U.S. patent application number 11/845946 was filed with the patent office on 2007-12-20 for n-phenyl-2-pyrimidine-amine derivatives.
Invention is credited to Stephan Abel, Hans Michael Burger, Daniel Kaufmann, Olivier Loiseleur, Mark Meisenbach, Beat Schmitz, Gottfried Sedelmeier.
Application Number | 20070293683 11/845946 |
Document ID | / |
Family ID | 9930607 |
Filed Date | 2007-12-20 |
United States Patent
Application |
20070293683 |
Kind Code |
A1 |
Loiseleur; Olivier ; et
al. |
December 20, 2007 |
N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES
Abstract
The present invention relates to novel amides and a process for
preparing these amides.
Inventors: |
Loiseleur; Olivier;
(Saint-Louis, FR) ; Kaufmann; Daniel; (Therwil,
CH) ; Abel; Stephan; (Weil am Rhein, DE) ;
Burger; Hans Michael; (Allschwil, CH) ; Meisenbach;
Mark; (Durmenach, FR) ; Schmitz; Beat;
(Allschwil, CH) ; Sedelmeier; Gottfried;
(Schallstadt, DE) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
9930607 |
Appl. No.: |
11/845946 |
Filed: |
August 28, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10503538 |
Jan 20, 2005 |
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PCT/EP03/01188 |
Feb 6, 2003 |
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11845946 |
Aug 28, 2007 |
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Current U.S.
Class: |
546/334 |
Current CPC
Class: |
C07D 295/155 20130101;
A61P 29/00 20180101; A61P 43/00 20180101; A61P 25/00 20180101; C07D
401/04 20130101; C07D 401/14 20130101; A61P 37/02 20180101; A61P
35/00 20180101; A61P 35/02 20180101 |
Class at
Publication: |
546/334 |
International
Class: |
C07D 211/70 20060101
C07D211/70 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 7, 2002 |
GB |
0202873.6 |
Claims
1-20. (canceled)
21. A compound of formula VI ##STR9## wherein R.sub.10 is 3-pyridyl
and R.sub.11 is hydrogen or lower alkyl.
22. A compound of formula VI according to claim 21, wherein
R.sub.11 is methyl.
Description
[0001] The present invention provides novel amides, a process for
preparing these amides and the use of these amides.
[0002] In particular, the present invention provides novel amides
of formula I ##STR1## wherein one of the radicals R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 is [0003] a) a radical selected from
the group consisting of lower alkyl, amino; mono- or di-lower
alkylamino; lower alkanoylamino; lower alkoxy-carbonyl; and lower
alkyl which is substituted by amino, mono- or di-lower alkylamino
or lower alkanoylamino, or [0004] b) an unsubstituted or
substituted radical selected from the group consisting of
benzylamino; benzoylamino; pyrrolidinyl; piperidyl; piperazinyl;
piperazinyl-carbonyl; morpholinyl, thiomorpholinyl; and lower alkyl
substituted by benzylamino, benzoylamino, halogene, pyrrolidinyl,
piperidyl, piperazinyl, e.g. 4-methyl-piperazinyl-,
thiomorpholinyl, or morpholinyl, the substituents of said
substituted radical being selected from the group consisting of
cyano; lower alkyl; hydroxy- or amino-substituted lower alkyl;
trifluoromethyl; free, etherified or esterified hydroxy; lower
alkoxy; lower alkanoyloxy; free, alkylated or acylated amino; mono-
or di-lower alkylamino; lower alkanoylamino; benzoylamino; free or
esterified carboxy; lower alkoxycarbonyl and halogen, and and the
other four radicals are independently hydrogen, cyano; lower alkyl;
hydroxy- or amino-substituted lower alkyl; trifluoromethyl; free,
etherified or esterified hydroxy; lower alkoxy; lower alkanoyloxy;
free, alkylated or acylated amino; mono- or di-lower alkylamino;
lower alkanoylamino; benzoylamino; free or esterified carboxy;
lower alkoxycarbonyl and halogen; or R.sub.1 and R.sub.2, R.sub.2
and R.sub.3, R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5 together
are a substituted or unsubstituted alkylene radical having 4 carbon
atoms, the substituents preferably being selected from cyano,
unsubstituted or hydroxy-, amino- or
4-methyl-piperazinyl-substituted lower alkyl, such as especially
methyl, trifluoromethyl, free, etherified or esterified hydroxy,
free, alkylated or acylated amino and free or esterified carboxy;
and the other three radicals are independently hydrogen, cyano;
lower alkyl; hydroxy- or amino-substituted lower alkyl;
trifluoromethyl; free, etherified or esterified hydroxy; lower
alkoxy; lower alkanoyloxy; free, alkylated or acylated amino; mono-
or di-lower alkylamino; lower alkanoylamino; benzoylamino; free or
esterified carboxy; lower alkoxycarbonyl and halogen; and one of
the radicals R.sub.6, R.sub.7 and R.sub.8 is halogen, NH.sub.2,
NO.sub.2, NHC(O)CF.sub.3, NHC(O)CH.sub.3, NHC(NH)NH.sub.2, and the
other two radicals are independently hydrogen, lower alkyl, lower
fluorinated alkyl, benzyl or phenyl; or a salt or crystal form
thereof.
[0005] Compounds of formula I may be in the form of a salt
preferably a pharmaceutically acceptable salt.
[0006] Such salts are formed, for example, as acid addition salts,
preferably with organic or inorganic acids, from compounds of
formula I or IV with a basic nitrogen atom, especially the
pharmaceutically acceptable salts. Suitable inorganic acids are,
for example, halogen acids, such as hydrochloric acid, sulfuric
acid, or phosphoric acid. Suitable organic acids are, for example,
carboxylic, phosphonic, sulfonic or sulfamic acids, for example
acetic acid, propionic acid, octanoic acid, decanoic acid,
dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic
acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic
acid, tartaric acid, citric acid, amino acids, such as glutamic
acid or aspartic acid, maleic acid, hydroxymaleic acid,
methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic
acid, benzoic acid, oxalic acid, salicylic acid, 4-aminosalicylic
acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic
acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic
acid, ethane-1,2-disulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3-
or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric
acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-,
N-ethyl- or N-propyl-sulfamic acid, or other organic protonic
acids, such as ascorbic acid.
[0007] For isolation or purification purposes it is also possible
to use pharmaceutically unacceptable salts, for example picrates or
perchlorates. For therapeutic use, only pharmaceutically acceptable
salts or free compounds are employed (where applicable in the form
of pharmaceutical preparations), and these are therefore
preferred.
[0008] Preferred salts of formula I, are chloride, bromide,
mesylate, acetate, trifluoroacetate.
[0009] The term "lower" within the scope of this application
denotes radicals having up to and including 7, preferably up to and
including 4 carbon atoms, preferably methyl or ethyl.
[0010] The term "lower fluorinated alkyl" within the scope of this
application denotes radicals having up to and including 7,
preferably up to and including 4 carbon atoms, preferably methyl or
ethyl, which are substituted by fluorine such as mono, di or
trifluoro-methyl, trifluoro-ethyl.
[0011] The term "piperazinyl" within the scope of this application
denotes unsubstituted piperazinyl or N-lower alkyl-piperazinyl such
as 4-methyl-piperazinyl-.
[0012] Halogen is especially fluorine, chlorine, bromine, or
iodine, especially fluorine, chlorine, or bromine.
[0013] Etherified hydroxy is preferably lower alkoxy. Esterified
hydroxy is preferably hydroxy esterified by an organic carboxylic
acid, such as a lower alkanoic acid, or a mineral acid, such as a
hydrohalic acid, for example lower alkanoyloxy or especially
halogen, such as iodine, bromine or especially fluorine or
chlorine.
[0014] Alkylated amino is, for example, lower alkylamino, such as
methylamino, or di-lower alkylamino, such as dimethylamino.
Acylated amino is, for example, lower alkanoylamino or
benzoylamino.
[0015] Esterified carboxy is, for example, lower alkoxycarbonyl,
such as methoxycarbonyl.
[0016] Preferably, R.sub.3 is lower alkyl substituted by
benzylamino, benzoylamino, halogene, pyrrolidinyl, piperidyl,
piperazinyl, e.g. 4-methyl-piperazinyl-, or morpholinyl,
thiomorpholinyl, the substituents of said substituted radical being
selected from the group consisting of cyano; lower alkyl; hydroxy-
or amino-substituted lower alkyl; trifluoromethyl; free, etherified
or esterified hydroxy; lower alkoxy; lower alkanoyloxy; free,
alkylated or acylated amino; mono- or di-lower alkylamino; lower
alkanoylamino; benzoylamino; free or esterified carboxy; lower
alkoxycarbonyl and halogen.
[0017] Preferably, R.sub.3 is lower alkyl substituted by
pyrrolidinyl, piperidyl, piperazinyl, e.g. 4-methyl-piperazinyl-,
or morpholinyl, thiomorpholinyl, the substituents of said
substituted radical being selected from the group consisting of
lower alkyl; hydroxy- or amino-substituted lower alkyl;
[0018] Preferably, R.sub.1, R.sub.2, R.sub.4, R.sub.5 and R.sub.8
are hydrogen.
[0019] Preferably, R.sub.7 is lower alkyl such as methyl or
fluorinated alkyl such as trifluoromethyl.
[0020] Most preferably, R.sub.3 is (4-methyl-piperazinyl)-methyl,
R.sub.1, R.sub.2, R.sub.4, R.sub.5 and R.sub.8 are hydrogen,
R.sub.6 is halogen, NH.sub.2, NO.sub.2, NHC(O)CF.sub.3,
NHC(O)CH.sub.3, NHC(NH)NH.sub.2, and R.sub.7 is methyl.
[0021] Amides of formula I may be prepared by a process as depicted
below: ##STR2## wherein R.sub.1 to R.sub.8 are as defined above and
R.sub.9 is hydrogen, methyl, ethyl or aryl.
[0022] However, direct conversion of unactivated carboxylic acids
or esters to amides, such as compounds of formula II, with amines
is difficult and typically requires high reaction temperature, e.g.
of about 200.degree. C., or use of strong bases, such as sodium
methoxide, sodium amide, n-butyl lithium, sodium hydride or
Grignard reagent. Thus there is a need for a more efficient
amidation process as hitherto known.
[0023] The present Applicants have found that direct conversion of
unactivated carboxylic acids or esters of compounds of formula II
with compounds of formula III to amides of formula I may
successfully be conducted under mild conditions
A) where R.sub.9 is methyl, ethyl or aryl:
[0024] in the presence of [0025] 1) a Lewis acid, [0026] 2) an
aprotic organic solvent, and optionally [0027] 3) a base, [0028] at
a temperature of between 20.degree. C. and 80.degree. C.,
preferably at about 40.degree. C., for a period of between 1 hour
and 1 day, preferably 8 hours, preferably under inert atmosphere,
preferably at atmospheric pressure, and hydrolysis of the resulting
product; or B) where R.sub.9 is hydrogen: [0029] in the presence of
[0030] 1) thionylchloride, [0031] 2) an aprotic organic solvent,
and optionally [0032] 3) a base, [0033] at a temperature of between
20.degree. C. and 70.degree. C., preferably 45.degree. C., for a
period of between 1 hour and 1 day, preferably 6 hours, preferably
under inert atmosphere, preferably at atmospheric pressure.
[0034] Thus, the present invention provides in another aspect
processes for the preparation of a compound of formula I by
reacting compounds of formula II with compounds of formula III
A) where R.sub.9 is methyl, ethyl or aryl:
[0035] in the presence of [0036] 1) a Lewis acid, [0037] 2) an
aprotic organic solvent, and optionally [0038] 3) a base [0039] at
a temperature of between 20.degree. C. and 80.degree. C.,
preferably at about 40.degree. C., for a period of between 1 hour
and 1 day, preferably 8 hours, preferably under inert atmosphere,
preferably at atmospheric pressure, and the resulting product is
hydrolyzed; or B) where R.sub.9 is hydrogen: [0040] in the presence
of [0041] 1) thionylchloride, [0042] 2) an aprotic organic solvent,
and optionally [0043] 3) a base, [0044] at a temperature of between
20.degree. C. and 70.degree. C., preferably 45.degree. C., for a
period of between 1 hour and 1 day, preferably 6 hours, preferably
under inert atmosphere, preferably at atmospheric pressure.
[0045] Suitable Lewis acids for process A) include Al(lower
alkyl).sub.3 (e.g. AlMe.sub.3, AlEt.sub.3, Al(Bu).sub.3),
AlCl.sub.3, AlBr.sub.3, EtAlCl.sub.2, MeAlCl.sub.2, Me.sub.2AlCl,
Et.sub.2AlCl and the corresponding sesquichlorides. Preferably, the
Lewis acid is selected from AlCl.sub.3, EtAlCl.sub.2 or
Et.sub.2AlCl, even more preferably is AlCl.sub.3. Typically, the
Lewis acid is present in an amount of 1 to 4 mole equivalents. In
the case of AlMe.sub.3, AlEt.sub.3, and Al(Bu).sub.3, e.g. 2 to 3
mole equivalents, preferably about 2.5 mole equivalents are
present; in the case of AlCl.sub.3, AlBr.sub.3, EtAlC.sub.2,
MeAlCl.sub.2, Me.sub.2AlCl, Et.sub.2AlCl and the corresponding
sesquichlorides, preferably 1.5 to 3.5, preferably 2.5 mole
equivalents are present.
[0046] Thionylchloride is preferably present in process B) in an
amount of 1.5 to 10 mole equivalents, preferably 1.5 mole
equivalents.
[0047] Suitable aprotic organic solvents for carrying out process
A) and B) include toluene/acetonitrile, toluene, benzene,
chlorobenzene, dichlorobenzene, acetonitrile, mesitylene and
pyridine.
[0048] A preferred base for process A) or B) is
N,N-diisopropylethylamine, lutidine, pyridine, or tertiary
amines.
[0049] In an alternative aspect, the present invention provides a
process for the preparation of compounds of formula I by reacting
compounds of formula V with compounds of formula R.sub.14--H
##STR3## wherein, R.sub.13 is a lower alkyl substituted by a
halogen, R.sub.14 is benzylamino, benzoylamino, pyrrolidinyl,
piperidyl, piperazinyl, optionally substituted by radicals being
selected from the group consisting of cyano; lower alkyl; hydroxy-
or amino-substituted lower alkyl, R.sub.3 is a lower alkyl
substituted by benzylamino, benzoylamino, pyrrolidinyl, piperidyl,
piperazinyl, optionally substituted by radicals being selected from
the group consisting of cyano; lower alkyl; hydroxy- or
amino-substituted lower alkyl.
[0050] The reaction is preferably carried out in the presence of an
organic solvents, such as THF (Tetrahydrofuran) or directly in the
amine solution R.sub.14--H.
[0051] Preferably piperazinyl is a N-lower-alkylpiperazine e.g.
N-methylpiperazine.
[0052] Preferably, R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are
independently hydrogen, cyano; lower alkyl; hydroxy- or
amino-substituted lower alkyl; trifluoromethyl; free, etherified or
esterified hydroxy; lower alkoxy; lower alkanoyloxy; free,
alkylated or acylated amino; mono- or di-lower alkylamino; lower
alkanoylamino; benzoylamino; free or esterified carboxy; lower
alkoxycarbonyl and halogen.
[0053] Compounds of formula V can be obtained by reacting compounds
of formula II' with compounds of formula III, ##STR4## in the
presence of [0054] 1) an organic solvent such as THF
(Tetrahydrofuran) [0055] 2) a base such as
N,N-diisopropylethylamine, lutidine, pyridine, or tertiary
amines.
[0056] Alternatively, R.sub.14--H is directly added in the
reactional medium without further purification in order to react
with the resulting compound of formula V.
[0057] THF can be used alone or in mixtures with other solvents to
increase overall solvent power.
[0058] The amides of formula I may be formed and isolated from the
reaction mixture, e.g. as conventional, e.g. by removal of solvent
from the reaction mixture, e.g. by concentration such as
evaporation, e.g. to dryness or almost dryness, e.g. until
crystallization or precipitation of an amide of formula I occurs;
or by extraction, e.g. as a salt, or into another solvent which may
be the same or different from that used in the amidation; and
precipitation or crystallization of an amide of formula I. The
amides of formula I may be purified by conventional techniques such
as recrystallization or chromatography.
[0059] Compounds of formula II or II' may be prepared by methods
known to the skilled person in the art. Compounds of formula III
are commercially available e.g. from Fluka, Aldrich or Acros or may
be prepared by methods known to the skilled person in the art.
[0060] The compounds of formula I may be used for the preparation
of compounds of formula IV, ##STR5## wherein R.sub.1 to R.sub.5 are
as defined above and one of the radicals R.sub.6', R.sub.7' and
R.sub.8' is ##STR6## [0061] wherein R.sub.10 is 4-pyperazinyl,
1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted
phenyl wherein the amino group in each case is free, alkylated or
acylated, 1H-indolyl or 1H-imidazolyl bonded at a five-membered
ring carbon atom, or unsubstituted or lower alkyl-substituted
pyridyl bonded at a ring carbon atom and unsubstituted or
substituted at the nitrogen atom by oxygen, and R.sub.11 and
R.sub.12 are each independently of the other hydrogen or lower
alkyl and the other two radicals are independently hydrogen, lower
alkyl, e.g. methyl, benzyl or phenyl; or a pharmaceutically
acceptable salt or crystal form thereof.
[0062] Compounds of formula IV may be in the form of a salt,
preferably a pharmaceutically acceptable salt, as described
above.
[0063] Preferred salts are for example chloride, bromide, mesylate,
acetate, trifluoroacetate.
[0064] Compounds of formula IV inhibit the tyrosine kinase activity
of the receptor for the epidermal growth factor (EGF) and are
useful, inter alia, for the treatment of benign or malignant
tumors. They are able to effect tumour regression and to prevent
metastatic spread and the growth of micrometastases. In particular,
they can be used for treating epidermal hyperproliferation
(psoriasis), for treating neoplasms of epithelial character, e.g.
mastocarcinoma, and leucemia. In addition, the compounds of formula
IV are useful for treating diseases of the immune system and
inflammations, subject to the involvement of protein kinases. The
compounds of formula IV may also be used for treating diseases of
the central or peripheral nervous system, subject to the
involvement of signal transmission by protein kinases.
[0065] Thus, in another aspect the present invention provides a
process for the preparation of compounds of formula IV from
compounds of formula I and the use of compounds of formula I for
the preparation of compounds of formula IV wherein R.sub.1 to
R.sub.8' are as herein described.
[0066] This invention relates to a process for the preparation of a
compound of formula IV or a pharmaceutically acceptable salt or
crystal form thereof, by reacting a compound of formula I as
described herein, with a compound of formula VII ##STR7## [0067]
wherein R.sub.10 is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or
amino-lower alkyl-substituted phenyl wherein the amino group in
each case is free, alkylated or acylated, 1H-indolyl or
1H-imidazolyl bonded at a five-membered ring carbon atom, or
unsubstituted or lower alkyl-substituted pyridyl bonded at a ring
carbon atom e.g. 3-pyridyl and unsubstituted or substituted at the
nitrogen atom by oxygen, and R.sub.11 and R.sub.12 are each
independently of the other hydrogen or lower alkyl, by conventional
methods.
[0068] Preferably in a first step, the compound of formula I is
prepared from compounds of formula II and III as described
herein.
[0069] The present invention also relates to a process for the
preparation of a compound of formula IV or a pharmaceutically
acceptable salt or crystal form thereof,
by reacting a compound of formula I as described herein, wherein
the radical R.sub.6 is --NHC(NH)NH.sub.2,
[0070] with a compound of formula VI ##STR8## wherein R.sub.10 is
4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower
alkyl-substituted phenyl wherein the amino group in each case is
free, alkylated or acylated, 1H-indolyl or 1H-imidazolyl bonded at
a five-membered ring carbon atom, or unsubstituted or lower
alkyl-substituted pyridyl bonded at a ring carbon atom e.g.
3-pyridyl and unsubstituted or substituted at the nitrogen atom by
oxygen, and R.sub.11 is hydrogen or lower alkyl; by conventional
methods.
[0071] Preferably the reaction is carried out in a polar organic
solvent such as n-butanol.
[0072] Preferably R.sub.10 is 3-pyridyl and R.sub.11 is methyl.
[0073] In one embodiment, a compound of formula I wherein R.sub.6
is NHC(NH)NH.sub.2, R.sub.7 is methyl and R.sub.8 is hydrogen may
e.g. be treated with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one
to a compound of formula IV wherein R.sub.6' is
4-(3-pyridyl)-2-pyrimidinamino, R.sub.7' is methyl and R.sub.8' is
hydrogen, corresponding to the compound of formula IV as described
in example 21 of EP 564 409. A compound of formula I wherein
R.sub.6 is Br, R.sub.7 is methyl and R.sub.8 is hydrogen may e.g.
be treated with 4-(3-pyridyl)-2-pyrimidine-amine, e.g. as available
from Chempacific, in the presence of Pd(0) or Pd(II) in the
presence of a phosphine ligand to give compound of formula IV
wherein R.sub.6' is 4-(3-pyridyl)-2-pyrimidinamino, R.sub.7' is
methyl and R.sub.8' is hydrogen.
[0074] In another embodiment, compounds of formula I wherein
R.sub.6 is NO.sub.2, R.sub.7 is methyl and R.sub.8 is hydrogen may
e.g. be transformed to a compound of formula I wherein R.sub.6 is
NH.sub.2, R.sub.7 is methyl and R.sub.8 is hydrogen using standard
methods known to the skilled person. Compounds of formula I wherein
R.sub.6 is halogen, NHC(O)CF.sub.3 or NHC(O)CH.sub.3, preferably
Br, R.sub.7 is methyl and R.sub.8 is hydrogen may e.g. be
transformed to a compound wherein R.sub.6 is NH.sub.2, R.sub.7 is
methyl and R.sub.6 is hydrogen using standard methods known to the
skilled person. Compounds of formula I wherein R.sub.6 is NH.sub.2,
R.sub.7 is methyl and R.sub.8 is hydrogen may e.g. be transformed
to a compound of formula I wherein R.sub.6 is NHC(NH)NH.sub.2,
R.sub.7 is methyl and R.sub.8 is hydrogen.
[0075] Accordingly, the present invention provides a process for
the preparation of compounds of formula IV wherein in a first step
a compound of formula I is prepared from compounds of formula II
and III as hereinabove described, preferably in the presence of
AlCl.sub.3, Al(lower alkyl).sub.3 e.g. AlMe.sub.3, AlEt.sub.3,
Al(iBu).sub.3 or SOCl.sub.2, and in a second step the compound of
formula I is reacted to a compound of formula IV by conventional
methods. Preferably, said process is provided for preparation of a
compound of formula IV wherein R.sub.1, R.sub.2, R.sub.4, R.sub.5
and R.sub.8' are hydrogen, R.sub.3 is
(4-methyl-piperazinyl)-methyl, R.sub.6' is
4-(3-pyridyl)-2-pyrimidinamino, and R.sub.7' is methyl.
[0076] The processes of the present invention allow the synthesis
of compounds of formula IV, preferably a compound of formula IV
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.5 and R.sub.8a are
hydrogen, R.sub.3 is (4-methyl-piperazinyl)-methyl, R.sub.6' is
4-(3-pyridyl)-2-pyrimidinamino, and R.sub.7' is methyl, in a more
efficient and higher yielding manner than previously described in
the literature e.g. in EP 564409. No expensive coupling reagents
have to be used. The higher throughput combined with less steps as
in the prior art will result in significantly lower production
costs In the previously described syntheses, mutagenic
intermediates may be formed. In the processes of the present
invention all intermediates show a negative AMES Test (a specific
test for mutagenicity; performed according to the OECD Guideline
for Testing of Chemicals, 471: Bacterial Reverse Mutation Test,
Adopted Jul. 21, 1997) which is a strong indication that no
mutagenic intermediates are formed which would be a significant
improvement of occupational health. Furthermore, these processes
allow the synthesis of e.g. radiolabeled compounds.
[0077] Following is a description by way of example only of the
process of the present invention. [0078] AlMe.sub.3
trimethylaluminium from FLUKA [0079] Al(iBu).sub.3
triisobutylaluminium from FLUKA [0080] AlCl.sub.3 aluminium
trichloride from Merck [0081] platinum on sulfide carbon from Acros
[0082] thionyl chloride from FLUKA [0083] Celite Filter Cel from
FLUKA [0084] Rochelle Salt potassium-sodium tartrate from FLUKA
[0085] platinum on carbon from Engelhardt [0086] cyanamide from
FLUKA [0087] 3-dimethylamino-1-pyridin-3-yl-propenone from FLUKA
[0088] sodium-tert.-butylate from FLUKA [0089] rac-BINAP
2,2'-bis-(diphenylphosphino)-1,1'-binaphthalin synthesized
according to literature procedure [0090]
Pd.sub.2(dba).sub.3*CHCl.sub.3
tris(dibenzylideneacetone)-dipalladium chloroform complex from
FLUKA
[0091] Preference is given above all especially to the compound of
formula IV which is
N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-p-
yridyl)-2-pyrimidine-amine.
N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-p-
yridyl)-2-pyrimidine-amine (also known as "Imatinib" [International
Non-proprietary Name]) and the use thereof, especially as an
anti-tumour agent, are described in Example 21 of European patent
application EP-A-0 564 409, which was published on 6 Oct. 1993, and
in equivalent applications and patents in numerous other countries,
e.g. in U.S. Pat. No. 5,521,184 and in Japanese patent 2706682.
Another preference is given to the .beta.-crystal form of
4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin--
2-ylamino)phenyl]-benzamide methanesulfonate as described in the
European patent application No. 998 473 published on May 10,
2000.
[0092] The term
"4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-
-2-yl-amino)phenyl]-benzamide" includes the .beta.-crystal form as
described in the European patent application No. 998 473.
[0093] Very preferably a compound of formula IV is in the form of a
pharmaceutically acceptable salt, especially in the form of its
monomesylate salt.
[0094] The compounds of formula IV are generically and specifically
disclosed in the patent applications EP 0 564 409 A1 and WO
99/03854, in particular in the compound claims and the final
products of the working examples, the subject-matter of the final
products, the pharmaceutical preparations and the claims are hereby
incorporated into the present application by reference to these
publications. Comprised are likewise the corresponding
stereoisomers as well as the corresponding polymorphs, e.g. crystal
modifications, which are disclosed therein.
[0095] Thus in a further aspect this invention relates to the use
of compounds of formula I for the synthesis of compounds of formula
IV, especially
4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin--
2-ylamino)phenyl]-benzamide or a pharmaceutically acceptable salt
thereof or crystal form thereof.
[0096] Furthermore, this invention also relates to a pharmaceutical
composition comprising,
a) one or more pharmaceutically acceptable excipients,
b) at least one pharmaceutically active compound of formula IV,
and
c) between 0.00001% and 5% by weight of at least one compound of
formula I, preferably between 0.00001% and 0.1%, most preferably
between 0.0001% and 0.1%.
[0097] The present invention particularly relates to pharmaceutical
compositions especially tablets comprising
4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin--
2-ylamino)phenyl]-benzamide or a pharmaceutically acceptable salt
or crystal form thereof.
[0098] Preferably c) is a compound of formula I wherein, R.sub.3 is
(4-methyl-piperazinyl)-methyl, R.sub.1, R.sub.2, R.sub.4, R.sub.5
and R.sub.8 are hydrogen, R.sub.6 is Br, Cl, NH.sub.2, NO.sub.2,
NHC(O)CF.sub.3, NHC(O)CH.sub.3 or NHC(NH)NH.sub.2, and R.sub.7 is
methyl, or a salt thereof.
[0099] One or more pharmaceutically acceptable excipients may be
present in the composition, e.g. those conventionally used, e.g.
(1.1) at least one binder, e.g. microcrystalline cellulose,
hydroxypropylmethyl cellulose, (1.2) at least one disintegrant,
e.g. cross-linked polyvinylpyrrolidinone, e.g. Crospovidone.RTM.,
(1.3) at least one glidant, e.g. colloidal silicon dioxide, (1.4)
at least one lubricant, e.g. magnesium stearate and/or (1.5) basic
coating. In the tablet according to the present invention,
microcrystalline cellulose is used as a binder.
EXAMPLE A
Capsules with Imatinib
(4-[(4-methyl-1-piperazin-1-ylmethyl)-N-[4-methyl-3-[[4-(3-pyridinyl)-2-p-
yrimidinyl]amino]phenyl]benzamide) methanesulfonate of formula IV,
.beta.-crystal form
[0100] Capsules containing 119.5 mg of the compound named in the
title (=SALT I) corresponding to 100 mg of Imatinib (free base) as
active substance are prepared in the following composition. The
composition containing also compounds of formula I wherein, R.sub.3
is (4-methyl-piperazinyl)-methyl, R.sub.1, R.sub.2, R.sub.4,
R.sub.5 and R.sub.8 are hydrogen, R.sub.6 is Br, Cl, NH.sub.2,
NO.sub.2, NHC(O)CF.sub.3, NHC(O)CH.sub.3, NHC(NH)NH.sub.2, and
R.sub.7 is methyl.
[0101] Composition TABLE-US-00001 SALT I 119.5 mg Compounds of
formula I 0.0005 mg Cellulose MK GR 92 mg Crospovidone XL 15 mg
Aerosil 200 2 mg Magnesium stearate 1.5 mg 230.0005 mg
[0102] The capsules are prepared by mixing the components and
filling the mixture into hard gelatin capsules, size 1.
EXAMPLE 1
Preparation of
N-(4-Methyl-3-bromo-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
[0103] A solution of trimethylaluminium (2M in toluene, 15.0 ml) is
added over a period of 30 min to a solution of
3-bromo-4-methyl-aniline (2.15 g, 11.5 mmol) and
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (2.87
g, 11.5 mmol) in toluene (20 ml) at 40.degree. C. under an
atmosphere of argon. After gas evolution ceases, the reaction
mixture is stirred 30 min before being cooled to 0.degree. C. and
partitioned between cold aqueous 1N NaOH (100 ml) and toluene (100
ml). The organic layer is extracted with aqueous saturated
NH.sub.4Cl (100 ml) and aqueous saturated NaCl (100 ml) The organic
layer is concentrated in vacuo to give 4.69 g (97 area % by HPLC)
of the title compound as pale yellow crystals.
4-(4-Methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester is
obtained as follows
[0104] A solution of 4-formyl-benzoic acid methyl ester (10.0 g, 61
mmol) in methanol (100 ml) is treated sequentially with
1-methylpiperazine (6.7 g, 67 mmol) and platinum (5%) on sulfided
carbon (0.5 g). The resulting solution is then heated at 90.degree.
C. and is subjected to a pressure of 5 bar of hydrogen for a period
of 4 hrs until the hydrogen uptake is complete. The reaction
mixture is cooled to room temperature and filtrated over a pad of
Celite. The methanol is removed under reduced pressure and replaced
with toluene (100 ml). The resulting organic solution is extracted
with aqueous HCl (2N, 2.times.50 ml). The aqueous layer is treated
with concentrated aqueous NaOH (30%) to set the pH to 12 and is
back-extracted with toluene (2.times.50 ml). The combined organic
layers are concentrated in vacuo to give 12.9 g (85%) of
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester as a
pale yellow oil which may be further purified by distillation under
reduced pressure.
EXAMPLE 2A
Preparation of
N-(4-Methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
[0105] A solution of trimethylaluminium (2M in toluene, 1.3 ml, 2.6
mmol) is added over a period of 5 min to a solution of
3-nitro-4-methyl-aniline (152 mg, 1.00 mmol) and
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (248
mg, 1.00 mmol) in toluene (3.0 ml) at 45.degree. C. under an
atmosphere of argon. After gas evolution ceases, the dark brown
reaction mixture is stirred 30 min before being cooled to 0.degree.
C. An aqueous saturated solution of potassium-sodium tartrate (20
ml), t-butyl methyl ether (15 ml) and methylene chloride (10 ml)
are added sequentially. The organic phase is separated and washed
with aqueous saturated NaHCO.sub.3 (10 ml) and aqueous saturated
NaCl (10 ml). The aqueous phases are back-extracted with t-butyl
methyl ether (2.times.15 ml). The organic phases are combined,
dried over MgSO.sub.4 and concentrated in vacuo to give 383 mg (96
area % by HPLC) of the title compound as pale yellow crystals.
EXAMPLE 2B
Preparation of
N-(4-Methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
[0106] To a solution of 10.95 g (72 mmol) of
3-nitro-4-methyl-aniline in 80 ml of toluene is added a solution of
triisobutylaluminium (28% in hexane), 66.5 ml (61 mmol) over a
period of 30 min at 0.degree. C. followed by the addition of a
solution of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl
ester (14.9 g, 60 mmol) in toluene (30 ml) during 1 hour at
0.degree. C. under an atmosphere of argon. After stirring for 12 h
at room temperature an other portion of triisobutylaluminium (66.5
ml (61 mmol) is added to the dark brown reaction mixture. The
mixture is stirred for additional 6 h, then 2 additional small
portions of triisobutylaluminium (each 18 ml, 18 mmol) are added
and stirring is continued for several hours at room temperature.
After acidic and basic workup with sulfuric acid and NaOH the
combined organic toluene phases are evaporated in vacuo to give a
brown crude product which was crystallized from t-butyl methyl
ether to give the title compound as brownish yellow crystals: first
crop (11.65 g), sec. crop (3.8 g) and a third crop (1.2 g). in
summary 16.65 g (75.3%).
EXAMPLE 2C
Preparation of
N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
[0107] 4-methyl-3-nitroaniline (30.0 g, 0.197 mol) is added to a
mixture of tetrahydrofuran (120 ml) and
N-ethyl-N,N-diisopropyl-amine at 23-25.degree. C. over a period of
5 to 10 min. To this solution chloromethyl-benzoylchloride (38.4 g,
0.20 mol) dissolved in tetrahydrofuran (35 ml) is added over a
period of 60-65 min maintaining a temperature of 25-30.degree. C.
The reaction mixture is stirred at this temperature for 30 min and
then added to N-methylpiperazine (138.2 g, 1.38 mol) over a period
of 60 to 90.degree. C. maintaining a temperature of 25-30.degree.
C. The resulting suspension is stirred at this temperature for 60
min. Tetrahydrofurane is distilled of at 50.degree. C. under
reduced pressure. At the end of the distillation the temperature is
adjusted to 45-48.degree. C. and water (300 ml) is added over a
period of 45-60 min at this temperature. The resulting suspension
is cooled to 23.degree. C. and stirred for 60 min. The suspension
is filtered, the filtercake washed with water (225 ml) and dried in
vacuo to give 69.2 g of the title compound (95% of theory) as an
of-white powder (99.5% area by HPLC).
[0108] Alternatively the intermediate
N-(4-methyl-3-nitro-phenyl)-4-chloromethyl-benzamide can be
isolated by distilling of half of the tetrahydrofuran under reduced
pressure and adding the residue to water (300 ml) at a temperature
of 20-25.degree. C. over a period of 30 min. After stirring for
another 30 min at 0-5.degree. C., the suspension is filtered,
washed with water (200 ml) and dried in vacuo. The intermediate is
dissolved in tetrahydrofuran (150 ml) and added to
N-methylpiperazine (138.2 g, 1.38 mol) over a period of 60 to 90
min maintaining a temperature of 25-30.degree. C. The title
compound can be isolated following the above described
procedure.
EXAMPLE 3
Preparation of
N-(4-Methyl-3-trifluoroacetimidate-phenyl)-4-(4-methyl-piperazin-1-ylmeth-
yl)-benzamide
[0109] A solution of trimethylaluminium (2M in toluene, 1.25 ml,
2.5 mmol) is added over a period of 5 min to a solution of
3-trifluoroacetimidate-4-methyl-aniline (218 mg, 1.00 mmol) and
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (248
mg, 1.00 mmol) in toluene (3.0 ml) at 0.degree. C. under an
atmosphere of argon. After gas evolution ceases, the dark brown
reaction mixture is stirred 3 hrs at 23.degree. C. before being
cooled to 0.degree. C. An aqueous saturated solution of
potassium-sodium tartrate (20 ml) and t-butyl methyl ether (40 ml)
are added sequentially. The organic phase is separated and washed
with aqueous saturated NaHCO.sub.3 (20 ml) and aqueous saturated
NaCl (20 ml). The aqueous phases are back-extracted with t-butyl
methyl ether (2.times.20 ml). The organic phases are combined,
dried over MgSO.sub.4 and concentrated in vacuo to give 458 mg (94
area % by HPLC) of the title compound as white crystals.
EXAMPLE 4
Preparation of
N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
[0110] A solution of AlCl.sub.3 (1000 mg, 7.5 mmol) in toluene (3
ml) and acetonitrile (3.0 ml) at 0.degree. C. under an atmosphere
of argon is treated dropwise with a solution of
3-amino-4-methyl-aniline (470 mg, 6.0 mmol) in toluene (6 ml). The
resulting brown solution is heated at 40.degree. C. A solution of
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (745
mg, 3.0 mmol) in toluene (2 ml) is then added dropwise over a
period of 30 min. The resulting mixture is stirred at 40.degree. C.
for 8 hrs and then cooled at 0.degree. C. An aqueous saturated
potassium-sodium tartrate (30 ml) and aqueous saturated NaHCO.sub.3
(40 ml) and t-butyl methyl ether (60 ml) are added sequentially.
The organic phase is separated and washed with aqueous saturated
NaCl. The aqueous phases are back-extracted with t-butyl methyl
ether. The organic phases are combined, dried over MgSO.sub.4 and
concentrated in vacuo. Purification by flash-chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 90:10+1% aq. NH.sub.3) gives 825
mg of the title compound (75%) as yellowish crystals.
EXAMPLE 5
Preparation of
N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
[0111] Thionyl chloride (53.3 g, 448 mmol) is added over a period
of 15 min to a suspension of
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (70.0 g, 299 mmol)
in toluene (300 ml) at 0.degree. C. At the end of the addition, the
reaction mixture is heated at 23.degree. C. over a period of 45
min. The excess of SOCl.sub.2 is removed by co-distillation with
toluene under reduced pressure at 40.degree. C. At the end of the
distillation, the resulting suspension id cooled down to 0.degree.
C. and the benzoyl chloride is filtered off, washed with toluene
(2.times.50 ml) and dried in vacuo at 45.degree. C. overnight.
Yield: 55.0 g, 79% of theory based on the di-hydrochloride salt of
the benzoylchloride, white solid. The dried benzoyl chloride (55 g)
is then resuspended in toluene (100 ml). A solution of
4-methyl-3-nitroaniline (22.75 g, 145 mmol) and pyridine (34.4 g,
435 mmol) in toluene (60 ml) is added dropwise at 23.degree. C.
over a period of 15 min. The resulting orange-brown reaction
mixture is heated at 45.degree. C. and is stirred for 6 hrs. The
suspension is filtrated and the filtercake is washed successively
with toluene (300 ml) and acetone (350 ml), and is then suspended
in water (350 ml). Aqueous NaOH (30%) is added until the pH of the
suspension reaches 11 and remains stable. The suspension is further
stirred for 1 h at 40.degree. C. before being filtrated. The
filtercake is washed with water (5.times.50 ml) and dried in vacuo
to give 51.3 g of the title compound (96%) as beige crystals,
(98.7% area by HPLC).
Preparation of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid
[0112] A suspension of 4-formyl-benzoic acid (10.0 g, 67 mmol) in
methanol (100 ml) is treated sequentially with 1-methylpiperazine
(7.3 g, 73 mmol) and platinum (5%) on sulfided carbon (1 g). The
resulting suspension is then heated at 80.degree. C. and is
subjected to a pressure of 5 bar of hydrogen for a period of 20 hrs
until the hydrogen uptake is complete. The reaction mixture is
cooled to room temperature and filtrated over a pad of Celite.
Water (20 ml) is used to rinse the reactor and dissolve the
fraction of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid that
crystallizes on the walls during the cooling of the reaction
mixture. The resulting aqueous solution is filtrated over the pad
of Celite employed previously. The combined filtrates are
concentrated in vacuo and crystallized in EtOH/H.sub.2O 9:1 v/v to
give 10.9 g (70%) of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid
as colorless crystals.
EXAMPLE 6
Preparation of
N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzami-
de
[0113] In analogous manner to Example 4,
3-guanidino-4-methyl-aniline (2.51 g, 11.5 mmol) and
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (70.0 g, 299 mmol)
in toluene (300 ml) in the presence of thionyl chloride (53.3 g,
448 mmol) give 12.1 g (89%) of the title compound as pale colorless
crystals.
EXAMPLE 7
Preparation of
4-dichloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pheny-
l]-benzamide
[0114] To a suspension of
4-methyl-N*3*-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine
(2.00 g mg, 7.21 mmol) in toluene (22 ml) at 45.degree. C. under an
atmosphere of argon is added sequentially 4-dichloromethyl-benzoic
acid methyl ester (1.90 g, 8.67 mmol) and AlMe.sub.3 (2 M in
toluene, 12.6 ml, 25.2 mmol). The resulting brown solution is
stirred at 45.degree. C. for a period of 3.5 hrs. The reaction
mixture is then cooled to 0.degree. C. and quenched by slow
addition of a saturated aqueous solution of Rochelle salt (70 ml)
which causes the precipitation of the crude product. t-Butyl methyl
ether (150 ml) and methylene chloride (100 ml) are added
sequentially to the suspension which are then washed with aqueous
saturated NaHCO.sub.3 (100 ml) and aqueous saturated NaCl (100 ml).
The aqueous phases are back-extracted with t-butyl methyl ether
(100 ml). The crude product, which is contained in the combined
organic phases, is filtered off with suction, washed with t-butyl
methyl ether and dried in vacuo. Yield: 3.35 g of the title
compound, 84% of theory, as beige crystals, (HPLC: 91% area).
EXAMPLE 8
Preparation of
N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzami-
de
[0115] In analogous manner to Example 4,
3-guanidino-4-methyl-aniline (1.00 g, 6.09 mmol) and
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (1.50
g, 6.04 mmol) in toluene (22 ml) and acetonitrile (6 ml) in the
presence of AlCl.sub.3 (2.0 g, 15.0 mmol) at 40.degree. C. give
1.26 g (55%) of the title compound as pale colorless crystals.
EXAMPLE 9
Preparation of
4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-
-2-ylamino)-phenyl]-benzamide
[0116] A suspension of
N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzami-
de (30 g, 79 mmol) in n-butanol (150 ml) at 120.degree. C. under an
atmosphere of nitrogen is treated with
3-dimethylamino-1-pyridin-3-yl-propenone (15.3 g, 87 mmol). The
resulting suspension is heated at 150.degree. C. for 5 hrs. The
reaction mixtures becomes a homogeneous deep orange solution and
dimethylamine is removed by the distillation of n-butanol (130 ml).
n-Butanol (20 ml) is added during the distillation. Butyl acetate
(60 ml) is added dropwise at 100.degree. C. and the solution is
cooled to 0.degree. C. within 1 hr and stirred at 0.degree. C. for
16 hrs. The resulting deep orange suspension is filtered off with
suction, the isolated solid is washed with n-butanol (2.times.50
ml) and water (2.times.50 ml) and dried in vacuo at 60.degree. C.
Yield: 36.4 g of the title compound, 93% based on theory, as
off-whitecrystals. (99.6% area by HPLC).
EXAMPLE 10
Preparation of
4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-
-2-ylamino)-phenyl]-benzamide
[0117] To a mixture of 4-(3-pyridyl)-2-pyrimidine-amine (172.2 mg,
1.0 mmol),
N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benz-
amide (402.4 mg, 1.0 mmol) and sodium tert.-butylate (144.2 mg, 1.5
mmol) is added a mixture of rac-BINAP (31.2 mg, 0.050 mmol) and
Pd.sub.2(dba).sub.3*CHCl.sub.3 (13 mg, 0.013 mmol) under argon.
After addition of 3 ml of xylene the suspension is sonicated for 10
minutes then stirred for 5 hours under reflux. After cooling to
room temperature, water (10 ml) is added to the dark brown oil and
the product extracted 4 times with methylene chloride (10 ml each).
The combined organic extracts are dried over MgSO.sub.4 and
concentrated in vacuo. The brown oil is purified by
flash-chromatography (SiO.sub.2, methanol). The product, a pale
yellow solid is dissolved in methylene chloride, filtered and
concentrated in vacuo. Yield: 484.3 mg of the title compound, 72%
of theory, (99.9% area by HPLC). The product contains typically
roughly 10% of isomers which can be eliminated by preparative
reversed phase chromatography.
EXAMPLE 11
Preparation of
N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
[0118] A solution of
N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
(100 g, 260 mmol) in n-butanol (1 l) is treated with platinum (5%)
on carbon (1.0 g). The resulting suspension is then heated to
70.degree. C. and hydrogen is applied with a pressure of 0.2 bar
for a period of 6 h until the hydrogen uptake is complete. The
reaction mixture is cooled to room temperature and filtrated.
n-Butanol is used to wash the catalyst. This solution is suitable
for example 12. For isolation of the product is reduced to a third
and crystallized by cooling down to 0.degree. C. (HPLC: 98.0%
area).
[0119] Alternatively a solution of
N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
(60 g, 163 mmol) in ethanol 90% (300 ml) at room temperature under
an atmosphere of nitrogen is treated sequentially with platinum
(5%) on carbon (6.0 g) and potassium formate (68.5 g, 814 mmol).
The resulting suspension is then heated at 80.degree. C. for a
period of 16 hrs. The reaction mixture is filtrated at 70.degree.
C. over a pad of Celite. Ethanol 90% (150 ml) and water (150 ml)
are used to rinse the reactor. Ethanol is removed from the combined
filtrates by distillation in vacuo at an external temperature
60.degree. C. The crude product separates from the aqueous
concentrate as an oil during the distillation, crystallizes upon
subsequent cooling to 23.degree. C. within 2 hrs and is filtered of
with suction, washed with ethanol (200 ml) and dried in vacuo.
Yield: 55 g of the title compound, 99% of theory, as yellowish
crystals. (HPLC: 98.0% area).
EXAMPLE 12
Preparation of
N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzami-
de
[0120] A suspension of
N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
(50 g, 144 mmol) in n-butanol (300 ml) at 85.degree. C. is treated
sequentially with concentrated aqueous HCl until the pH reaches 2.5
(HCl 37%, 35 g) and with a solution of cyanamide (12.1 g, 288 mmol)
in water (12 ml) over a period of 30 min. The resulting reaction
mixture is stirred at 85.degree. C. for 20 hrs during which time
the starting material dissolves and the desired product
crystallizes out of solution as the di-hydrochloride salt.
Concentrated HCl (37%, 6.3 g) is added during the reaction to
maintain the pH at 2.5. The reaction mixture is then allowed to
cool down to room temperature within 1.5 hrs. The product is
filtered off with suction, washed with n-butanol (3.times.50 ml)
and dried in vacuo at 60.degree. C. Yield 60.7 g of the
di-hydrochloride salt, 93% of theory (99% area by HPLC).
[0121] The di-hydrochloride salt is dissolved in water (250 ml) at
35.degree. C. An aqueous solution of NaOH (2N, 150 ml) is added and
the pH of the solution increases to 13.2. The desired product
separates from the aqueous solution as an oil which crystallizes
upon cooling to 0.degree. C. After 1 hr stirring at 0.degree. C.,
the product is filtered off, washed with an aqueous solution of
K.sub.2CO.sub.3 (5.5 g/L, 2.times.50 ml) and dried in vacuo at
50.degree. C. Yield: 41.2 g of the title compound, 89% of theory
based on the intermediate di-hydrochloride salt, as beige crystals,
(98.7% area by HPLC).
* * * * *