Note: Descriptions are shown in the official language in which they were submitted.
ThiS invention relates to a process for the production
of ketoamines.
Compounds corresponding to the formula:
Rl X ~ C~2-Nl~-cH(cH3)-CH(O~ R3
in which
X represents the group ~ CO or )CH(OH),
R2 represents hydrogen or a Cl-C6 alkyl group,
10 R3 represents hydrogen or a hydroxy group, and
Ri represents the adamantyl radical or a saturated or mono-
unsaturated C3-C16 cycloalkyl radical, which C3-C16 cyclo-
alkyl radical may also be substituted by a Cl-C4 alkyl
group or a halogen atom,
and salts thereof are know from German Offenlegungsschrift No.
2,919,495. This Offenlegungsschrift also describes various pro-
cesses for the production of these compounds.
The present invention provides a further process for
the production of these compounds. More particularly the inven-
tion provides a process for the production of compounds correspond-
ing to the formula: R3
Rl-co-cH-cH2-NH-cH(cH3)-cH(oH) - ~
R2
in which
R2 represents hydrogen or a Cl-C6 alkyl group,
R3 represents hydroge~ or a hydroxy group, and
Rl represents an adamantyl radical or a saturated or mono-
unsaturated C3-C16 cycloalkyl radical, which C3-C16 cyclo-
alkyl radical may also be substituted by a Cl-C4 alkyl group
or a halogen atom,
and for the production of the salts thereof, which comprises re-
-- 1
9~:~
ducing one or two non-aromatic double bonds in a compound corres-
ponding ~o the general formula:
R1-CO-C=CH-NH-CH(CH3)-CH(OH R3 II
R2
ln which R1, R2 and R3 are as defined above, and in the case where
1ll in the compound produced contains a double bond, optionally
reducing this double bond.
The process according to the present invention has the
advantage over the known production processes that it produces
better yields and/or may be carried out in an easier and improved
manner. The production of the starting materials corresponding
to formula II which are used in the process according to the
present invention is also easier and provides a much improved
yield in many cases, compared to the production of the correspond-
ing starting materials for the known processes.
The process of the present invention may be carried out
in an organic solvent using hydrogen in the presence of metal
catalysts or using complex metal hydrides at a temperature of from
20 20 to 150C.
The following are suitable as solvents: water, lower
aliphatic saturated alcohols having from 1 to 6 carbon atoms,
such as methanol, ethanol, propanol, butanol or hexanol; saturated
acyclic ethers haviny from 2 to 6 carbon atoms, such as diethyl-
ether or 1,2-dimethoxyethane, or saturated cyclic ethers having
4 carbon atoms, such as tetrahydrofuran, dioxan or mixtures of
these solvents.
Conventional metallic hydrogenation catalysts are suit-
able as metal catalysts, for example: Raney nickel, e:lementary
nickel, palladium catalysts and platinum containing catalysts,
such as platinum, platinum, oxide or platinised charcoal. Polar
solvents are preferred in this case as solvents, such as alcohols
or alcohol-water mix-tures r -the process preferably being carried
out at from 50 to 150C, in particular from 90 to 120C and at
a pressure of from 30 to 150 bars. Hydroyenation is carried
out unitl the quantity of hydrogen necessary for saturating one
or two double bonds has been absorbed.
The fo:Llowing, for example, are suitable as complex
metal hydrides: lithium aluminium-hydride, sodium-bis(2-methoxy-
ethoxy)-aluminium-dihydride, and lithium-tri-tert.-butoxy-alumini-
um-hydride, acyclic and cyclic ethers preferably being used as
solvent, preferably at a temperature of from 20 to 100C.
When complex metal hydrides or elementary nickel is
used, only the exocyclic double bond is reduced in the starting
material corresponding~to formula II, but not a double bond of
the radical Rl. In a case of this type, a double bond of the
radical Rl may then be selectively reduced using Raney nickel,
catalysts containing platinum or palladium, in the above-mentioned
manner or even under milder conditions (for example, at from
20 to 50C and from 1 to 5 bars).
The starting materials corresponding to formula II
may be obtained, for example, by reacting a compound
Rl-CO-C(R2)H-CHO
or reacting the alkali metal enolate thereoE
(-C(R )=CHO-alkali metal)
2 ~`3
with a compound
H2N-CH(CH3)-cH-(OH ~ ~
in a solventconventional for this purpose (water, lower alcohols)
at from 0 -to 50C. The first reactant
Rl-CO-C(R2)H-CHO
may be obtained by conven-tional ester condensation of a compound
R -CO-C(R )H
with ethyl formate in the presence of sodium. A double bond which
is present in Rl may then optionally be reduced in conventional
-- 3 --
~'7 ~
manner, for example as described above.
Moreover, the starting materials corresponding to
formula II may be obtained by Friedel-Crafts acylation of acetyl-
ene or a compound C(R2)-CH with a compound:
R1COHal (Hal = chlorine or bromine)
into the compound:
RlCO-C(R2)=CH~Ial
and by subsequen-t alkylation with a compound:
~2N-CH(cH3)-C~(oH) ~ 3
Alkylation takes place, for example, in a solvent or dispersing
agent (lower aliphatic ethers, cycloaliphatic ethers, such as
dioxan, aromatic hydrocarbons, such as xylene, acetonitrile) at
from 20 to 150~C, optionally in the presence of a base (for
example, K2CO3, tertiary amine). A double bond in the radical
Rl may optionally be hydrogenated in conventional manner in the
presence of Raney nickel or catalysts containing palladium or
platinum.
Depending on the conditions of the process and on the
starting materials, the end products corresponding to formula I
are obtained in a free form or in the form of salts thereof. The
salts of the end products may be convertred again into the free
base in known manner, for example using alkali or ion exchangers.
Salts may be obtained from the free bases by a reaction with an
organic or inorganic acid, in particuiar those acids which are
suitable for the formation of pharmacologically acceptable salts.
The following are mentioned as examples of such acids: hydrohalic
acids, sulphuric acid, phosphorus acids, nitric acid, perchloric
acid, organic mono-, di- or tri-carboxylïc acids of the alipha-tic~
alicyclic, aromatic or heterocyclic series and sulphonic acids.
Specific examples of these acids are as follows: formic, acetic,
propionic, succinic, glycolic, lactic, malic, tartaric, citric,
ascorbic, maleic, fumaric, hydroxymaleic or pyruvic acid; phenyl
acetic, benzoic, p-amino-ben~oic, anthranilic, p-hydroxy-benzoic,
salicylic or p-amino-salicylic acid, embonic acid, methane sul-
phonic, e-thane sulphonic, hydroxy ethane sulphonic, ethylene sul-
phonic acid, halogen-benzene sulphonic, toluene sulphonic, naphth-
alene sulphonic acid or sulphanilic acid or 8-chloro-theophylline.
Those compounds which contain asymmetric carbon atoms
and are usually produced as racemic compounds may be split into
the optically active isomers in a known manner, for example using
an optically active acid. However, it is also possible to use
optically active or even diastereomeric starting materials from
the outset, in which case a corresponding pure, optically active
form or a diastereomeric configuration is then obtained as the
end product. These compounds are, for example, of the norephedrine
and the pseudonorephedrine configuration. Diastereomeric racemic
compounds may also occur, because two or more asymmetric carbon
atoms are present in the compounds which are produced. Separation
may be carried out in a conventional manner, for example by re-
crystallisation.
The corresponding -isomers or the racemic compound
are obtained if, for example, instead of using the levoro-tatory
norephedrine starting compound, the corresponding dextrorotary
form or the racemic compound is used.
The invention is illustrated by the following Examples:
_ample 1
Production of Q-[3-hydroxy-3 phenyl-prop~ LI=L ~ycL~ y~
oxo-propyl]-amine
O CH 3 OH
C~ - CH2CH2 ~ NH - CH - CH4~
A) 5.75 g (0.02 mols) of Q-[3-hydroxy-3-phenyl-propyl-(2)]-[3-
-- 5 --
cyclohexyl-3-oxo-propenyl]amine, dissolved in 50 ml oE absolute ether are
added dropwise with s-tirring to a suspension of 2.2 g (0.06 mols)
of LiAlH4 in 30 ml of absolute ether. After -the addition, the
reaction mixture is heated for 2 hours at reflux, then mixed
successively with 10 ml of ethyl acetate, 10 ml of methanol and 10
ml of H2O. The resulting deposit is separated. The ether phase
is dried over sodium sulphate and the hydrochloride is produced
by adding 3.5 ml of 6N-isopropanolic hydrochloric acid.
M.p. of the hydrochloride 219-220C;
Yield: 75%.
B) I4.37g (0.05 mols) of Q-[3-hydroxy-3-phenyl-propyl-(2)]-[3-
cyclohexyl-3-oxo-propenyl]-amine are dissolved in 250 ml of ethanol,
mixed with 3 g of Pd-C (10%) and hydrogenated at 100C and 125
bars until the end of hydrogen absorption (4 hours). The catalyst
is then filtered off and the solvent is distilled off under vacuum.
The resulting raw product is converted into the hydrochloride by
adding 9 ml of 6N-isopropanolic hydrochloric acid at room tempera-
ture.
M.p. of the hydrochloride 219-220C;
Yield: 47%.
The starting material Q-[3-hydroxy-3-phenyl-propyl-(2)]-
[3-cyclohexyl-3-oxo-propenyl]-amine is produced, for example, as
follows: 15 g (0.1 mol) of Q-norephedrine base are added at 55C
to a solution of 15 g (0.1 mol) of 3-oxo-3-cyclohexyl-propanal
(produced by condensation from 7.4 g (0.1 mol) of ethylformate,
12.6 g (0.1 mol) of acetylcyclohexane and 3 g (0.1 mol) of 80%
NaH)` in 150ml of cyclohexane. The mixture is heated for 1 hour
at reflux. After cooling, the reaction mixture is mixed with 60 ml
of H2O, the phases are separated, the organic phase is dried over
30 Na2SO4, filtered and concentrated under vacuum. The raw product
is recrystallised from methylisobutylketone.
M.p.: 98C;
-- 6
Yield: 48~.
Table 1 contains a list of other Examples produced
according to the method of Example 1, corresponding to the general
:Eormula: CH3 CH
Rl- CO ~ CH2CH2 ~ NH - CH - CH ~ R3
---- ~ ~ ~ -------~ ~
~ ' ~ ' ~ ~ ' ~ o ~ b
~.~ ~o ~ ~ ~ ~ ~ ~ ~ ~ ~
O I O I O I ~ O I O I ~ . r~ . r~
~ o ~ o ~ ~ ~Y~ o ~ ~ o ~ o ~
-- I -- 2 .,~ -- I ~ ~ I -- ~ ~ ~ ~
~ ~ ~ ~ ~, ~ ~ ~, ~ ~
~ .~, ~ ~ ~ ~ ~ o _
CO -- r~ O -- ~ n ~ a) o Q ~ . ~ I
~ ~ ~o
u~ ~ ~ Ia) ~ I O ~ (~ a) ~ ~ ~ ~ ~ ~
v $ ~ $ ~ ~~ B ~8 ~ ~ ~ ~ $ ~ ~ $ ~,
~ ~ ~ ~I ~ ~I~ ~ ~ ~ ~~
. ~ O .,~ ~ ~ . r~ I . ~ I) .
~ ~ ~ o ~-- ~b ~ ~ ' ~ ~ 4~ N o o~ ~ V o
_ _ ____
q~ ~o\O ~D Lr) r~ O ~ ,~ a~
__
o :
r-l r-l
~ r-l r-l r-J r-l
:~ ____ _ ~ _
r~) ~ O
m
_ _ . _
~ ~ ~N O
_ _ _ l . _
~ ~ ~ ~r u~ ~9 ~ __
._ _ _ __
~3 ~
~ ~ ~ ~ ~-
~ l ~ ~ ~
.~ ~ ~ ~ o a
1~ ~ $ ~ ~ ~ o~
~1 ~ J ~ N ~
~ 80 ~ 80 ~X
'~ ~ _ ~ ~
~ ~ _ ~r N
~ ~ _ __
- \
~ 7~
Example 11
Q-[3-Hydroxy-3-phenyl-propyl-(2)]-[3-cyclohexyl-3-oxo-propyl]-
amine
-CO-CH2-CH2-NH-CH(CH3)-CII(OH)-- ~
25 g of Q-[3-hydroxy-3-phenyl-propyl-(2)]-[3-(1-cyclo-
hexen-l-yl-(1)-3-oxo-propyl]-amine-HCl are dissolved in 250 ml
o~ methanol/water (2:1), mixed with 2.5 g of Pd-C (10~) and
hydrogenated at 50C and at 5 bars until the end of hydrogen
absorption. The catalyst is then filtered off, the solvent is
distilled off under vacuum and the product is recrystallised
from ethanol.
M.p. of the hydrochloride 219-220C;
Yield: 85%.
-- 10 --
