CN111440188A

CN111440188A - Preparation method of Relugol (Relugolix) key intermediate

Info

Publication number: CN111440188A
Application number: CN202010279740.9A
Authority: CN
Inventors: 沈浩建; 章建明; 陈赓; 裴欣宇; 姜春阳; 谢军; 李惠
Original assignee: Jiangsu Haiyuekang Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Haiyuekang Pharmaceutical Technology Co ltd
Priority date: 2020-04-10
Filing date: 2020-04-10
Publication date: 2020-07-24
Anticipated expiration: 2040-04-10
Also published as: CN111440188B

Abstract

The invention relates to a preparation method of a Ruogeli key intermediate, which takes 4-nitrophenylacetic acid as a raw material and obtains a target product through 4 steps of reaction. The method avoids the use of toxic reagents, has mild reaction conditions, low cost, high yield and simple route, and is suitable for industrial scale-up production.

Description

Preparation method of Relugol (Relugolix) key intermediate

Technical Field

The invention relates to a key intermediate of Ruogeli, in particular to a preparation method of the key intermediate of Ruogeli.

Background

Endometriosis (EMs) refers to a common gynecological disease in women with intimal cells planted in abnormal locations. The incidence rate of the disease reaches 10.0 percent and is in a remarkably rising trend. It is mainly characterized by dysmenorrhea, pelvic pain and infertility. Statistically, up to 1.76 million women suffer from endometriosis worldwide.

Ruogeli (Relugolix) is a novel, non-peptide, orally available GnRH antagonist that has been approved by the Japanese food and drug administration for the treatment of pain due to endometriosis. A key intermediate 3- (6-methoxypyridazin-3-yl) -5-methyl-6- (4-nitrophenyl) thiophene [2,3-d ] pyrimidine-2, 4(1H, 3H) -dione (hereinafter referred to as compound A) is used in the synthesis process.

Patent CN 109053766A reports a synthesis method of the key intermediate, which uses 4-nitrophenylacetic acid as raw material, and performs acyl chlorination, substitution and decarboxylation to obtain compound 2, wherein the reaction route is shown as the following formula:

the route has long steps and is fussy to operate, and is not suitable for large-scale industrial production.

Patent CN 109053766A reports a method for synthesizing the key intermediate, in the method, ethyl chloroformate and potassium hydroxide are used for hydrolysis, and then the ethyl chloroformate and potassium hydroxide are reacted with 2-amino-6-methoxypyridazine, and then sodium methoxide is used for cyclization. The reaction route is shown as the following formula:

the route has longer steps, complicated reaction and post-treatment operations, more three wastes and unfavorable cost reduction.

Document j.org.chem.2006,71, 6640-sa 6643 discloses a synthesis method of this key intermediate, which uses 4-nitrophenylacetic acid as raw material, and reacts with acetic anhydride under the action of 1-methylimidazole to obtain compound 2, with a possible reaction mechanism as shown in the following formula:

the condition has lower yield and more byproducts, and is not suitable for industrialization.

The invention provides a new preparation method of 3- (6-methoxypyridazin-3-yl) -5-methyl-6- (4-nitrophenyl) thiophene [2,3-d ] pyrimidine-2, 4(1H, 3H) -diketone by improving document J.org.chem.2006,71, 6640-ketone 6643.

Disclosure of Invention

The invention aims to solve the problems and designs a preparation method of a Ruugeli key intermediate.

The technical scheme of the invention is that the preparation method of the Ruugeli key intermediate comprises the following steps:

the method comprises the following steps:

(1) under the condition that a catalyst, acetic anhydride and acetic acid participate, the compound 1 reacts to generate a compound 2.

(2) The compound 2, ethyl cyanoacetate and sulfur generate a compound 3 under the action of a catalyst.

(3) Under the triphosgene condition, the compound 3 and 3-amino-6-methoxypyridazine generate a compound 4.

(4) Under the alkali condition, the compound 4 is subjected to ring closure to generate the compound A.

The mol ratio of the compound 1 to the catalyst in the step (1) is 1: (0.05-1); the catalyst is selected from methylimidazole and DMAP.

The mass-volume ratio of the compound 1 to the acetic anhydride in the step (1) is 1g, (2-5) m L, the mass-volume ratio of the compound 1 to the acetic acid in the step (1) is 1g, (0.1-1) m L, and the reaction temperature in the step (1) is 10-40 ℃.

The mol ratio of the compound 2 to ethyl cyanoacetate in the step (2) is 1: (1-2), wherein the molar ratio of the compound 2 to the catalyst in the step (2) is 1: (0.1-2); the catalyst is n-butylamine, and in the step (2), the reaction temperature is 40-reflux temperature.

The molar ratio of the compound 3 to the triphosgene in the step (3) is 1: (0.33-0.5), wherein the molar ratio of the compound 3 to the 3-amino-6-methoxypyridazine in the step (3) is 1: (0.9-2). More preferably 1: 1.

the molar ratio of the compound 3 to the base in the step (3) is 1: (1-5), more preferably 1: 3; the acid-binding agent is selected from triethylamine and diisopropylethylamine.

The reaction temperature of the triphosgene and the compound 3 in the step (3) is-20 ℃ to 10 ℃, and the reaction temperature is 0 ℃ to 30 ℃ when the 3-amino-6-methoxypyridazine is added in the step (3).

The molar ratio of the compound 4 to the base in the step (4) is 1: 20; the base is selected from sodium methoxide. .

The solvent used in step (4) is selected from alcohols (e.g., methanol, ethanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, etc.), amides (e.g., dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.); among them, methanol is preferred.

The reaction temperature in the step (4) is 25-70 ℃, and the preferable temperature is 50 ℃.

The method has the advantages that the target product can be obtained only through four-step reaction, and the total yield is high (the total molar yield of the four steps is about 60%); the use of dangerous and toxic reagents is avoided in the reaction; the post-treatment of the reaction is simple, the generated three wastes are less, the cost is effectively reduced, and the method is suitable for industrial scale-up production.

Drawings

FIG. 1 is the formula of compound 3- (6-methoxypyridazin-3-yl) -5-methyl-6- (4-nitrophenyl) thieno [2,3-d ] pyrimidine-2, 4(1H, 3H);

FIG. 2 shows nuclear magnetic hydrogen spectrum data of compound 1- (4-nitrophenyl) propan-2-one;

FIG. 3 shows nuclear magnetic hydrogen spectrum data of compound 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid ethyl ester;

FIG. 4 is L CMS data for the compound ethyl 2- (3- (6-methoxypyridazin-3-yl) ureido) -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate;

FIG. 5 is L CMS data for the compound 3- (6-methoxypyridazin-3-yl) -5-methyl-6- (4-nitrophenyl) thieno [2,3-d ] pyrimidine-2, 4(1H, 3H) -dione.

Detailed Description

The invention is specifically described below with reference to the accompanying drawings, and designs a preparation method of a Ruugeli key intermediate. The present invention will be described in detail below with reference to fig. 1 to 5.

the method comprises the following steps:

(1) under the condition of catalyst, acetic anhydride and acetic acid, the compound 1 reacts to generate a compound 2.

(2) The compound 2 reacts with ethyl cyanoacetate and sulfur under the action of a catalyst to generate a compound 3.

Example 1

Preparation of 1- (4-nitrophenyl) propan-2-one:

2kg of 4-nitrophenylacetic acid, 6L acetic anhydride, 1L acetic acid and nitrogen are added into a 10L reaction bottle and stirred for 2 hours, then 450g of 1-methylimidazole is added, the internal temperature is kept at 30-35 ℃, the mixture is stirred for 24 hours, the reaction solution is dropwise added into 12L water and stirred for 16 hours at 30 ℃, ethyl acetate 10L is added, the mixture is stirred, kept stand, separated, and concentrated to obtain 1.82kg of a product with the yield of 93.4%.

The nuclear magnetic hydrogen spectrum data of the product are as follows: 1H NMR (400MHz, Chloroform-d) 8.23(dd, J ═ 8.6,1.7Hz,2H),7.39(dd, J ═ 8.6,1.7Hz,2H),3.87(s,2H),2.27(s,3H) (fig. 2).

Example 2

Preparation of ethyl 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate:

1kg of 1- (4-nitrophenyl) propan-2-one is dissolved in 4L ethanol, 685g of ethyl cyanoacetate and 195g of sulfur are added, stirring is carried out, the temperature is increased to 40 ℃, 200g of n-butylamine are added, the temperature is increased to 50 ℃, stirring is carried out for 2 hours, the temperature is reduced to about 10 ℃, stirring is carried out for 1 hour, filtering is carried out, and a filter cake is leached by 2L ethanol to obtain 1.37kg of a product with the purity of 99% and the yield of 85.0%.

The nuclear magnetic hydrogen spectrum data of the product are as follows: 1H NMR (400MHz, Chloroform-d): 8.28-8.23 (m,2H), 7.53-7.48 (m,2H),6.29(s,2H),4.36(q, J ═ 7.1Hz,2H),2.42(s,2H),1.41(t, J ═ 7.1Hz,3H) (fig. 3).

Example 3

Preparation of ethyl 2- (3- (6-methoxypyridazin-3-yl) ureido) -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate:

dissolving 1.6kg of triphosgene in 50L dichloromethane, cooling to below 0 ℃, preparing 4.74kg of 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid ethyl ester and 4.4kg of triethylamine 50L dichloromethane suspension, slowly dripping the triphosgene-dichloromethane suspension into the triphosgene-dichloromethane solution, controlling the temperature in the whole process to be below 0 ℃, stirring for 3 hours, adding 2kg of 3-amino-6-methoxypyridazine, reacting for 24 hours at about 10 ℃, filtering the reaction solution, leaching a filter cake by using 20L dichloromethane, adding the filter cake into 100L methanol and 50L water, heating to 40 ℃, pulping, cooling to 10 ℃, stirring for 1 hour, filtering, leaching the filter cake by using 20L methanol, drying to obtain 5.74kg, and obtaining the yield of 81.2%.

L CMS (M/z): 458.10[ M +1] (FIG. 4);

example 4

3- (6-methoxypyridazin-3-yl) -5-methyl-6- (4-nitrophenyl) thieno [2,3-d ] pyrimidine-2, 4(1H, 3H) -dione:

adding 2kg of ethyl 2- (3- (6-methoxypyridazin-3-yl) ureido) -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate and 50L methanol into a reaction kettle, adding a 2.2L 30% sodium methoxide methanol solution, heating to reflux, preserving heat for 3 hours, adding the reaction liquid into 100L water, adjusting the pH value to 5-6 with acetic acid, stirring for 1 hour, filtering, and drying a filter cake to obtain 1.6kg of a product, wherein the yield is 88.9%.

L CMS (M/z): 412.29[ M +1] (FIG. 5);

technical solution of the present invention is described above with reference to the specific embodiments, and it is obvious that the specific implementation of the present invention is not limited by the above-mentioned manner, and it is within the scope of the present invention to adopt various insubstantial modifications of the method concept and technical solution of the present invention, or to directly apply the concept and technical solution of the present invention to other occasions without the modifications.

Claims

1. A preparation method of a Ruogeli key intermediate is characterized by comprising the following steps: the synthetic route comprises:

the method comprises the following steps:

2. A method for preparing a relogeli key intermediate according to claim 1, wherein the molar ratio of compound 1 to catalyst in step (1) is 1: (0.05-1); the catalyst is selected from methylimidazole and DMAP.

3. A Rugol key intermediate preparation method according to claim 1, wherein the mass-to-volume ratio of compound 1 to acetic anhydride in step (1) is 1g (2-5) m L, the mass-to-volume ratio of compound 1 to acetic acid in step (1) is 1g (0.1-1) m L, and the reaction temperature in step (1) is 10-40 ℃.

4. A method for preparing a relogeli key intermediate according to claim 1, wherein the molar ratio of compound 2 to ethyl cyanoacetate in step (2) is 1: (1-2), wherein the molar ratio of the compound 2 to the catalyst in the step (2) is 1: (0.1-2); the catalyst is n-butylamine, and in the step (2), the reaction temperature is 40-reflux temperature.

5. A method for preparing a key intermediate of rilogeli according to claim 1, wherein the molar ratio of compound 3 to triphosgene in step (3) is 1: (0.33-0.5), wherein the molar ratio of the compound 3 to the 3-amino-6-methoxypyridazine in the step (3) is 1: (0.9-2). More preferably 1: 1.

6. a process for the preparation of a rilogeli key intermediate according to claim 1, wherein the molar ratio of compound 3 to base in step (3) is 1: (1-5), more preferably 1: 3; the acid-binding agent is selected from triethylamine and diisopropylethylamine.

7. A Ruugeli key intermediate preparation method according to claim 1, wherein the triphosgene and compound 3 in step (3) react at-20 ℃ to 10 ℃, and the reaction temperature when 3-amino-6-methoxypyridazine is added in step (3) is 0 ℃ to 30 ℃.

8. A method for preparing a key intermediate of rilogeli according to claim 1, wherein the molar ratio of compound 4 to base in step (4) is 1: 20; the base is selected from sodium methoxide.

9. A Rugol key intermediate as claimed in claim 1, wherein the solvent used in step (4) is selected from alcohols (e.g. methanol, ethanol, etc.), aromatic hydrocarbons (e.g. benzene, toluene, etc.), amides (e.g. dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.); among them, methanol is preferred.

10. A process for the preparation of a key intermediate of rilogeli according to claim 1, wherein the reaction temperature in step (4) is 25 ℃ to 70 ℃, preferably 50 ℃.