CA1132139A - Dithienyl alkyl amines and process for their production - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention provides compounds correspond-ing to the general formula:

(II) in which Alk represents a straight-chain or branched chain C1-C5 alkylene group and X represents chlorine, bromine or iodine.
These compounds are intermediates in the preparation of pharma-ceuticals.

Description

The present in~ention relates to diethienyl compounds useful in the production of compounds having pharmaceutical properties. This application is a divisional applicaJion ofcopen~-ing application No. 294,846 filed January 12, 1978.
Canadian Patent Application No. 294,846 Patent No. pro-vides compounds having the general formula ~ ~5 B - Alk - NHY

wherein ~-B- has either the structure >C(OH)-CH2-- or the struc-ture ~C=CH, Alk represents a straight or branched Cl-C5- alkylene group and Y a C3-C7-cycloalkyl radical, a methylene-dioxy-benzyl radical, a benzyl radical which is si.ngly, doubly or triply sub-stituted by Cl-C4-alkoxy groups, or it represents a straight or branched Cl-C6-alkyl radical, substituted by a di-Cl-C4-alkyl-amino group, or a morpholino group, or it represents the radical OH

- CH(R) - CH(OH) ~

wherein R represents a Cl-C4-alkyl group and the hydroxyl group can also be acylated by a C2-C6-alkanoyl group or wherein the group -NHY represents the radical /~
- N N-R' and R' represents a phenyl radical, a phenyl radical, which is singly or doubly substituted by Cl-C4-alkyl groups, Cl-C4 alkoxy groups or halogen atoms, a Cl-C4-oxy-alkyl radical or a phenyl -Cl-C~-alkyl radical, which can also be substituted in tlle phenyl ring by l to 3 Cl-C4-alkoxy group or the radical -NI~-CH(R)-CH~OH)-~1 3~3~

C6~l5 (wherein R has the meaning defined above) if Alk consists of2 to 5 carbon atoms or a pharmaceutically acceptable salt thereof.
One particular embodiment of such compounds is repre-sented by compounds corresponding to the general formula:

I-CH2-NH-C~-CH ~ 5 0H

OH
in which >A-B- has either the structure ~C (OH) -CH2- or the structure >C=CH- and R" represents a hydrogen atom or a C1 C4 alkyl group, and their salts.
The radical R in the structural moiety -CH(R)-CH~OH)~

is preferably met.lyl orethyl. The hydroxy group on the phenyl ring may be in the ortho, para or meta position. If it is acylated, the aliphatic C2-C6-carboxylic acid on which it is based maybe linear or branched and may consist in particular of

2 to 4 carbon atoms. The alkylene chain Alk is preferably straight and preferably consists of l,2 or 3 carbon atoms.
The compounds of formula (I) according to the Canadian application No. 294,846 show pharmacodynamic activity, especially in disorders of the heart and circulation system. In particular they produce an increase in peripheral and cerebral circulation and in this respect for example are considerably more active, especially in regard to peripheral circulation, than the kno~n compounds according to German Patent Specification No. 1,921,453.
In some cases, the compounds according to the parent invention ~3~3~

also dilate the coronary arteries and increase the power of the heart.
Canadian application No. 294,846 provides a process for the production of compounds corresponding to general forrnula (I) of the parent application which comprises condensing a compound corresponding to the general formula OH

I

~ j ~S
CEI2-Alk-X

3L~3~3~
in which Alk is a linear or branched Cl-C5-alkylene group and X
represents chlorine, bromine or iodine, with an amine correspond-ing to the general formula NH2Y tIII) in which Y is as defined above, and optionally converting compounds corresponding to general formula I of the p:arent application, in which A~B- = C(OH)-CH2-, into the corresponding unsaturated compounds (A-B- = C=CH-) with a dehydrating agent by known methods and optionally producing salts from the basic compounds obtained.

~1~3~L3~3 .. The present in~-ention relates to compounds correspo~d- -ing to the eeneral formula OH
I

S ~ ¦ ~ S~ (II) . CH2 Al~_g ~herein Al~ is a linear or branched Cl-C5-alLylene group and X represents chlorine, bromille or iodine.
Unless other~ise indicated, the term 'tlower" as used herein means having up to 6 carbon atoms~ in particular ha~ing upto 4 carbon atoms.

In one embodiment, the compounds preferably correspond to the general formula L3~

OH

~ S ~ 53 (IIA) erein ~ represeIlts chlorine~ bromine or iodine.

The present in~ention also relates to a process for producing compounds of general formula (II) ~hich comprises reacting thien-(~)-yl ~-ith a compound corresponding to the ~ormula.

O

C-CH2-Alk-Hal (IV) Z

s in ~hich Alk is a linear or branched C1-C5-alLylene group, preferably a linear Cl-C3-alkylene group, Z is an al~oxy group having from 1 to 6 carbon atoms, preferably from to 4 carbon atoms, chlorine, bromine, iodine or a thienyl radlcal, and Hal is chlorine, bromine or iodine, in an inert medium a~ a temper~ture belo~ -50C. The compound of lormula II is Iormed in a ~ield of, for e~ample, 96~ ol ~ 3~

the theoretical.
By contrast, hitherto known reaction of this type, for example of thien-(3)-yl lithium with ~-phenyl-ethylamino-propi-onic acid esters (see German Patent Specification No. 1,921,453) do not take the place uniformly and the required dithien-(3)-yl compound can only be isolated in yields of at most 30~. In par-ticular, other thienyl isomers are always formed in relatively large quantities. In addition, separation of the required di-thienyl compound from the other reaction products and its purifi-cation are extremely difficult and can only be carried out, forexample, by complicated and elaborate recrystallisation several times in combination with treatment with active carbon.
In general formula IV, the radical Z is in particular an alkoxy group having from 1 to 6 carbon atoms, preferably hav-ing from 1 to 4 carbon atoms, which may be branched or chlorine or bromine. However, Z can also be a thien-(3)-yl radical.
The reaction of the thienyl lithium compound especially (thien-(3)-yl lithium~ with compound IV preferably takes place in an inert solvent mixture liquid at -80C consisting of a satur-ated ether and a saturated hydrocarbon and/or a mono- or di-Cl-C4-alkyl benzene. Suitable halogen -C3-C7-alkane carboxylic acid esters are for example ~-halogen propionic acid esters, butyric acid esters or valeric acid esters.
If the solvent mixture consists of an ether and a saut~ated hydrocarbon, from 0.3 to 3 parts by volume and prefer-ably from 0.8 to 3 parts ~y volume of ether are used for example to 1 part by volume of hydrocarbon. If the solvent mixture con-sists of an ether and a monoalkyl or dialkyl benzene, from 0.1 to 3 parts by volume and preferably from 0.2 to 1 part by volume of ether are used for example to 1 part by volume of alkyl benzene.

If the solvent mixture consists of the three components ether, saturated hydrocarbon and alkyl benzene, the ratio in which the ,. ?

~3~13~-3 .
three components are mixed is, for example 0.1-0.5 : 0.1-0.9 :
O . 1- 0 . 9 .
Suitable saturated ethers are, in particular, aliphatic symmetrical or asymmetrical dialkyl ethers, the alkyl groups pre-ferably consisting of 1 to 6 carbon atoms and being for example, methyl, ethyl, isopropyl, propyl isobutyl or butyl. Other suit-able ethers are, for example, C1-C6-alkyl ethers of saturated cycloalkanols and alkyl substituted cycloalkanols, the cycloalkan-ol rings each consisting of 3, 4, 5 or 6 carbon atoms. The ethers are preferably liquid at temperatures in the range from -80 to +20C
The saturated hydrocarbons are preferably aliphatic or cycloaliphatic hydrocarbons which are liquid at temperatures in the range from -80 to +20 C and which may contain for example from 5 to 9 and preferably 6 or 7 carbon atoms and may be branched.
The cycloaliphatic hydrocarbons are preferably substituted once or even several times (twice, three times), by Cl-C4-alkyl radi-cals,~especially methyl, ethyl or propyl radicals, the number of ring atoms amounting to 3, 4, 5, 6 or 7. The saturated alkyl radicals which may be used as substituents for the benzene are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, l-methyl propyl.
Examples of the solvents which may be used are diethyl ether, diisopropyl ether, methyl cyclopentyl ether, hexane, cyclohexane, toluene, xylene, methyl cyclohexane, methyl cyclopen-tane, ethyl cyclohexane and dimethyl cyclohexane.
It is of advantage to add compound (IV~, particularly when it is a ~-halogen alkane carkoxylic acid ester,as such or in the form of a solution in the hydrocarbon and/or ether (for example diiso~ropyl ether and/or toluene) to the thien~l lithium, such as thien-(3)-yl lithium, pre-cooled to the reaction te~perature and then to keep t~e reaction mixture at the reaction temperature for about 1 to 4 hours. T~ereafter~ater for example is ~ ~ 3 ;~ A,~
added to the reaction solution, optionally after heating to -20 to ~20C. The organic phase is dried (MgSO4 or NaSO4~ and concen-trated by evaporation under reduced pressure. The crude l,l-bis-[thien-(3)-yl]-3-halogenoalkanol thus obtained may be used with-out further purification for the reaction with the amine of formu-la III. The thienyl lithium compound thien-(3)-yl lithium is generally produced before hand from 3-bromothio~hene or from

3-iodothiophene in an ether and a Cl-C5-alkyl lithium or aryl lithium compound in an ether/hydrocarbon mixture, the ethers and hydrocarbons already mentioned (including the alkyl benzenes) being suitable for this prupose (dialkyl ether being particularly preferred as theether component). The alkyl radical of the alkyl lithium compounds may be linear or branched. Examples of suitable alkyl and aryl lithium compounds are butyl lithium, sec-butyl lithium, tert.-butyl lithium, methyl lithium, ethyl lithium, phenyl lithium and naphthyl lithium. The concentration of the alkyl or aryl lithium co~pound in the particular solvent used is, for example, from 5 to 30% by weight. The concentrations of the bro-mothiophene or iodothiophene in the particular solvent is, for 20 example, rom 10 to 100% by weight.
In general, the bromothiophene or iodothiophene, either as such or in the form of a solution in an ether, liquid aliphatic hydrocarbon or alkyl benzene, is added to the lithium alkyl or lithium aryl, which is dissolved or suspended in one of the above mentioned ethers or a mixture of ether and aliphatic hydrocarbon - in a ratis of 1-1.5:1 or ether and alkyl benzene in a ratio of 0.2-0.5:1 (concentration of the lithium compound from 5 to 30% by weight) and cooled to a temperature below -70C, in such a way that the temperature does not exceed -70C. The reaction component of formula (IV) is then added, for example, in the form of a 10 to 100% solution (% by weight) in one of the above-mehtioned di-alkyl ethers or alkyl benzenes, again in such a way that the 9 _ 1~1 3Z~39 temperature does not exceed -70C.
In one preferred embodiment of the process according to the present invention, the reaction is carried out in a solvent mixture of toluene and diisopropyl ether and, after the reaction mixture has been hydrolysed, the organic phase is subjected to fractional vacuum distillation, the low-boiling constituents of the mixture, such as diisopropyl ether, thiophene and butyl bro-mide, toge-ther with some of the toluene used being removed over-head, whilst a solution of l,l-bis[thien-(3 or 2)-yl]-~-halogeno-alkanol in toluene is recovered as sump residue and is directlyintroduced into the next stage of the process.
The reactants may be used for example in the following molar ratios: thienyl lithium: compound (IV) = 2.0 - 4.0 : 1.
Based on lithium alkyl and bromo- or iodothiophene, the following molar ratio for example may be applied: alkyl lithium -compound: bromo(iodo)thiophene: compound (IV) = 2.5-5.0 : 2.0-4.0 : 1, more especially 2.0-5.0 : 2.0-4.0 : 1.
The reaction temperature should never exceed -50 C. It is of advantage to carry out the reaction at a temperature of Zo from -65C to -75C,/the reaction preferably being carried out at a temperature below -70C, for example at a temperature of from -80C to -70 C.
The reaction mixture obtained may be subjected to fur-ther condensation with an oryanic compound containing a primary or secondary nitrogen atom, the further condensation taking place without compound II first being isolated from the reaction mix-ture.
Thus, the resulting 1,1-bis[thien-(3)-yl]-~-halogeno-alkanol of formula II may be reacted with compound III directly, i.e. without further purification. This reaction may be càrried out in the presence or absence of solvent or suspending agent.

Suitable inert solvents or suspending agents are, for example, the ~' .39 same solvents or suspending agents wnich are used for the reaction of the thienyl lithium with compound IV, for example diisopropyl ether and toluene. In addition, it is also possible for example to use other alkyl and dialkyl benzenes, dialkyl ethers, aliphatic ketones and aliphatic and cycloaliphatic alcohols. It is also possible directly to react the reac ~on mixturel in which the com-pound o- formula II is formed, with compound III. Since a reac-tion mixture such as this still contains the alkyl halide formed during the reaction, it may be necessary to use a corresponding excess of compound III.
The derivatives obtained frcm the intermediate ccmpound of formu-la II produced in accordance with the present invention are sub-stantially isomer-free and are obtained in satisfactorily pure form after a single recrystallisation.
In one embodiment of the process of the present inven-tionr thienyl-(3)-lithium is reacted with a compound corresponding to the general formula:
0~
C-CH -CH -Hal (IVA) Z
wherein Z represents an alkoxy group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, chlorine, bromine, iodine or a thienyl radical and Hal represents chlorine, bromine or iodine, in an inert medium at a temperature below -50 C.
Preferably, the reaction of the thienyl lithium compound with the compound of formula (IVA~ is carried out in a solvent mixture which is liquid at -80C and which consists of a saturat-ed ether and a saturated hydrocarbon and/or a mono -Cl-C4-alkyl benzene.
The reaction mixture obtained may be subjected to fur-ther condensation with an organic compound containing a primary or secondary ni-trogen atom, the further condensation taking place ~3~39 without compound (IIA) first being isolated from the reaction mi~-ture.
The present invention is illustrated by the .ollowing Examples.

Production of l,l-dithien-3-yl-3-bromo-l-propanol:
In a 1.5 litre four-necked flask equipped with a drop-ping funnel, a drying tube, a stirrer, a thermometer and an inlet for nitrogen, 300 ml of absolute diisopropyl ether are cooled under nitrogen with a cooling bath of methanol and dry iC2. Dur-ing cooling, a 15% solution of 335.2 ml of n-butyl lithium in hexane (O.S5 mole) is added and the mixture cooled to -75C. A
solution of 81.5 g of 3-bromothiophene ~0.5 mole) in 100 ml of absolute diisopropyl ether is then added dropwise over a period of 90 minutes in such a way that a temperature of -70 C is not exceeded. The reaction mixture is then left to afterreact for l hour at -70C to -75C. A solution of 36.2 g of ~-bromopropionic acid ethyl ester (0.2 mole) in 60 ml of absolute diisopropyl ether is then added dropwise over a period of 90 minutes in such a way that a temperature of -70C is not exceeded. The reaction mixture is then left to react for another 4 hours. The cooling bath is then removed and 160 ml of water are added to the reaction mixture. The temperature rises to -20 C. The reaction mixture is then stirred for a while until the temperature has risen above 0 C, after which the organic phase is separated off, dried with ~gSO4, filtered and all the low-boiling constituents are distill-ed off _ vacuo in a rotary evaporator. ~ light oil is obtained as residue.
~ield: 54 g (96% of the theoretical, based on the bromopropionic acid ester~.

1,1-dithien-3-yl-4-bromo-1-butanol and l,l-dithien-3-yl-'3 S-bromo-l-pentanol may be obtained using a method analoyous to the one described in Example 1 in the form of light oils.

~.

Claims (10)

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 general formula:

(II) in which Alk represents a straight-chain or branched-chain C1-C5-alkylene group and X represents chlorine, bromine or iodine which comprises reacting thienyl-(3)-lithium with a compound corresponding to the formula:

(IV) in which Alk represents a straight-chain or branched-chain C1-C5-alkylene group, Z represents an alkoxy group having from 1 to 6 carbon atoms, chlorine, bromine, iodine or a thienyl radical and Hal represents chlorine, bromine or iodine, in an inert medium at a temperature below -50°C.

2. A process as claimed in claim 1, wherein the reaction of the thienyl lithium compound with the compound of formula (IV) is carried out in a solvent mixture, liquid at -80°C, consisting of a saturated ether and a saturated hydrocarbon and/or a mono- or di-C1-C4-alkyl benzene.

3. A process as claimed in claim 1 or 2, wherein the reaction mixture obtained is subjected to further con-densation with an organic compound containing a primary or secondary nitrogen atom, the further condensation taking place without compound II first being isolated from the reaction mixture.

4. A process as claimed in claim 1, which comprises reacting thienyl-(3)-lithium with a compound corresponding to the formula:

( IVA) in which Z is an alkoxy group having from 1 to 6 carbon atoms, chlorine, bromine, iodine or a thienyl radical and Hal repre-sents chlorine, bromine or iodine, in an inert medium at a temperature below -50 C.

5. A process as claimed in claim 4, wherein reaction of the thienyl lithium compound with the compound of formula (IVA) is carried out in a solvent mixture which is liquid at -80°C and which consists of a saturated ether and a saturated hydrocarbon and/or a mono- or di-C1-C4-alkyl benzene.

6. A process as claimed in claim 4 or 5, wherein the reaction mixture obtained is subjected to further condensa-tion with an organic compound containing a primary or secondary nitrogen atom, the further condensation taking place without compound II first being isolated from the reaction mixture.

7. A compound corresponding to general formula:

(II) in which Alk represents a straight-chain or branched-chain C1-C5-alkylene group and X represents chlorine, bromine or iodine whenever prepared or produced by the process as claimed in claim 1 or 2 or an obvious chemical equivalent thereof.

8. A compound corresponding to the general formula:

(IIA) in which X represents chlorine, bromine or iodine whenever prepared or produced by the process as claimed in claim 4 or 5 or an obvious chemical equivalent thereof.

9. A process as claimed in claim 1, in which Alk is methyl, ethyl or propyl and X is bromine.

10. A compound of formula II given in claim 1, where Alk and X are as in claim 9 whenever prepared or produced by the process as claimed in claim 9 or an obvious chemical equivalent thereof.