Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-17
2004-12-14
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06831178
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparation of N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]sulfonyl]-D-tryptophan and crystals thereof.
BACKGROUND ART
N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]sulfonyl]-D-tryptophan is disclosed in such as WO97/27174.
A coupling reaction (Sonogashira reaction) of a halogenated aryl and an acetylene derivative which is used as a key-step for the preparation of this compound, it is disclosed in WO97/27174 and Tetrahedron Lett. 1975, 4467-4470.
Generally, in Sonogashira reaction, a halogenated aryl, a halogenated heteroaryl etc. are reacted with an acetylene derivative in a solvent such as N,N-dimethylformamide in the presence of a copper iodide, a base and a palladium catalyst. An example of using ethyl acetate as a solvent and an example of using palladium on carbon as a catalyst have not been reported.
An example of Sonogashira reaction by using tetrahydrofuran as a solvent is disclosed in J. Org. Chem. 1998, 8551-8553.
An example of Sonogashira reaction by using a solvent containig water is disclosed in Tetrahedron Lett. 1996, 897-900 and Tetrahedron Lett. 1996, 5527-5530, but an example by using ethyl acetate and water as a solvent is not described.
Generally, in an industrial preparation, it is not preferred to use a solvent, such as N,N-dimethylformamide having a high mutual solubility for water, in view of a post-treatment of the reaction. Preferred is a solvent, such as acetic acid ester exampled as ethyl acetate, isopropyl acetate, isobutyl acetate, and-n-butyl acetate, or toluene, dichloromethane and the like, which have a low mutual solubility for water.
An organopalladium catalyst having such as a phosphine ligand, usually used in Sonogashira reaction, is high fat-soluble. Thus, in a case the resulting product is also high fat-soluble, it is difficult to separate the product and the organopalladium catalyst. Specially in a case for the preparation of medicaments, an amount of residual palladium may cause a serious problem because the upper limit of concentration of a heavy metal in a final bulk is regulated by the Japanese Pharmacopoeia.
N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]sulfonyl]-D-tryptophan is disclosed in such as WO97/27174, however a crystal form thereof is not disclosed.
DISCLOSURE OF INVENTION
An object of the present invention is to provide an industrial process for the preparation of N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]sulfonyl]-D-tryptophan suitable for the standard. Another object of the present invention is to prepare a crystal of N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]sulfonyl]-D-tryptophan which has a high stability and bioavailability.
In the above situation, the inventors of the present invention have studied and found a process for the preparation of N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]-sulfonyl]-D-tryptophan which is used as a medicament, and a crystal thereof.
The present invention relates to:
1) A process for the preparation of a compound of the formula (I′):
which comprises reacting in a solvent a compound of the formula (III):
wherein X is halogen,
with p-tolylacetylene, a copper (I) salt, a catalyst, and a base, and then treating the resulting reaction mixture with an acid.
In more detail, the invention relates to the following 2) to 21).
2) A process for the preparation of a compound of the formula (II):
wherein A
+
is a cation derived from a basic substance,
which comprises reacting in a solvent a compound of the formula (I′):
with the basic substance in the presence of an alcohol.
3) The process according to 2) wherein a starting material is the compound (I′) obtained by the process according to 1).
4) A process for the preparation of a compound of the formula (I):
which comprises reacting a compound of the formula (II) obtained by the process according to 3):
wherein A
+
is a cation derived from a basic substance, with an acid.
5) A process for the preparation of a compound of the formula (III):
wherein X is halogen,
which comprises reacting in a solvent a compound of the formula (IV):
with a compound of the formula (V):
wherein X and X′ are independently halogen,
in the presence of a base.
6) A process for the preparation of a compound of the formula (1):
which comprises steps (1) to (4),
(1) a step for the preparation of a compound of the formula (III):
wherein X is halogen,
which comprises reacting in a solvent a compound of the formula (IV):
with a compound of the formula (V):
wherein X and X′ are independently halogen,
in the presence of a base,
(2) a step for the preparation of a compound of the formula (I′):
which comprises reacting in a solvent a compound of the formula (III) with p-tolylacetylene, a copper (I) salt, a catalyst, and a base, and then treating the resulting reaction mixture with an acid,
(3) a step for the preparation of a compound of the formula (II):
wherein A
+
is a cation derived from a basic substance,
which comprises reacting in a solvent a compound of the formula (I′):
with a basic substance,
(4) a step for the treatment of the compound (II) with an acid.
7) The process according to 1) wherein the solvent is N,N-dimethylformamide.
8) The process according to 1) wherein the solvent is a mixture of ethyl acetate and water.
9) The process according to 1) wherein the catalyst is selected from the group consisting of palladium black, palladium on carbon, bistriphenylphosphinepalladium (II) cholride, tetraxis(triphenylphosphine)palladium (0), palladium (II) oxide, palladium (II) chloride, palladium (II) bromide, and palladium (II) acetate.
10) The process according to 1) wherein the solvent is N,N-dimethylformamide, and the catalyst is palladium on carbon.
11) The process according to 1) wherein the solvent is a mixture of ethyl acetate and water, and the catalyst is bistriphenylphospinepalladium (II) chloride.
12) The process according to 1) wherein the solvent is a mixture of ethyl acetate and water, and the catalyst is tetraxis(triphenylphospine)palladium (0).
13) The process according to 2) wherein the alcohol is methanol.
14) The process according to 2) wherein the basic substance is sodium hydroxide or sodium methoxide.
15) The process according to 2) wherein the alcohol is methanol, and the basic substance is sodium hydroxide or sodium methoxide.
16) The process according to 5) wherein the solvent is a mixture of acetone and water, and the base is sodium carbonate.
17) A process for the preparation of a compound of the formula (I):
which comprises steps (1) to (2),
(1) a step for the preparation of a compound of the formula (II′):
which comprises reacting in a mixture of ethyl acetate and water a compound of the formula (III):
wherein X is halogen,
with p-tolylacetylene, a copper iodide or copper bromide, a bistriphenylphosphinepalladium (II) cholride or tetraxis(triphenylphosphine)palladium (0), and a base, and then treating the resulting reaction mixture with an acid, and then treating the resulting reaction mixture with sodium hydroxide or sodium methoxide in the presence of methanol.
(2) a step for the treatment of the compound (II′) with an acid.
18) A compound of the formula (II″):
wherein B
+
is Na
+
, K
+
or NH
4
+
.
19) A crystal of N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]sulfonyl]-D-tryptophan wherein a powder X-ray diffraction pattern has a primary peak at a diffraction angle (2&thgr;)=10.86, 18.14, 19.62, 21.60, 22.74, 23.38, 25.54, 27.22 and 28.12 (degree).
20) A crystal of N
&agr;
-[[2-[5-[[4-methylphenyl]ethynyl]thienyl]]sulfonyl]-D-tryp
Konoike Toshiro
Masui Yoshiyuki
Okuyama Akira
Sakata Teruo
Shionogi & Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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