CA1187490A - Process for the production of ketoamines - Google Patents

Abstract

Abstract of the Disclosure This invention relates to a process for the production of ketoamines corresponding to the form i in which R2 represents hydrogen or a C1-C6 alkyl group, R3 represents hydrogen or a hydroxy group, and R1 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 C1-C4 alkyl group or a halogen atom, and salts thereof by reducing an unsaturated compound correspond-ing to the formula:

Description

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) - ~

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-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

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 ~'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 C~ - CH2CH2 ~ NH - CH - CH4~
A) 5.75 g (0.02 mols) of Q-[3-hydroxy-3-phenyl-propyl-(2)]-[3-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;

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%.

Claims (13)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of a compound corres-ponding to the formula:

I

in which R2 represents hydrogen or a C1-C6 alkyl group, R3 represents hydrogen or a hydroxy group, and R1 represents an ad-amantyl radical or a saturated or mono-unsaturated C3-C16 cyclo-alkyl radical, which C3-C16 cycloalkyl radical may also be sub-stituted by a C1-C4 alkyl group or a halogen atom, or a salt thereof, which comprises reducing one or two non-aromatic double bonds in a compound corresponding to the general formula:

II

in which R1, R2 and R3 are as defined above, and when R1 in the compound produced contains a double bond, optionally reducing this double bond, and when required converting the compound obtained to said salt.

2. A process as claimed in claim 1, in which the reduction is effected in water or an organic solvent using hydrogen in the pressence of a metal catalyst.

3. A process as claimed in claim 1, in which the reduction is effected in water or an organic solvent using a complex metal hydride.

4. A process as claimed in claim 2 or 3, in which the temperature is from 20 to 150°C.

5. A process as claimed in claim 2 or 3, in which the solvent is selected from lower saturated aliphatic alcohols of 1 to 6 carbon atoms, saturated acyclic ethers having 2 to 6 carbon atoms and saturated cyclic ethers having 4 carbon atoms.

6. A process as claimed in claim 2, in which the metal catalyst is selected from Raney nickel, elementary nickel, palladium catalysts, and platinum containing catalysts.

7. A process as claimed in claim 6, in which the solvent is a polar solvent and the temperature is from 50 to 150°C and the pressure is from 30 to 150 bars.

8. A process as claimed in claim 7, in which the temperature is from 90 to 120°C.

9. A process as claimed in claim 3, in which the complex metal hydride is selected from lithium aluminium-hydride, sodium-bis(2-methoxy-ethoxy)-aluminium-dihydride, and lithium-tri-tert.-butoxy-aluminium-hydride.

10. A process as claimed in claim 3 or 7, in which the solvent is an acyclic or cyclic ether and the temperature is from 20 to 100°C.

11. A process as claimed in claim 1, in which the compound obtained is split into an optical isomer.

12. A process as claimed in claim 1, 2 or 3, in which R1 is cyclohexyl, adamantyl, 2-methylcyclohexyl, cyclopentyl, cycloheptyl, cyclooctyl, cyclododecyl, or cyclohexen-1-yl-(1), R2 is hydrogen and R3 is hydrogen or a hydroxy group in the 4-position.

13. A process as claimed in claim 1, in which the product obtained is converted to a pharmaceutically acceptable salt.