Vinylating of pyrimidine derivatives

Details Vinylating of pyrimidine derivatives Vinylating of pyrimidine derivatives

2000-05-23

2002-08-20

Richter, Johann (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S028520, C544S242000

Reexamination Certificate

active

06437118

ABSTRACT:

FIELD OF THE INVENTION
The present invention is concerned with a process for the preparation of vinyl pyrimidine derivatives. More particularly, the present invention is concerned with a process for vinylating pyrimidine derivatives, such as cytosine and cytidine derivatives.
BACKGROUND
5′-Deoxy-5-vinylcytidine derivatives are of interest in the therapy of cancer, see International application PCT/EP99/00710. However, the preparation of these compounds as disclosed in said International application does not proceed in satisfactory yield and involves the use of tri-n-butyl vinyl stannane, a costly and toxic reagent which also gives rise to tedious purification of the final product and problems in disposing of toxic waste.
In accordance with the present invention it has been found that the vinylation of pyrimidine derivatives can be accomplished with the use of vinyl boranes. The process in accordance with the present invention proceeds in superior yield and does not provide the economic and environmental problems of the prior art process.
SUMMARY OF THE INVENTION
In one aspect, the present invention is concerned with a process for the preparation of compounds of the formula I
wherein R
1
is hydrogen or a carboxylic ester group, and R
2
is hydrogen or a group of the formula (a)
wherein R
a
is hydrogen, a hydroxy protecting group or a group easily hydrolyzable under physiological conditions, which comprises reacting a compound of the formula II
wherein R
21
is hydrogen or a group (a) wherein hydroxy groups are optionally protected, R
3
is bromo, chloro or iodo, and R
1
is as above, with a vinyl borane compound of the formula IIIa or IIIb
(CH
2
═CH)
n
B(R
6
)
3−n
L
m
  (IIIa)
[(CH
2
═CH)
p
B(R
6
)
4−p
]X
+
  (IIIb)
wherein
n is 1, 2 or 3;
m is 0 or 1;
R
6
is hydrogen, halogen, alkyl, cycloalkyl, alkoxy, cycloalkoxy, hydroxy or aryl, and wherein, if more than one group R
6
is present, these groups may be different from each other, or two groups R
6
may, together with—A—(CH
2
)
q
—Y—(CH
2
)
r
—A—, form a carbocyclic or heterocyclic ring wherein A and Y are CH
2
or NH or O and q and r are an integer from 0-4, or two groups R
6
may also form a catechol moiety
 in which R is hydrogen or lower alkyl;
L is an amine, a Schiff base or an ether;
p is 1, 2, 3 or 4;
X
+
is a cation;
in the presence of a Pd complex and a base, and, if desired, removing any protecting group from a compound of formula I wherein R
2
is a group (a).
The compounds of formula I are known (for example, see U.S. patent application Ser. No. 09/484,174, filed Jan. 14, 2000 and U.S. Pat. No. 6,005,098, both herein incorporated by reference).
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term “carboxylic ester group” preferably denotes a group —COOR
4
wherein R
4
is —(CH
2
)
n
-cycloalkyl [wherein cycloalkyl consists of 3 to 6 carbon atoms, n is an integer from 0 to 4], heteroaryl-(lower-alkyl), (lower-alkoxy)-(lower-alkyl), aryloxy-(lower-alkyl), aralkyloxy-(lower-alkyl), (lower-alkylthio)-(lower-alkyl), arylthio-(lower-alkyl), aralkylthio-(lower-alkyl), oxo-(lower-alkyl), acylamino-(lower-alkyl), cyclic amino-(lower-alkyl), (2-oxocyclic amino)-(lower-alkyl) wherein the alkylene chain may be further substituted with one or two lower-alkyl group(s). The term “lower” means groups containing up to and including 5 carbon atoms. “Acyl” denotes aliphatic or aromatic carboxylic moieties such as lower alkanoyl or benzoyl.
Examples of the group —(CH
2
)
n
-cycloalkyl are cyclobutyl, cyclopropylmethyl and cyclopentylmethyl. Examples of heteroaryl-(lower-alkyl) are pyridin-3-ylmethyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 1-(pyridin-4-yl)ethyl, (6-methylpyridin-2-yl)methyl and 1-(6-ethylpyridin-2-yl)propyl. Examples of (lower-alkoxy)-(lower-alkyl) are 2-methoxy-ethyl, 2-thoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-methoxy-3-methylbutyl, 3-ethoxy-3-methylbutyl, 3-methoxy-2,2-dimethylpropyl, 3-ethoxy-2,2-dimethylpropyl, 2-ethyl-2-methoxymethylbutyl and 2-ethyl-2-ethoxymethylbutyl. Examples of aryloxy-(lower-alkyl) are 2-phenoxyethyl, 1-phenoxypropyl and 3-phenoxypropyl. Examples of aralkyloxy-(lower -alkyl)are 2-benzyloxyethyl, 3-benzyloxypropyl and 5-benzyloxypentyl. Examples of (lower-alkylthio)-(lower-alkyl) are 2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl and 3-ethylthiopropyl. Examples of arylthio-(lower-alkyl) are 2-phenylthioethyl and 3-phenylthiopropyl. Examples of aralkylthio-(lower-alkyl) are 2-(benzylthio)ethyl and 3-(benzylthio)propyl. Examples of oxo-(lower-alkyl) are 4-oxopentyl, 3-oxo-2-methylbutyl and 2-oxobutyl. Examples of acylamino-(lower-alkyl) are 2-(acetylamino)-ethoxy, 3-(acetylamino)propyl, 3-(n-propionylamino)propyl and 3-(benzoylamino)propyl. Examples of cyclic amino-(lower-alkyl) are 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-pyrrolidinoethyl and 3-pyrrolidinopropyl. Examples of (2-oxocyclic amino)-(lower-alkyl) are 2-oxopyrrolidin-1-ylethyl and 2-oxopiperidin-1-ylethyl. Preferably, R
1
is hydrogen.
The term “a group easily hydrolyzable under physiological conditions” preferably means acetyl, propionyl, benzoyl, toluoyl, glycyl, alanyl, &bgr;-alanyl, valyl or lysyl. Examples of hydroxy protecting groups are acetyl, benzoyl, trimethylsilyl and tert.butyldimethylsilyl. Preferably, R
a
is acetyl which serves as physiologically hydrolyzable and protecting group as well.
Preferred vinyl boranes of formula IIIa and IIIb are those of the formulae
The preferred vinyl boranes are potassium vinyl trifluoroborate and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan.
The Pd complex used as a catalyst in the vinylation reaction according to the invention can be a neutral Pd(0) or Pd(II) complex or a cationic Pd(II) complex. Examples of such Pd complexes are Pd(OAc)
2
, Pd(OAc)
2
/dppf, Pd(OAc)
2
/dppp, Pddba
2
, Pd
2
dba
3
, Pd
2
dba
3
/PPh
3
, Pd
2
dba
3
/P(O.Tol)
3
, Pd
2
dba
3
/P(mTol)
3
, Pd
2
dba
3
/P(2-Furyl)
3
, PdCl
2
dppf, PdCl
2
(PPh
3
)
2
, PdCl
2
dppe, PdCl
2
(NCMe)
2
, PdCl
2
(NCMe)
2
/(R)-BIPHEMP, Pd
2
Cl
2
(&pgr;-allyl)
2
, Pd(PPh
3
)
4
, [Pd(NCMe)
4
](BF
4
)
2
, Pd/C, and Bedford's catalyst, wherein the structures of the phosphines present in the above recited catalysts are as shown below:
As used above, the term “Ph” means phenyl and “dba” means dibenzylideneacetone.
The preferred catalysts for the vinylation reaction are PdCl
2
(dppf) and Pd
2
dba
3
/PPh
3
. All the Pd catalysts are known from literature and are commercially available, e.g. from Fluka, Buchs S G, Switzerland, or Strem Chemicals, Kehl, Germany, or can be prepared in situ from commercially available components. The synthesis of (R)-BIPHEMP is described in EP 104 375.
Suitably, the vinylation reaction according to the invention is carried out in the presence of a base. The base can be an organic base such as a tertiary, secondary and primary amine, e.g. triethyl amine, diisopropyl ethylamine, tert-butyl amine, pyrrolidine, pyridine, alkali alcoholates such as potassium ethylate, or a salt of a carboxylic acid such as sodium acetate; or an inorganic base e.g., a carbonate such as sodium carbonate and potassium hydrogen carbonate, or hydroxide, or salt of phosphoric acid, sulfuric acid and fluoric acid such as K
3
PO
4
and CsF
2
. Preferred bases are triethyl amine and tributyl amine.
Suitably, the vinylation is carried out in the presence of a solvent such as water, lower aliphatic alcohols, e.g. methanol, ethanol, n-propanol, iso-propanol or n-butanol, nitrites, e.g. acetonitrile, hydrocarbons such as toluene, halogenated hydrocarbons, e.g. methylene chloride, esters, e.g., ethyl acetate, amides, e.g. dimethylformamide, pyridine or N-methyl pyridine, ethers, e.g. tetrahydrofuran or dioxan, urethanes, e.g. TMU, sulfoxides, e.g. DMSO or mixtures thereof. The preferred solvent for the vinylation reaction is ethanol or methanol.
The reaction temperature is not critical and can be, e.g., within the range of 0-200° C., preferably 40-150° C. The amount of catalyst

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