WO2021023143A1

WO2021023143A1 - Method for preparing pharmaceutical intermediate of relugolix

Info

Publication number: WO2021023143A1
Application number: PCT/CN2020/106499
Authority: WO
Inventors: 王鹏; 李丕旭; 谷向永; 高峰; 葛亚东; 刘远华
Original assignee: 苏州鹏旭医药科技有限公司
Priority date: 2019-08-05
Filing date: 2020-08-03
Publication date: 2021-02-11
Also published as: CN112321602A

Abstract

Disclosed are a synthetic scheme for a Relugolix intermediate and Relugolix. The synthetic scheme efficiently avoids the use of a highly toxic substance, i.e. methyl chloroformate or ethyl chloroformate, and uses other kinds of chloroformates that are low in toxicity and convenient to use. The synthetic scheme can reduce the usage risk in a raw material production process, and is easy to operate, safer in process, and beneficial to industrialized production.

Description

A kind of preparation method of Relugoli drug intermediate

Technical field

This application relates to the field of drug synthesis, in particular, to a method for preparing a thieno[2,3-d]pyrimidine compound exhibiting gonadotropin releasing hormone (GnRH) antagonistic activity and its intermediates.

Background technique

Endometriosis is caused by the growth of the endometrium in any part of the uterine cavity. It is a common estrogen-dependent gynecological disease, which often occurs during the reproductive age of women, and its mechanism of action is unclear. The diagnosis of endometriosis is difficult and the cause is unknown, and other complex symptoms have severely blocked the discovery of effective treatment methods. At present, endometriosis is mainly diagnosed through laparoscopic surgery and treated by surgery, or controlled by taking contraceptives, GnRH receptor agonists or progesterone to reduce the level of estrogen in the body. In July 2018, the world's first oral GnRH antagonist in this field was approved by the FDA for marketing.

Relugolix is a small molecule gonadotropin releasing hormone (GnRH) receptor antagonist developed by Japan's Takeda Pharmaceutical Co., Ltd., which can rapidly reduce female estrogen and progesterone. In January 2019, Relugolix was approved for marketing in Japan and was approved for the treatment and symptom relief of uterine fibroids. It is expected that a new drug application will be submitted to the FDA in the third quarter of 2019.

So far, there are few reports on the synthesis process of Relugolix at home and abroad. The original research company Takeda Pharmaceutical Co., Ltd. disclosed its synthesis route for the first time (WO2004067535A1). The specific synthesis route is as follows:

Another synthetic route of Relugolix published in patent WO2014051164A2 is as follows:

In the two synthetic routes disclosed above, the highly toxic substance ethyl chloroformate is used in the synthesis process, and the flash point is very low, and it is highly flammable, and has high requirements for the production environment.

Summary of the invention

This application provides a new synthetic scheme of Relugoli, the synthetic route is as follows:

First, compound 1 is reacted with chloroformate to obtain compound 2. Compound 2 and compound 3 undergo a nucleophilic substitution reaction to obtain compound 4. Compound 4 undergoes bromination reaction to obtain compound 5. Compound 5 reacts with dimethylamine hydrochloride to produce compound 6. Compound 6 is hydrolyzed under alkaline conditions to obtain compound 7. Compound 7 and compound 8 undergo condensation reaction to form compound 9. Compound 9 undergoes a reduction reaction to obtain compound 10. Compound 10 undergoes condensation reaction with methoxyamine hydrochloride to produce compound 11. Compound 11 undergoes an intramolecular ring-closure reaction to obtain compound 12 (Relugolix).

Compared with the prior art, the method for synthesizing Relugoli intermediates in this application has the following advantages:

(1) Avoid the use of ethyl chloroformate and methyl chloroformate, which are highly toxic, low flash point, and highly flammable substances;

(2) It can effectively avoid the risks in the storage and use of ethyl chloroformate and methyl chloroformate.

(3) Compared with the WO2014051164A2 route, the Pd/C catalytic hydrogenation step is moved forward, which avoids the risk of heavy metal pollution to the final product, and is also more conducive to the production of bulk drugs under cGMP conditions.

(4) Compared with the WO2004067535A1 route, it is more concise and efficient, avoids the substitution reaction of methoxyethyl methylamine, and is safer and more environmentally friendly.

Specific implementation

The following examples describe the implementation of the present application. Those skilled in the art should realize that these specific examples only show the implementation technical solutions selected to achieve the purpose of the application, and are not limitations on the technical solutions. According to the teachings of the present application, it is obvious that the technical solutions of the present application are improved in combination with the prior art, and they all fall within the protection scope of the present application.

The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually conditions in routine experiments. Among them, the chemical reagents used in the following examples are all commercially available chemical reagents.

Example 1

Toluene (450 mL) and compound 1 (150 g) were sequentially added to a 2L reaction flask, stirring was turned on, propyl chloroformate (120 g) was added dropwise, and the reaction was heated to reflux for 2 hours. The temperature was lowered to 50-60°C, and ethanol (1350 mL) was added dropwise to control the internal temperature at 50-60°C. After the addition is completed, slowly lower the temperature to the internal temperature of 0-10°C, stir for 1 h, filter, and rinse the filter cake with ethanol (300 mL). Vacuum drying at 45°C gave a yellow solid with a yield of 84.4% and a purity of 98%.

The NMR data of compound 2-a are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ 10.67 (s, 1H), 8.31-8.22 (m, 2H), 7.59-7.52 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 4.21 ( t, J = 6.7 Hz, 2H), 2.42 (s, 3H), 1.80-1.67 (m, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H).

Example 2

Toluene (1.5 mL) and compound 1 (0.5 g) were sequentially added to a 10 mL reaction flask, stirring was turned on, isopropyl chloroformate (0.4 g) was added dropwise, and the reaction was heated to reflux for 2 h. The temperature was lowered to 20～30℃, purified water (4mL) and dichloromethane (4mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (4mL), the organic phases were combined, and concentrated under reduced pressure to obtain the crude compound 2-b Column purification (ethyl acetate:n-heptane=1:10) to obtain 0.58 g of bright yellow solid with a yield of 90% and a purity of 98%.

The NMR data of compound 2-b are as follows:

¹ H NMR (400MHz, DMSO-d6) δ 10.45 (s, 1H), 8.29-8.23 (m, 2H), 7.69-7.63 (m, 2H), 5.02-4.91 (m, 1H), 4.32 (m, J=7.1 Hz, 2H), 2.34 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.29 (d, J=6.3 Hz, 6H).

Example 3

Toluene (1.5 mL), compound 1 (0.10 g), K ₂ CO ₃ (90 mg) were added to a 10 mL reaction flask, stirring was turned on, benzyl chloroformate (0.136 g) was added dropwise, and the reaction was heated at reflux for 4 h. Cool to 20～30℃, add purified water (4mL) and toluene (4mL), separate the layers and extract the aqueous phase with toluene (4mL), combine the organic phases and concentrate under reduced pressure to obtain the crude compound 2-c, which is purified by column (Ethyl acetate:n-heptane=1:6) to obtain 0.103 mg of bright yellow solid with a yield of 71.5% and a purity of 98%.

The NMR data of compound 2-c are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ10.75 (s, 1H), 8.37-8.16 (m, 2H), 7.62-7.50 (m, 2H), 7.49-7.32 (m, 5H), 5.27 (s, 2H) ), 4.37 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

Example 4

Add N,N-dimethylacetamide (480mL) and compound 2-a (160g) to a 2L reaction flask, turn on the stirring, add potassium carbonate (62.0g), and add 35% 2,6-difluorobenzyl bromide Acetonitrile solution (265.3g), heated to internal temperature at 80-90°C and stirred for 2h. Cool to 50～60℃, add ethyl acetate (1280mL), add water (900mL), stir, stand for liquid separation, collect the organic phase, extract the aqueous phase with ethyl acetate (48mL) once, combine the organic phases, and the organic phases Wash twice with 10% brine (900 mL) and once with water (900 mL); the organic phase is concentrated under reduced pressure until no liquid is evaporated to obtain crude compound 4-a in oily form, with a purity of 98% by HPLC, which is directly used in the next reaction . Part of the column purification was used for NMR data characterization.

The NMR data of compound 4-a are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ 8.26 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.36-7.20 (m, 1H), 6.86 (t, J = 7.8Hz, 2H), 4.98 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.22-4.00 (m, 2H), 2.40 (s, 3H), 1.83-1.49 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.07-0.71 (m, 3H).

Example 5

Add ethyl acetate (1.64L) and trifluoromethylbenzene (1.64L) to a 5L reaction flask, turn on the stirring, add compound 4-a (211g), add N-bromosuccinimide (90.7g) , Add 2,2-azobis(2,4-dimethylvaleronitrile) (10.1g), stir and heat to react at an external temperature of 65-75°C for 1h. After the reaction was completed, it was cooled to room temperature, ethyl acetate (633 mL) was added, washed twice with water (844 mL), the organic phase was collected, concentrated under reduced pressure to 750-800 mL, and ethanol (2x576 mL) was added for steaming twice. Add n-heptane (1.6vol) to the system, stir the above mixture at 20-30℃ for 30min, add n-heptane (1.2vol) again, cool to 0-10℃, stir for 1h, filter, filter cake with ethanol and n-heptane Wash with alkane mixed solution (1:2, 337 mL). The filter cake was vacuum dried at 45°C to obtain a light yellow solid with a yield of 73% and a purity of 98.7% by HPLC.

The NMR data of compound 5-a are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.43-8.27 (m, 2H), 7.81-7.65 (m, 2H), 7.36-7.18 (m, 1H), 6.87 (t, J=7.8Hz, 2H), 4.99(s,2H),4.71(s,2H), 4.32(q,J=6.9Hz,2H),4.08(br,2H),1.61(br,3H),1.37(t,J=7.2Hz,3H ), 1.10-0.71 (m, 3H).

Example 6

Add ethyl acetate (4mL) and trifluoromethylbenzene (4mL) to a 100mL reaction flask, turn on the stirring, add compound 4-a (0.5g), add liquid bromine (0.193g), add 2,2-azo Bis(2,4-dimethylvaleronitrile) (0.024g) was stirred and heated at an external temperature of 65-75°C for 22h, and the product peak area of the reaction solution was 34.7%.

Example 7

Add ethyl acetate (4mL) and trifluoromethylbenzene (4mL) to a 100L reaction flask, turn on the stirring, add compound 4-a (0.5g), add dibromohydantoin (0.172g), add 2,2- Azobis(2,4-dimethylvaleronitrile) (0.024g) was stirred and heated at an external temperature of 65-75°C for 1 hour, and the product peak area of the reaction solution was 91%.

Example 8

Add N,N-dimethylformamide (962mL), dimethylamine hydrochloride (35.8g), and triethylamine (77.1g) to a 3L reaction flask in sequence, turn on the stirring, and stir the above mixture at 20-30°C for 0.5h. The internal temperature was reduced to 0-10°C, compound 5-a (175g) and N,N-dimethylformamide (87.5 mL) were added, and the mixture was stirred at 10-20°C for 1 h. After the reaction was completed, ethyl acetate (875 mL) and water (875 mL) were added, stirred and separated, and the organic phase was collected. The aqueous phase was extracted once with ethyl acetate (525 mL), and the organic phases were combined. The organic phase was washed with 10% brine (3x875 mL), and washed once with water (875 mL). The organic phase was concentrated under reduced pressure until no liquid was evaporated to obtain crude compound 6-a with an HPLC purity of 92%, which was directly used in the next reaction. Part of the column purification was used for NMR data characterization.

The NMR data of compound 6-a are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ 8.31-8.18 (m, 2H), 7.70-7.61 (m, 2H), 7.32-7.19 (m, 1H), 6.92-6.78 (m, 2H), 5.02 (s ,2H),4.23(q,J=7.2Hz,3H),4.19-4.05(m,2H),3.52(s,2H),2.06(s,6H),1.77-1.50(m,3H),1.32( t, J = 7.1 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H).

Example 9

Add ethanol (1.5L), water (450mL), compound 6-a (173g) to a 5L reaction flask, add 48% potassium hydroxide aqueous solution (54g), and heat to 55-65°C for 5h. Cool down to 20～30℃, adjust the pH to 6.0～7.0 with 6mol/L hydrochloric acid, concentrate under reduced pressure and the volume of the mixed solution is less than 605mL, add dichloromethane (865mL), then water (865mL); stir, separate, collect the lower layer The organic phase, the aqueous phase were extracted with dichloromethane (2x519 mL), and the organic phases were combined. The organic phase was washed once with 10% brine (865 mL) and once with water (865 mL), and concentrated under reduced pressure to about 175 mL. Ethyl acetate (2x692mL) was steamed to 175mL, and 346mL ethyl acetate was added. Stir at 20-30°C for 3h, filter, rinse the filter cake with cold ethyl acetate (346 mL), and dry the filter cake at 40-50°C to obtain a yellow solid with a yield of 86% and an HPLC purity of 94.3%.

The NMR data of compound 7-a are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ 8.29 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.33-7.15 (m, 1H), 6.94-6.74 (m, 2H),5.08(s,2H),4.26-3.98(m,2H),3.79(s,2H),2.41(s,6H),1.83-1.49(m,2H),1.11-0.66(m,3H) .

Example 10

Add N,N-dimethylacetamide (550mL), compound 7-a (110g) and compound 8 (39.98g) in sequence to a 2L reaction flask, N ₂ protection, control the temperature at 10～40℃ and add N, N dropwise -Diisopropylethylamine (66.6g), heated to 50-60°C for 0.5h. Control the temperature not higher than 60°C to add 50% T3P ethyl acetate solution (157.4g) dropwise, and after the addition, stir and react at 50-60°C for 1h. Cool down, control the internal temperature to 20-30°C, and add water (825g) dropwise. Adjust the pH to 7.5～8.5 with 8mol/L sodium hydroxide aqueous solution by controlling the internal temperature at 20～30℃, stir for 0.5h, filter, add the filter cake to methanol (440mL), stir at 20～30℃ for more than 2h, filter, filter The cake was rinsed with methanol (220 mL). The material was vacuum dried at 45°C to obtain a yellow solid with a yield of 78.1% and a purity of 99.3%.

The NMR data of compound 9-a are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ13.87 (s, 1H), 8.55 (d, J = 9.5 Hz, 1H), 8.29 (d, J = 8.6 Hz, 2H), 7.567.45 (m, 2H) ,7.207.07(m,1H),7.00(d,J=9.6Hz,1H), 6.75(t,J=7.7Hz,2H), 5.04(s,2H), 4.37-3.99(m,5H), 3.51 (s, 2H), 2.20 (s, 6H), 1.85-1.49 (m, 2H), 1.09-0.85 (m, 3H).

Mass spectrum data of compound 9-a: [M+H] ⁺ =641.3.

Example 11

Add methanol (16mL), compound 9-a (2g), concentrated hydrochloric acid (0.27g), hydrogen pressure 0.1～0.3Mpa, control temperature 20～30℃ and react for 15h in a 50mL reaction flask. After the reaction is complete, filter with celite, rinse the filter cake with methanol (4mL), concentrate the mother liquor under reduced pressure until no distillate is evaporated, add dichloromethane (20mL) and saturated sodium bicarbonate solution (10mL), separate the layers The aqueous phase was extracted with dichloromethane (20 mL), the organic phases were combined, and concentrated under reduced pressure to obtain the crude compound 10-a, which was purified by column (ethyl acetate:n-heptane=3:2) to obtain 1.62 g of bright yellow solid. The yield is 85% and the purity is 97%.

The NMR data of compound 10-a are as follows:

¹ H NMR(400MHz,DMSO-d ₆ )δ14.05(s,1H), 8.38(d,J=9.5Hz,1H), 7.38-7.23(m,2H), 7.04-6.89(m,4H), 6.67-6.57(m,2H),5.41(s,2H),4.89(s,2H),4.00(s,5H),3.54(s,J=21.9Hz,2H),2.10(s,6H),1.71 -1.37(d,2H),0.73(d,3H).

Mass spectrum data of compound 10-a: [M+H] ⁺ =611.2.

Example 12

Add acetonitrile (2mL), triethylamine (28.1mg), N,N-carbonyldiimidazole (102mg) to a 10mL reaction flask, and replace with nitrogen three times. Add methoxyamine hydrochloride (53mg) to the system under ice water bath and replace with nitrogen. Three times, add compound 10-a (198mg), replace with nitrogen three times, the system reacts at 45～55℃ for 2h, add triethylamine (42mg) and N,N-carbonyldiimidazole (102mg) to continue the reaction for 15h, the reaction is over, add two Chloromethyl (2ml) and purified water (2mL). After layering and separating, the aqueous phase was extracted with dichloromethane (2mL), the organic phases were combined, concentrated, and purified by column (ethyl acetate: n-heptane = 2:1) 118 mg of off-white solid was obtained, the yield was 52%, and the purity was 87%.

The NMR data of compound 11-a are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ 14.00 (s, 1H), 9.62 (s, 1H), 9.07 (s, 1H), 8.38 (d, J = 9.5 Hz, 1H), 7.83-7.62 ( m,2H),7.43-7.11(m,4H),6.98(t,J=7.9Hz,2H), 4.91(s,2H), 4.00(s,5H), 3.64(s,3H), 3.54(d ,J=3.1Hz,3H),2.10(s,6H),1.43(d,J=18.2Hz,2H),0.79(d,J=42.4Hz,3H).

Mass spectrum data of compound 11-a: [M+H] ⁺ =684.1.

Example 13

Add compound 11-a (100mg), methanol (2.5mL), tetrahydrofuran (0.2mL), sodium methoxide (4mg) in a 10mL reaction flask, replace the system with nitrogen three times, control the temperature at 60～65℃ and react for 2h, the reaction is over, add Dichloromethane (2ml) and purified water (2mL). After layer separation, the aqueous phase was extracted with dichloromethane (2mL), the organic phases were combined, concentrated under reduced pressure, and purified by column (ethyl acetate: methanol = 40:1 ) To obtain 19.7 mg of off-white solid with a yield of 21.6% and a purity of 95%. The NMR data of compound 12 are as follows:

¹ H NMR(400MHz,DMSO-d ₆ )δ9.66(s,1H),9.10(s,1H),7.75(dd,J=12.4,8.9Hz,3H),7.50(dd,J=27.9,8.8 Hz, 4H), 7.15 (t, J = 8.1 Hz, 2H), 5.31 (dd, J = 63.3 Hz, 2H), 4.10 (s, 3H), 3.65 (s, 5H), 2.05 (s, 6H).

Mass spectrum data of compound 12: [M+H] ⁺ =624.1.

This application includes but is not limited to the above embodiments. Any equivalent substitution or partial improvement made under the principle of the spirit of this application will be deemed to be within the protection scope of this application.

Claims

A synthetic method for preparing Relugoli drug, characterized in that it comprises one or more of the following steps:

(1) The step of heating and refluxing compound 1 and chloroformate in an aprotic solvent to produce compound 2;

(2) The step of substitution reaction between compound 2 and compound 3 to produce compound 4;

(3) The step of reacting compound 4 with bromination reagent to produce compound 5;

(4) The step of reacting compound 5 with dimethylamine or its salt to produce compound 6;

(5) Compound 6 undergoes a hydrolysis reaction under alkaline conditions to generate compound 7;

(6) The step of reacting compound 7 with compound 8 or its salt to produce compound 9;

(7) The step of reducing the nitro functional group of compound 9 to produce compound 10;

(8) The step of reacting compound 10 with methoxyamine or its salt in the presence of an activating reagent to produce compound 11;

(9) Compound 11 undergoes ring-closure reaction under heating conditions to generate compound Relugolix 12 (Relugolix);
The method for preparing Relugoli drug intermediate 2 according to claim 1, wherein the aprotic solvent is toluene, tetrahydrofuran, dioxane, acetonitrile, acetone, N,N-dimethylformamide, etc. One or more,

The R group is a C3-C7 alkyl or aryl group.
The preparation method of Relugoli pharmaceutical intermediate 5 according to claim 1, comprising the step of compound 4 undergoing bromination reaction to produce compound 5. The bromination reagent is N-bromosuccinimide, Dibromohydantoin, liquid bromine,

The R group is a C3-C7 alkyl or aryl group.
A relugoli drug intermediate compound, the compound having the structure of formula 2:

The R group is a C3-C7 alkyl or aryl group.
A kind of Relugoli drug intermediate compound, the compound has the structure of formula 4:

The R group is a C3-C7 alkyl or aryl group.
A relugoli drug intermediate compound, the compound having the structure of formula 5:

The R group is a C3-C7 alkyl or aryl group.
A kind of Relugoli drug intermediate compound, the compound has the structure of formula 6:

The R group is a C3-C7 alkyl or aryl group.
A kind of Relugoli drug intermediate compound, the compound has the structure of formula 7:

The R group is a C3-C7 alkyl or aryl group.
A kind of Relugoli drug intermediate compound, the compound has the structure of formula 9:

The R group is a C3-C7 alkyl or aryl group.
A kind of Relugoli drug intermediate compound, the compound has the structure of formula 10:

The R group is a C3-C7 alkyl or aryl group.
A relugoli drug intermediate compound, the compound having the structure of formula 11:

The R group is a C3-C7 alkyl or aryl group.
A method for preparing compound 12 (Relugolix) from compound 10, comprising:

The R group is a C3-C7 alkyl or aryl group,

Steps of reacting compound 10 with methoxyamine or its salt to produce compound 11:

The R group is a C3-C7 alkyl or aryl group.

Compound 11 undergoes ring-closure reaction under heating conditions to generate compound Relugolix 12 (Relugolix) steps:

The R group is a C3-C7 alkyl or aryl group.