Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-08-23
2001-05-22
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S298000, C544S318000, C544S299000
Reexamination Certificate
active
06235903
ABSTRACT:
The present invention relates to a novel process for preparing carboxylic acid derivatives of the general formula I
where
R
1
is hydroxyl, alkoxy, sulfonamidyl, amino,
R
2
is alkyl, aryl or hetaryl, optionally substituted,
R
3
, R
4
, R
5
are identical to or different from one another and are alkyl or aryl, optionally substituted.
Substances of the general formula I are disclosed in WO 94/25442, WO 95/26716 and WO 96/11914. These substances have in some cases a herbicidal effect and sometimes also affinity for endothelin receptors.
These substances are prepared by nucleophilic substitution of a leaving group in the a position of the corresponding carboxylic acid derivative by a thiol.
However, this mode of preparation is unsatisfactory in terms of the yield.
It is an object of the present invention to provide alternative processes for preparing carboxylic acid derivatives of the general formula I.
Seebach et al. (Journal Am. Soc 105, 1983, pp. 5390) describe the following reaction which makes it possible to introduce a thioether in 81% [lacuna] into the a position of a lactone.
The invention relates to a process for preparing carboxylic acid derivatives of the general formula I
where
R
1
[sic] is hydroxyl, alkoxy, sulfonamidyl, amino,
R
2
[sic] is alkyl, aryl or hetaryl, optionally substituted,
R
3
, R
4
, R
5
are identical to or different from one another and are alkyl or aryl, optionally substituted,
by nucleophilic reaction of a carboxylic acid derivative of the formula II with a sulfide of the formula III
where
x is SR
6
or SO
2
R
6
,
R
6
is alkyl or aryl, optionally substituted.
The carboxylic acid derivatives of the formula II are disclosed in WO 97/09294 or can be prepared from known precursors.
The preparation of the sulfides III is disclosed in, for example, Heckel et al., Helv. Chim. Acta 69, 1986; Harpp et al. J. Org. Chem. 35, 1970, 3259, and normally takes place by oxidizing the corresponding thiols, for example with iodine. The sulfides III preferably employed are symmetrical diaryl disulfides and dihetaryl disulfides.
Good results can be obtained when suitably strong bases are employed for deprotonating the ester or the acid in the a position, such as, for example, LDA or NaH, in a solvent suitable for this type of reaction, such as THF, dioxane or ether.
The base is normally employed in a molar excess based on the carboxylic acid derivatives II, and preferably 2 mol of base are employed per mole of II.
If further acidic protons are present in II, correspondingly more base must be employed.
The diaryl disulfide component is generally employed in 1-10, preferably 1-3, equivalents.
The reaction can be carried out in a temperature range between −80° C. and up to +100° C., preferably at −78° C. to room temperature. Reaction temperatures outside this range result in no particular advantages for the yield.
REFERENCES:
patent: 94/25442 (1994-11-01), None
patent: 95/26716 (1995-10-01), None
patent: 96/11914 (1996-04-01), None
Amberg Wilhelm
Jansen Rolf
Klinge Dagmar
BASF - Aktiengesellschaft
Keil & Weinkauf
McKane Joseph K.
Murray Joseph
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