Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-08
2003-07-01
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S431000, C549S009000, C544S351000
Reexamination Certificate
active
06586434
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the preparation of apical sodium co-dependent bile acid transporter (ASBT) inhibitors and more particularly to the preparation of benzothiepine ASBT inhibitors. This invention especially relates to methods of preparing tetrahydrobenzothiepine oxide ASBT inhibitors.
2. Description of Related Art
It is well established that agents which inhibit the transport of bile acids across the tissue of the ileum can also cause a decrease in the levels of cholesterol in blood serum. Stedronski, in “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,” Biochimica et Biophysica Acta, 1210 (1994) 255-287 discusses biochemistry, physiology, and known active agents surrounding bile acids and cholesterol. Bile acids are actively transported across the tissue of the ileum by an apical sodium co-dependent bile acid transporter (ASBT), alternatively known as an ileal bile acid transporter (IBAT).
A class of ASBT-inhibiting compounds that was recently discovered to be useful for influencing the level of blood serum cholesterol comprises tetrahydrobenzothiepine oxides (THBO compounds, PCT Patent Application No. WO 96/08484). Further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 97/33882. Additional THBO compounds useful as ASBT inhibitors are described in U.S. Pat. No. 5,994,391. Still further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 99/64409. Included in the THBO class are tetrahydrobenzothiepine-1-oxides and tetrahydrobenzothiepine-1,1-dioxides. THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring.
Published methods for the preparation of THBO compounds include the synthesis through an aromatic sulfone aldehyde intermediate. For example 1-(2,2-dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene (29) was cyclized with potassium t-butoxide to form tetrahydrobenzothiepine-1,1-dioxide (syn-24) as shown in Eq. 1.
Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acid chloride with anisole in the presence of aluminum trichloride to produce a chlorobenzophenone compound; the chlorobenzophenone compound was reduced in the presence of trifluoromethanesulfonic acid and triethylsilane to produce a chlorodiphenylmethane compound; the chlorodiphenylmethane compound was treated with lithium sulfide and 2,2-dibutyl-3-(methanesulfonato)propanal to produce 1-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene (40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29. The first step of that method of preparing compound 29 requires the use of a corrosive and reactive carboxylic acid chloride that was prepared by the reaction of the corresponding carboxylic acid with phosphorus pentachloride. Phosphorus pentachloride readily hydrolyzes to produce volatile and hazardous hydrogen chloride. The reaction of 2,2-dibutyl-3-(methanesulfonato)propanal with the lithium sulfide and the chlorodiphenylmethane compound required the intermediacy of a cyclic tin compound to make the of 2,2-dibutyl-3-(methanesulfonato)propanal. The tin compound is expensive and creates a toxic waste stream.
In WO 97/33882 compound syn-24 was dealkylated using boron tribromide to produce the phenol compound 28. Boron tribromide is a corrosive and hazardous material that generates hydrogen bromide gas and requires special handling. Upon hydrolysis, boron tribromide also produces borate salts that are costly and time-consuming to separate and dispose of.
An alternative method of preparing THBO compounds was described in WO 97/33882, wherein a 1,3-propanediol was reacted with thionyl chloride to form a cyclic sulfite compound. The cyclic sulfite compound was oxidized to produce a cyclic sulfate compound. The cyclic sulfate was condensed with a 2-methylthiophenol that had been deprotonated with sodium hydride. The product of the condensation was a (2-methylphenyl) (3′-hydroxypropyl)thioether compound. The thioether compound was oxidized to form an thioether aldehyde compound. The thioether aldehyde compound was further oxidized to form an aldehyde sulfone compound which in turn was cyclized in the presence of potassium t-butoxide to form a 4-hydroxytetrahydrobenzothiepine 1,1-dioxide compound. This cyclic sulfate route to THBO compounds requires an expensive catalyst. Additionally it requires the use of SOCl
2
, which in turn requires special equipment to handle.
PCT Patent Application No. WO 97/33882 describes a method by which the phenol compound 28 was reacted at its phenol hydroxyl group to attach a variety of functional groups to the molecule, such as a quaternary ammonium group. For example, (4R,5R)-28 was reacted with 1,4-bis(chloromethyl)benzene (?,??′-dichloro-p-xylene) to produce the chloromethyl benzyl ether (4R,5R)-27. Compound (4R,5R)-27 was treated with diazabicyclo[2.2.2]octane (DABCO) to produce (4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride (41). This method suffers from low yields because of a propensity for two molecules of compound (4R,5R)-28 to react with one molecule of 1,4-bis(chloromethyl)benzene to form a bis(benzothiepine) adduct. Once the bis-adduct forms, the reactive chloromethyl group of compound (4R,5R)-27 is not available to react with an amine to form the quaternary ammonium product.
A method of preparing enantiomerically enriched tetrahydrobenzothiepine oxides is described in PCT Patent Application No. WO 99/32478. In that method, an aryl-3-hydroxypropylsulfide compound was oxidized with an asymmetric oxidizing agent, for example (1R)-(−)-(8,9-dichloro-10-camphorsulfonyl)oxaziridine, to yield a chiral aryl-3-hydroxypropylsulfoxide. Reaction of the aryl-3-hydroxypropylsulfoxide with an oxidizing agent such as sulfur trioxide pyridine complex yielded an aryl-3-propanalsulfoxide. The aryl-3-propanalsulfoxide was cyclized with a base such as potassium t-butoxide to enantioselectively produce a tetrahydrobenzothiepine-1-oxide. The tetrahydrobenzothiepine-1-oxide was further oxidized to produce a tetrahydrobenzothiepine-1,1-dioxide. Although this method could produce tetrahydrobenzothiepine-1,1-dioxide compounds of high enantiomeric purity, it requires the use of an expensive asymmetric oxidizing agent.
Some 5-amidobenzothiepine compounds and methods to make them are described in PCT Patent Application Number WO 92/18462.
In
Synlett,
9, 943-944(1995) 2-bromophenyl 3-benzoyloxy-1-buten-4-yl sulfone was treated with tributyl tin hydride and AIBN to produce 3-benzoyloxytetrahydrobenzothiepine-1,1-dioxide.
SUMMARY OF THE INVENTION
The ongoing work in the area of tetrahydrobenzothiepine synthesis and the utility of 4-hydroxy-5-phenyltetrahydrobenzothiepine-1,1-dioxide compounds as cholesterol-lowering therapeutics point to the continuing need for economical and practical methods to prepare these compounds.
We now report a novel method for preparing tetrahydrobenzothiepine compounds. Among the several embodiments of the present invention may be noted the provision of an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds.
Briefly, therefore, the present invention is directed to a method for the preparation of a benzylammonium compound having the structure of Formula 60
wherein the method comprises treating a benzyl alcohol ether compound having the structure of Formula 61
under derivatization conditions to form a derivatized benzy
Babiak Kevin A.
Carpenter Andrew
Chou Shine
Colson Pierre-Jean
Farid Payman
G.D. Searle LLC
Lambkin Deborah C.
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