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A kind of synthetic method of Relugoli or its salt

A synthesis method and compound technology, applied in the field of medicine and chemical industry, can solve the problems of difficult removal of dimerization impurities, high cost, high cost of enlarged production route, etc.

Active Publication Date: 2022-08-05
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • 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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  • A kind of synthetic method of Relugoli or its salt
  • A kind of synthetic method of Relugoli or its salt
  • A kind of synthetic method of Relugoli or its salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079]

[0080] Compound 1 (22.22g, 100mmol), ethyl 2-cyanoacetoacetate 2a (11.88g, 105mmol) and ethanol (111mL) were added to the three-necked flask, and after stirring and dissolving, diisopropylethylamine (25.85g, 200mmol) was added dropwise. ), added sulfur powder (3.37 g, 105 mmol), stirred evenly, heated to 75~80 ℃ and reacted overnight. After the reaction was completed, dilute hydrochloric acid (3%, 222 mL) was added to quench the reaction, part of the ethanol was removed, ethyl acetate was added to extract and the organic phase was discarded, the aqueous phase was collected, and sodium bicarbonate solution was added to adjust the pH to 8 to 9, and a large amount of solid was precipitated , and slowly cooled and crystallized, filtered and dried to obtain compound 3a (29.18 g, 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)....

Embodiment 2

[0085]

[0086]Compound 1 (22.22 g, 100 mmol), isopropyl 2-cyanoacetoacetate 2b (13.35 g, 105 mmol) and isopropanol (111 mL) were added to the three-necked flask, and after stirring and dissolving, diisopropylethylamine (25.85 mmol) was added dropwise. g, 200 mmol), added sulfur powder (3.37 g, 105 mmol), stirred evenly, heated to 80~85 ℃ and reacted overnight. At the end of the reaction, dilute hydrochloric acid (3%, 222 mL) was added to quench the reaction, part of the isopropanol was removed, ethyl acetate was added for extraction and the organic phase was discarded, the aqueous phase was collected, and sodium bicarbonate solution was added to adjust the pH to 8 to 9. A large amount of solid was slowly cooled and crystallized, filtered and dried to obtain compound 3b (30.71 g, 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).

[008...

Embodiment 3

[0091]

[0092] Compound 3a (34.94 g, 100 mmol) was added to the three-necked flask, 175 mL of dichloromethane was added, and the mixture was stirred and dissolved. The reaction flask was placed in an ice bath and cooled to 0-5° C., triethylamine (20.24 g, 200 mmol) was added, methyl chloroformate (10.39 g, 110 mmol) was slowly added dropwise, and the temperature was raised to room temperature to react overnight. After the reaction was completed, water (349 mL) was added, 175 mL of dichloromethane was added to extract and the aqueous phase was discarded, the organic phase was collected, washed with water, concentrated to a small volume, n-heptane was added, slowly cooled and crystallized, filtered and dried to obtain compound 4a (35.90 g, 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 embodiment 3, methyl chloroformate c...

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Abstract

The synthetic method of relugolix provided by the invention or its salt comprises taking 1-(dimethylamino)-3-(4-nitrophenyl)-2-acetone and cyanoacetate as starting materials, After condensation cyclization, alkylation reaction, Ullmann reaction, coupling reaction, Relugolix 4 free base form or salt form is obtained: this synthetic route optimizes the process, shortens the route steps, improves the route efficiency, and The use of precious metal catalysts can be reduced, which greatly reduces the process cost. The route is simple to operate, not only the total yield is high, but also the obtained product has high purity, which is suitable for scale-up production. We also found three salt forms of relugolix, which have better crystallinity and are easy to purify, which is beneficial to improve product purity.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new method for preparing relugolix. Background technique [0002] Relugolix is ​​a once-daily oral small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist developed by Myovant and Japan's Takeda Pharmaceutical. Rapidly lowers estrogen and progesterone levels in women. Myovant is studying relugolix in the treatment of some diseases mediated by sex hormones, and a phase III clinical trial of uterine fibroids with severe menstrual bleeding is currently underway. Once successful, it will have great market prospects. [0003] Relugoli's chemical name: 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 structure is as follows: [0004] [0005] J.Med.Chem.2011, Vol. 54, Page 4998, reported the synthetic method of Relugoli, using ethyl...

Claims

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Application Information

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Patent Type & Authority Patents(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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