Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-02-15
2002-10-01
Rausuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06458986
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to a novel process for the preparation of (R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-&agr;]imidazol-2-one. This compound is useful as an intermediate in the preparation of certain small molecules that are useful in the treatment or prevention of inflammatory and immune cell-mediated diseases. The present invention also relates to certain novel intermediates used in this novel process.
BACKGROUND OF THE INVENTION
(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-&agr;]-imidazol-2-one (1) is an advanced intermediate used in the preparation of certain small molecules that inhibit the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especially CD18/CD11a or “LFA-1”). As a result, these small molecules are useful in the treatment or prevention of inflammatory and immune cell-mediated diseases. See U.S. application Ser. No. 09/604,312, Wu et al., filed on Jun. 27, 2000, herein incorporated by
reference.
The method that has been used to prepare compound 1 is illustrated in Scheme 1 below.
In this procedure, an amino-ester 2 was reacted with 3,5-dichlorophenylisothiocyanate 3 to provide thiohydantoin 4. To a solution of triphenylphosphine (PPh
3
) was added the azide 5. After stirring at room temperature overnight, thiohydantoin 4 was added to provide 6. Treatment of 6 with trifluoroacetic acid provided 7. Iodination was then 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.
SUMMARY OF THE INVENTION
The present invention is directed to a novel process 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:
said process comprising the following steps:
a) reacting a compound of the formula I with a compound of the formula
where R is C
1-6
alkyl, 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 C
1-6
alkyl:
b) optionally hydrolyzing a compound of the formula IIa produced in step a) by reacting the compound of formula IIa with a base to form a compound of the formula IIb:
c) reacting a compound of the formula IIa produced in step a) with a Lewis acid and a phosphine oxide compound of the formula (R
1
)
3
PO, wherein R
1
is C
1-6
alkyl or aryl, in an aprotic organic solvent to form a compound of the formula III:
or
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 organic solvent to form a compound of the formula III:
d) reacting a compound of the formula III produced in step c) with a strong base and a compound of the formula (R
2
O)
2
POCl, wherein R
2
is C
1-6
alkyl or aryl, in a polar organic solvent at a temperature of about −90° C. to about 0° C. to form a compound of the formula IV where R
2
is C
1-6
alkyl or aryl:
e) reacting a compound of the formula IV produced in step d) with trimethylsilyl iodide, or with sodium iodide and trimethylsilyl chloride, in an aprotic organic solvent to form a compound of the formula 1:
A second aspect of the invention is directed to the individual novel steps of the above inventive process. A third aspect of the invention is directed to the novel intermediates IIa, IIb, III and IV. A final aspect of the invention is directed to the novel urea intermediate of the following formula Ia produced in the first step of the inventive process and its process of preparation:
wherein R is C
1-6
alkyl.
DETAILED DESCRIPTION OF THE INVENTION
The individual steps of the inventive process are described in detail below, along with other aspects of the present invention.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, a “C
1-6
alkyl” is an alkyl group having from 1 to 6 carbon atoms, which group can be branched or unbranched. The term “aryl”, either alone or as part of another group, shall be understood to mean an optionally substituted 6-10 membered aromatic carbocycle; “aryl” includes, for example, phenyl and naphthyl, each of which may be optionally substituted.
Optimum reaction conditions and reaction times for the individual steps may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, 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. Typically, reaction progress may be monitored by thin layer chromatography (TLC) if desired. Intermediates and products may be purified by chromatography on silica gel and/or recrystallization. Unless otherwise set forth, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature.
Step (a)
Step a) of the inventive process comprises reacting a compound of the formula I with a compound of the formula
where R is C
1-6
alkyl, 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 C
1-6
alkyl:
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 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:
The commercially available (D)-N-Boc-alanine 9 is reacted with 3,5-dichloroaniline via a mixed anhydride intermediate (i-BuOCOCl, N-methylmorpholine, −10° C. to rt, THF) to give amide 10. Deprotection of the crude amide 10 by TFA in dichloromethane afforded amino N-aryl amide 11 in 92% yield over two steps.
The amino amide 11 is treated with pivalaldehyde in refluxing pentane. A crystalline solid is directly formed from the reaction mixture and identified as the desired trans imidazolidinone 12 as a single diastereomer in 74% yield. After protection of 12 (TFAA, Et
3
N, 0° C. to rt, CH
2
Cl
2
, 98% yield) to obtain 13, the crude 13 in THF is deprotonated with LiN(TMS)
2
at −30 to −20° C. and then the resulting enolate is alkylated at −30° C. to 0° C. with 4-bromobenzyl bromide from the opposite face of the t-butyl group to give the 5,5-disubstituted 14 as a single diastereomer in 96% yield.
The trifluoroacetamide group of 14 is first hydrolyzed (1.5 eq. BnMe
3
NOH, 2.0 eq. 50% NaOH, rt to 40° C., dioxane) to give a mixture of the corresponding partially hydrolyzed N-unsubstituted acetal of 14, Schiff base of I, and I itself. Subsequent direct addition of 6N HCl to the above mixture resulted in complete hydrolysis to afford amino amide I in quantitative yield.
In step (a) of the present inventive process, the compound of formula I is first reacted with an isocyanatoacetate of the formula
where R is C
1-6
alkyl to form a urea of the following formula Ia in situ:
where R is C
1-6
alkyl. It is not necessary to isolate the novel urea Ia, although it has been isolated and characterized. The urea of formula Ia is dehydrated in situ by adding a triarylphosphine, a carbon tetrahalide and a tertiary amine to the reaction mixture. The resulting carbodiimide undergoes a spontaneous cyclization to provide the ester of formula IIa in good yield.
The formation of ureas from isocyanates in general is documented in the scientific literature (See, e.g.,
Chem. Rev
. 1981, 589, and references cited therein). In the process of the present invention, however, it is not necessary to isolate the urea, which can be dehydrated in situ to afford a carbodiimide that further undergoes a spon
Frutos Rogelio P.
Johnson Michael Dale
Anderson Rebecca
Boehringer Ingelheim Pharmaceuticals Inc.
Datlow Philip I.
Rausuer Robert W.
Raymond Robert P.
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