Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-08-21
1999-12-28
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549 57, 548578, 546202, 540596, 544146, C07D33356, C07D20702, C07D40910, C07D41310
Patent
active
060083778
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to chemical processes for preparing 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)-benzoyl]benzo[b]thiophenes. The synthesis of aromatic ketones was reviewed by Gore in Olah, Friedel-Crafts and Related Reactions, Volume 3, Part 1, Chapter XXXI (1964). Generally, an acyl component and an aromatic substrate are reacted in the presence of a Lewis acid catalyst to produce the aromatic ketone. Suitable Lewis acid catalysts for this type of reaction include metal halides such as aluminum chloride, aluminum bromide, ferric chloride, and ferric bromide. See Olah, Friedel-Crafts and Related Reactions, Volume 1, Chapters II, III, and IV (1963).
The compounds prepared by the present processes were first described in U.S. Pat. No. 4,133,814. This patent described a number of processes for preparing the compounds, including the reaction of 2-arylbenzo[b]thiophenes-3-carboxylic acids with alkyl phenyl ethers. This patent taught the use of phenacyl, halophenacyl, End alkyl protecting groups for the phenolic hydroxyl groups. The alkyl protecting groups were removed by treating the phenolic ethers with pyridine hydrochloride. This patent also taught that the phenolic methyl ethers could be cleaved without affecting the 3-aroylalkoxy group by reacting with boron tribromide; however, the yield of the 3-aroylalkoxy-substituted compound was low.
The process described in U.S. Pat. No. 4,358,593 used particularly advantageous protecting groups for preparing 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]-benzo[b]thiophe nes. These advantageous protecting groups are acetyl, substituted acetyl, benzoyl, alkylsulfonyl, and arylsulfonyl groups. This patent taught the use of classical Friedel-Crafts catalysts in the acylation of the protected 2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene, including metal halides such as aluminum chloride, aluminum bromide, zinc chloride, boron trifluoride, boron tribromilde, titanium tetrachloride, titanium tetrabromide, stannic chloride, stannic bromide, bismuth trichloride, and ferric chloride. Subsequent to acylation, the protecting group was generally removed under basic conditions.
A particularly useful compound from this series of 2-aryl-3-[4-(2-aminoethoxy)benzoyl]benzo[b]thiophenes is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]th iophene. This compound, as well as methods for its preparation, was first described in U.S. Pat. No. 4,418,068. This compound is a selective estrogen receptor modulator, useful for alleviating an estrogen-dependent pathological condition of an endocrine target organ. U.S. Pat. No. 5,393,763 described methods for the treatment of bone loss using this compound.
An improved process for the synthesis of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]b was described in U.S. Pat. No. 4,380,635. These compounds were prepared by Friedel-Crafts acylation, using aluminum chloride as the catalyst, of a di-O-methyl-protected benzo[b]thiophene. The intermediate acylation product was demethylated by treating the acylation reaction mixture with a sulfur compound, such as methanethiol, ethanethiol, diethyl sulfide, and methionine. The product of this reaction generally contains aluminum salts and vario(us thioester by-products, which are difficult to remove from the benzothiophene. Also, the product has an unpleasant residual thiol or sulfide odor.
Boron halides, such as boron trichloride and boron tribromide, are useful for the cleavage of arylmethyl ethers. See Bahtt and Kulkarni, Synthesis, 249-282 (1983). Boron tribromide has previously been used to cleave arylmethyl ethers in benzothiophene compounds. See German Patent No. DE 4117512 A1.
The processes described above are not suitable for a large-scale synthetic process for preparing 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl]benzo[b]thiophenes. A preferred process would use simple phenolic protecting groups, (such as methyl ethers), readily available starting materials, Friedel-Crafts acylation catalysts that are easily r
REFERENCES:
patent: 3869485 (1975-03-01), DeLong
patent: 4007204 (1977-02-01), Descamps et al.
patent: 4133814 (1979-01-01), Jones et al.
patent: 4358593 (1982-11-01), Jones et al.
patent: 4380635 (1983-04-01), Peters
patent: 4418068 (1983-11-01), Jones
patent: 5169860 (1992-12-01), Mohamadi et al.
patent: 5470854 (1995-11-01), von Angerer et al.
patent: 5472962 (1995-12-01), Koizumi et al.
Jones, et al., "Antiestrogens 2. Structure-Activity Studies in a Series of 3-Aroyl-2-arylbenzo [b]thiophene Derivatives Leading to [6-Hydroxy-[2-(4-hydroxyphenyl) benzo [b]thien-3-yl] [4-2-(1-piperidinyl) ethoxy]methanone Hydrochloride (LY156758), a Remarkably Effective Estrogen Antagonist with Only Minimal Instrinsic Estrogenicity," J. Med. Chem., 27, 1057-1066 (1984).
Pinney and Katzenellenbogen, Synthesis of a Tetrafluoro-Substituted Aryl Azide and its Protio Analogue as Photoaffinity Labeling Reagents for the Estrogen Receptor, J. Org. Chem., 56, 3125-3133 (1991).
Cheronis, Semimicro Experimental Organic Chemistry, pp. 31-42 (J. de Graff Publish., 1958).
Wagner and Zook, Synthetic Organic Chemistry, pp. 171-172 (John Wiley & Sons, 1953).
Jackson, et al., "Cleavage of 12-alkylbenzo [a] phenothiazines with Lithium in Tetrahydrofuran: A Dealkylation-Desulphurization Reaction", J. Chem. Soc. (C.), pp. 1728-1729 (1969).
Kametani, et al., "A Novel Cleavage of Aryl Benzyl Ethers and Allyl Aryl Ethers by Sodium Bis (2-methoxyethoxy) aluminum Hydride. An Alternative Synthesis of Pentazocine", J. Org. Chem., 41(5 ), pp. 2545-2548 (1976).
Myerson and Toyokura, Crystallization as a Separations Process, Am. Chem. Society Symposium Series No. 438, 59 and 87, (1990).
Hanney, Treastise on Solid State Chemistry, vol. 3, Crystalline and Noncrystalline Solids, Plenum Press, pp. 89-90, (1977).
Zhu, et al., Synsthesis of bisflavone-type compounds (III). Selective demethoxylation of 1,4-bis (2',4',6'-trimethoxtphenyl-1, 4-butanedione CA 112: (1977).
Knight, "Its time to stop discriminating against PCT-USA National Phase Phatets", JPTOS Jun., pp. 386-400 (1997).
Fox, et al., "Physics and chem. Of the organic solid state" Interscience Pub. pp. 133-156 (1963).
Evans "An Introduction to Cyrstal Chemistry", Cambridge Press pp. 352-397 (1964).
Jones Charles D
McGill John M.
Eli Lilly and Company
Lambkin Deborah C.
Voy Gilbert T.
LandOfFree
Synthesis of 3-[4-(2-aminoethoxy)-benzoyl]-2-aryl-6-hydroxy-benz does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Synthesis of 3-[4-(2-aminoethoxy)-benzoyl]-2-aryl-6-hydroxy-benz, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of 3-[4-(2-aminoethoxy)-benzoyl]-2-aryl-6-hydroxy-benz will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2383397