Process for the preparation of tolvaptan intermediates and tolvaptan

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one which is a tolvaptan intermediate, and a preparation method of tolvaptan. The method has low cost of raw materials, few steps, and high reaction efficiency of each step. Tolvaptan is finally prepared by the method, the overall cost is reduced, and a low-energy-consumption and green environmental protection implementation scheme is provided for synthesis of the medicine.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to tolvaptan intermediates and methods for preparing tolvaptan. Background Technology

[0002] Tolvaptan is a specific antagonist of arginine vasopressin, used to treat hypervolemic or isovolemic hyponatremia accompanied by heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion. Tolvaptan is well-tolerated, and water restriction is not required during treatment. Therefore, further research and development of its process and related intermediates are of significant practical importance.

[0003] 7-Chloro-2,3,4,5-Tetrahydro-1H-1-benzozazepine-5-one is an important intermediate in the synthesis of tolvaptan, and its ease of synthesis and cost have a crucial impact on the entire process of tolvaptan synthesis. Several existing publications have reported on the synthesis of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzozazepine-5-one.

[0004] The original research company, Otsuka Pharmaceutical Co., Ltd. of Japan, disclosed the following preparation method (Bioorg. Med. Chem., 1999, 7(8): 1743-1754):

[0005]

[0006]

[0007] CN103896842A discloses a method for synthesizing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzozazepine-5-one, as follows:

[0008]

[0009] CN103601678A discloses a method for synthesizing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzozazepine-5-one, as follows:

[0010]

[0011] Despite numerous research reports on existing technologies, the synthesis of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzozazepine-5-one still faces challenges such as complex process steps, demanding conditions, low overall yield, or expensive raw materials. Therefore, developing green, environmentally friendly, and efficient process routes is essential for this field. Summary of the Invention

[0012] To address the aforementioned technical problems, this invention provides a method for synthesizing the tolvaptan intermediate 7-chloro-2,3,4,5-tetrahydro-1H-1-benzo[b]azaporin-5-one, i.e., 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaporin-5-one. This method uses inexpensive raw materials, involves fewer steps, and has high reaction efficiency in each step. Tolvaptan is ultimately obtained through this method, reducing the overall cost and providing a low-energy, green, and environmentally friendly implementation scheme for the synthesis of this type of drug.

[0013] Specifically, on one hand, the present invention provides a method for synthesizing the tolvaptan intermediate 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one (compound 5), comprising the steps of:

[0014]

[0015] Step 1: Chlorobenzene (compound 1), maleic anhydride, and aluminum trichloride are reacted at 40-60°C for 1-5 hours to obtain intermediate product 1; intermediate product 1 is reacted in 98% concentrated sulfuric acid at 160-180°C for 5-15 minutes to generate 6-chloronaphth-1,4-dione (compound 2); wherein, the molar ratio of chlorobenzene, aluminum trichloride, and maleic anhydride is (20-6):(5-3):1;

[0016] Step 2: 6-Chloronaphth-1,4-dione (compound 2), 70-98% concentrated sulfuric acid, and sodium azide are reacted in a first solvent at room temperature for 5-15 hours to generate 7-chloro-1H-benzo[b]azapine-2,5-dione (compound 3); wherein the molar ratio of 6-chloronaphth-1,4-dione to sodium azide is 1:(3-5); and the volume-to-mass ratio of the 70-98% concentrated sulfuric acid to 6-chloronaphth-1,4-dione is (5-8):1, mL / g;

[0017] Step 3: 7-Chloro-1H-benzo[b]azapine-2,5-dione (compound 3) reacts with 1,2-ethylene glycol in a second solvent under the action of p-toluenesulfonic acid monohydrate to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one (compound 4);

[0018] Step 4: 7-Chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one (compound 4) was reduced by palladium-catalyzed hydrogenation and then by LiAlH4-catalyzed reduction to obtain intermediate 2; intermediate 2 was deprotected by hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one (compound 5).

[0019] In some embodiments, in step 1, the molar ratio of chlorobenzene, aluminum trichloride, and maleic anhydride is 6:3:1; and / or

[0020] In step 1, the volume-to-mass ratio of 98% concentrated sulfuric acid to maleic anhydride is (10-15):1, mL / g.

[0021] In some embodiments, in step 2, after cooling the mixture of 70-98% concentrated sulfuric acid and the first solvent to -5-5°C, 6-chloronaphthalene-1,4-dione and sodium azide are added. After the addition is complete, the reaction mixture is reacted at room temperature for 5-15 hours to obtain 7-chloro-1H-benzo[b]azapine-2,5-dione.

[0022] In some embodiments, in step 2, the molar ratio of 6-chloronaphth-1,4-dione and sodium azide is 1:3; and / or

[0023] In step 2, the first solvent is selected from one or more of dichloromethane, chloroform, and toluene.

[0024] In some embodiments, in step 3, 7-chloro-1H-benzo[b]azapine-2,5-dione, under the action of p-toluenesulfonic acid monohydrate, reacts with 1,2-ethylene glycol in a second solvent at 100–150°C for 3–5 hours to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one, wherein the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione, 1,2-ethylene glycol, and p-toluenesulfonic acid monohydrate is 1:(1.5–4):

[0025] (0.1~0.5).

[0026] In some embodiments, in step 3, the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione to 1,2-ethylene glycol is 1:2:0.1; and / or

[0027] In step 3, the second solvent is selected from toluene and xylene.

[0028] In some embodiments, in step 4, 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one is reduced by hydrogenation on carbon with 10% palladium at room temperature; then, it is catalytically reduced by heating under reflux in LiAlH4 tetrahydrofuran solution to obtain intermediate product 2; intermediate product 2 is deprotected by 3-6M hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one.

[0029] On the other hand, the present invention provides a method for synthesizing tolvaptan, characterized by comprising the following steps:

[0030]

[0031] Step 1: Chlorobenzene, maleic anhydride and aluminum trichloride are reacted at 40-60℃ for 1-5 hours to obtain intermediate product 1; intermediate product 1 is reacted in 98% concentrated sulfuric acid at 160-180℃ for 5-15 minutes to generate 6-chloronaphth-1,4-dione; wherein, the molar ratio of chlorobenzene, aluminum trichloride and maleic anhydride is (20-6):(5-3):1;

[0032] Step 2: 6-Chloronaphth-1,4-dione, 70-98% concentrated sulfuric acid, and sodium azide are reacted in a first solvent at room temperature for 5-15 hours to generate 7-chloro-1H-benzo[b]azapine-2,5-dione; wherein the molar ratio of 6-chloronaphth-1,4-dione to sodium azide is 1:(3-5); and the volume-to-mass ratio of the 70-98% concentrated sulfuric acid to 6-chloronaphth-1,4-dione is (5-8):1, mL / g;

[0033] Step 3: 7-Chloro-1H-benzo[b]azapine-2,5-dione reacts with 1,2-ethylene glycol in a second solvent under the action of p-toluenesulfonic acid monohydrate to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one;

[0034] Step 4: 7-Chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one was reduced by palladium-catalyzed hydrogenation and LiAlH4-catalyzed reduction to obtain intermediate 2; intermediate 2 was deprotected by hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one;

[0035] Step 5: 7-Chloro-1,2,3,4-tetrahydro-5H-benzo[b]aza-5-one reacts with 2-methyl-4-(2-methylbenzamido)benzoyl chloride to obtain N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide;

[0036] Step 6: N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide was reduced to obtain tolvaptan.

[0037] In some embodiments, in step 5, 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaporin-5-one and 2-methyl-4-(2-methylbenzamido)benzoyl chloride are reacted in a third solvent at room temperature for 5-15 hours to obtain N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide; wherein the molar ratio of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaporin-5-one to 2-methyl-4-(2-methylbenzamido)benzoyl chloride is 1:(1.2-2); and / or

[0038] In step 6, N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide is reduced to tolvaptan by reacting with sodium borohydride in a fourth solvent at room temperature for 1-3 hours; wherein the molar ratio of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide to sodium borohydride is 1:(1.2-5).

[0039] In some embodiments, in step 5, the molar ratio of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one to 2-methyl-4-(2-methylbenzamido)benzoyl chloride is 1:1.5; the third solvent is selected from N,N-dimethylacetamide; and / or

[0040] In step 6, the molar ratio of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide and sodium borohydride is 1:1.5; the fourth solvent is selected from methanol and ethanol.

[0041] Beneficial effects

[0042] This invention employs a novel route for the synthesis of tolvaptan intermediate 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one. The raw materials, chlorobenzene and maleic anhydride, are inexpensive and readily available. The reaction involves fewer steps and higher efficiency in each step, ultimately yielding tolvaptan. This method reduces overall costs and provides a low-energy, green, and environmentally friendly approach for the synthesis of this type of drug.

[0043] Terminology Explanation

[0044] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0045] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0046] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0047] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0048] In the following content, all figures disclosed herein, whether or not they use words such as "approximately" or "about," are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%, etc. Whenever a figure with a value of N is disclosed, any figure with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction.

[0049] Room temperature is expressed as 20–35°C, and in some embodiments, room temperature is expressed as approximately 25°C.

[0050] Detailed description

[0051] Specifically, in one aspect, the present invention provides a method for synthesizing the tolvaptan intermediate 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one, comprising the steps of:

[0052]

[0053] Step 1: Chlorobenzene reacts with maleic anhydride to produce 6-chloronaphth-1,4-dione;

[0054] Step 2: 6-Chloronaphth-1,4-dione reacts with sodium azide to produce 7-chloro-1H-benzo[b]azapine-2,5-dione;

[0055] Step 3: 7-Chloro-1H-benzo[b]azapine-2,5-dione reacts with 1,2-ethylene glycol to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one;

[0056] Step 4: 7-Chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one was reduced and deprotected to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one.

[0057] In some embodiments, in step 1, chlorobenzene and maleic anhydride are first reacted in the presence of aluminum trichloride to obtain intermediate product 1; intermediate product 1 is then reacted in the presence of 98% concentrated sulfuric acid to obtain 6-chloronaphth-1,4-dione.

[0058] In some embodiments, in step 1, chlorobenzene, maleic anhydride and aluminum trichloride are reacted at 40-60°C for 1-5 hours to obtain intermediate product 1; intermediate product 1 is reacted in 98% concentrated sulfuric acid at 160-180°C for 5-15 minutes to obtain 6-chloronaphthalene-1,4-dione.

[0059] Intermediate product 1 is

[0060] In some embodiments, in step 1, the molar ratio of chlorobenzene, aluminum trichloride, and maleic anhydride is (20-6):(5-3):1.

[0061] In some embodiments, in step 1, the molar ratio of chlorobenzene, aluminum trichloride, and maleic anhydride is 6:3:1.

[0062] In some embodiments, the 98% concentrated sulfuric acid in step 1 not only participates in the reaction but also serves as a reaction solvent.

[0063] In some embodiments, the volume-to-mass ratio of 98% concentrated sulfuric acid to maleic anhydride in step 1 is (10-15):1, mL / g.

[0064] In some embodiments, in step 2, 6-chloronaphth-1,4-dione reacts with sodium azide in 70-98% concentrated sulfuric acid and a first solvent to generate 7-chloro-1H-benzo[b]azapine-2,5-dione.

[0065] In some embodiments, in step 2, a mixture of 70-98% concentrated sulfuric acid and the first solvent is cooled to -5 to 5°C, and then 6-chloronaphth-1,4-dione and sodium azide are added. The reaction mixture is then reacted at room temperature for 5-15 hours to obtain 7-chloro-1H-benzo[b]azapine-2,5-dione.

[0066] In some embodiments, in step 2, the molar ratio of 6-chloronaphth-1,4-dione and sodium azide is 1:(3-5).

[0067] In some embodiments, in step 2, the molar ratio of 6-chloronaphthalene-1,4-dione and sodium azide is 1:3.

[0068] In some embodiments, in step 2, the first solvent is selected from one or more of dichloromethane, chloroform, and toluene.

[0069] In some embodiments, in step 2, the volume-to-mass ratio of 70-98% concentrated sulfuric acid to 6-chloronaphthalene-1,4-dione is (5-8):1, mL / g.

[0070] In some embodiments, in step 3, 7-chloro-1H-benzo[b]azapine-2,5-dione reacts with 1,2-ethylene glycol in a second solvent under the action of p-toluenesulfonic acid monohydrate to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one.

[0071] In some embodiments, in step 3, 7-chloro-1H-benzo[b]azapine-2,5-dione is reacted with 1,2-ethylene glycol in a second solvent in the presence of monohydrated p-toluenesulfonic acid for 3-5 hours at 100-150°C to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one.

[0072] In some embodiments, in step 3, 7-chloro-1H-benzo[b]azapine-2,5-dione is reacted with 1,2-ethylene glycol in a second solvent at 100-150°C for 3-5 hours under the action of p-toluenesulfonic acid monohydrate to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one, wherein the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione, 1,2-ethylene glycol and p-toluenesulfonic acid monohydrate is 1:(1.5-4):(0.1-0.5).

[0073] In some embodiments, in step 3, the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione to 1,2-ethylene glycol is 1:(1.5-4).

[0074] In some embodiments, in step 3, the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione to 1,2-ethylene glycol is 1:2.

[0075] In some embodiments, in step 3, the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione to p-toluenesulfonic acid monohydrate is 1:(0.1 to 0.5).

[0076] In some embodiments, in step 3, the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione to p-toluenesulfonic acid monohydrate is 1:0.1.

[0077] In some embodiments, in step 3, the second solvent is selected from toluene and xylene.

[0078] In some embodiments, in step 4, 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one is subjected to palladium-catalyzed hydrogenation reduction and LiAlH4-catalyzed reduction to obtain intermediate product 2. Intermediate product 2 is deprotected by hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one.

[0079] In some embodiments, in step 4, 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one is reduced by hydrogenation on carbon with 10% palladium at room temperature; then, it is catalytically reduced by heating under reflux in LiAlH4 tetrahydrofuran solution to obtain intermediate product 2; intermediate product 2 is deprotected by 3-6M hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one.

[0080] Intermediate product 2 is

[0081] On the other hand, the present invention also provides a method for synthesizing tolvaptan, comprising the following steps:

[0082]

[0083] Step 1: Chlorobenzene reacts with maleic anhydride to produce 6-chloronaphth-1,4-dione;

[0084] Step 2: 6-Chloronaphth-1,4-dione reacts with sodium azide to produce 7-chloro-1H-benzo[b]azapine-2,5-dione;

[0085] Step 3: 7-Chloro-1H-benzo[b]azapine-2,5-dione reacts with 1,2-ethylene glycol to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one;

[0086] Step 4: 7-Chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one was reduced and deprotected to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one;

[0087] Step 5: 7-Chloro-1,2,3,4-tetrahydro-5H-benzo[b]aza-5-one reacts with 2-methyl-4-(2-methylbenzamido)benzoyl chloride to obtain N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide;

[0088] Step 6: N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide was reduced to obtain tolvaptan.

[0089] In some embodiments, step 1 is performed using the method steps described in this invention.

[0090] In some embodiments, step 2 is performed using the method steps described in this invention.

[0091] In some embodiments, step 3 is performed using the method steps described in this invention.

[0092] In some embodiments, step 4 is performed using the method steps described in this invention.

[0093] In some embodiments, in step 5, the molar ratio of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one to 2-methyl-4-(2-methylbenzoamido)benzoyl chloride is 1:(1.2-2).

[0094] In some embodiments, in step 5, the molar ratio of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaporin-5-one to 2-methyl-4-(2-methylbenzamido)benzoyl chloride is 1:1.5.

[0095] In some embodiments, in step 5, 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]aza-5-one reacts with 2-methyl-4-(2-methylbenzamido)benzoyl chloride in a third solvent at room temperature to obtain N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide.

[0096] In some embodiments, in step 5, 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaporin-5-one and 2-methyl-4-(2-methylbenzamido)benzoyl chloride are reacted in a third solvent at room temperature for 5-15 hours to obtain N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide; wherein the molar ratio of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaporin-5-one to 2-methyl-4-(2-methylbenzamido)benzoyl chloride is 1:(1.2-2).

[0097] 7-Chloro-1,2,3,4-Tetrahydro-5H-benzo[b]azaline-5-one and 2-methyl-4-(2-methylbenzamido)benzoyl chloride can be obtained by reacting 2-methyl-4-(2-methylbenzamido)benzoic acid with thionyl chloride.

[0098] In some embodiments, in step 6, N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide is reduced to tolvaptan in a fourth solvent under the action of sodium borohydride.

[0099] In some embodiments, in step 6, the molar ratio of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide and sodium borohydride is 1:(1.2-5).

[0100] In some embodiments, in step 6, the molar ratio of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide and sodium borohydride is 1:1.5.

[0101] In some embodiments, in step 6, the fourth solvent is selected from methanol and ethanol.

[0102] In some embodiments, in step 6, N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide is reduced to tolvaptan by reacting with sodium borohydride in a fourth solvent at room temperature for 1 to 3 hours.

[0103] In some embodiments, in step 6, N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide is reduced to tolvaptan by reacting with sodium borohydride in a fourth solvent at room temperature for 1 to 3 hours; wherein the molar ratio of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide to sodium borohydride is 1:(1.2 to 5). Detailed Implementation

[0104] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0105] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0106] Synthesis of tolvaptan intermediate (7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one, compound 5)

[0107]

[0108] Example 1: Synthesis of 6-chloronaphth-1,4-dione (compound 2)

[0109] Chlorobenzene (10 g, 88.84 mmol, 6 eq), anhydrous aluminum trichloride (5.9 g, 44.42 mmol, 3 eq), and maleic anhydride (1.45 g, 14.81 mmol, 1 eq) were rapidly stirred at 50 °C for 1.5 hours, then poured into crushed ice. The mixture was subjected to reduced pressure to remove chlorobenzene, resulting in a solid precipitate, which was then filtered. The solid was washed with water and dissolved in a 10% NaOH aqueous solution. The solution was filtered, and the pH of the filtrate was adjusted to approximately 1 with 0.1 mol / L sulfuric acid. The precipitate was stirred to precipitate, filtered, and the solid was washed with water and dried. The dried solid was dispersed in 15 mL of 98% concentrated sulfuric acid. The mixture was heated to 180 °C and stirred for 8 minutes, then cooled and poured onto crushed ice. The solid precipitated by stirring and was filtered while cold. The solid was rapidly washed with a saturated aqueous solution of Na₂CO₃ at 0 °C and ice water, respectively, to obtain compound 2, 2.65 g, with a yield of 93%.

[0110] 1 ¹H NMR (400MHz, CDCl₃): δ 8.12 (s, 1H), 8.09 (d, J = 5.5Hz, 1H), 7.78 (dd, J = 8.3, 2.0Hz, 1H), 7.10 (s, 2H). HRMS calculated values ​​[C 10 H5ClNaO2] + (M+Na + )214.9870, detected value 214.9870.

[0111] Comparative Example: Chlorobenzene (10 g, 88.84 mmol, 6 eq), anhydrous aluminum trichloride (5.9 g, 44.42 mmol, 3 eq), and maleic anhydride (1.45 g, 14.81 mmol, 1 eq) were rapidly stirred at 100 °C for 0.5 hours, then poured into crushed ice. The chlorobenzene was removed under reduced pressure, and a solid precipitated. The solid was filtered. After washing with water, it was dissolved in a 10% NaOH aqueous solution, filtered, and the pH of the filtrate was adjusted to approximately 1 with 0.1 mol / L sulfuric acid. The solution was stirred to precipitate, filtered, and the solid was washed with water and dried. The dried solid was dispersed in dioxane (20 mL), and 98% concentrated sulfuric acid (10 mL) was added dropwise. The mixture was heated to 100 °C and stirred for 8 minutes, then cooled and poured into an ice-water mixture (50 mL). Part of the dioxane was removed by rotary evaporation under reduced pressure. Dichloromethane was added, and the solution was washed with a saturated aqueous solution of Na2CO3 and water. After drying with anhydrous sodium sulfate, the solution was concentrated to give compound 2, 1.05 g, yield 37%.

[0112] Example 2: Synthesis of 7-chloro-1H-benzo[b]azapine-2,5-dione (compound 3)

[0113] A mixture of concentrated sulfuric acid (11 mL) and dichloromethane (3 mL) was cooled to 0 °C. Compound 2 (1.93 g, 10 mmol, 1 eq) was added, followed by the addition of sodium azide (1.95 g, 30 mmol, 3 eq) in portions over 10 minutes at 0 °C. The reaction mixture was stirred overnight at room temperature and then poured onto crushed ice. Dichloromethane was added for extraction, and the organic phase was collected. The mixture was washed with water (50 mL x 3) and saturated sodium bicarbonate solution (50 mL x 3). After drying the organic phase with anhydrous sodium sulfate, the mixture was concentrated to give compound 3, 2.04 g, yield 98%, HPLC purity 99.3%.

[0114] 1 H NMR (400MHz, CDCl3): δ9.52 (s, 1H), 8.45 (d, J = 2.6Hz, 1H), 8.04 (s, 1H), 7.72 (d, J = 5.4Hz, 1H), 7.51 (d, J = 6.4Hz, 1H), 7.12 (d, J = 7.1Hz, 1H).

[0115] Comparative Example: At 0°C, with stirring, sodium azide (0.98 g, 15 mmol, 1.5 eq) was added in portions to a mixture of compound 2 (1.93 g, 10 mmol, 1 eq) and concentrated sulfuric acid (20 mL). After the addition was complete, the reaction mixture was stirred at 0°C for 30 min, then at room temperature for 20 h. Sodium azide (0.98 g, 15 mmol, 1.5 eq) was then added, and stirring continued at room temperature for another 20 h. The reaction mixture was poured onto crushed ice, extracted with dichloromethane, and the organic phase was collected. The organic phase was washed with water (50 mL x 3) and saturated sodium bicarbonate solution (50 mL x 3). After drying the organic phase with anhydrous sodium sulfate, it was concentrated to obtain crude compound 3. Purification by silica gel column chromatography yielded compound 3, 0.96 g, 46%.

[0116] Example 3: Synthesis of 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one (compound 4)

[0117] Compound 3 (5 g, 24.1 mmol, 1 eq), ethylene glycol (3 g, 48.2 mmol, 2 eq), and p-toluenesulfonic acid monohydrate (0.46 g, 2.4 mmol, 0.1 eq) were added to toluene (60 mL). The reaction mixture was stirred at 120 °C for 3 hours, and water was removed using a separator. After the reaction was complete, the reaction mixture was washed with water (50 mL x 3) and saturated sodium bicarbonate aqueous solution (50 mL x 3). The washed reaction mixture was concentrated to obtain the crude product. The crude product was slurried with methanol and water (mL, v / v = 1:1) to obtain compound 4, 5.58 g, 92%.

[0118] LC-MS(ESI)[M+1] + 252.06.

[0119] Example 4: Synthesis of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one (compound 5)

[0120] A catalytic amount of 10% Pd / C was added to an ethanol solution of compound 4 (5 g, 19.9 mmol), and the reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The concentrated residue was dissolved in anhydrous tetrahydrofuran (50 mL), and a tetrahydrofuran solution of LiAlH4 (39 mL, 1 M) was added at 0 °C under a nitrogen atmosphere; after the addition was complete, the reaction mixture was refluxed for 12 hours. The reaction mixture was cooled and poured into ice water (200 mL), and the tetrahydrofuran was removed by rotary evaporation under reduced pressure. The solid was stirred to precipitate, washed with water, and redissolved in tetrahydrofuran (60 mL). Hydrochloric acid (30 mL, 3 M) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ice water, and a solid precipitated. The solid was filtered, and the solid was slurried with methanol and water (v / v = 1:1) to obtain compound 5, 3.7 g, 95%.

[0121] 1 H NMR (400MHz, CDCl3): δ7.71(d,J=2.5Hz,1H),7.23(dd,J=8.4,2.5Hz,1H),6.75(d,J=8.5 Hz, 1H), 4.74 (brs, 1H), 3.37-3.13 (m, 2H), 2.85 (t, J = 7.1Hz, 2H), 2.21 (q, J = 7.1Hz, 2H).

[0122] Synthesis of Tolvaptan

[0123]

[0124] Compound 5 was synthesized using the methods shown in Examples 1-4.

[0125] Example 5: Synthesis of 2-methyl-4-(2-methylbenzamido)benzoic acid (compound 6)

[0126] At room temperature, o-methylbenzoyl chloride (5.00 g, 32.3 mmol, 1 eq) was dissolved in chloroform (80 mL), and 4-amino-2-methylbenzoic acid (4.88 g, 32.3 mmol, 1 eq) and triethylamine (9.81 g, 96.9 mmol, 3 eq) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by slurrying with methanol and water (v / v = 2:1) to obtain compound 6.

[0127] 1 H NMR (400MHz, DMSO-d6) δ10.58 (s, lH), 7.92 (d, J = 8.3Hz, lH), 7.73-7.62 (m, 2H), 7 .55-7.47(m,lH),7.48-7.40(m,lH),7.36-7.23(m,2H),2.55(s,3H),2.41(s,3H).

[0128] Example 6: Synthesis of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide (compound 7)

[0129] Compound 6 (5 g, 18.6 mmol, 1.5 eq) was dissolved in N,N-dimethylacetamide (40 mL) at room temperature. The solution was cooled to 0 °C, and thionyl chloride (3.3 g, 27.8 mmol, 2 eq) was added under nitrogen protection. After stirring the reaction mixture at room temperature for 3 hours, a solution of compound 5 (2.7 g, 13.9 mmol, 1 eq) in N,N-dimethylacetamide (10 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction solution was added to water (200 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed successively with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with methanol to give compound 7, 5.65 g, yield: 91%.

[0130] LC-MS(ESI)[M+1] + 447.18.

[0131] Example 7: Synthesis of tolvaptan (compound 8)

[0132] Compound 7 (5 g, 11.2 mmol, 1 eq) was dissolved in anhydrous methanol (25 mL) and stirred. Sodium borohydride (0.64 g, 16.8 mmol, 1.5 eq) was then added in portions to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was slurried with methanol to give tolvaptan, 4.8 g, 95%.

[0133] LC-MS(ESI)[M+1] + 449.17.

[0134] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for synthesizing the tolvaptan intermediate 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one, characterized in that, Including the following steps: ； Step 1: Chlorobenzene, maleic anhydride, and aluminum trichloride are reacted at 40-60℃ for 1-5 hours to obtain intermediate product 1; intermediate product 1 is reacted in 98% concentrated sulfuric acid at 160-180℃ for 5-15 minutes to generate 6-chloronaphth-1,4-dione; wherein, the volume-to-mass ratio of 98% concentrated sulfuric acid to maleic anhydride is (10-15):1, mL / g; the molar ratio of chlorobenzene, aluminum trichloride, and maleic anhydride is 6:3:1; Step 2: After cooling the mixture of 70-98% concentrated sulfuric acid and the first solvent to -5 to 5°C, 6-chloronaphth-1,4-dione and sodium azide are added. After the addition is complete, the reaction mixture is reacted at room temperature for 5-15 hours to obtain 7-chloro-1H-benzo[b]azapine-2,5-dione; wherein, the molar ratio of 6-chloronaphth-1,4-dione and sodium azide is 1:(3-5); the volume-to-mass ratio of the 70-98% concentrated sulfuric acid to 6-chloronaphth-1,4-dione is (5-8):1, mL / g; the first solvent is selected from one or more of dichloromethane, chloroform and toluene. Step 3: 7-Chloro-1H-benzo[b]azapine-2,5-dione reacts with 1,2-ethylene glycol in a second solvent under the action of p-toluenesulfonic acid monohydrate to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one; Step 4: 7-Chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one was reduced by palladium-catalyzed hydrogenation and LiAlH4-catalyzed reduction to obtain intermediate 2; intermediate 2 was deprotected by hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one.

2. The method according to claim 1, characterized in that, In step 2, the molar ratio of 6-chloronaphthalene-1,4-dione and sodium azide is 1:

3.

3. The method according to claim 1, characterized in that, In step 3, 7-chloro-1H-benzo[b]azapine-2,5-dione is reacted with 1,2-ethylene glycol in a second solvent at 100-150°C for 3-5 hours under the action of p-toluenesulfonic acid monohydrate to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one, wherein the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione, 1,2-ethylene glycol and p-toluenesulfonic acid monohydrate is 1:(1.5-4):(0.1-0.5).

4. The method according to claim 1 or 3, characterized in that, In step 3, the molar ratio of 7-chloro-1H-benzo[b]azapine-2,5-dione to 1,2-ethylene glycol is 1:2; and / or In step 3, the second solvent is selected from toluene and xylene.

5. The method according to claim 1, characterized in that, In step 4, 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one was reduced by hydrogenation on carbon with 10% palladium at room temperature; then, it was catalytically reduced by heating under reflux in LiAlH4 tetrahydrofuran solution to obtain intermediate 2; intermediate 2 was deprotected by 3-6 M hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one.

6. A method for synthesizing tolvaptan, characterized in that, The steps include the following: ； Step 1: Chlorobenzene, maleic anhydride, and aluminum trichloride are reacted at 40-60℃ for 1-5 hours to obtain intermediate product 1; intermediate product 1 is reacted in 98% concentrated sulfuric acid at 160-180℃ for 5-15 minutes to generate 6-chloronaphth-1,4-dione; wherein, the volume-to-mass ratio of 98% concentrated sulfuric acid to maleic anhydride is (10-15):1, mL / g; the molar ratio of chlorobenzene, aluminum trichloride, and maleic anhydride is 6:3:1; Step 2: After cooling the mixture of 70-98% concentrated sulfuric acid and the first solvent to -5 to 5°C, 6-chloronaphth-1,4-dione and sodium azide are added. After the addition is complete, the reaction mixture is reacted at room temperature for 5-15 hours to obtain 7-chloro-1H-benzo[b]azapine-2,5-dione; wherein, the molar ratio of 6-chloronaphth-1,4-dione and sodium azide is 1:(3-5); the volume-to-mass ratio of the 70-98% concentrated sulfuric acid to 6-chloronaphth-1,4-dione is (5-8):1, mL / g; the first solvent is selected from one or more of dichloromethane, chloroform and toluene. Step 3: 7-Chloro-1H-benzo[b]azapine-2,5-dione reacts with 1,2-ethylene glycol in a second solvent under the action of p-toluenesulfonic acid monohydrate to generate 7-chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one; Step 4: 7-Chlorospiro[benzo[b]azapine-5,2'-[1,3]dioxolane]-2(1H)-one was reduced by palladium-catalyzed hydrogenation and LiAlH4-catalyzed reduction to obtain intermediate 2; intermediate 2 was deprotected by hydrochloric acid to obtain 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azapine-5-one; Step 5: 7-Chloro-1,2,3,4-tetrahydro-5H-benzo[b]aza-5-one reacts with 2-methyl-4-(2-methylbenzamido)benzoyl chloride to obtain N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide; Step 6: N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide was reduced to obtain tolvaptan.

7. The method according to claim 6, characterized in that, In step 5, 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one and 2-methyl-4-(2-methylbenzamido)benzoyl chloride are reacted in a third solvent at room temperature for 5-15 hours to obtain N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide; wherein the molar ratio of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one to 2-methyl-4-(2-methylbenzamido)benzoyl chloride is 1:(1.2~2); and / or In step 6, N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide is reduced to tolvaptan by reacting with sodium borohydride in a fourth solvent at room temperature for 1-3 hours; wherein the molar ratio of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide to sodium borohydride is 1:(1.2-5).

8. The method according to claim 7, characterized in that, In step 5, the molar ratio of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azaphylin-5-one to 2-methyl-4-(2-methylbenzamido)benzoyl chloride is 1:1.5; the third solvent is selected from N,N-dimethylacetamide; and / or In step 6, the molar ratio of N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-1-carbonyl)-3-methylphenyl)-2-methylbenzamide and sodium borohydride is 1:1.5; the fourth solvent is selected from methanol and ethanol.

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