Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2003-03-13
2004-04-27
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S167000, C544S367000, C546S208000, C548S247000
Reexamination Certificate
active
06727360
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a general and convergent synthesis of &agr;-aryl-&bgr;-ketonitriles. Base-promoted isomerization of 3-unsubstituted-4-arylisoxazoles, followed by acidification of the resulting enolates provides the title &agr;-aryl-&bgr;-ketonitriles. The corresponding 3-unsubstituted-4-arylisoxazoles were prepared from cross coupling reaction between 4-iodo-5-substituted isoxazole or 4-bromo-5-substituted isoxazole and arylboronic acids under the influence of a suitable catalyst. The &agr;-aryl-&bgr;-ketonitriles of the present invention serve as synthetic intermediates in the preparation of a series of biologically important molecules such as corticotropin releasing factor (CRF) receptor antagonists.
BACKGROUND
&agr;-Aryl-&bgr;-ketonitriles are important building blocks in the construction of complicated molecular system including natural products and biologically important molecules. They are generally prepared from condensation of &agr;-aryl acetonitriles with the corresponding alkyl carboxylates in the presence of a base, such as sodium ethoxide (Scheme 1)(J. Am. Chem. Soc. 1951, 73, 3763; J. Med. Chem. 1991, 34, 1721). However, &agr;-arylacetonitriles, which are usually prepared from cyanation of the corresponding benzyl halides, sometimes are not readily accessible due to the substitution pattern on the corresponding aromatic ring.
3-Unsubstituted isoxazoles may be cleaved by bases (Advances in Heterocyclic Chemistry, 1979, 25, 147; Tandem Organic Reactions, 1992, 288; Tetrahedron Lett. 1986, 27, 2027; J. Org. Chem. 1996, 61, 5435). Claisen showed that treatment of 5-phenylisoxazole with sodium ethoxide in absolute ethanol or with aqueous sodium hydroxide at room temperature yields, after acidification; &ohgr;-cyano-acetophenone (Ber. 1891, 24, 130). Isoxazole itself is cleaved to the sodium salt of cyanoacetaldehyde (Ber. 1903, 36, 3664). The isomerization of 3-unsubstituted isoxazoles to &agr;-cyano carbonyl compounds under the influence of bases takes place readily at room temperature (Scheme 2).
Kinetic studies on the isomerization of 3-unsubstituted isoxazoles have established that the reaction is second order (first order in base and in substrate) and that the mechanism of the reaction belongs to a concerted one-stage E2 type rather than to a two-step E1cB type (Scheme 3) (Gazz. Chim. Ital. 1960, 90, 356; Chim. Ind. (Milan), 1966, 48, 491; Gazz. Chim. Ital. 1967, 97, 185). The effective isolation of the &agr;-cyanoketone, however, depends on the stability of the latter compound, which is often unstable and readily dimerizes and/or polymerizes (Helv. Chim. Acta, 1963, 46, 543; Ger. Offen. 2,623,170; Chem. Abstr. 1978, 88, 62159).
The &agr;-aryl-&bgr;-ketonitriles of the present invention serve as synthetic intermediates in the preparation of a series of biologically important molecules such as corticotropin releasing factor (CRF) receptor antagonists. The present invention describes a process for preparing 3-unsubstituted 4-aryl-isoxazoles and their use in preparing &agr;-aryl-&bgr;-ketonitriles. Although methods are available for the preparation of some substituted isoxazoles, selective, high-yielding methods which produce pure crude intermediates for the preparation of 3-unsubstituted 4-arylisoxazoles are unknown in the art.
The present invention describes a convergent preparation of substituted &agr;-aryl-&bgr;-ketonitriles (I).
The process includes reacting a substituted isoxazole with a halogenating agent to give a haloisoxazole (Scheme 4).
The literature teaches the synthesis of 4-iodo-5-methylisoxazole by iodination of 5-methylisoxazole with I
2
in the presence of a oxidizing agent such as concentrated nitric acid but gives poor conversion under the reported optimized conditions. The present invention discloses an efficient synthesis of 4-iodo-5-methylisoxazole by treating commercially available 5-methylisoxazole with NIS in strong organic acidic medium, such as trifluroacetic acid, which results in an unexpected yield and purity which is critical for commercial drug preparation.
The present invention also discloses an efficient and regioselective aromatic bromination method for the effective production of the brominated aromatic compound. A phenyl group containing an electron donating functionality in the aromatic ring, is reacted with N-bromosuccinimide followed by reacting the lithium salt of the product with a alkylborate in situ to produce a phenyl boronic after acidic hydrolysis (Scheme 5). This intermediate is coupled directly with the haloisoxale to give the isomerization precursor (Scheme 6).
Finally, a very efficient protocol for the isomerization of 4-aryl substituted isoxazoles to the corresponding &agr;-aryl-&bgr;-ketonitriles under the influence of a base, such as sodium methoxide is described. (Scheme 7). Due to the efficiency of the preceeding reaction, a crude cross coupling product can be used to conduct this base-promoted isomerization reaction, providing the corresponding &agr;-aryl-&bgr;-ketonitriles directly, with exceptional purity which is beneficial for large-scale preparation of the drug substance.
Commonly-assigned U.S. provisional application No. 08/899,242, filed Jul. 23, 1997, disclosed 2,4,7,8-tetra-substituted pyrazolo[1,5-a]-1,3,5-triazines derivatives and their use in treating CRF-related abnormalities. By improving the core structure synthesis, a convergent, and therefore more efficient synthesis has been developed. This general synthetic method has been successfully used in the large-scale synthesis of this important class of corticotropin releasing factor (CRF) receptor antagnists.
SUMMARY OF THE INVENTION
The present invention relates generally to processes for the conversion of &agr;-aryl-&bgr;-ketonitriles to pyrazolo[1,5-a]-1,3,5-triazine derivatives for the purpose of producing compounds, and intermediates therefore, which are useful antagonists of the corticotropin releasing factor (CRF) receptor. These compounds may be used for the treatment of (CRF) related abnormalities such as depression and anxiety. There is provided by this invention a process for the preparation of compounds of formula (I), (III), (IV), (V) and (VI):
wherein:
r is an integer from 0 to 4;
R
1
is independently selected at each occurrence from the group consisting of:
H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
6
cycloalkyl, C
4
-C
12
cycloalkylalkyl, —NR
1c
R
1d
, —OR
1e
, and —SR
1e
;
R
1c
and R
1d
are independently selected at each occurrence from the group consisting of:
H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
6
cycloalkyl and C
4
-C
12
cycloalkylalkyl;
alternatively, R
1c
and R
1d
are taken together to form a heterocyclic ring selected from the group consisting of:
piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine and thiomorpholine, each heterocyclic ring optionally substituted with 1-3 C
1
-C
4
alkyl groups;
R
1e
is independently selected at each occurrence from the group consisting of:
H, C
1
-C
10
alkyl, C
3
-C
6
cycloalkyl, and C
4
-C
6
cycloalkylalkyl;
R
2
is selected from the group consisting of:
H, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, C
3
-C
6
cycloalkyl, C
4
-C
10
cycloalkylalkyl, C
1
-C
4
hydroxyalkyl, C
1
-C
4
haloalkyl, and C
1
-C
4
alkyl substituted with 0-5 R
2a
,
R
2a
is independently selected at each occurrence from the group consisting of:
H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
6
cycloalkyl, C
4
-C
12
cycloalkylalkyl, halo, CN, C
1
-C
4
haloalkyl, —OR
2e
, and —SR
2e
; and
R
2e
is independently selected at each occurrence from the group consisting of:
H, C
1
-C
10
alkyl, C
3
-C
6
cycloalkyl, and C
4
-C
6
cycloalkylalkyl;
said process comprising the steps of:
(1) contacting a compound of formula (II):
with a suitable halogenating agent to form a compound of formula (III);
(2) contacting the compound of formula (III) with alkylborate in the presence of a strong base to give a compound of formula (IV) after acidic hydrolysis;
(3) contacti
Ma Philip
Oh Lynette May
Zhou Jiacheng
Bristol-Myers Squibb Pharma Company
Makujina Shah
McKane Joseph K.
Sackey Ebenezer
Woodcock & Washburn LLP
LandOfFree
Convergent synthesis of &agr;-aryl-&bgr;-ketonitriles does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Convergent synthesis of &agr;-aryl-&bgr;-ketonitriles, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Convergent synthesis of &agr;-aryl-&bgr;-ketonitriles will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3198031