737789-87-6

Basic information

• Product Name: TAK-385
• Synonyms: TAK-385;Relugolix;Altropane;TKA-385 Relugolix;1-[4-[1-[(2,6-difluorophenyl)methyl]-5-(dimethylaminomethyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-6-thieno[4,5-e]pyrimidinyl]phenyl]-3-methoxyurea;Relugolix TAK-385;TAK-385,Relugolix
• CAS NO: 737789-87-6
• Molecular Formula: C29H27F2N7O5S
• Molecular Weight: 623.6303864
• Product Categories: API
• Mol File: 737789-87-6.mol

Chemical Properties

• Melting Point: 228 °C (decomp)(Solv: ethyl acetate (141-78-6); tetrahydrofuran (109-99-9))
• Appearance: /
• Density: 1.442±0.06 g/cm3(Predicted)
• PKA: 13.17±0.70(Predicted)
• CAS DataBase Reference: TAK-385(CAS DataBase Reference)
• NIST Chemistry Reference: TAK-385(737789-87-6)
• EPA Substance Registry System: TAK-385(737789-87-6)

Safety Data

• Hazardous Substances Data: 737789-87-6(Hazardous Substances Data)

Usage

Mechanism of action

The mechanism of action of relugolix is as a?Gonadotropin Releasing Hormone?Receptor Antagonist, and Cytochrome P450 3A Inducer, and Cytochrome P450 2B6 Inducer, and Breast Cancer Resistance Protein Inhibitor, and P-Glycoprotein Inhibitor. The physiologic effect of relugolix is by means of Decreased?GnRH?Secretion.

Pharmacokinetics

Relugolix is a?selective?antagonist?of the?gonadotropin-releasing hormone receptor?(GnRHR) (IC50?= 0.12?nM).A single oral administration of relugolix at a dose of 3?mg/kg has been found to suppress?luteinizing hormone?(LH) levels for more than 24?hours in?castrated?cynomolgus monkeys, indicating a long?duration of action. The drug (80–160?mg/day) has been found to reduce?testosterone?levels to sustained?castrate?levels in men with once-daily administration.[8]?Lower dosages (10–40?mg/day) are being studied in the treatment of endometriosis and uterine fibroids to achieve partial?sex hormone?suppression.? The reasoning behind partial suppression for these conditions is to reduce the incidence and severity of?menopausal?symptoms such as?hot flushes?and to avoid?bone mineral density?changes caused by?estrogen deficiency?that can eventually lead to?osteoporosis.

Clinical Use

Relugolix was first approved in Japan in 2019, under the brand name Relumina, for the symptomatic treatment of uterine fibroids, and more recently by the United States' FDA in 2020, under the brand name Orgovyx, for the treatment of advanced prostate cancer. Relugolix has also been studied in the symptomatic treatment of endometriosis.

Upstream product

• 308831-93-8 2-((ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester 
• 308831-94-9 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester 
• 308831-95-0 4-(bromomethyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester 
• 308832-01-1 ethyl 2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-4-{[(2-methoxyethyl)(methyl)amino]methyl}-5-(4-nitrophenyl)thiophene-3-carboxylate 
• 577780-07-5 ethyl 5-(4-aminophenyl)-2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-4-{[(2-methoxyethyl)(methyl)amino]methyl}thiophene-3-carboxylate 
• 737789-92-3 ethyl 2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-{4-[(methoxycarbamoyl)amino]phenyl}-4-{[(2-methoxyethyl)(methyl)amino]methyl}thiophene-3-carboxylate 
• 737789-93-4 2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-{4-[(methoxycarbamoyl)amino]phenyl}-4-{[(2-methoxyethyl)(methyl)amino]methyl}thiophene-3-carboxylic acid 
• 124-40-3 dimethyl amine 
• 174072-89-0 2-Amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester 
• 1589503-93-4 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-6-(4-aminophenyl)thiophene[2,3-d]pyrimidine-2,4(1H,3H)-dione 
• 593-56-6 N-methoxylamine hydrochloride 
• 530-62-1 1,1'-carbonyldiimidazole 
• 697-73-4 2,6-difluorobenzyl chloride 
• 5332-96-7 1-(4-nitrophenyl)propan-2-one 

Relevant articles and documents

Synthetic method of Relugolix

The invention provides a synthesis method of Relugolix, and belongs to the field of medicine synthesis. The method comprises the following steps: (i) subjecting a compound 8 and a halogenating reagent to a halogenating reaction to obtain a compound 9, wherein in the compound 9, X is halogen; and (ii) carrying out a reaction on the compound 9 and N,N-diisopropyl ethyl amine to obtain Relugolix. The method provided by the invention is simple to operate, mild in reaction condition, few in side reaction, high in yield and purity, easy to purify the product, and suitable for commercial large-scale production.

Preparation method of Rurugolix

The invention provides a preparation method of rerugolix. The preparation method comprises the following steps: S1, reducing a compound 1 under the condition of palladium carbon/formic acid or palladium carbon/hydrazine hydrate to obtain a compound 2; s2, reacting the compound 2 with t-butyloxycarboryl or trifluoroacetyl to obtain a compound 3; s3, hydrolyzing the compound 3 to obtain a compound 4; s4, the compound 4 and 3-amino-6-methoxypyridazine are subjected to a reaction, and a compound 5 is obtained; according to the invention, the synthesis steps are fewer, the synthesis efficiency is higher, the high-quality Rurugolil intermediate can be safely obtained with high yield, the palladium-carbon catalyzed reduction reaction is preposed, the Rurugolil is effectively controlled as the heavy metal content index of the raw material medicine, and the reduction is carried out in a non-hydrogen manner, so that the industrial production is more facilitated, and the method is suitable for industrial production. The production risk caused by the use of a high-pressure reaction kettle is avoided, the amino protection is ingeniously adopted, and the protecting group is removed after the pyridazine ring is introduced, so that the route has higher yield.

Rayleigh intermediate and preparation method thereof

The invention discloses an intermediate and a preparation method thereof. The preparation method of the compound F comprises the following steps: carrying out cyclization reaction on the compound E in the presence of an organic solvent and/or water as a s

Intermediate compound for preparing relugolix, preparation method of intermediate compound and preparation method of relugolix

The invention relates to the technical field of medicine synthesis, in particular to an intermediate compound for preparing relugolix, a preparation method of the intermediate compound and a preparation method of relugolix. The intermediate compound for preparing the relugolix is any one of compounds shown in the following structural formula, wherein R is a leaving group. The embodiment of the invention provides a novel intermediate for preparing the relugolix, and provides a novel method for synthesizing the relugolix, so that the yield can be increased, and the impurity content can be reduced.

Preparation method of Relugolix and intermediate compounds

The invention provides a novel preparation method of Relugolix and two novel intermediate compounds. The preparation method comprises the following steps: reducing an existing compound 2 to obtain an amino compound 3, then, carrying out a condensation rea

Preparation method of Relugolix

The invention provides a preparation method of the Relugolix, intermediates of the Relugolix, namely, a compound shown as a formula (VI), a compound shown as a formula (V) and a compound shown as a formula (III) defined in the description, and a preparation method of the intermediates of the Relugolix. The method is simple to operate, safe, efficient, high in reaction purity and yield and relatively low in process cost, and is a preparation method which conforms to a green chemical principle and is suitable for large-scale production.

Preparation method of Relugolix

The invention belongs to the field of medicine preparation, and relates to a preparation method of Relugolix or a salt thereof with a gonadotropin releasing hormone (GnRH) antagonism effect, compared with a preparation method of Relugolix provided by an original research, the method has the advantages that impurities containing aniline structures, RS-1 and the like are removed, the synthesis process is simple, the reaction yield is high, hydrogenation is avoided, industrial production is easier to realize, an aniline warning structure impurity RS-2 in a finished product is not detected, and RS-1 and RS-3 are both controlled to be 0.01% or below.

Synthesis method of relugolix or salt thereof

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.

Intermediate of relugolian and preparation method and application thereof

The invention discloses brand-new intermediates (including compounds shown in formulas B, C, D and E) of relugolian. The brand-new intermediates can be used for preparing relugolian and salts, derivatives or analogues of relugolian. The invention also discloses a preparation method of the rugolian, the preparation method is simple, the raw materials are easy to obtain, the content of a product uret byproduct is less than 0.10%, the purification cost of a crude product can be greatly reduced, and large-scale production is facilitated.

Relugolix intermediate compound, preparation method and application thereof

The invention discloses a brand-new intermediate compound of Relugolix and a preparation method thereof. The intermediate compound is high in purity, and can be used for preparing Relugolix and salts,derivatives or analogues thereof. The invention also discloses a preparation method of Relugolix, the obtained finished product is high in yield and purity, and no uret by-product is detected.