Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-06-06
2002-06-04
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S057000, C548S525000, C544S146000, C544S376000, C540S596000
Reexamination Certificate
active
06399778
ABSTRACT:
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, ferric bromide, and boron trifluoride. 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 acylation of suitably protected 2-arylbenzothiophenes. This patent taught the use of phenacyl, halophenacyl, and 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]thiophenes. 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 tribromide, titanium tetra-chloride, 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]-thiophene. This compound, as well as methods for its preparation, was first described in U.S. Pat. No. 4,418,068. This compound is a nonsteroidal antiestrogen, useful for alleviating an estrogen-dependent pathological condition of an endocrine target organ.
An improved process for the synthesis of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]benzo[b]thiophenes 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 various 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.
SUMMARY OF THE INVENTION
The present invention is directed to efficient syntheses of 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl]benzo[b]thiophenes which comprises acylating a suitably protected starting compound, and dealkylating the protected phenolic group(s) to provide the desired product. In accordance with the preferred aspect of the present invention, the acylation and dealkylation steps are performed successively in a single reaction vessel. More specifically, the present invention is directed to a process for preparing a crystalline solvate of a compound of the formula
wherein:
R
1
is hydrogen or hydroxyl;
R
2
and R
3
are independently C
1
-C
4
alkyl, or R
2
and R
3
together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr; comprising the steps of:
(a) acylating a benzothiophene of the formula
wherein:
R
4
is hydrogen or C
1
-C
4
alkoxy, and
R
5
is C
1
-C
4
alkyl,
with an acylating agent of the formula
wherein:
R
6
is chloro, bromo, or hydroxyl, and
HX, R
2
, and R
3
are as defined above,
in the presence of BX′
3
, wherein X′ is chloro or bromo;
(b) dealkylating one or more phenolic groups by reacting with additional BX′
3
, wherein X′ is as defined above; and
(c) isolating the crystalline solvate.
A second aspect of the present invention is directed to a process for preparing a compound of the formula
or the hydrochloride or hydrobromide salt thereof, wherein:
R
4
is hydrogen or C
1
-C
4
alkoxy,
R
5
is C
1
-C
4
alkyl, and
R
2
and R
3
are independently C
1
-C
4
alkyl, or R
2
and R
3
together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
comprising acylating a benzothiophene of the formula
wherein:
R
4
is hydrogen or C
1
-C
4
alkoxy, and
R
5
is C
1
-C
4
alkyl,
with an acylating agent of the formula
wherein:
R
6
is chloro, bromo, or hydroxyl;
R
2
and R
3
are independently C
1
-C
4
alkyl, or R
2
and R
3
together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
in the presence of BX′
3
, wherein X′ is chloro or bromo.
A third aspect of the present invention is directed to a second process for preparing a crystalline solvate of a compound of the formula
wherein:
R
1
is hydrogen or hydroxyl;
R
2
and R
3
are independently C
1
-C
4
alkyl, or R
2
and R
3
together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
comprising dealkylating one or more phenolic groups of a compound of the formula
wherein:
R
4
is hydrogen or C
1
-C
4
alkoxy,
R
5
is C
1
-C
4
alkyl, and
HX, R
2
, and R
3
are as defined above, by reacting with BX′
3
, wherein X′ is chloro or bromo.
Further aspects of the present invention are crystalline solvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidino-ethoxy)benzoyl]benzo[b]thiophene hydrochloride and an unsolvated crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride, as well as processes for their preparation.
DETAILED DESCRIPTION OF THE INVENTION
In the above formula, the term “C
1
-C
4
alkyl” represents a straight alkyl chain having from 1 to 4 carbon atoms. Typical C
1
-C
4
alkyl groups include methyl, ethyl, n-propyl, and n-butyl. The term “C
1
-C
4
alkoxy” represents groups such as methoxy, ethoxy, n-propoxy, and n-butoxy. The preferred C
1
-C
4
alkoxy group is methoxy.
The term “molar equivalents”, as used herein, refers to the number of moles of the boron trihalide reagent in relation to the number of moles of the starting benzothiophene compound.
For example, three millimoles of boron trichloride reacted with one millimole of the benzothiophene compound would represent three molar equivalents of boron trichloride.
The term “solvate” represents an aggregate that comprises one or more molecules of the solute, such as a formula I c
LaBell Elizabeth Smith
McGill John McNeill
Miller Randal Scot
Chang Ceila
Eli Lilly and Company
Leeds James P.
Voy Gilbert T.
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