Synthesis method of relugolix or salt thereof

A synthetic method and compound technology, applied in the field of medicine and chemical industry, can solve the problems of difficult condensation reaction, high cost of enlarged production route, and too long route steps

Active Publication Date: 2021-03-26
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The initial cost of raw materials for the above two routes is relatively high, the route steps are too long, the process is relatively cumbersome, and the cost of enlarging the production route is relatively high
The aromatic ring methyl bromination reaction needs to use NBS to carry out under the catalysis of free radicals, the reaction selectivity is poor, the yield is low, and it is easy to produce dibromo impurities due to excessive bromination; 6-methoxypyridazin-3-amine and carboxylic acid The condensation reaction is difficult, and the special price of the condensing agent is expensive; finally, the aromatic amine is condensed with O-methylhydroxylamine under the action of CDI, which is easy to produce dimerization impurities, and the dimerization impurities are difficult to remove in the finished product

Method used

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  • Synthesis method of relugolix or salt thereof
  • Synthesis method of relugolix or salt thereof
  • Synthesis method of relugolix or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079]

[0080] Add compound 1 (22.22g, 100mmol) and ethyl 2-cyanoacetoacetate 2a (11.88g, 105mmol) and ethanol (111mL) into the three-necked flask, stir and dissolve and drop diisopropylethylamine (25.85g, 200mmol ), adding sulfur powder (3.37g, 105mmol), stirring evenly and then heating to 75-80°C to react overnight. Add dilute hydrochloric acid (3%, 222mL) to quench the reaction at the end of the reaction, spin off part of the ethanol, add ethyl acetate for extraction and discard the organic phase, collect the water phase, add sodium bicarbonate solution to adjust the pH to 8-9, and precipitate a large amount of solid , and slowly cooled to crystallize, filtered and dried to obtain compound 3a (29.18g, 83.5%).

[0081] MS(ESI)m / z=350.1[M+H] +

[0082] 1 H NMR (500MHz, DMSO) δ8.23(d, J=8.8Hz, 2H), 7.79(d, J=8.8Hz, 2H), 7.60(s, 2H), 4.24(q, J=7.2Hz, 2H ),3.55(s,2H),2.07(s,6H),1.32(t,J=7.2Hz,3H).

[0083] In embodiment 1, 2-cyanoacetoacetate ethyl ester can be used 2-c...

Embodiment 2

[0085]

[0086]Add compound 1 (22.22g, 100mmol) and isopropyl 2-cyanoacetoacetate 2b (13.35g, 105mmol) and isopropanol (111mL) into the three-necked flask, stir and dissolve and drop diisopropylethylamine (25.85 g, 200mmol), add sulfur powder (3.37g, 105mmol), stir evenly and heat to 80-85°C to react overnight. Add dilute hydrochloric acid (3%, 222mL) to quench the reaction at the end of the reaction, spin off part of the isopropanol, add ethyl acetate to extract and discard the organic phase, collect the aqueous phase, add sodium bicarbonate solution to adjust the pH to 8-9, and precipitate A large amount of solid was crystallized by slow cooling, and filtered and dried to obtain compound 3b (30.71g, 84.5%).

[0087] MS(ESI)m / z=364.2[M+H] +

[0088] 1 H NMR (500MHz, DMSO) δ8.24 (d, J = 8.8Hz, 2H), 7.80 (d, J = 8.8Hz, 2H), 7.58 (s, 2H), 4.74-5.08 (m, 1H), 3.53 (s,2H),2.08(s,6H),1.18(d,J=6.4Hz,3H).

[0089] In embodiment 2, 2-cyanoacetoacetate isopropyl ester can use 2-...

Embodiment 3

[0091]

[0092] Compound 3a (34.94 g, 100 mmol) was added into a three-necked flask, and 175 mL of dichloromethane was added and stirred to dissolve. The reaction flask was cooled to 0-5°C in an ice bath, triethylamine (20.24g, 200mmol) was added, methyl chloroformate (10.39g, 110mmol) was slowly added dropwise, and after the addition was completed, the temperature was raised to room temperature for overnight reaction. Add water (349mL) at the end of the reaction, add 175mL dichloromethane to extract and discard the aqueous phase, collect the organic phase, wash with water, concentrate to a small volume, add n-heptane, slowly cool and crystallize, filter and dry to obtain compound 4a (35.90g, 88.1%). MS(ESI)m / z=408.1[M+H] + , 1 H NMR (400MHz, CDCl 3 )δ10.55(s,1H),8.26(d,J=8.8Hz,2H),7.72(d,J=8.8Hz,2H),4.30-4.56(m,2H),3.79(s,3H), 3.66(s,2H),2.12(s,6H),1.33(t,J=7.2Hz,3H).

[0093] In Example 3, methyl chloroformate can be replaced by ethyl chloroformate, isopropyl chlorof...

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Abstract

The invention provides a synthesis method of relugolix or a salt thereof, wherein thesynthesis method comprises the steps: taking 1-(dimethylamino)-3-(4-nitrophenyl)-2-acetone and cyanoacetate as initial raw materials, and carrying out condensation cyclization, alkylation reaction, Ullmann reaction and coupling reaction to obtain a relugolix 4 free alkali form or salt form. The synthetic route optimized the process, the route steps are shortened, the route efficiency is improved, the use of noble metal catalysts can be reduced, and the process cost is greatly reduced. The route is simple to operate, the total yield is high, the purity of the obtained product is high, and the method is suitable for large-scale production. The forms of the three salts of relugolix are also found, the crystallinity is good, the purification is easy, and the product purity is favorably improved.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new method for preparing relugoli. Background technique [0002] Relugolix (Relugolix) is a once-daily oral small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist developed by Myovant and Takeda Pharmaceuticals, which inhibits the pituitary gonadotropin-releasing hormone receptor, Rapidly lowers estrogen and progesterone levels in women. Myovant is studying relugoli to treat some diseases mediated by sex hormones. Currently, the phase III clinical trial of uterine fibroids with heavy menstrual bleeding is also underway. Once successful, it will have great market prospects. [0003] The chemical name of Relugoli: 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazine- 3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea. The structural formula is as follows: [0004] [0005] J.Med.Chem. 20...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D333/38C07D333/40
CPCC07D495/04C07D333/38C07D333/40
Inventor 郑旭春张一平付晨晨刘巧灵
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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