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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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CAS 2379889-71-9
Chemical Formula: C27H32N4O3
Molecular Weight: 460.58


1H-1-Benzazepine-4-carboxamide, 2,3,4,5-tetrahydro-N-((1S)-2-hydroxy-1-methylethyl)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-, (4S)-

(4S)-N-[(2S)-1-hydroxypropan-2-yl]-methyl-1-[2-methyl-4-(3- methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxamide

Vasopressin V2 receptor agonist

Kyorin Pharmaceutical under license from Sanwa Kagaku Kenkyusho , is developing SK-1404 ([14C]-SK-1404, presumed to be lazuvapagon), for the iv treatment of nocturia, and as an oral formulation, as KRPN-118







Process for preparing benzazepine derivatives, particularly lazuvapagon a V2 receptor agonist, and their intermediates, useful for treating diabetes insipidus, hemophilia and overactive bladder.

[Fifth Step] to [Sixth Step]
Formula 33] [In the formula, R 1 and R 2 have the same meanings as those in the first step, and * represents an asymmetric center. ]

 In the fifth step and the sixth step, the reaction can be performed according to a conventional method.
In the fifth step, compound (IX) is treated with a base (eg, sodium hydroxide, potassium hydroxide, etc.) in a suitable solvent (eg, alcohol solvent such as methanol, ethanol, etc., water), usually at room temperature to an organic solvent. A carboxylic acid compound of the compound (X) can be obtained by reacting at a temperature of the boiling point of the solvent for 30 minutes to 1 day. Next, in the sixth step, the obtained carboxylic acid compound is subjected to amidation with L-alaninol to obtain the compound (V). For the amidation, a method using a condensing agent, a method of reacting L-alaninol with a mixed acid anhydride or acid chloride of carboxylic acid, and the like can be used. In the method using a condensing agent, for example, the carboxylic acid compound and L-alaninol are condensed in a suitable organic solvent (chloroform, dimethylformamide, etc.) in the presence of a base (eg, diisopropylethylamine, triethylamine, etc.) (for example, 1 , 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), etc.) alone or in combination with 1-hydroxybenztriazole (HOBt). (V) can be obtained. Further, in the method using a mixed acid anhydride, for example, a carboxylic acid derivative in an appropriate organic solvent (eg, dichloromethane, toluene, etc.) in the presence of a base (eg, pyridine, triethylamine, etc.), an acid chloride (eg, pivaloyl chloride, Tosyl chloride, etc.) or an acid derivative (eg, ethyl chloroformate, isobutyl chloroformate, etc.), and the resulting mixed acid anhydride is reacted with L-alaninol usually at 0° C. to room temperature to give compound (V). Can be obtained. Further, in the method of passing through an acid chloride, for example, an acid chloride is obtained by using a chlorinating agent (eg, thionyl chloride, oxalyl chloride, etc.) in a suitable organic solvent (eg, toluene, xylene, etc.) Acid chloride in the presence of a base (eg sodium carbonate, triethylamine etc.) in a suitable organic solvent (eg ethyl acetate, toluene etc.) with L-alaninol,

 Compound (V) can also exist as a solvate. The solvate of compound (V) can be obtained by a conventional method for producing a solvate. Specifically, it can be obtained by mixing the compound (V) with a solvent while heating if necessary, and then cooling and crystallizing the mixture while stirring or standing. It is desirable that the cooling be carried out while adjusting the cooling rate if necessary in consideration of the influence on the quality of crystal, grain size and the like. For example, cooling at a cooling rate of 20 to 1° C./hour is preferable, and cooling at a cooling rate of 10 to 3° C./hour is more preferable. As the organic solvent used in these methods, alcohol solvents such as methanol, ethanol, propanol, isopropanol, normal propanol, and tertiary butanol are preferable. The amount of the organic solvent used is preferably 3 to 20 times by weight, more preferably 5 to 10 times by weight, of the compound (V).



The present inventors have investigated the method described in Patent Document 1 by using N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H). -Pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide chiral compound was prepared and analyzed. As a result, the compound was amorphous (amorphous). Solid). Amorphous is known to be a thermodynamically non-equilibrium metastable state and generally has high solubility and dissolution rate, but is low in stability and is often unfavorable in terms of drug development. Therefore, an object of the present invention is to increase the applicability as a drug substance to (S)-N-[(S)-1-hydroxypropan-2-yl]-4 represented by the formula (I). -Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide It is to provide an alcohol solvate or a crystal thereof.
[Chemical 1]

[Reference Example 1] Compound (I) (amorphous)
Compound (I) was produced by the following method.
[Chemical 5]

(First Step)
1-(2-Methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b] Azepine-4-carboxylic acid ethyl ester was treated with methyl bromide in the presence of (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide, cesium carbonate and cesium fluoride in a mixed solvent of benzene bromide and water. By carrying out methylation using (R)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4 ,5-Tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester was obtained.

(Second Step)
(R)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5- Reduction of the ketone portion of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester with a borane-ammonia complex prepared from sodium borohydride and ammonium sulfate in a toluene solvent gave (4R)-5. -Hydroxy-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine- 4-Carboxylic acid ethyl ester was obtained.

(Third Step)
(4R)-5-hydroxy-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5- By chlorinating the hydroxyl group of tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester with phosphorus oxychloride in the presence of pyridine in a toluene solvent, (4S)-5-chloro-4-methyl-1 -(2-Methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester was obtained. It was

(Step 4)
(4S)-5-chloro-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5- By stirring tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester in a methanol solvent in the presence of 10% palladium-carbon under slightly pressurized conditions of hydrogen gas, (S)-4-methyl- 1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester Obtained.

(Fifth Step)
(S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H- Benzo[b]azepine-4-carboxylic acid ethyl ester is hydrolyzed with 30% sodium hydroxide in a solvent of water and methanol to give (S)-4-methyl-1-(2-methyl-4-( 3-Methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid was obtained.

(Sixth Step)
(S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H- Benzo[b]azepine-4-carboxylic acid was converted to an acid chloride form using thionyl chloride in a toluene solvent. This acid chloride and L-alaninol are reacted in a mixed solvent of ethyl acetate and water in the presence of sodium carbonate to give (S)-N-((S)-1-hydroxypropan-2-yl)-4-methyl. -1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (compound ( I)) was obtained.

 FIG. 7 shows the powder X-ray diffraction spectrum of the compound (I) obtained in the first to sixth steps. No clear peak was observed in the X-ray diffraction pattern, and the compound (I) of Reference Example 1 was found to be amorphous.

[Example 1] Isopropanol solvate
of compound (I) To 5.0 g of amorphous compound (I) of Reference Example 1, 65 mL of isopropanol was added, and the mixture was stirred at room temperature for 30 minutes. After the precipitated suspension was dissolved by heating, it was allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with chilled isopropanol and dried at 40° C. overnight to give 4.9 g of a white solid.

 When the obtained compound was analyzed by a thermogravimetric apparatus, the content of isopropanol was 8.2% with respect to the compound (I), and the molar ratio was 0.7 times the amount with respect to the compound (I). It was

 The powder X-ray diffraction spectrum and the infrared absorption spectrum of the compound obtained in Example 1 are shown in FIG. 1 and FIG. 2, respectively. The characteristic peaks shown in Table 1 were shown as the diffraction angle (2θ) or as the interplanar spacing d. The obtained compound was crystalline.

[table 1]
FIG. 2 shows an infrared absorption spectrum of the compound obtained in Example 1.

/////////////LAZUVAPAGON, KRPN-118


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