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A novel intermediate for the preparation of dimethyl ((2S,2'S)-((2S,2'S)-(((S)-6-phenyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole-3,10-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate

IP.com Disclosure Number: IPCOM000247025D
Publication Date: 2016-Jul-27
Document File: 5 page(s) / 330K

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The IP.com Prior Art Database

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A novel intermediate for the preparation of dimethyl ((2S,2'S)-((2S,2'S)-(((S)-6- phenyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole-3,10-diyl)bis(1H-imidazole-5,2-


Di-tert-butyl 2,2'-(((S)-6-phenyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole-3,10-diyl)bis(1H- imidazole-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylate) bis-(pentafluorophenol) salt, referred to as Compound A, of the following formula:

is a novel intermediate in the synthesis of dimethyl ((2S,2'S)-((2S,2'S)-(((S)-6-phenyl- 6H-benzo[5,6][1,3]oxazino[3,4-a]indole-3,10-diyl)bis(1H-imidazole-5,2- diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate

Disclosed herein after is a crystalline form of Compound A

Crystalline form I of Compound A

The XRPD pattern of crystalline form I of compound A is presented in Figure 1.

Figure 1: XRPD pattern of Crystalline form I of Compound A


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Main PXRD peaks:

7.6, 7.8, 10.0, 10.2, 11.2, 11.7, 13.8, 14.1, 15.3, 17.9, 18.7, 19.1, 20.9 and 22.3 deg-2- theta ± 0.1 deg 2-theta.

PXRD Method

X-ray diffraction was performed on X-Ray powder diffractometer:

Bruker D8 Advance; CuK_ radiation (λ = 1.54 Å); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

Measurement parameters:

Scan range: 2 - 40 degrees 2-theta; Scan mode: continuous; Step size: 0.05 degrees; Time per step: 0.5 s; Sample spin: 30 rpm; Sample holder: PMMA specimen holder ring.

Example-1 : Preparation of Crystalline form I of Compound A:

Charged (S)-3,10-dibromo-6-phenyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole in suitable solvent such as DME, 2-methyl THF, THF, DMF, Toluene, 1,4-Dioxane, acetonitrile, dimethylacetamide, cyclopentyl methyl ether, isopropanaol, ethanol, ethyl acetate,



10 30 40


2Theta (Coupled TwoTheta/Theta) WL=1.54060

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isopropyl acetate and mixture thereof. Charged bis pinacolato diborane (1.0 eq to 4 eq) and added suitable base such as potassium acetate, potassium carbonate, sodium acetate, sodium carbonate, cesium carbonate, potassium pivalate or sodium pivalate (2 eq to 8 eq.). Degassed the reaction mass. Charged transition metal catalyst like Pd2dba3, Pd(OAc)2, and PdCl4 and phosphine ligand like N-Bu(Ad)2P, Am-phos, n- BuP(t-Bu)2HBF4 Xphos, Sphos, Brett Phos, DTBPF, PCy3 or P(t-Bu)3. The reaction mass was refluxed and stirred. After the completion of reaction, cooled the reaction mass to room temperature. Charged suitable base such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate or cesium carbonate (2.0 eq to 10.0 eq) and (S)-tert-butyl 2-(5- bromo-1H-imidazol-2-yl...