Preparation of dialkylpyridylboranes

Details Preparation of dialkylpyridylboranes Preparation of dialkylpyridylboranes

2002-08-23

2003-05-27

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S004000

Reexamination Certificate

active

06570017

ABSTRACT:

BACKGROUND OF THE INVENTION
Dialkylpyridylboranes are very useful reagents in cross-coupling reactions to prepare substituted pyridine derivatives. Substituted pyridine derivatives may be used in the synthesis of the compounds of formula (I) referred to in WO 99/57101, published Nov. 11, 1999, which are inhibitors of p38 MAP kinase inhibitors. Compounds that inhibit p38 MAP kinase are reported to be effective in inhibiting bone resorption, inflammation, and other immune and inflammation based pathologies. The present invention relates to an improved process for the preparation of dialkylpyridylboranes.
The current process for the synthesis of these materials involves the lithium-bromine exchange on the bromopyridine followed by trapping of the lithiopyridine with diethylmethoxyborane or triethylborane. This type of process is referred to in the following references (a) Ishikura, M.; Mano, T.; Oda, I.; Terashima, M.
Heterocycles
1984, 22, 2471-2474; (b) Ishikura, M.; Ohta, T.; Terashima, M.
Chem. Pharm. Bull.
1983, 31, 4573-4577; (c) Morris, G. A.; Nguyen, S. T.
Tetrahedron Lett.
2001, 42, 2093-2096; (d) Labadie, S. S.; Rotstein, D. M.; Sjogren, E. B.; Talamas, F. X., PCT International Application No. WO 99/57101 and is illustrated in the following scheme.
The above reaction must be run at low temperature (<−40° C. in ether or <−100° C. in tetrahydrofuran (“THF”)) in order to prevent the anion from migrating, elimination of the bromide to form pyridynes, deprotonation, migration of the halide, and addition of the alkyllithium to the pyridine during the metal-halogen exchange (see, (a) Gilman, H.; Spatz, S. M.
J. Org. Chem.
1951, 16, 1485-1494; (b) Mallet, M.; Branger, G.; Marsaia, F.; Quenguiner, G.
J. Organomet. Chem.
1990, 382, 319-332). The required use of low temperature for this reaction adds to the cost and difficulty of producing large quantities of these materials in an industrial setting. Accordingly, it is desirable to have a method of preparing dialkylpyridylboranes without the use of low temperatures for their commercial production.
SUMMARY OF THE INVENTION
The present invention relates to a method for the preparation of dialkylpyridylboranes comprising reacting a pyridine Grignard reagent and an alkoxydialkylborane or a trialkylborane. The reaction may be performed at a temperature from about 0° C. to about 40° C.
In one preferred embodiment the invention relates to a method for the preparation of a compound of formula 2:
wherein R
1
and R
2
are each independently C
1
-C
10
alkyl; R
3
is H, halo, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —C(O)(C
1
-C
10
alkyl), —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(4-10 membered heterocyclic), —C(O)(CH
2
)
t
(C
6
-C
10
aryl), or —C(O)(CH
2
)
t
(5-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R
6
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said R
3
aryl and heterocyclic groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 5-10 membered heterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety; the —(CH
2
)
t
— moieties of the foregoing R
3
groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5 and wherein m is 0-4; and the foregoing R
3
groups, except H, are optionally substituted by 1 to 3 R
4
groups; R
4
is C
1
-C
10
alkyl or C
1
-C
10
alkoxy and R
6
is H or C
1
-C
10
alkyl, comprising reaction a compound of formula 1,
wherein R
3
and m are defined for formula 2 above and X is a halo with a compound of the formula R
5
BR
1
R
2
, wherein R
1
and R
2
are as defined above for formula 2 and wherein R
5
is C
1
-C
10
alkyl or C
1
-C
10
alkoxy.
In one preferred embodiment R
1
and R
2
are each independently C
1
-C
5
alkyl. In another preferred embodiment R
1
and R
2
are each independently C
1
-C
3
alkyl. In a more preferred embodiment R
1
and R
2
are each independently methyl or ethyl.
In a preferred embodiment of the present invention R
3
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —C(O)(C
1
-C
10
alkyl), —(CH
2
)
t
(C
6
-C
10
aryl), wherein t is an integer from 0 to 5; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R
6
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said R
3
aryl group is optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 5-10 membered heterocyclic group; the —(CH
2
)
t
— moieties of the foregoing R
1
groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5; and the foregoing R
3
groups, except H, are optionally substituted by 1 to 3 R
4
groups; and wherein R
4
is C
1
-C
10
alkyl or C
1
-C
10
alkoxy.
In a preferred embodiment of the present invention X is Cl, Br, or I. In a more preferred embodiment X is Br.
The term “halo”, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are chloro, bromo, and iodo.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group.
The term “alkenyl”, as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon double bond and also having straight, cyclic or branched moieties as provided above in the definition of “alkyl”.
The term “alkynyl”, as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon triple bond and also having straight, cyclic or branched moieties as provided above in the definition of “alkyl”.
The term “alkoxy”, as used herein, unless otherwise indicated, includes O-alkyl groups wherein “alkyl” is as defined above.
The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term “4-10 membered heterocyclic”, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furaz

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