe". Can be used for treating hyponatremia caused by congestive heart failure, liver cirrhosis and syndrome of insufficient secretion of antidiuretic hormone.

Tolvaptan as a BCS classified IV drug has poor solubility and is very easy to wrap other impurities in the synthesis and purification processes. The related impurities of tolvaptan reported in the prior patents are as follows:

if impurities generated in the intermediate synthesis process cannot be removed in time, the impurities can be further derived into other impurities along with the process in the subsequent reaction, and the impurities are almost not removed by any method after the derivation, so that the API with higher purity is not easy to obtain.

In order to better control the quality of tolvaptan, various impurities of a front-end intermediate of tolvaptan are generally required to be researched and controlled, the application provides a brand new compound formula I serving as a new impurity of the tolvaptan intermediate and a synthesis method thereof, provides a synthesis method for preparing a compound formula VII from the compound formula I, and provides guarantee for controlling the quality of a tolvaptan bulk drug. In addition, the compound shown in the formula VI and VII also has vasopressin antagonistic activity and can be used as a vasopressin antagonist.

Disclosure of Invention

In the existing typical synthetic route of tolvaptan, various impurities are often generated, and experiments show that the content of the impurity shown in formula I in the intermediate in the route is 0.48%, the content of the impurity shown in formula VI in the intermediate is 0.76%, the compound shown in formula I can be remained in the intermediate, or a finished product impurity compound shown in formula VII is further generated in the subsequent steps, and the content of the impurity shown in formula VII in the finished product of tolvaptan is 0.35%, which is far beyond the limit specified in ICH. Therefore, the research on the tolvaptan intermediate impurities is particularly important in the preparation process.

The invention develops a new compound and a preparation method thereof for the first time, and lays a foundation for effectively controlling and tamping the quality of a tolvaptan bulk drug and a tolvaptan preparation.

Specifically, the present invention provides a compound represented by the following structure:

meanwhile, the invention also provides a synthesis method of the compound, which comprises the following steps:

dispersing 2-methyl-4- (2-methylbenzamido) benzoyl chloride in an organic solvent, and reacting under an alkaline condition to obtain a compound shown as a formula I

Further, the air conditioner is provided with a fan,

in the method, the organic solvent is an aprotic solvent such as dichloromethane, chloroform, 1, 4-dioxane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate and the like; preferably dichloromethane;

in the method, the base is organic base such as triethylamine, pyridine, N-diisopropylethylamine and N-methylmorpholine, or inorganic base such as sodium carbonate and potassium carbonate, preferably N-methylmorpholine;

in the method, the amount of the base is 1.0 to 5.0 equivalents, and further 2.0 equivalents;

the reaction temperature of the method is 0-40 ℃, and further 15-20 ℃;

the reaction time of the method is 0.5-10 hours, and further 6 hours.

The above synthesis steps are further carried out in the step of,

after the reaction is finished, a reaction system is respectively washed by water and dilute hydrochloric acid, concentrated and subjected to column chromatography to obtain the target compound shown in the formula I.

The compound of the formula I can be used as a raw material for synthesizing the compounds of the formula VI and the formula VII, and the synthesis steps are as follows:

step 1) converting a compound of formula I into an intermediate state under the action of thionyl chloride;

step 2) the intermediate state and 7-chloro-1, 2,3, 4-tetrahydrobenzo [ B ] azepine-5-ketone are subjected to condensation reaction in the presence of alkali to generate a formula VI;

and 3) reducing the formula VI to obtain a formula VII.

Further, the air conditioner is provided with a fan,

the preparation method of the intermediate state in the step 1 comprises the following steps: taking a compound shown in the formula I, adding 10 times of dichloromethane and 1.5 equivalents of thionyl chloride, performing reflux reaction for 5-6 hours, and performing reduced pressure evaporation to dryness to obtain the compound;

in the step 2, the organic solvent is an aprotic solvent, and the aprotic solvent is one or a mixture of dichloromethane, chloroform, 1, 4-dioxane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate and the like; preferably dichloromethane;

the base in the step 2 is organic base, such as triethylamine, pyridine, N-diisopropylethylamine and N-methylmorpholine, or inorganic base, such as sodium carbonate and potassium carbonate, preferably N-methylmorpholine;

the amount of the alkali in the step 2 is 1.0 to 6.0 equivalents, and further 1.5 equivalents;

step 2, the reaction temperature is 0-40 ℃, and is further 25 ℃;

the reaction time of the step 2 is 0.5 to 6 hours, and further 6 hours.

And 2, after the reaction is finished, washing the reaction system with water and dilute hydrochloric acid respectively, concentrating, and carrying out column chromatography to obtain the compound shown in the formula VI.

The organic solvent in the step 3 is anhydrous methanol, anhydrous ethanol, anhydrous isopropanol or anhydrous tetrahydrofuran, and preferably is the anhydrous methanol;

the reducing agent in the step 3 is sodium borohydride, sodium triacetyl borohydride and the like, and preferably sodium borohydride;

the amount of the reducing agent in the step 3 is 0.5-3.0 equivalent, preferably 0.6 equivalent;

the reaction temperature in the step 3 is-20-50 ℃, and the preferable temperature is 0-10 ℃;

or, in the step 3, isopropanol is used as a solvent, and aluminum isopropoxide is used as a catalyst to carry out reaction; the dosage of the isopropanol is preferably 7-10 times of the weight of the formula VI, and the dosage of the aluminum isopropoxide is preferably 0.4-0.5 time of the weight of the formula VI; the reaction temperature is preferably 70-80 ℃;

the invention has the beneficial effects that a new compound and a synthesis method thereof are provided; the obtained compound is used as an impurity reference substance of a tolvaptan bulk drug intermediate, is further derivatized to form a tolvaptan impurity formula VII, can be used for quality research of tolvaptan bulk drugs and tolvaptan-containing preparations, and can effectively and accurately monitor related substances and suspected genotoxicity residues in tolvaptan, so that the tolvaptan bulk drug meets related substance standards and genotoxicity standards, and the safety and the effectiveness of clinical use of tolvaptan drugs are ensured.

The method for synthesizing the tolvaptan key impurity of the formula VI and the formula VII by using the compound is simple and convenient, the cost is saved, the obtained product has high purity and high yield, and the obtained product meets the requirement of green chemistry.

Drawings

FIG. 1 is a nuclear magnetic spectrum of a compound of formula I;

FIG. 2 is a nuclear magnetic spectrum of a compound of formula VI;

FIG. 3 is an intermediate HPLC chromatogram;

FIG. 4 is a HPLC chromatogram of a tolvaptan finished product.

Detailed Description

To more fully explain the practice of the present invention, examples of methods for preparing tolvaptan hybrids the compounds of formula I and VI, formula VII are provided. These examples are merely illustrative and do not limit the scope of the invention.

In the present disclosure, unless specifically defined, the abbreviations used have the following meanings:

min means minutes;

h means hours;

d is day;

DEG C means centigrade;

mol/L refers to mol per liter;

TLC refers to thin layer chromatography;

HPLC refers to high performance liquid chromatography;

LC-MS refers to liquid chromatography-mass spectrometry.

Example 1: effect of the amount of pyridine on the Synthesis of the Compound of formula I

15.0g of 2-methyl-4- (2-methylbenzamido) benzoyl chloride (formula V) was dissolved by adding 150g of dichloromethane, and the solution was divided equally into A, B parts and C three parts: 1.38g (1.0 eq) of pyridine was added to A, 2.06g (1.5 eq) of pyridine was added to B, and 2.75g (2.0 eq) of pyridine was added to C. Reacting for 10 hours at room temperature (15-20 ℃).

The reaction system was washed with 1mol/L hydrochloric acid (50mL) and saturated brine (20mL), dried over sodium sulfate, concentrated, and then separated by column chromatography to give the product.

¹H-NMR(400MHz,d⁶-DMSO):δ10.72(s,2H),8.09(d,J＝8.8Hz,2H),7.85-7.78(m,4H),7.51-7.31(m,8H),2.80(s,2H),2.61(s,6H),2.40(s,6H)ppm.

LC-MS excimer ions 559.1621, [ M + K ]]⁺

The yield ratio for each group of compounds of experimental formula i is as follows:

TABLE 1 product yield at different pyridine amounts

Experimental groups	Number of pyridine equivalents	Yield of formula I	Molar yield
				A	1.0	0.76g	16.8％
B	1.5	0.91g	20.1％
				C	2.0	1.15g	25.4％

As can be seen from the above table, the yield of pyridine as a base was low. The yield is slightly improved by increasing the pyridine dosage, and TLC shows that a large amount of raw materials are remained, which indicates that pyridine is used as alkali and the reaction activity is possibly insufficient.

Example 2: effect of the amount of Triethylamine on the Synthesis of the Compound of formula I

18.2g of 2-methyl-4- (2-methylbenzamido) benzoyl chloride (formula V) was dissolved in 185.6g of dichloromethane, and the solution was divided into A, B and C three portions: 2.14g (1.0 equivalent) of triethylamine was added to A, 3.22g (1.5 equivalents) of triethylamine was added to B, and 4.28g (2.0 equivalents) of triethylamine was added to C. Reacting at room temperature (20-25 ℃) for 8 hours.

The reaction system was washed with 1mol/L hydrochloric acid (50mL) and saturated brine (20mL), dried over sodium sulfate, concentrated, and then subjected to column chromatography to isolate the product.

TABLE 2 comparison of the yields of different triethylamine amounts

Experimental groups	Number of equivalents of triethylamine	Yield of formula I	Molar yield
				A	1.0	2.36g	42.8％
B	1.5	3.35g	61.1％
				C	2.0	3.31g	60.3％

As can be seen by comparing example 2 and example 3, the yield of the triethylamine group is significantly higher than that of the pyridine group. Wherein, when the dosage of triethylamine is 1.5 to 2.0 equivalents, the yield can reach about 60 percent at most. Before column chromatography, TLC showed more impurity spots.

Example 3: effect of the amount of N-methylmorpholine on the Synthesis of Compounds of formula I

21.3g of 2-methyl-4- (2-methylbenzamido) benzoyl chloride (formula V) is dissolved by adding 220.6g of dichloromethane, and the solution is divided equally into A, B parts and C three parts: 2.51g (1.0 eq) of N-methylmorpholine was added to A, 3.80g (1.5 eq) of N-methylmorpholine was added to B, and 5.02g (2.0 eq) of N-methylmorpholine was added to C. Reacting at room temperature (20-25 ℃) for 8 hours.

The reaction system was washed with 1mol/L hydrochloric acid (50ml) and saturated brine (20ml), dried over sodium sulfate, and then separated by column chromatography to give the product.

TABLE 3 comparison of the yields of different N-methylmorpholine amounts

Experimental groups	Number of equivalents of N-methylmorpholine	Yield of formula I	Molar yield
				A	1.0	4.27g	66.5％
B	1.5	4.64g	72.3％
				C	2.0	4.75g	74.0％

As can be seen from comparative examples 1-3, the yield of the N-methylmorpholine group is obviously higher than that of the pyridine and triethylamine group. As can be seen from the above table, the yield is highest when the amount of N-methylmorpholine is 1.5-2.0 equivalents, which is about 73%. Before column chromatography, TLC showed impurity spots, but the impurity spots were significantly lighter than the triethylamine group.

Example 4: effect of different solvents on the Synthesis of Compounds of formula I

28.0g of 2-methyl-4- (2-methylbenzamido) benzoyl chloride (formula V) was divided into 4 parts. 70g of four solvents, i.e., ethyl acetate, dichloromethane, acetonitrile and toluene, were added thereto, and 3.94g (1.6 equivalents) of N-methylmorpholine was added dropwise thereto at room temperature. After 12 hours of reaction, the product was worked up and isolated by column chromatography with the following results:

table 4 reaction solvent investigation

Reaction solvent	Yield of formula I	Molar yield
			Ethyl acetate	1.62g	25.6％
Methylene dichloride	4.54g	71.7％
			Acetonitrile	4.38g	69.2％
Toluene	4.49g	70.9％

In the above table, the yield of the dichloromethane group is the highest. The yield of acetonitrile and toluene is still acceptable, but the post-treatment needs concentration and extraction and is slightly complicated. The ethyl acetate can be exchanged with the intermediate ester to generate a large amount of impurities, so the yield is low.

Example 5: influence of the reaction temperature on the Synthesis of the Compounds of formula I

Adding 52.5g of dichloromethane into 5.2g of 2-methyl-4- (2-methylbenzamido) benzoyl chloride (formula V), dropwise adding 2.91g (1.6 equivalent) of N-methylmorpholine at different temperatures, reacting for 12 hours, carrying out post-treatment and separating a product by column chromatography;

the yields of the groups were compared as follows:

TABLE 5 reaction temperature investigation

Reaction temperature	Yield of formula I	Molar yield
			0～3℃	2.67g	56.7％
15～20℃	3.50g	73.1％
			40℃	3.02g	64.2％

In the table, the reaction temperature is lower at 0-3 ℃, and the raw materials are remained due to low reaction activity; the reaction is carried out at 40 ℃, and the generated impurities are large; the reaction yield is highest at 15-20 ℃. Therefore, it is preferably 15 to 20 ℃.

Example 6: influence of reaction time

Taking 15.6g of the compound of the formula V, adding 156.2g of dichloromethane, dropwise adding 8.78g (1.6 equivalents) of N-methylmorpholine at room temperature (15-20 ℃), reacting at room temperature, sampling and detecting after reacting for 0.5h, 3h, 6h and 10h respectively, and calculating the content of the product of the formula I in the reaction system by a single-point external standard method, wherein the results are as follows:

TABLE 6 reaction time examination

As can be seen from the data in the above table, the product content gradually increased as the reaction time was prolonged in the early stage of the reaction. When the reaction time reaches 6h, the content of the product formula I in the reaction system basically reaches the highest, and no obvious benefit is gained by prolonging the reaction time.

Example 7: preparation of 2-methyl-4- (2-methyl-N- (2-methyl-4- (2-methylbenzamido) benzoyl) benzamido) benzoyl chloride

Taking the compound shown in the formula I, adding 10 times of dichloromethane and 1.5 equivalents of thionyl chloride, performing reflux reaction for 5-6 hours, and performing reduced pressure evaporation to dryness to obtain the compound.

Example 8: effect of different bases on the Synthesis of Compounds of formula VI

6.36g of the compound of the formula I are prepared as intermediate (in the form of the acid chloride of the formula I) in example 17. 65.6g of dichloromethane is added for dissolution, and the solution is divided into A, B parts and C parts. Respectively adding 1.5 equivalents of pyridine, triethylamine and N-methylmorpholine, and reacting at room temperature (15-20 ℃) for 5-6 hours. Separating the product by column chromatography. The yields for each set of formula VI are compared as follows:

TABLE 7 examination of organic bases

Experimental groups	Number of alkali/equivalent	Yield of formula VI	Molar yield
				A	Pyridine/1.5	2.42g	85.2％
B	Triethylamine/1.5	1.27g	44.6％
				C	N-methylmorpholine/1.5	2.05g	72.3％

As can be seen from the above table, the yield of pyridine group is highest. Triethylamine is more basic, resulting in more impurities. And pyridine can form a complex with an intermediate (acyl chloride of the formula I) while neutralizing HCl generated in the reaction, so that the reactivity of the acyl chloride of the formula I is increased to a certain extent, and the reaction is promoted.

¹H-NMR(400MHz,d⁶-DMSO,333.2K):δ10.26(s,1H),7.65-7.56(m,5H),7.47-7.38(m,2H),7.32-7.24(m,5H),7.18-7.05(m,5H),3.86-3.84(m,2H),2.80(t,J＝5.4,2H),2.40(s,3H),2.35-2.30(m,9H),1.99(m,2H)ppm.

LC-MS excimer ion 698.2418, [ M + H ]]⁺

Example 9: influence of the amount of base on the Synthesis of the Compound of formula VI

6.48g of the compound of formula I, prepared according to step 1, are in the intermediate state (the acid chloride form of formula I). 65.0g of dichloromethane was added and dissolved, and 2.21g of the compound of formula III (formula I: formula III: 1.1:1, molar ratio) was added and the solid was dissolved and then the system was divided into A, B and C portions. Pyridine (0.33 g, 1.0 equivalent), pyridine (1.01 g, 3.0 equivalent) and pyridine (1.97 g, 6.0 equivalent) are added thereto, and the mixture is reacted at room temperature (15 to 20 ℃) for 5 to 6 hours. Separating the product by column chromatography. The yields for each set of formula VI are compared as follows:

TABLE 8 examination of the amount of base

As can be seen from the above table, 1.5 equivalents of pyridine are more reasonable. The yield is slightly lower at lower (1.0 equivalent) and no significant benefit is gained at higher (3.0 or 6.0).

Example 10: influence of reaction temperature and time on the Synthesis of the Compound of formula VII

5.20g of the compound of formula I, prepared according to step 1, are in the intermediate state (the acid chloride form of formula I). 52.3g of dichloromethane were added and dissolved, and 1.78g of the compound of formula iii (formula i: formula iii: 1.1:1, molar ratio) was added. 1.20g (1.5 equivalents) of pyridine was added and the reaction was carried out at different temperatures, respectively, and the product contents were as follows with the reaction time:

TABLE 9 examination of different temperatures and times

The reaction speed is slow at 0 +/-3 ℃, the reaction lasts for 6 hours, and the content of the product still does not reach the highest value. The reaction is carried out for 2 hours at the temperature of 25 plus or minus 5 ℃, the concentration of the formula VI in the system is basically the highest, and no obvious benefit is generated after the reaction time is prolonged. When the reaction is carried out at 40 ℃ (dichloromethane reflux), the reaction is carried out for 2 hours, the concentration of the formula VI in the system is basically the highest, and no obvious benefit is generated after the reaction time is prolonged. Compared with 25 +/-5 ℃, the reaction temperature at 40 ℃ is higher, the content of impurities is slightly larger, and the yield is slightly reduced.

Example 11: effect of different solvents on the Synthesis of Compounds of formula VII

And in the groups A to D, respectively dissolving the compound VI in four solvents of dry methanol, ethanol, isopropanol and tetrahydrofuran. And cooling in ice bath, and adding 0.6 equivalent of sodium borohydride into each component. And after reacting for 3 hours at 0-10 ℃, respectively adding 0.5mol/L hydrochloric acid for quenching, extracting and drying by using dichloromethane, and concentrating to obtain a compound VII.

The yields of the groups were compared as follows:

TABLE 10 examination of solvents

Group of	Solvent(s)	Molar yield
			A	Anhydrous methanol	89.7％
B	Anhydrous ethanol	83.6％
			C	Isopropanol (I-propanol)	85.6％
D	Dried tetrahydrofuran	Large amount of raw material remains

The yield difference between the groups A to C is not too large, and the methanol is slightly better. Since tetrahydrofuran is an aprotic solvent, sodium borohydride is difficult to react in the system.

¹H NMR(400MHz,d₆-DMSO):δ10.43(s,1H),7.71-7.55(m,4H),7.49-7.26(m,7H),7.22-7.11(m,3H),6.93-6.78(m,2H),6.61-6.44(m,1H),5.74-5.58(m,1H),4.87-4.60(m,2H),2.72-2.66(m,1H),2.37-2.28(m,12H),2.12-2.09(m,1H),1.97-1.94(m,1H),1.75-1.59(m,1H),1.52-1.44(m,1H)ppm.

LC-MS excimer ion 700.2575, [ M + H ]]⁺

Example 12: effect of different reducing Agents on the Synthesis of Compounds of formula VII

A. And respectively taking 6.20g and 6.22g of the compound of the formula VI in the group B, respectively adding 62.2g and 63.0g of absolute methanol, and magnetically stirring at room temperature. 0.17g (0.5 equivalent) of sodium borohydride is added into the group A, 1.89g (1.0 equivalent) of sodium triacetoxyborohydride is added into the group B, the raw material is checked to be remained by TLC after 2 hours, and the reducing agent is supplemented as required, and the results are as follows:

TABLE 11 screening of reducing Agents

0.6 equivalent of sodium borohydride can completely react; sodium triacetoxyborohydride has weak reduction capability, and trace amount of raw materials still remain after 3.0 equivalent of reaction.

Example 13: effect of different temperatures on the Synthesis of the Compound of formula VII

A. B, C, D, E five groups respectively take 6.00g, 6.02g, 6.01g, 6.00g and 6.00g of the compound of formula VI, and respectively add 60.2g, 60.0g, 60.2g and 60.3g of anhydrous methanol; cooling the group A to-20 ℃ by using a cold trap, adding 0.20g (0.6 equivalent) of sodium borohydride, and carrying out heat preservation reaction; cooling group B to 0 deg.C with ice water bath, adding 0.21g (0.6 equivalent) of sodium borohydride; group C sodium borohydride 0.21g (0.6 equiv.) was added at 10 deg.C; group D, adding 0.21g (0.6 equivalent) of sodium borohydride at room temperature (15-20 ℃); the group E water bath is heated to 47 ℃, and 0.21g (0.6 equivalent) of sodium borohydride is added; after the addition, each group was kept warm for 2h and then TLC was observed for the remaining starting material, with the following results:

TABLE 12 screening of reducing Agents

The temperature is preferably 0 to 10 ℃ in view of the above-mentioned surplus of raw materials and the generation of impurities

Example 14: effect of the amount of Isopropanol used on the Synthesis of the Compound of formula VII

In the reduction reaction, isopropanol is used as a solvent, and aluminum isopropoxide is used as a catalyst to carry out reaction; the dosage of the isopropanol is preferably 5-10 times of the weight of the formula VI, and the dosage of the aluminum isopropoxide is preferably 0.3-0.5 time of the weight of the formula VI; the reaction temperature is preferably 70-80 ℃;

investigation of the amount of isopropanol:

respectively weighing 5.00g, 5.01g and 5.00g of the compound shown in the formula VI, respectively adding 25.0g, 35.2g and 50.0g of isopropanol, and respectively adding 2.00g, 2.01g and 2.01g of aluminum isopropoxide; the reaction is carried out for 2 hours under the condition of magnetic stirring and temperature rising to 70-75 ℃, and the result is as follows:

TABLE 13 screening of the amount of isopropanol used

The 5.0 times of solvent is less, so that the compound of the formula VI as the raw material can not be completely dissolved in the reaction process, and can not participate in the reaction.

Example 15: effect of the amount of aluminum isopropoxide used on the Synthesis of the Compound of formula VII

Respectively weighing 5.00g, 5.01g and 5.01g of the compound shown in the formula VI, respectively adding 35.0g, 35.5g and 35.1g of isopropanol, and respectively adding 1.50g (0.3 time), 2.01g (0.4 time) and 2.51g (0.5 time) of aluminum isopropoxide; the reaction is carried out for 2 hours under the condition of magnetic stirring and temperature rising to 70-75 ℃, and the result is as follows:

TABLE 14 screening of aluminum isopropoxide dosage

Aluminum isopropoxide is used as a reaction catalyst, the use amount of 0.3 time is less, and the reaction is slow.

Example 16: influence of the reaction temperature on the Synthesis of the Compound of formula VII

Respectively weighing 5.00g, 5.01g and 5.01g of the compound shown in the formula VI, respectively adding 35.1g, 35.1g and 35.3g of isopropanol, and respectively adding 2.01g (0.4 times) of aluminum isopropoxide; magnetically stirring, heating to 50 deg.C, 65 deg.C and 79 deg.C (reflux) respectively, reacting for 2 hr, and tracking by TLC the residue of raw material

TABLE 15 screening of aluminum isopropoxide dosage

Aluminum isopropoxide catalytically reduces carbonyl groups in isopropanol, with the byproduct acetone (boiling point 56 ℃) which is formed after oxidation of isopropanol, which itself is understood to be a reversible reaction. At a lower reaction temperature, the acetone product cannot be evaporated out of the system and is accumulated in the system, so that the forward reaction is difficult to carry out, and the raw materials are remained. The relatively high temperature is favorable for acetone to escape from the reaction system, so that the positive reaction is smoothly carried out.

Claims

1. A compound of formula I

2. A method of synthesizing the compound of claim 1:

3. The method of synthesis of claim 2, wherein:

in the method, the organic solvent is an aprotic solvent, and the aprotic solvent is one or a mixture of dichloromethane, chloroform, 1, 4-dioxane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate and the like;

in the method, the alkali is organic alkali or inorganic alkali; preferably selected from triethylamine, pyridine, N-diisopropylethylamine, N-methylmorpholine, sodium carbonate, potassium carbonate;

in the method, the amount of the alkali is 1.0-5.0 equivalent;

the reaction temperature of the method is 0-40 ℃;

the reaction time of the method is 0.5-10 hours.

4. The method of synthesis of claim 2, wherein:

in the method, the organic solvent is dichloromethane;

in the method, the base is N-methylmorpholine;

the amount of base in the process is 2.0 equivalents;

the reaction temperature of the method is 15-20 ℃;

the reaction time of the process was 6 hours.

5. The method of synthesis of claim 2, wherein: after the reaction is finished, washing the reaction system with water and dilute hydrochloric acid respectively, concentrating and carrying out column chromatography to obtain the target compound shown in the formula I.

6. The method for synthesizing the compound of the formula VII from the compound of the formula I comprises the following steps:

step 1) reacting a compound of formula I into an intermediate state under the action of thionyl chloride;

step 2) carrying out a condensation reaction on the intermediate state obtained in the step 1 and 7-chloro-1, 2,3, 4-tetrahydrobenzo [ B ] azepine-5-ketone in the presence of alkali to generate a formula VI;

step 3) reduction of the formula VI to obtain a formula VII

7. The method of synthesis of claim 6, wherein:

the preparation method of the intermediate state in the step 1 comprises the following steps: taking the compound shown in the formula I, adding 10 times of dichloromethane and 1.5 equivalents of thionyl chloride, performing reflux reaction for 5-6 hours, and performing reduced pressure evaporation to dryness to obtain the compound.

8. The method of synthesis of claim 6, wherein:

in the step 2, the organic solvent is an aprotic solvent, and the aprotic solvent is one or a mixture of dichloromethane, chloroform, 1, 4-dioxane, tetrahydrofuran, toluene, acetonitrile and ethyl acetate; the alkali is triethylamine, pyridine, N-diisopropylethylamine, N-methylmorpholine, sodium carbonate and potassium carbonate; the amount of the alkali is 1.0-6.0 equivalent; the reaction temperature is 0-40 ℃; the reaction time is 0.5-6 hours.

9. The method of synthesis of claim 6, wherein:

the organic solvent in the step 3 is selected from anhydrous methanol, anhydrous ethanol, anhydrous isopropanol and anhydrous tetrahydrofuran; the reducing agent is selected from sodium borohydride and sodium triacetyl borohydride; the amount of the reducing agent is 0.5-3.0 equivalent; the reaction temperature is-20 ℃ to 50 ℃.

10. The method of synthesis of claim 6, wherein:

in the step 3, isopropanol is used as a solvent, and aluminum isopropoxide is used as a catalyst to carry out reaction; the dosage of the isopropanol is preferably 7-10 times of the weight of the formula VI, and the dosage of the aluminum isopropoxide is preferably 0.4-0.5 time of the weight of the formula VI;

the reaction temperature is preferably 70-80 ℃.

11. The method of synthesis of claim 6, wherein:

the preparation method of acyl chloride in the step 1 comprises the following steps: taking a compound shown in the formula I, adding 10 times of dichloromethane and 1.5 equivalents of thionyl chloride, performing reflux reaction for 5-6 hours, and performing reduced pressure evaporation to dryness to obtain the compound;

the organic solvent in the step 2 is dichloromethane; the base is N-methylmorpholine; the amount of base is 1.5 equivalents; the reaction temperature is 25 ℃; the reaction time is 6 hours;

step 2, after the reaction is finished, washing the reaction system with water and dilute hydrochloric acid respectively, concentrating and carrying out column chromatography to obtain a compound shown in the formula VI;

in the step 3, the organic solvent is absolute methanol; the reducing agent is sodium borohydride; the amount of reducing agent is 0.6 equivalents; the reaction temperature is 0-10 ℃.

12. The use of the compound of claim 1 as a tolvaptan drug substance or as a single active ingredient formulation or a control for quality studies of combination formulations, the active ingredient being tolvaptan.