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United States Patent (10) Patent No.: US 7,304,156 B2
United States Patent (10) Patent No.: US 7,304,156 B2
FOREIGN PATENT DOCUMENTS Andrew J. Blacker et al., US. Appl. No. 10/275,092, ?led Nov. 1,
2002, WO 01/85975, Nov. 15, 2001.
WO 01/85702 A1 11/2001
W0 WO 01/85975 11/2001 Robert P. Hof, U.S. Appl. No. 10/501,250, ?led Jul. 8, 2004, WO
W0 WO 02/06266 1/2002 03/059901, Jul. 24, 2003.
W0 W0 03/059901 7/2003 Hermanus C. Bakel Van et al., US. Appl. No. 10/518,164, ?led Jul.
WO 03/097614 A2 11/2003 25, 2005, WO 03/106447, Dec. 24, 2003.
W0 W0 03/106447 12/2003
W0 WO 2004/014872 2/2004 John Horbury et al., US. Appl. No. 10/524,235, ?led Feb. 10,2005,
W0 WO 2004/054986 7/2004 WO 2004/014872, Feb. 19, 2004.
W0 WO 2004/103977 12/2004 Lee Newton et al., US. Appl. No. 10/537,723, ?led Jun. 7, 2005,
W0 WO 2004/108691 12/2004 WO 2004/054986, Jul. 1, 2004.
W0 WO 2005/023779 3/2005
Jeffrey N. Crabb et al., US. Appl. No. 10/558,390, ?led Nov. 29,
W0 WO 2005/028450 3/2005
W0 WO 2005/042522 5/2005 2005, WO 2004/108691, Dec. 16, 2004.
W0 WO 2005/092867 10/2005 Rebecca J. Booth et al., US. Appl. No. 10/571,254, ?led Mar. 9,
W0 WO 2006/067456 6/2006 2006, WO 2005/023779, Mar. 17, 2005.
OTHER PUBLICATIONS Simon N. Black et al., US. Appl. No. 10/572,635, ?led Mar. 17,
2006, WO 2005/028450, Mar. 31, 2005.
Grohe et al., Synthese und Reaktionen von 2,4-Dichlorpyrimidin Tetsuo Okada et al., US. Appl. No. 10/576,774, ?led Apr. 21, 2006,
5-carbon-sauereestern, Libigs Ann. Chem., 1973, pp. 1025-1035. WO 2005/042522, May 12, 2005.
Kaneko et al. “Preparation of optically active 5,6-epoXyheXanoic
acid esters as materials for physiologically active substances” Jacob H. Kooistra et al., US. Appl. No. 11/053,090, ?led Feb. 7,
Chemical Abstracts+IndeXes, American Chemical Society, Colum 2005, WO 02/06266, Jan. 24, 2002.
bus, US 118(11):832 (1993). Andrew J. Blacker et al., US. Appl. No. 11/412,047, ?led Apr. 27,
Menges et al. “Oxidation Degradation of y-Butyrolactons into 2006, WO 01/85975, Nov. 15, 2001.
1,3-Diols via a Criegee Rearrangement of PeroXosulfonates. An
Enantioselective Synthesis of Compactin Lactone and its Hannah et al. “Structural studies on bioactive compounds. Part 29:
Diastereomer” Synlett 12:901-905 (1993). palladium catalysed arylations and alkynylations of sterically hin
Presentation given at the 20th International Congress of Heterocy dered immunomodulatory 2-amino-5-halo-4,6
clic Chemistry in Palermo, Aug. 1-5, 2005. (disubstituted)pyrimidines” Bioorg Med Chem. 8(4):739-750
Presentation given at the Gordon Conference on Heterocyclic (2000).
Compounds, Salve Regina University, Newport, Rhode Island, Jul. Hauser et al. “Synthesis of 5-phenyl-4,6-dimethyl-2-pyrimidol and
4-9, 2004. derivatives from the cycliZation of urea with 3-phenyl-2,4
Sakaki et al. “Lipase-catalyzed asymmetric synthesis of 6-(3 pentanedione” Journal of Organic Chemistry 18(5): 588-593
chloro-2-hydroXypropyl)-1,3-dioXin-4-ones and their conversion to (1953).
chiral 5,6-epoXyheXanoates” Tetrahedron: Asymmetry 2(5):343
Watanabe et al.; Bioorganic & Medicinal Chemistry, vol. 5, No. 2,
346 (1991).
Shao et al. “Asymmetric hydrogenation of 3,5-DioXoesters cata 1997, pp. 437-444.
lyZed by Ru-binap complex: A short step asymmetric synthesis of Ma et al., “Lanthanide Tri?ate Catalyzed Biginelli Reaction. One
6-substituted 5,6-dihydro-2-pyrones” Tetrahedron 49(10):1997 Pot Synthesis of Dihydropyrimidinones under Solvent-Free Condi
2010 (1993). tions,” Jouranl ofOrganic Chemistry, 2000, 65(12), 3864-3868.
US 7,304,156 B2
1 2
PREPARATION OF AMINOPYRIMIDINE BACKGROUND OF THE INVENTION
COMPOUNDS
Bioorg. Med Chem., 5, 437(1997) describes that the
FIELD OF THE INVENTION 2-(N-methyl-N-methanesulfonylamino)pyrimidine com
pound is employable as an intermediate compound forpro
The present invention relates to the preparation of ami ducing a cholesterol reducing agent (HMG-CoA reductase
nopyrimidine compounds having the following forrnla (8): inhibitor: S-4522) having the folloWing formula:
(3)
20
25
30
(4)
(3)
20
(1)
40
in Which R is a hydrocarbyl group,
With 4-?uorobenZaldehyde and urea in the presence of a
protonic compound and a metal salt.
45 The invention furthermore resides in a method for pre
paring an aminopyrimidine compound having the formula
(8)1
50 (3)
in Which R' is the same as above, and 65 Wherein R is a hydrocarbyl group, and each of Rland R2
reacting the resulting reaction product With N-methyl-N independently is hydrogen atom, an alkyl group, an alkyl
methanesulfonamide. sulfonyl group, or an arylsulfonyl group,
US 7,304,156 B2
5 6
Which comprises reacting a 2-substituted pyrimidine com The invention furthermore resides in a method for pre
pound having the formula (6): paring the halogenopyrimidine compound of the formula
(9), Which comprises reacting a hydroxypyrimidine com
pound of the aforementioned formula (1) With a halogenat
ing agent.
The invention furthermore resides in an organic sulfony
(6) loxypyrimidine compound having the formula (10):
(10)
20
30
Wherein each of R1 and R2 is the same as above. Wherein R' is a hydrocarbyl group, and X is a halogen atom,
or an organic sulfonic anhydride having the formula (2a):
The invention furthermore resides in a halogenopyrimi
dine compound having the formula (9): (Rysozbo (2a)
45 in Which R' is the same as above.
The invention furthermore resides in a process for pre
paring a 2-(N-methyl-N-methanesulfonylamino)pyrimidine
of the formula (3) Which comprises the steps of:
(I) reacting an isobutyrylacetate ester of the formula (5)
(9) 50
With 4-?uorobenZaldehyde and urea in the presence of a
protonic compound and a metal salt;
(II) oxidizing the reaction product of the step (I);
(III) reacting the oxidation product of the step (II) With an
organic sulfonyl halide of the formula (2) or an organic
55
sulfonic anhydride of the formula (2a); and
(IV) reacting the reaction product of the step (III) With
N-methyl-N-methanesulfonamide.
In the above-mentioned process, the steps (III) and (IV)
can be carried out continuously in the same reaction mixture.
60
DETAILED DESCRIPTION OF THE
INVENTION
(5)
002R
CH0 0
NH2 10
o NH2 + COZR
[R is a hydrocarbyl group].
15
is reacted With 4-?uorobenZaldehyde and urea in the pres
ence of a protonic compound and a metal salt.
F The hydrocarbyl group (i.e., hydrocarbon group) repre
sented by R in the formulas of the compounds involved in
the reactions of the invention can be an alkyl group such as
20
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,
nonyl, or decyl, more particularly an alkyl group having 1-6
carbon atoms and especially an alkyl group having 1-4
COZR OXIDATION
carbon atoms; a cycloalkyl group such as cyclopropyl,
—
cyclobutyl, cyclopentyl, or cyclohexyl; an aralkyl group
HN I (n) 25 such as benZyl, phenylethyl, or phenylpropyl; or an aryl
group such as phenyl or methylphenyl. The hydrocarbyl
0% N H group can take any isomer con?gurations such as normal,
iso, and tertiary. The hydrocarbyl group can have one or
(4) 30 more substituents, provided that the substituents do not
disturb the reaction involved.
The protonic compound can be an inorganic acid or its salt
such as hydrochloric acid, sulfuric acid, potassium hydro
F
gensulfate, sodium hydrogen sulfate, nitric acid, or phos
35 phoric acid; an organic sulfonic acid such as methane
sulfonic acid, ethanesulfonic acid, benZenesulfonic acid,
p-toluenesulfonic acid, or p-bromobenZenesulfonic acid; an
organic carboxylic acid such as acetic acid, propionic acid,
butyric acid, or benZoic acid; an alcohol such as methanol,
40 ethanol, or propanol. Preferred are protonic acids such as
002R hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and
N (111) + (W) acetic acid. Most preferred is sulfuric acid. The protonic
HO
)\ compounds can be employed singly or in combination.
The protonic compound can be employed in an amount of,
45 preferably, 0.01 to 3 mol., more preferably 0.1 to 1 mol., per
one mol. of the isobutyrylacetate ester.
The metal salt employed in the reaction can be copper(l)
chloride, copper(ll) chloride, copper(ll) acetate, iron(ll)
chloride, iron(lll) chloride, aluminum chloride, nickel(ll)
bromide, tin(lV) chloride, titanium tetrachloride, or magne
sium bromide. Preferred are copper(l) chloride, copper(ll)
chloride, iron(lll) chloride and nickel(ll) bromide. Most
preferred is copper(l) chloride. The metal salts may contain
Water of crystallization The metal salts can be employed
singly or in combination.
The metal salt can be employed in an amount of, prefer
ably, 0.001 to 5 mol., more preferably 0.01 to 0.1 mol., per
one mol. of the isobutyrylacetate ester.
The 4-?uorobenZaldehyde can be employed in an amount
of, preferably, 0.5 to 10 mol., more preferably 0.9 to 1.1
mol., per one mol. of the isobutyrylacetate ester.
The urea can be employed in an amount of, preferably, 0.5
to 10 mol., more preferably 1.5 to 2 mol., per one mol. ofthe
65 isobutyrylacetate ester.
Each step in the above-illustrated reaction scheme is The reaction can be performed in the presence or absence
described below in more detail. of a solvent. There are no speci?c limitations With respect to
US 7,304,156 B2
9 10
the solvent employed, so far as the solvent does not disturb The oxidation can be conducted by reacting the dihydro
the desired reaction. Examples of the employable solvents pyrimidinone compound and nitric acid in a solvent under
include alcohols such as methanol, ethanol, n-propyl alco inert gas atmosphere. The oxidation can be carried out at a
hol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, temperature of, preferably —l0 to 1000 C., more preferably
sec-butyl alcohol, and t-butyl alcohol; ethers such as diethyl 0 to 500 C. There are no speci?c limitations With respect to
ether, diisopropyl ether, tetrahydrofuran, and dimethoxy the surrounding pressure. Areaction initiator such as sodium
ethane; nitriles such as acetonitrile, propionitrile, butyroni nitrite may be incorporated into the reaction system to
trile, and isobutyronitrile; halogenated aliphatic hydrocar accelerate the oxidation rate.
bons such as dichloromethane, dichloroethane, chloroform, The resulting product of the reaction, that is, the hydroxy
and carbon tetrachloride; aromatic hydrocarbons such as pyrimidine compound of the formula (1), can be isolated and
benzene, toluene, and xylene; halogenated aromatic hydro puri?ed according to the conventional procedures such as
carbons such as chlorobenzene; and nitrated aromatic hydro distillation, crystallization, recrystallization, and column
carbons such as nitrobenzene. Preferred are methanol, etha chromatography.
nol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol,
diisopropyl ether, tetrahydrofuran, dimethoxyethane, aceto Steps (III) and (IV)
nitrile, butyronitrile, isobutylonitrile, dichloromethane, In the steps (III) and (IV), a hydroxypyrimidine com
dichloroethane, chloroform, toluene, xylene, and chloroben pound of the formula (1), that is, the reaction product of the
zene. Especially preferred are methanol, ethanol, and iso step (II), is reacted With an organic sulfonyl halide of the
propyl alcohol. The solvents can be employed singly or in formula (2):
combination. 20
R'SO2X (2)
The solvent can be employed in an amount of, preferably
0.1 to 10 liters, more preferably 0.3 to 2 liters, per one mole or an organic sulfonic anhydride of the formula (2a):
of the isobutyrylacetate ester. The amount may vary depend
ing on homogeneity and dispersability of the reaction mix (R'SO2)2O (2a)
ture. 25
and
The reaction can be conducted by reacting the isobutyry reacting the resulting reaction product With N-methyl-N
lacetate ester, 4-?uorobenzaldehyde, and urea, in a solvent methanesulfonamide.
in the presence of a protonic compound and a metal salt
under inert gas atmosphere. The reaction can be carried out
In the formulas (2) and (2a), R' is a hydrocarbyl group
30 Which can have one or more substituents. Examples of the
at a temperature of, preferably —l0 to 2000 C., more pref
hydrocarbyl groups include alkyl groups such as methyl,
erably 30 to 100° C. There are no speci?c limitations With
respect to the surrounding pressure.
ethyl, propyl, butyl, pentyl, heptyl, octyl, nonyl, and decyl,
more particularly an alkyl group having l-6 carbon atoms
The resulting product of the reaction, that is, a dihydro and especially an alkyl group having l-4 carbon atoms;
pyrimidinone compound of the formula (4), can be isolated ?uorinated alkyl groups such as tri?uoromethyl, nona?uo
and puri?ed according to the conventional procedures such robutyl, trideca?uorohexyl, heptadeca?uorooctyl, and
as distillation, crystallization, recrystallization, and column uncosa?uorodecyl; cycloalkyl groups such as cyclopropyl,
chromatography. cyclobutyl, cyclopentyl, and cyclohexyl; aralkyl groups
Step (II) such as benzyl, phenylethyl, and phenylpropyl; and aryl
40 groups, including unsubstituted and substituted phenyl or
In the step (II), a dihydropyrimidinone compound of the
formula (4), that is, the reaction product of the step (I), is naphthyl groups, such as phenyl, naphthyl, tolyl, xylyl,
oxidized to give a hydroxypyrimidine compound of the mesityl, triisopropylphenyl, methoxyphenyl, chlorophenyl,
and nitrophenyl. Thus, the hydrocarbyl group can have one
formula (1).
or more substituents, provided that the substituents do not
The oxidation (or dehydrogenation oxidation) can be disturb the reaction involved. The hydrocarbyl group can
45
performed in various conventional manners. Preferred is take any isomer con?gurations such as normal, iso, and
oxidation utilizing nitric acid, because this oxidation proce tertiary. A particularly suitable value for R' When it is aryl
dure is easily carried out and the post-treatment of the includes, for example, a phenyl or naphthyl group (particu
reaction product is easy. larly phenyl) Which is unsubstituted or bears l, 2 or 3
The nitric acid can be employed in an amount of, pref 50 substituents. The substituents may be independently selected
erably l to 20 mol., more preferably 3 to 15 mol., per one from, for example, alkyl having l-4 carbon atoms, alkoxy
mole of the dihydropyrimidinone compound of the formula having l-4 carbon atoms, halogeno, and nitro.
(4). The nitric acid of a concentration of, preferably 40 to In the formula (2), X is a halogen atom such as ?uorine,
80%, more preferably 50 to 70%, can be preferably chlorine, bromine, and iodine.
employed. 55 Examples of the sulfonyl halides include methanesulfonyl
The oxidation can be performed in the presence or ?uoride, methanesulfonyl chloride, ethanesulfonyl chloride,
absence of a solvent. There are no speci?c limitations With l-propanesulfonyl chloride, 2-propanesulfonyl chloride, tri
respect to the solvent employed, so far as the solvent does ?uoromethanesulfonyl ?uoride, tri?uoromethanesulfonyl
not disturb the desired reaction. Examples of the preferred chloride, nona?uorobutanesufonyl ?uoride, trideca?uoro
solvents include carboxylic acids such as acetic acid, pro 60 hexanesulfonyl ?uoride, heptadeca?uorooctanesulfonyl
pionic acid, and butyric acid. The solvents can be employed ?uoride, uncosa?uorodecanesulfonyl ?uoride, benzene
singly or in combination. sulfonyl chloride, l-naphthalenesulfonyl chloride, 2-naph
The solvent can be employed in an amount of, preferably thalenesulfonyl chloride, p-toluenesulfonyl ?uoride, p-tolu
0.1 to 7 mL, more preferably 0.5 to 3 mL, per 1 g of the enesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl
dihydropyrimidinone compound. The amount may vary 65 chloride, 2,4,6-triisopropylbenzenesulfonyl chloride,
depending on homogeneity and dispersability of the reaction p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfo
mixture. nyl chloride, and 2-nitrobenzenesulfonyl chloride. Preferred
US 7,304,156 B2
11 12
are tri?uoro-methanesulfonyl ?uoride, benZenesulfonyl The reaction can be performed by reacting the hydroxy
chloride, l-naphthalenesulfonyl chloride, 2-naphthalene pyrimidine compound and the organic sulfonyl halide or
sulfonyl chloride, p-toluenesulfonyl chloride, 2,4,6-trimeth sulfonic anhydride in a solvent in the presence of a base With
ylbenZenesulfonyl chloride, 2,4,6-triisopropylbenZenesulfo stirring under inert gas atmosphere. The base can be added
nyl chloride, p-methoxybenZenesulfonyl chloride, and portionWise. The reaction can be carried out at a temperature
p-chlorobenZenesulfonyl chloride. Particularly preferred are of, preferably —30 to 2500 C., more preferably 0 to 1500 C.
p-toluenesulfonyl chloride, 2,4,6-trimethylbenZenesulfonyl There are no speci?c limitations With respect to the sur
chloride, 2,4,6-triisopropylbenZenesulfonyl chloride, and rounding pressure.
p-methoxybenZenesulfonyl chloride. The resulting product of the reaction, that is, the 2-(N
Examples of the sulfonic anhydrides include methane methyl-N-methanecarbonsulfonylamino)pyrimidine com
sulfonic anhydride, tri?uoromethanesulfonic anhydride, pound of the formula (3), can be isolated and puri?ed
benZenesulfonic anhydride, and p-toluenesulfonic anhy according to the conventional procedures such as distilla
dride. Preferred are tri?uoromethanesulfonic anhydride, tion, crystallization, recrystallization, and column chroma
benZenesulfonic anhydride, and p-toluenesulfonic anhy tography.
dride. Particularly preferred are tri?uoromethanesulfonic The 2-(N-methyl-N-methanesulfonylamino)pyrimidine
anhydride and p-toluenesulfonic anhydride. compound of the formula (3) and other pyrimidine com
The sulfonyl halide or sulfonic anhydride can be pounds of the formula (8) can be prepared from a hydroxy
employed in an amount of, preferably 0.1 to 20 mol., more pyrimidine compound of the formula (1) via a 2-substituted
preferably 0.5 to 5 mol., most preferably 1 to 2 mol., per one pyrimidine compound of the formula (6) in the folloWing
mole of the hydroxypyrimidine compound. 20 steps (V) and (VI):
In the sub sequent step, N-methylmethanesulfonamide can
be employed in an amount of, preferably 0.1 to 30 mol.,
more preferably 1 to 5 mol., per one mol. of the hydroxy
pyrimidine compound.
The reactions of the steps (III) and (IV) can be preferably
performed in the presence of a base. Examples of the bases
include alkali metal carbonates such as sodium carbonate
and potassium carbonate; alkali metal hydrogencarbonates
such as sodium hydrogencarbonate; alkali metal hydroxides
such as lithium hydroxide, sodium hydroxide and potassium
hydroxide; alkali metal alkoxides such as sodium methox
ide, sodium t-butoxide, potassium t-butoxide, and sodium
t-pentoxide; and tertiary amines such as triethylamine, tri
isopropylamine, diisopropylethylamine, and pyridine. Pre
ferred are sodium carbonate, potassium carbonate, potas
sium t-butoxide, sodium t-pentoxide, triethylamine, and
pyridine. Particularly preferred are potassium carbonate,
sodium t-pentoxide, and triethylamine. Most preferred are
potassium carbonate and sodium t-pentoxide. The bases can
be employed singly or in combination.
The base can be employed in an amount of, preferably 0.1
to 30 mol., more preferably 1 to 5 mol., per one mol. of the
hydroxypyrimidine compound. The Whole amount of the
base can be incorporated in the reaction system before the
reaction begins, or the base can be portionWise added to the
reaction system after the reaction begins.
The reaction can be performed in the presence or absence
of a solvent. There are no speci?c limitations With respect to
the solvent, so far as the solvent does not disturb the
reaction. Examples of the solvents include Water; ketones
such as acetone, methyl ethyl ketone, and diethyl ketone;
ethers such as diethyl ether and tetrahydrofuran; esters such
as ethyl acetate, propyl acetate, and butyl acetate; nitrites
such as acetonitrile and propionitrile; amides such as N,N
dimethylformamide and N-methylpyrrolidone; sulfoxides
such as dimethylsulfoxide; ureas such as N,N'-dimethylimi
daZolinone. Preferred are acetone, tetrahydrofuran, ethyl
acetate, butyl acetate, acetonitrile, N,N-dimethylformamide,
and dimethylsulfoxide. Particularly preferred are ethyl
acetate, butyl acetate and acetonitrile. Most preferred are
butyl acetate and acetonitrile. The solvents can be employed
singly or in combination.
The solvent can be employed in an amount of, preferably
0.01 to 100 liters, more preferably 0.5 to 5 liters, per one In the formula (8), R has the same meaning as described
mole of the hydroxypyrimidine compound. The amount may 65 above, and each of R1 and R2 independently is a hydrogen
vary depending on homogeneity and dispersability of the atom, an alkyl group, an alkylsulfonyl group, or aryl
reaction mixture. sulfonyl group.
US 7,304,156 B2
13 14
Step (V) preferably —30 to 200° C., more preferably 0 to 50° C. There
In the step (V), a hydroxypyrimidine compound of the are no speci?c limitations With respect to the surrounding
formula (1) is reacted With a halogenating agent such as a pressure.
chlorinating agent, an organic sulfonyl halide of the formula The resulting product of the reaction, that is, a 2-substi
(2)1 tuted pyrimidine compound such as a chloropyrimidine
compound or a sulfonyloxypyrimidine compound, can be
R'SO2X (2) isolated and puri?ed according to the conventional proce
in Which R' has the same meaning as above and X is a
dures such as distillation, crystallization, recrystallization,
and column chromatography.
halogen atom, or an organic sulfonic anhydride of the
formula (2a): Step (VI)
In the step (Vl), the 2-substituted pyrimidine compound,
(R'SO2)2O (2a) such as a chloropyrimidine compound or a sulfonyloxypy
in Which R' has the same meaning as above. rimidine compound prepared in the step (V) is reacted With
an amine compound having the formula (7):
Examples of the halogenating agents include phosphorus
oxychloride and thionyl chloride. The halogenating agents
can be employed singly or in combination.
(7)
The halogenating agent can be employed in an amount of, R1
preferably 0.1 to 50 mol., more preferably 1 to 20 mol., most \
NH
preferably 1.5 to 10 mol., per one mol. of the hydroxypy 20 /
rimidine compound. R2
Examples of the organic sulfonyl halides and sulfonic
anhydrides are those described hereinbefore.
Wherein each of R1 and R2 is the same as above.
The organic sulfonyl halide or sulfonic anhydride can be
25 Examples of the groups of R1 and R2 include a hydrogen
employed in an amount of, preferably 0.1 to 20 mol., more
preferably 0.5 to 5 mol., most preferably 1 to 2 mol., per one
atom, alkyl groups such as methyl, ethyl, propyl, butyl,
pentyl and hexyl; alkylsulfonyl groups such as methane
mol. of the hydroxypyrimidine compound.
sulfonyl; and arylsulfonyl groups such as benZenesulfonyl
The reaction can be performed in the presence or absence and p-toluenesulfonyl.
of a solvent. There are no speci?c limitations With respect to The amine compound can be employed in an amount of,
30
the solvent, so far as the solvent does not disturb the
preferably 0.1 to 30 mol., more preferably 1 to 5 mol., per
reaction. Examples of the solvents include aromatic hydro one mol. of the 2-substituted pyrimidine compound.
carbons such as toluene; halogenated aromatic hydrocarbons The reaction is preferably performed in the presence of a
such as chlorobenZene; nitrated hydrocarbons such as base. Examples of the bases are those described hereinbe
nitrobenZene; halogenated aliphatic hydrocarbons such as fore.
35
methylene chloride and 1,2-dichloroethane; amides such as The base can be preferably employed in an amount of,
N,N-dimethylformamide; Water (not for a halogenating preferably 0.1 to 30 mol., more preferably 1 to 5 mol., per
agent); nitriles such as acetonitrile and propionitrile; car one mol. of the 2-substituted pyrimidine compound.
boxylic acid esters such as ethyl acetate, propyl acetate, The reaction can be performed in the presence or absence
butyl acetate; ketones such as acetone, methyl ethyl ketone, of a solvent. There are no speci?c limitations With respect to
diethyl ketone; and ethers such as diethyl ether and tetrahy the solvent, so far as the solvent does not disturb the
drofuran. Preferred are butyl acetate, toluene, methylene reaction. Examples of the solvents include Water; ketones
chloride, acetonitrile, chlorobenZene, nitrobenZene, and such as acetone, methyl ethyl ketone, and diethyl ketone;
N,N-dimethylformamide. The solvents can be employed ethers such as diethyl ether and tetrahydrofuran; esters such
singly or in combination.
45 as ethyl acetate, propyl acetate, and butyl acetate; nitriles
The solvent can be employed in the reaction utiliZing the such as acetonitrile and propionitrile; amides such as N,N
halogenating agent in an amount of, preferably 0.01 to 10 dimethylformamide and N-methylpyrrolidone; sulfoxides
liters, more preferably 0.1 to 2 liters, per one mole of the such as dimethylsulfoxide; ureas such as N,N'-dimethylimi
hydroxypyrimidine compound. The amount may vary daZolidinone. Preferred are acetone, tetrahydrofuran, ethyl
depending on homogeneity and dispersability of the reaction 50 acetate, butyl acetate, acetonitrile, N,N-dimethylformamide,
mixture. and dimethylsulfoxide. Particularly preferred are ethyl
The solvent can be employed in the reaction utiliZing the acetate, butyl acetate and acetonitrile. The solvents can be
sulfonyl chloride or sulfonic anhydride in an amount of, employed singly or in combination.
preferably 0.1 to 50 liters, more preferably 0.5 to 2 liters, per The solvent can be employed in an amount of, preferably
one mole of the hydroxypyrimidine compound. The amount 0.01 to 100 liters, more preferably 0.5 to 5 liters, per one
may vary depending on homogeneity and dispersability of mole of the 2-substituted pyrimidine compound. The
the reaction mixture. amount may vary depending on homogeneity and dispers
The reaction can be carried out by reacting the hydroxy ability of the reaction mixture.
pyrimidine compound and the halogenating agent, in a The reaction can be conducted by reacting the 2-substi
solvent With stirring under inert gas atmosphere. The reac 60 tuted pyrimidine compound and the amine compound in a
tion can be carried out at a temperature of, preferably 0 to solvent in the presence of a base With stirring under inert gas
200° C., more preferably 50 to 120° C. There are no speci?c atmosphere. The reaction can be carried out at a temperature
limitations With respect to the surrounding pressure. of, preferably —20 to 250° C., more preferably 25 to 150° C.
The reaction can be carried out by reacting the hydroxy There are no speci?c limitations With respect to the sur
pyrimidine compound and the sulfonyl halide or sulfonyl 65 rounding pressure.
anhydride in a solvent With stirring under inert gas atmo The reaction can be conducted in tWo separate liquid
sphere. The reaction can be carried out at a temperature of, phases in the presence of a phase transfer catalyst. Examples
US 7,304,156 B2
15 16
of the phase transfer catalysts include tetramethylammo g (20 mmol.) of iron(III) chloride.hexahydrate. There Was
nium chloride, tetramethylammonium bromide, tetraethy obtained 35.6 g of 4-(4-?uorophenyl)-6-isopropyl-5-meth
lammonium ?uoride, tetraethylammonium chloride, tetra oxycarbonyl-3,4-2(1H)-dihydropyrimidinone. The yield
ethylammonium bromide, tetrapropylammonium bromide, Was 61% (based on the amount of methyl isobutyrylacetate).
tetrapropylammonium iodide, tetrabutylammonium ?uo
ride, tetrabutylammonium chloride, tetrabutylammonium EXAMPLE 3
bromide, tetrabutylammonium iodide, tetrapentylammo
nium bromide, tetrahexylammonium bromide, tetrahepty Preparation of 4-(4-?uorophenyl)-2-hydroxy-6-iso
lammonium bromide, tetraoctylammonium bromide, ben propyl-5-methoxycarbonylpyrimidine
Zyldimethyltetradecylammonium chloride,
benZyltriethylammonium chloride, phenyltrimethylammo
nium chloride, phenyltrimethylammonium iodide, and hexa In a 50 mL-volume glass ?ask equipped With a stirrer and
decyltrimethylammonium chloride. Preferred are tetrabuty a thermometer Was placed 11 mL (144 mmol.) of nitric acid
lammonium chloride, tetrabutylammonium bromide, (60-61%, sp.gr.: 1.38). To the nitric acid Was sloWly added
tetrabutylammonium iodided, benZyltriethylammonium at room temperature 4.00 g (13.7 mmol.) of 4-(4-?uorophe
chloride, and hexadecyltrimethylammonium chloride. Most nyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropy
preferred are tetrabutylammonium bromide, benZyltriethy rimidinone prepared in the same manner as in Example 1,
lanmonium chloride, and hexadecyltrimethylammonium and the mixture Was subjected to reaction for 30 minutes at
chloride. room temperature. After the reaction Was complete, the
The phase transfer catalyst can be employed in an amount 20 reaction mixture Was neutraliZed by placing the mixture in
of 0.01 to 0.5 mol., preferably 0.05 to 0.2 mol., per one mol. 140 mL of saturated aqueous sodium hydrogen carbonate
of the 2-substituted pyrimidine compound. solution. The reaction mixture Was then extracted With ethyl
The resulting product of the reaction, that is, a 2-(N acetate. The organic liquid portion Was separated and con
methyl-N-methanesulfonylamino)pyrimidine compound of centrated under reduced pressure. The residue Was crystal
the formula (3) or other aminopyrimidine compounds of 25 liZed from toluene. The crystalline product Was collected on
formula (8), can be isolated and puri?ed according to the a ?lter and Washed With toluene to obtain 3.64 g of 4-(4
conventional procedures such as distillation, crystallization, ?uorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbon
recrystallization, or column chromatography. ylpyrimidine as a colorless crystalline product having the
The present invention is further described by the folloW beloW-mentioned characteristics. The yield Was 92% (based
ing non-limiting examples. 30 on the amount of 4-(4-?uorophenyl)-6-isopropyl-5-meth
oxycarbonyl-3,4-2(1H)-dihydropyrimidinone).
EXAMPLE 1
mp: 1930 C. (decomposed) UV km“ (CH3CN, nm):
Preparation of 4-(4-?uorophenyl)-6-isopropyl-5 196.6, 243.2, 317.9 IR (KBr, cm“): 2991, 2887, 1717, 1653,
1589, 1433, 1280, 1223.
methoxycarbonyl-3 ,4 -2 (1 H)-dihydropyrimidinone 35
lH-NMR (DMSO-d6, 6 (ppm)): 1.23 (6H, d, 1:68 HZ),
In a 500 mL-volume glass ?ask equipped With a stirrer, a 3.0-3.2 (1H, m), 3.56 (3H, s), 7.3-7.4 (2H, m), 7.5-7.6 (2H,
thermometer and a re?ux condenser Were placed 28.8 g (0.2 m), 12.25 (1H, brs).
mol.) of methyl isobutyrylacetate, 24.8 g (0.2 mol.) of HRMS: 290.1054 (theoretical value (Cl5H15FN2O3(M+))
4-?uorobenZaldehyde, 21.0 g (0.35 mol.) of urea, 200 mg (2 40 290.1067)
mmol.) of copper(I) chloride, 2 mL of sulfuric acid, and 200
mL of methanol. The content of the ?ask Was heated to EXAMPLE 4
64-650 C. for 24 hours under re?ux With stirring, to carry out
the reaction. There Was precipitated crystalline product. The Preparation of 4-(4-?uorophenyl)-2-hydroxy-6-iso
crystalline product Was collected on a ?lter paper and 45 propyl-5-methoxycarbonylpyrimidine
Washed With methanol to obtain 49.7 g of 4-(4-?uorophe
nyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropy In a 50 mL-volume glass ?ask equipped With a stirrer and
rimidinone as a colorless crystalline product having the a thermometer Were placed 2.92 g (10 mmol.) of 4-(4
beloW-mentioned characteristics. The yield Was 85% (based ?uorophenyl)-6-isopropyl-5 -methoxycarbonyl-3,4-2(1H)
on the amount of methyl isobutyrylacetate). 50 dihydropyrimidinone prepared in the same manner as in
mp: 223-2250 C. UV km“ (CH3CN, nm): 194.3, 278.6 Example 1 and 5 mL of acetic acid. To the mixture Was
IR (KBr, cm“): 3296, 3229, 3137, 2963, 1685, 1629, 1504, sloWly added 3.74 mL (50 mmol.) of nitric acid (60-61%,
1225, 1097. sp.gr.: 1.38). To the mixture Was further added 0.07 g (1
lH-NMR (DMSO-d6, 6 (ppm)): 1.14 (6H, dd, 1:68, 6.9 mmol.) of sodium nitrite, and the reaction Was carried out for
HZ), 3.52 (3H, s), 4.0-4.2 (1H, m), 5.15 (1H, d, J:3.4HZ), 55 one hour at room temperature. After the reaction Was com
7.1-7.2 (2H, m), 7.2-7.3 (2H, m), 7.76 (1H, d, 1:32 HZ), plete, the reaction mixture Was neutraliZed by placing the
8.91 (1H, s). mixture in 50 mL of saturated aqueous sodium hydrogen
HRMS: 292.1247 (theoretical value (CISHUFNZO3 carbonate solution; The reaction mixture Was then extracted
(M+)) 292.1223) With ethyl acetate. The organic liquid portion Was separated
60 and concentrated under reduced pressure. The residue Was
EXAMPLE 2 crystalliZed from toluene. The crystalline product Was col
lected on a ?lter and Washed With toluene to obtain 2.61 g
Preparation of 4-(4-?uorophenyl)-6-isopropyl-5 of 4-(4-?uorophenyl)-2-hydroxy-6-isopropyl-5-methoxy
methoxycarbonyl-3 ,4 -2 (1 H)-dihydropyrimidinone carbonyl-pyrimidine as a colorless crystalline product. The
65 yield Was 90% (based on the amount of 4-(4-?uorophenyl)
The procedures of Example 1 Were repeated except for 6-isopropyl-5 -methoxycarbonyl-3,4-2(1H)-dihydropyrimi
replacing 200 mg (2 mmol.) of copper(I) chloride With 5.41 dinone).
US 7,304,156 B2
17 18
EXAMPLE 5 (same as above). The mixture Was heated to 110-1250 C. for
2 hours under re?uxing to carry out a reaction. After the
Preparation of 4-(4-?uorophenyl)-2-hydroxy-6-iso reaction Was complete, the mixture Was cooled to room
propyl-5-methoxycarbonylpyrimidine temperature. To the cooled mixture Were added 25 mL of
Water and 20 mL of acetone, and the organic liquid portion
In a 200 mL-Volume glass ?ask equipped With a stirrer Was separated. The organic liquid portion Was Washed With
and a thermometer Was placed 54.0 g (735 mmol.) of nitric a saturated aqueous sodium chloride solution and dried over
acid (60-61%, sp.gr.: 1.38). To the nitric acid Was slowly anhydrous magnesium sulfate. The dry organic liquid por
added at room temperature 30.6 g (105 mmol.) of 4-(4 tion Was ?ltered and concentrated under reduced pressure.
?uorophenyl)-6-isopropyl-5 -methoxycarbonyl-3,4-2(1H) The residue Was crystalliZed from heptane, to obtain 6.58 g
dihydropyrimidinone prepared in the same manner as in of 4-(4-?uorophenyl)-6-isopropyl-5-methoxycarbonyl-2
Example 1, and the mixture Was subjected to reaction for 30 (N -methyl-N-methanesulfonylamino)pyrimidine as a pale
minutes at room temperature. After the reaction Was com
yelloW crystalline product. The yield Was 86% (based on the
plete, the reaction mixture Was poured into 162 mL of Water. amount of 4-(4-?uorophenyl)-2-hydroxy-6-isopropyl-5
The aqueous mixture Was neutraliZed by adding 61 g of methoxycarbonylpyrimidine).
aqueous sodium hydroxide solution (48 Wt. %) to precipitate
a crystalline product. The crystalline product Was collected
EXAMPLE 8
by ?ltration and dried to obtain 27.6 g of 4-(4-?uorophenyl)
2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine as a
colorless crystalline product. The yield Was 91% (based on 20
Preparation of 4-(4-?uorophenyl)-6-isopropyl-5
the amount of 4-(4-?uorophenyl)-6-isopropyl-5-methoxy
methoxycarbonyl-2-(N-methyl-N-methanesulfony
carbonyl-3,4-2(1H)-dihydropyrimidinone). lamino)pyrimidine
50
(4)
(3)
55
60
(3) (7)
R1
30
\
NH
/
R2
It is certified that error appears in the above-identi?ed patent and that said Letters Patent is
hereby corrected as shown below:
In the specification (Column 1, lines 40 - 65), formula (3) should appear as follows:
UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
It is certified that error appears in the above-identi?ed patent and that said Letters Patent is
hereby corrected as shown below:
In the specification (Column 3, lines 10 - 25), formula (3) should appear as follows:
In the specification (Column 7, lines 50 - 65), formula (3) should appear as follows:
UNITED STATES PATENT AND TRADEMARK oPPIcE
CERTIFICATE OF CORRECTION
It is certified that error appears in the above-identi?ed patent and that said Letters Patent is
hereby corrected as shown below:
In claim 1 (Column 27, lines 45 - 65), formula (3) should appear as follows:
E NI \ 603R (3)
H3C/ISI\NJ\N/
° |
m Wall,”
JON W. DUDAS
Director ofthe United States Patent and Trademark O?ice