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(12) Patent Application Publication (10) Pub. No.: US 2002/0028949 A1 Frutos Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2002/0028949 A1 Frutos Et Al US 20020028949A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0028949 A1 Frutos et al. (43) Pub. Date: Mar. 7, 2002 (54) SYNTHESIS OF (52) U.S. Cl. .......................................................... 548/303.1 (R)-3-(4-BROMOBENZYL)-1-(3,5- DICHLOROPHENYL)-5-IODO-3-METHYL-1- H-IMIDAZO12-AIMIDAZOL-2-ONE (57) ABSTRACT (76) Inventors: Rogelio P. Frutos, Sandy Hook, CT A novel process for the preparation of (R)-3-(4-Bromoben (US); Michael Dale Johnson, Danbury, Zyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo CT (US) 1,2-Cimidazol-2-one (1): Correspondence Address: BOEHRINGER INGELHEM CORPORATION 900 RIDGEBURY ROAD PO BOX 368 RIDGEFIELD, CT 06877 (US) (21) Appl. No.: 09/918,915 (22) Filed: Jul. 31, 2001 Related U.S. Application Data (63) Non-provisional of provisional application No. 60/224,166, filed on Aug. 9, 2000. This compound is useful as an intermediate in the prepara tion of certain Small molecules that are useful in the treat Publication Classification ment of prevention of inflammatory and immune cell mediated diseases. The present invention also relates to (51) Int. Cl." ............................................. C07D 471/04 certain intermediates used in this novel process. US 2002/0028949 A1 Mar. 7, 2002 SYNTHESIS OF (R)-3-(4-BROMOBENZYL)-1-(3,5- DICHLOROPHENYL)-5-IODO-3-METHYL-1-H- -continued IMIDAZO1,2-AIMIDAZOL-2-ONE C Cl RELATED APPLICATIONS 0001 Benefit of U.S. Provisional Application Serial No. 60/224,166, filed on Aug. 9, 2000, is hereby claimed, and that application is herein incorporated by reference in its entirety. O Cl Br 2. FIELD OF THE INVENTION 0002 The present invention relates generally to a novel N process for the preparation of (R)-3-(4-Bromobenzyl)-1-(3, 5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-C. S Cl imidazol-2-one. This compound is useful as an intermediate 4 in the preparation of certain Small molecules that are useful in the treatment or prevention of inflammatory and immune Rh cell-mediated diseases. The present invention also relates to O N3 O N certain novel intermediates used in this novel process. C ) / PPh3 - C ) / 4 - BACKGROUND OF THE INVENTION O O 0003) (R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5- iodo-3-methyl-1-H-imidazol.2-O-imidazol-2-one (1) is an C advanced intermediate used in the preparation of certain Small molecules that inhibit the interaction of cellular adhe Sion molecules, Specifically by antagonizing the binding of He human intercellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especially O is/ CD18/CD11a or “LFA-1”). As a result, these small mol C N C ecules are useful in the treatment or prevention of inflam matory and immune cell-mediated diseases. See U.S. Non O provisional Application No. 09/604,312 (Attorney Docket 6 No. 9/162), Wu et al., filed on Jun. 27, 2000, herein O C incorporated by Br 2. N H Cl A. 0004) reference. HQs/ Cl 0005 The method that has been used to prepare com pound 1 is illustrated in Scheme 1 below. 0006. In this procedure, an amino-ester 2 was reacted Scheme 1 with 3,5-dichlorophenylisothiocyanate 3 to provide thiohy dantoin 4. To a solution of triphenylphosphine (PPh3) was added the azide 5. After Stirring at room temperature over night, thiohydantoin 4 was added to provide 6. Treatment of 6 with trifluoroacetic acid provided 7. lodination was then NH2 OMe carried out by reaction of 7 with N-iodosuccinimide and pyridinium p-toluenesulfonate to provide 1. Recovered 7 may be recycled to provide additional 1. US 2002/0028949 A1 Mar. 7, 2002 SUMMARY OF THE INVENTION compound of formula IIa with a base to form a 0007. The present invention is directed to a novel process compound of the formula IIb: for the preparation of compound 1. A first aspect of the invention is directed to a process for preparing a compound of the formula 1: Br -( )- O C HN base RO2CN N C IIa Cl Br -( } a r 9 Cl 0008 said process comprising the following steps: HN N 0009 a) reacting a compound of the formula I with Y a compound of the formula HOCN-N Cl Ib ROC 0012 c) reacting a compound of the formula IIa NRCRO produced in Step a) with a Lewis acid and a phos phine oxide compound of the formula (R)-PO, wherein R is Calkyl or aryl, in an aprotic organic solvent to form a compound of the formula III: 0010 where R is a Calkyl, in an aprotic organic Solvent, followed by adding a triarylphosphine, a carbon tetrahalide and a tertiary amine, to form a compound of the formula IIa where R is Calkyl: n-( )- A. O C HNY N- HeLewis acid ROC2n-1 N C IIa HN N NECEO H Cl I Br 2. r O Cl n-( )- A. O C Ny N Cl ". III ROC N 2 N1 C 0013) or 0014) when the optional step b) is performed, reacting a compound of the formula IIb produced in Step b) with a coupling agent in an aprotic 0011 b) optionally hydrolyzing a compound of the organic Solvent to form a compound of the for formula IIa produced in Step a) by reacting the mula III: US 2002/0028949 A1 Mar. 7, 2002 n-( )- A. O C Br 2. O C Coupling Agent // TMS H He N. N. Nal, MSCI Y al- Ni? HOC N1 N C C IV b Br 2. r O C O y N C ( C III 0017. A second aspect of the invention is directed to the 0015 d) reacting a compound of the formula III individual novel steps of the above inventive process. A third produced in Step c) with a strong base and a com aspect of the invention is directed to the novel intermediates pound of the formula (RO)2POCl, wherein R is IIa, IIb, III and IV. A final aspect of the invention is directed Calkyl or aryl, in a polar organic Solvent at a to the novel urea intermediate of the following formula Ia temperature of about -90° C. to about 0°C. to form produced in the first Step of the inventive process and its a compound of the formula IV where R is Calkyl process of preparation: or aryl: Ia n-( )- A. O C base (RO)2POCl O NN C / N Cl III 0018 wherein R is Calkyl. DETAILED DESCRIPTION OF THE INVENTION O N N 0019. The individual steps of the inventive process are described in detail below, along with other aspects of the 1 N C present invention. IV 0020 All terms as used herein in this specification, unless otherwise Stated, shall be understood in their ordinary mean ing as known in the art. For example, a "Calkyl is an alkyl group having from 1 to 6 carbon atoms, which group 0016 e) reacting a compound of the formula IV can be branched or unbranched. The term “aryl', either produced in step d) with trimethylsilyl iodide, or alone or as part of another group, Shall be understood to with sodium iodide and trimethylsilyl chloride, in an mean an optionally Substituted 6-10 membered aromatic aprotic organic Solvent to form a compound of the carbocycle, “aryl' includes, for example, phenyl and naph formula 1: thyl, each of which may be optionally substituted. US 2002/0028949 A1 Mar. 7, 2002 0021 Optimum reaction conditions and reaction times for the individual StepS may vary depending on the particular -continued reactants used. Unless otherwise Specified, Solvents, tem C peratures, preSSures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples Section. O Typically, reaction progreSS may be monitored by thin layer / N C chromatography (TLC) if desired. Intermediates and prod H ucts may be purified by chromatography on Silica gel and/or NH recrystallization. Unless otherwise Set forth, the Starting Boc1 materials and reagents are either commercially available or may be prepared by one skilled in the art using methods 1O described in the chemical literature. Cl 0022. Step (a) 1O TFA O t-BuCHO 92% A. 74% 0023 Step a) of the inventive process comprises reacting o, a compound of the formula I with a compound of the w Cl formula 11 ROC NRCRO HN N Cl TFAA EtN 0024 where R is Calkyl, in an aprotic organic He Solvent, followed by adding a triarylphosphine, a 98% carbon tetrahalide and a tertiary amine, to form a compound of the formula IIa where R is Calkyl: Cl 12 single diastereomer n-( )- A. O Cl LiN(TMS)2 13 4-Br-BnBr, THF N1 N Cl -30 to O. C. 96% 0.025 The starting material of formula I is prepared as described in Yee, N., “Self-Regeneration of Stereocenters: A Practical Enantiospecific Synthesis of LFA-1 Antagonist N N Cl BIRT-377, Org. Lett. 2000, 2, 2781-2783, which is herein incorporated by reference in its entirety. This process is Set forth in detail below: O I C 14 CO2H NMM, i-BuOCOCI A. r 3,5-dichloroaniline BnMeNOH - 50% NaOH HN-Boc 14 then 6NHCI 9 quant. yield US 2002/0028949 A1 Mar. 7, 2002 0031 where R is Calkyl. It is not necessary to isolate -continued the novel urea Ia, although it has been isolated and charac terized. The urea of formula Ia is dehydrated in situ by adding a triarylphosphine, a carbon tetrahalide and a tertiary Br -( )- A. O amine to the reaction mixture.
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