Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-10-15
2000-11-14
Huang, Evelyn Mei
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
564184, C07D21704, C07C23380
Patent
active
06147214&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to an improved process and intermediates useful in the preparation of 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (I), below. Compound I is useful in the preparation of 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1H-[1,2,4-triazol-3-ylmethyl)]-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-a mide whose formula is ##STR1## Compound II is useful as an inhibitor of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion, and which are accordingly useful for the prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and related diseases.
BACKGROUND OF THE INVENTION
Microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride, cholesteryl ester, and phospholipids. It has been implicated as a probable agent in the assembly of Apo B-containing lipoproteins, biomolecules which contribute to the formation of atherosclerotic lesions. See European Patent application publication no. 0 643 057 A1, European Patent application publication no. 0 584 446 A2, and Wetterau et al., Science, 258, 999-1001, (1992). Compounds which inhibit MTP and/or otherwise inhibit Apo B secretion are accordingly useful in the treatment of atherosclerosis. Such compounds are also useful in the treatment of other diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels can be reduced. Such conditions include hypercholesterolemia, hypertriglyceridemia, pancreatitis, and obesity; and hypercholesterolemia, hypertriglyceridemia, and hyperiipidemia associated with pancreatitis, obesity, and diabetes.
PCT application serial no. PCT/IB95/00448 (hereafter "the '448 application") and U.S. Patent Application Serial No. 60/032307 (hereafter "the '307 application"), assigned to the Assignee of this application and incorporated herein in their entirety, describe methods for the preparation of compound I and its conversion to compound II. All other documents referred to herein are also incorporated herein in their entirety.
SUMMARY OF THE INVENTION
According to one embodiment of the invention there is provided an improved process for the preparation of the compound of the formula ##STR2## which comprises treating the compound of formula ##STR3## m is 0 or 1 and R.sup.5 H is a first acid, with a source of formaldehyde, such as formalin, paraformaldehyde and trioxane, in the presence of a second acid, wherein said first and second acids may be the same or different and are selected from mineral acids such as hydrochloric, sulfuric, nitric and phosphoric, organic acids such as sulfonic acids, e.g. benzenesulfonic (besylic), p-toluenesulfonic (PTSA, tosylic), methanesulfonic (MSA, mesylic) and trifluoromethanesulfonic (triflic); carboxylic acids e.g., formic, acetic, proprionic, benzoic, citric, tartaric, maleic, fumaric, succinic and malic. Preferably the source of formaldehyde is paraformaldehyde, the first acid is HCl or formic acid and the second acid is formic acid.
According to another aspect of the above embodiment there is provided a process wherein the compound of formula III, wherein m is 1, is prepared by treating the compound of the formula ##STR4## in an inert medium, containing a first acid, with a reducing agent selected from hydrogen in the presence of a hydrogenation catalyst such as Raney Ni, Pd/C and Pd(OH).sub.2 ; and aluminum hydrides; and borane; and borohydrides. The compound (group) of the formula III, wherein m is 0 is prepared therefrom by neutralization of the the R.sup.5 H.
Another aspect of the above embodiment provides a process wherein the compound of formula IV is prepared by treating the compound of the formula V ##STR5## with a dehydrating agent, selected from (C.sub.1 -C.sub.6)alkyl or (C.sub.6 -C.sub.10)aryl sulfonyl or carbonyl halide or anhydride, in the presence of a base. A preferred dehydrating agent is mesyl chloride.
Yet another aspect of the above embodiment provides a p
REFERENCES:
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G. Stokker, Tetrahedron Lett. 1996, 5453-5456.
K. Isobeb et al., Chem. Pharm Bull. 1998, 1275-1282. Selective Cleavage of Aromatic Rings by Ozonolysis. I. Application to o-Dimethoxybenzene Derivatives.
F. Kuffner et al., Monatshefte Fur Chemie., col. 91, 1960, Wein at pp. 1152-1161, XP002070019 see p. 1160, Uber die Konstitution eines Nebenalkaloides aus Adhatoda vasica Nees.
A. Pictet et al., Bericate der Deutschen Chemischen Gesellschgft (1911) 44, pp. 2030-2036. Search Report for PCT/IB98/00493.
March J. Advanced Organic Chemistry. Second Edition. pp. 854, 1125, 1977.
Ginsburg Paul H.
Huang Evelyn Mei
Jacobs Seth H.
Pfizer Inc
Richardson Peter C.
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