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Crystalline forms and process for preparing spiro-hydantoin compounds

Inactive Publication Date: 2008-10-30
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This process enables the production of spiro-hydantoin compounds on a larger scale while facilitating the separation of enantiomers and providing crystalline forms with beneficial properties, making them suitable for treating immune or inflammatory diseases.

Problems solved by technology

However, there are recognized difficulties associated with the adaptation of the disclosed multistep synthesis for preparing such spiro-hydantoin compounds to larger scale, such as production in a pilot plant or on a manufacturing scale.

Method used

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  • Crystalline forms and process for preparing spiro-hydantoin compounds
  • Crystalline forms and process for preparing spiro-hydantoin compounds
  • Crystalline forms and process for preparing spiro-hydantoin compounds

Examples

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examples

[0299]The following examples illustrate embodiments of the inventive process, and are not intended to limit the scope of the claims. For ease of reference, the following abbreviations are used herein;

Abbreviations

[0300]DMSO=dimethyl sulfoxide

DTTA=(+)-Di-p-toluoyl-D-tartaric acid

EtOH=ethanol

HCl=hydrochloric acid

HPLC=high performance liquid chromatography

kg=kilogram

L=liter

M=molar

MTBE=methyl tertiary butyl ether

MeOH=methanol

mol=mole

mp=melting point

NMR=nuclear magnetic resonance

TBME=t-butyl methyl ether

THF=tetrahydrofuran

preparation 1

3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione

[0301]

[0302]Triethylamine (0.78 kg, 7.75 mol) was added in 15-30 minutes with stirring to a thin suspension of sarcosine ethylene hydrochloride (1.00 kg, 6.51 mol) in dichloromethane (6.00 L). After stirring at room temperature for 1.5-2.0 hours, the mixture was filtered to remove the resulting triethylamine hydrochloride salt. The salt cake was washed with dichloromethane (2.00 L). The filtrate was cooled to 0-5° C.

[0303]A solution of 3,5-dichlorophenyl isocyanate (1.47 kg, 7.81 mol) in dichloromethane was prepared at 20-25° C. The solution was added to the above cooled filtrate slowly in 30-60 minutes. The temperature was maintained below 10° C. during the addition. After the addition, the mixture was stirred at 20-25° C. for 12-14 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, TBME (16.00 L) was added in one portion. The resulting suspension was stirred at 20-25° C. for 2-3 hours and wa...

preparation 2

(E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile

[0304]

[0305]A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol) and pyrrolidone (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20-24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5-10 minutes. The suspension was cooled to 20-25° C. in 3-4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239-241° C. 1H NMR (DMSO-d6): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). 13C NMR (DMSO-d6): 14...

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Abstract

A process is provided for preparing spiro-hydantoin compounds of the formula IIwherein Z is N or CR4b; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A2 is a linker, G′ is a linker; Q is a linker; and R2, R4a, R4c, and Rh are defined in the specification. The process optionally includes the enantiomeric separation of intermediates to allow preparation of enantiomers of the spiro-hydantoin compounds of formula II. Substituted spiro-hydantoin compounds may be prepared from the spiro-hydantoin compounds of formula II. The spiro-hydantoin compound of formula II and the substituted spiro-hydantoin compounds are useful in the treatment of immune or inflammatory diseases. Also, provided are products made by the instant inventive process and crystalline forms (prepared by any process) of the substituted spiro-hydantoin compound, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof, as well as methods of use thereof. Crystalline forms of certain intermediates are provided.

Description

RELATED APPLICATIONS[0001]This application is a continuation of co-pending U.S. patent application Ser. No. 11 / 238,427, filed on Sep. 29, 2005, which claims the benefit of U.S. Provisional Application Nos. 60 / 615,292 filed on Oct. 1, 2004; 60 / 617,905 filed on Oct. 12, 2004; and 60 / 717,290 filed on Sep. 15, 2005, incorporated herein by reference in their entirety.FIELD OF INVENTION[0002]The present invention relates to a process for preparing spiro-hydantoin compounds and substituted spiro-hydantoin compounds. Also provided are crystalline forms of the substituted spiro-hydantoin compound, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof as well as methods of use thereof. Crystalline forms of certain intermediates are also provided.BACKGROUND OF INVENTION[0003]A key event in an immune response involves the migration of leukocytes to a disease site. During an i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/10
CPCC07D487/10A61P1/04A61P1/16A61P1/18A61P11/00A61P11/06A61P11/08A61P13/12A61P17/00A61P17/02A61P17/06A61P19/02A61P19/10A61P25/00A61P25/28A61P27/02A61P27/16A61P29/00A61P31/14A61P31/20A61P37/02A61P37/06A61P37/08A61P39/02A61P43/00A61P7/00A61P9/00A61P9/10A61P3/10
Inventor DELMONTE, ALBERT J.DHAR, T.G. MURALIFAN, YUGOUGOUTAS, JACK Z.MALLEY, MARY F.MCLEOD, DOUGLAS D.WALTERMIRE, ROBERT E.WEI, CHENKOU
Owner BRISTOL MYERS SQUIBB CO
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