CA1048547A - Process for the preparation of benzylamines - Google Patents
Process for the preparation of benzylaminesInfo
- Publication number
- CA1048547A CA1048547A CA74197924A CA197924A CA1048547A CA 1048547 A CA1048547 A CA 1048547A CA 74197924 A CA74197924 A CA 74197924A CA 197924 A CA197924 A CA 197924A CA 1048547 A CA1048547 A CA 1048547A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxy
- dibromo
- hydrochloride
- benzylamine
- cyclohexyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to a new process for the preparation of benzylamine derivatives having interesting pharmacological properties, in particular a secretolytic and antitussive activity as well as a stimulating effect on the production of the surfactant or antiatelectasis factor of the alveoli. The new process comprises the reaction of certain benzylamine derivatives with appropriate amines whereby amino group interchange occurs. Examples of the preparation of certain of the new benzylamine derivatives by means of the new process are given.
The invention relates to a new process for the preparation of benzylamine derivatives having interesting pharmacological properties, in particular a secretolytic and antitussive activity as well as a stimulating effect on the production of the surfactant or antiatelectasis factor of the alveoli. The new process comprises the reaction of certain benzylamine derivatives with appropriate amines whereby amino group interchange occurs. Examples of the preparation of certain of the new benzylamine derivatives by means of the new process are given.
Description
-- ~~
1~48547 .- The invention relates to a new process for the preparation of benzylamine derivatives having interesting physiological properties.
Our Canadian Patent Application Serial No. 183,899 describes and claims benzylamine compounds of general formula:
~ / 2 ,~ Rl ~ CH2-N
Y (Hal)y OH
. ~
, in which Hal represents an atom of chlorine or bromine, Rl represents an atom ~- of hydrogen, chlorine or bromine, R2 represénts morpholino-carbonylmethyl, ~ a branched alkyl radical containing 3 to 5 carbon atoms substituted by l to " 3 hydroxyl groups, the isopropyl, tert, butyl or tert.pentyl group, or a j~ group of the for:ula: (CH2)n ,'.,~;i-, ~ J
; B
: in which R3 represents a hydrogen atom, or hydroxy group or an alkyl group containing 1 to 4 carbon atoms, n represents zero, one or two and the two substituents A and B either both represent hydrogen atomsor together represent the group:
,.:
",~.,,. CR5-C-R5)m ,.:
in which R5 represents a hydrogen atom or an alkyl radical containing one or two carbon atoms and m represents the integer l or 2; R4 represents a straight or branched alkyl group containing from l to 4 carbon atoms, an alkenyl group containing from 2 to 4 carbon atoms, a cycloa'kyl group containing 3 or 4 carbon atoms, or a hydrogen atom (if R3 is other than hydrogen or R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by l to 3 hydroxyl groups, the isopropyl, tert.butyl or tert.pentyl group); and y represents the ..:
integer l or 2.
In general the compounds described and claimed in Application Serial No. 183,899 and their physiologically compatible acid addition salts ~: possess valuable pharmacological properties, in particular a secretolytic and .: "
.
antitussive effect as well as a stimulating effect on the production of the surfactant or antiatelectasis factor of the alveoli.
~ It is an object of the present inventlon to provide a new - process for the preparation of certain of the compounds of Application Serial No. 183,899 and acid addition salts thereof.
According to the present invention there is thus provided a ; process for the preparation of compounds of general formula . ` , ' Rl / R2 ~ CH2 - N
.. ~
'.
~ (Hal) OH
. ' .
~ wherein Hal represents a chlorine or bromine atom, Rl represents a hydrogen, i~,;
chlorine or bromine atom, R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, a cyclohexyl, a hydroxy-cyclohexyl, an isopropyl, a tert~ butyl or a tert. pentyl group, R4 repre-sents a straight or branched alkyl group with 1 to 4 carbon atoms, with the proviso that if R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, a hydroxycyclohexyl, isopropyl, tert.
. .
butyl or tert. pentyl group, R~ may be a hydrogen atom, and acid addition salts thereof which comprises reacting at a temperature in the range of from -0 to 180C. a compound of formula R
1 ~ 2 R 6 (II) '.,'' / \ ~-(Hal~ OH
wherein Rl and Hal are as hereinbefore defined and R6 represents an amino, a - (lower alkyl)amino, a di-(lower alkyl)amino, a tri-(lower alkyl)alkylammonium or pyridinium group with a compound of formula:
~ - 3 -',' ~
.
; :
;
. 1048S~7 wherein R2 and R4 are as defined above, and if desired converting the com-pound of formula I to a pharmacologically acceptable acid addition salt , thereof.
,~ .
;
~';
' -3a-~ r ~ --\
~ 1~4~S4'7 (wherein R2 and R4 are as hereinbefore defined) and if desired subsequently - converting the compound of formula I thereby obtained into an acid addition salt thereof.
Using the process according to the invention we have prepared compounds of general formula I and acid addition salts thereof in excellent yields.
Compounds of general formula II which may be used for the process ''! according to the invention include for example those wherein Rl, Hal and I
are as hereinbefore defined and R6 represents an amino group which may optionally be mono- or di-substituted, for example an amino, methylamino, dimethylamino, diethylamino, dipropylamino or methylethylamino group, a trialkylammonium group, for example a trimethylammonium, triethylammonium or methyl-diethylammonium group, or a pyridinium group.
The reaction is preferably carried out in the presence of an `
excess of the compound of formula III used, which excess serves as solvent.
The reaction may with advantage be effected in the presence of a catalytic quantity of an acid such as hydrochloric or sulphuric and in the presence of a metal salt or iodine. The reaction temperature used is in general con-veniently in the range from 0 to 180C, preferably however from 100 to 160C.
The compounds of general formula I obtained may if desired be con-verted into their acid addition salts and in particular into their physio-logically compatible acid addition salts. Suitable acids for this purpose include for example hydrochloric acidJ hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, and maleic acid.
The compounds of general formula II used as starting materials ; may for example be obtained by reaction of the corresponding benzylamine with an alkylating agent such as methyl iodide or by reaction of the cor-responding benzyl halid wlth pyridine.
The following Examples serve to illustrate the new process accord-3Q ing to the invention.
' .~ .
t~
-)4~5~7 :, ~i .
~ in the range from 0 to 180C, preferably however from ~q 100 to 160C.
The cornpounds of general formuia I obtained m~y if desired be converted into their acid addition salts ard in plrticular into their physiologically compatible acid addition salts. Suitable acids for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, and maleic acid.
The cornpounds of general formula II used as starting materials may for example be obtained by reaction of the corresponding benzylamine with an alkylating agent such as methyl iodide or by reaction I of the corresponding b~nzyl halide with pyridine.
¦ 15 The following Examples serve to illustrate the new process accordint to the invention.
.
.
: . . .
:
' ' ~ Example 1 .
3,5-Dibromo-2-hydroxy-N-(tr.~ns-:~-hydroxy-cyclohexyl)-. . .
benzylamine 10 g of 3,5-dibromo-N,N-dimeth~rl-2-hydroxy-benzylam;ne hydrochloride were heated with 30 g of trans-4-amino-cyclohexanol for 1 hour at 160C. The reaction mixture was then allowed to cool, diluted with water and the precipitate was suction filtered. The crude base obtained was dissolved in isopropanol and aci.dified with ethan~lic hydrochloric acid, whereupon 3,5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benæylamine hydrochloride crystallized out.
M.p.: 212 to 218C (decomp.).
~:~ Ex~mple 2 -,;' ':
b~ 15 3~Dibromo-2-h~droxy-N-(trans-4-hydroxy-cyclohexyl)-','~
benzylamir.e . 4.5 g of N-(3,5-dibromo-2-hydroxy-benzyl)-trimethyl-ammonium iodide were heated with 8 g of trans-4-~nino-cyclohexanol for 15 minutes at 160C. The cooled reaction produ~t was treated with water and the precipitate was , suction filtered. 3,5-Dibromo-2-hydroxy-N-(trans-4-`. hydroxy-cyclohexyl)-benzylasnine hydrochloride was obtained A ~6 !
~ ' ' ' . ' ' , ... . . . .
, ~1 - ' 1~485~7 rrom t;he crude base by dissolving in isopropanol and acidifying with ethanolic hydrochloric acid.
M~p.: 212 tc 218C (decomp.).
Exa~ple 3 N-Ethyl-N-cyclohexyl-3,5-dibromo 2-hydroxy-benzylamine M.p. of the hydrochloride: 193 to 194C (decomp.).
Prepared from 3,5-dibromo-N,N-dimethyl-2-hydroxy-benzylamine hvdrochloride and N-ethyl-cyclohexylamine analogously to Example 1.
Example 4 ohexyl)-benz~lamine M.p. of the hydrochloride: 216 to 218C (decomp.).
Prepared from 3,5-dibromo-N,N-dimethyl-4-hydro~y-benæylamine hydrochloride and cis-3-amino-cyciohexanol analogously to Example 1.
Example 5 3,5-Dibromo_2-hydroxy-N-(trans-4-h-;droxy-cyclohex-yl)-M.p. of the hydrochloride: 21~ to 218C (decomp.).
Prepared from N-(3,5-dil,romo-2-hydroxy-benzyl)-.~ q .
~ , , 1¢~4~547 -pyridinium bromide and trans-4-amino-cyclohexanol analog~u~ly to Exa~ple 2. ..
Example 6 . N-Ethyl-N-cyclohe~yl-3,5-dibromo-2-hydro.~y-benzyla~ine M.p. of the hydrochloride: 1~3.to 194C (decomp.).
Prepared from N-(3,5-dibromo-2-hydroxy-benzyl)-pyr4.dinium bromide and N-ethyl-cyclohexylamine analogously ~.
. to Example 2.
Example 7 .; .
. 10 3,5-D;.bromo-4-hydroxy-N-(cis-3-hydroxy-cycloh2xyl)-benzylamine ... .
- M.p. of.the hydrochloride: 216 to 218C (decomp.).
~I. Prepared from N-(3,5-dibromo-4-hydroxy-benzyl)-,~ pyridinium bromide and cis-3-amino-cyclohexanol analogously to Example 2.
, . The following compounds have been prepared ~' analogously to Examples 1 to 7:
N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine . M.p. of the hydrochloride: 180 to 181C (decomp.).
3-Bromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-beilzy'-.' amine .
.. , ~ . .
. , ~ 9~
,, .
.. .
' .
: -,, ~ ..
1~48S47 ,~
M.p. of the hydrochloride: 194 to 196C (decomp.).
3-Bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine M.p.: 136 to 138C.
3,5-Dibromo-N-(dihydroxy-tert.-buty13-2-hydroxy-benzyl-amine M.p. of the hydrochloride: 187 to 189C.
3,5-Dichloro-N-(dihydroxy-tert.-butyl)-4-hydroxy-benzyl-amine M.p. of the hydrochloride: 166 to 169C (decomp.).
3,5-Dibromo-2-hydroxy-N tert.-pentyl-benzylamine M.p. of the hydrochloride: 202 to 206C (decomp.~.
3,5-Dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-:~ benzylamine M.p. of the hydrochloride: 215 to 215.5C (decomp.).
... . .
r ~ ' i ~'"',.~,"~
';. ' ; '':
.' ' ' . .
~:.'. ,, .~ ' .
.~, .
:' ', ' ':
, ~, . ' , , ' ; : "'; '' . "' - '
1~48547 .- The invention relates to a new process for the preparation of benzylamine derivatives having interesting physiological properties.
Our Canadian Patent Application Serial No. 183,899 describes and claims benzylamine compounds of general formula:
~ / 2 ,~ Rl ~ CH2-N
Y (Hal)y OH
. ~
, in which Hal represents an atom of chlorine or bromine, Rl represents an atom ~- of hydrogen, chlorine or bromine, R2 represénts morpholino-carbonylmethyl, ~ a branched alkyl radical containing 3 to 5 carbon atoms substituted by l to " 3 hydroxyl groups, the isopropyl, tert, butyl or tert.pentyl group, or a j~ group of the for:ula: (CH2)n ,'.,~;i-, ~ J
; B
: in which R3 represents a hydrogen atom, or hydroxy group or an alkyl group containing 1 to 4 carbon atoms, n represents zero, one or two and the two substituents A and B either both represent hydrogen atomsor together represent the group:
,.:
",~.,,. CR5-C-R5)m ,.:
in which R5 represents a hydrogen atom or an alkyl radical containing one or two carbon atoms and m represents the integer l or 2; R4 represents a straight or branched alkyl group containing from l to 4 carbon atoms, an alkenyl group containing from 2 to 4 carbon atoms, a cycloa'kyl group containing 3 or 4 carbon atoms, or a hydrogen atom (if R3 is other than hydrogen or R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by l to 3 hydroxyl groups, the isopropyl, tert.butyl or tert.pentyl group); and y represents the ..:
integer l or 2.
In general the compounds described and claimed in Application Serial No. 183,899 and their physiologically compatible acid addition salts ~: possess valuable pharmacological properties, in particular a secretolytic and .: "
.
antitussive effect as well as a stimulating effect on the production of the surfactant or antiatelectasis factor of the alveoli.
~ It is an object of the present inventlon to provide a new - process for the preparation of certain of the compounds of Application Serial No. 183,899 and acid addition salts thereof.
According to the present invention there is thus provided a ; process for the preparation of compounds of general formula . ` , ' Rl / R2 ~ CH2 - N
.. ~
'.
~ (Hal) OH
. ' .
~ wherein Hal represents a chlorine or bromine atom, Rl represents a hydrogen, i~,;
chlorine or bromine atom, R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, a cyclohexyl, a hydroxy-cyclohexyl, an isopropyl, a tert~ butyl or a tert. pentyl group, R4 repre-sents a straight or branched alkyl group with 1 to 4 carbon atoms, with the proviso that if R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, a hydroxycyclohexyl, isopropyl, tert.
. .
butyl or tert. pentyl group, R~ may be a hydrogen atom, and acid addition salts thereof which comprises reacting at a temperature in the range of from -0 to 180C. a compound of formula R
1 ~ 2 R 6 (II) '.,'' / \ ~-(Hal~ OH
wherein Rl and Hal are as hereinbefore defined and R6 represents an amino, a - (lower alkyl)amino, a di-(lower alkyl)amino, a tri-(lower alkyl)alkylammonium or pyridinium group with a compound of formula:
~ - 3 -',' ~
.
; :
;
. 1048S~7 wherein R2 and R4 are as defined above, and if desired converting the com-pound of formula I to a pharmacologically acceptable acid addition salt , thereof.
,~ .
;
~';
' -3a-~ r ~ --\
~ 1~4~S4'7 (wherein R2 and R4 are as hereinbefore defined) and if desired subsequently - converting the compound of formula I thereby obtained into an acid addition salt thereof.
Using the process according to the invention we have prepared compounds of general formula I and acid addition salts thereof in excellent yields.
Compounds of general formula II which may be used for the process ''! according to the invention include for example those wherein Rl, Hal and I
are as hereinbefore defined and R6 represents an amino group which may optionally be mono- or di-substituted, for example an amino, methylamino, dimethylamino, diethylamino, dipropylamino or methylethylamino group, a trialkylammonium group, for example a trimethylammonium, triethylammonium or methyl-diethylammonium group, or a pyridinium group.
The reaction is preferably carried out in the presence of an `
excess of the compound of formula III used, which excess serves as solvent.
The reaction may with advantage be effected in the presence of a catalytic quantity of an acid such as hydrochloric or sulphuric and in the presence of a metal salt or iodine. The reaction temperature used is in general con-veniently in the range from 0 to 180C, preferably however from 100 to 160C.
The compounds of general formula I obtained may if desired be con-verted into their acid addition salts and in particular into their physio-logically compatible acid addition salts. Suitable acids for this purpose include for example hydrochloric acidJ hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, and maleic acid.
The compounds of general formula II used as starting materials ; may for example be obtained by reaction of the corresponding benzylamine with an alkylating agent such as methyl iodide or by reaction of the cor-responding benzyl halid wlth pyridine.
The following Examples serve to illustrate the new process accord-3Q ing to the invention.
' .~ .
t~
-)4~5~7 :, ~i .
~ in the range from 0 to 180C, preferably however from ~q 100 to 160C.
The cornpounds of general formuia I obtained m~y if desired be converted into their acid addition salts ard in plrticular into their physiologically compatible acid addition salts. Suitable acids for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, and maleic acid.
The cornpounds of general formula II used as starting materials may for example be obtained by reaction of the corresponding benzylamine with an alkylating agent such as methyl iodide or by reaction I of the corresponding b~nzyl halide with pyridine.
¦ 15 The following Examples serve to illustrate the new process accordint to the invention.
.
.
: . . .
:
' ' ~ Example 1 .
3,5-Dibromo-2-hydroxy-N-(tr.~ns-:~-hydroxy-cyclohexyl)-. . .
benzylamine 10 g of 3,5-dibromo-N,N-dimeth~rl-2-hydroxy-benzylam;ne hydrochloride were heated with 30 g of trans-4-amino-cyclohexanol for 1 hour at 160C. The reaction mixture was then allowed to cool, diluted with water and the precipitate was suction filtered. The crude base obtained was dissolved in isopropanol and aci.dified with ethan~lic hydrochloric acid, whereupon 3,5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benæylamine hydrochloride crystallized out.
M.p.: 212 to 218C (decomp.).
~:~ Ex~mple 2 -,;' ':
b~ 15 3~Dibromo-2-h~droxy-N-(trans-4-hydroxy-cyclohexyl)-','~
benzylamir.e . 4.5 g of N-(3,5-dibromo-2-hydroxy-benzyl)-trimethyl-ammonium iodide were heated with 8 g of trans-4-~nino-cyclohexanol for 15 minutes at 160C. The cooled reaction produ~t was treated with water and the precipitate was , suction filtered. 3,5-Dibromo-2-hydroxy-N-(trans-4-`. hydroxy-cyclohexyl)-benzylasnine hydrochloride was obtained A ~6 !
~ ' ' ' . ' ' , ... . . . .
, ~1 - ' 1~485~7 rrom t;he crude base by dissolving in isopropanol and acidifying with ethanolic hydrochloric acid.
M~p.: 212 tc 218C (decomp.).
Exa~ple 3 N-Ethyl-N-cyclohexyl-3,5-dibromo 2-hydroxy-benzylamine M.p. of the hydrochloride: 193 to 194C (decomp.).
Prepared from 3,5-dibromo-N,N-dimethyl-2-hydroxy-benzylamine hvdrochloride and N-ethyl-cyclohexylamine analogously to Example 1.
Example 4 ohexyl)-benz~lamine M.p. of the hydrochloride: 216 to 218C (decomp.).
Prepared from 3,5-dibromo-N,N-dimethyl-4-hydro~y-benæylamine hydrochloride and cis-3-amino-cyciohexanol analogously to Example 1.
Example 5 3,5-Dibromo_2-hydroxy-N-(trans-4-h-;droxy-cyclohex-yl)-M.p. of the hydrochloride: 21~ to 218C (decomp.).
Prepared from N-(3,5-dil,romo-2-hydroxy-benzyl)-.~ q .
~ , , 1¢~4~547 -pyridinium bromide and trans-4-amino-cyclohexanol analog~u~ly to Exa~ple 2. ..
Example 6 . N-Ethyl-N-cyclohe~yl-3,5-dibromo-2-hydro.~y-benzyla~ine M.p. of the hydrochloride: 1~3.to 194C (decomp.).
Prepared from N-(3,5-dibromo-2-hydroxy-benzyl)-pyr4.dinium bromide and N-ethyl-cyclohexylamine analogously ~.
. to Example 2.
Example 7 .; .
. 10 3,5-D;.bromo-4-hydroxy-N-(cis-3-hydroxy-cycloh2xyl)-benzylamine ... .
- M.p. of.the hydrochloride: 216 to 218C (decomp.).
~I. Prepared from N-(3,5-dibromo-4-hydroxy-benzyl)-,~ pyridinium bromide and cis-3-amino-cyclohexanol analogously to Example 2.
, . The following compounds have been prepared ~' analogously to Examples 1 to 7:
N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine . M.p. of the hydrochloride: 180 to 181C (decomp.).
3-Bromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-beilzy'-.' amine .
.. , ~ . .
. , ~ 9~
,, .
.. .
' .
: -,, ~ ..
1~48S47 ,~
M.p. of the hydrochloride: 194 to 196C (decomp.).
3-Bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine M.p.: 136 to 138C.
3,5-Dibromo-N-(dihydroxy-tert.-buty13-2-hydroxy-benzyl-amine M.p. of the hydrochloride: 187 to 189C.
3,5-Dichloro-N-(dihydroxy-tert.-butyl)-4-hydroxy-benzyl-amine M.p. of the hydrochloride: 166 to 169C (decomp.).
3,5-Dibromo-2-hydroxy-N tert.-pentyl-benzylamine M.p. of the hydrochloride: 202 to 206C (decomp.~.
3,5-Dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-:~ benzylamine M.p. of the hydrochloride: 215 to 215.5C (decomp.).
... . .
r ~ ' i ~'"',.~,"~
';. ' ; '':
.' ' ' . .
~:.'. ,, .~ ' .
.~, .
:' ', ' ':
, ~, . ' , , ' ; : "'; '' . "' - '
Claims (18)
ROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula (I) wherein Hal represents a chlorine or bromine atom, R1 represents a hydrogen, chlorine or bromine atom, R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, a cyclohexyl, a hydroxy-cyclohexyl, an isopropyl, a tert.butyl or a tert, pentyl group, R4 repre-sents a straight or branched alkyl group with 1 to 4 carbon atoms, with the proviso that if R2 represents a branched alkyl group with 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, a hydroxycyclohexyl, isopropyl, tert.
butyl or tert.pentyl group, R4 may be a hydrogen atom, and acid addition salts thereof which comprises reacting at a temperature in the range of from 0 to 180°C a compound of formula:
(II) wherein R1 and Hal are as hereinbefore defined and R6 represents an amino, a (lower alkyl)amino, a di-(lower alkyl)amino, a tri-(lower alkyl)alkyl-ammonium or pyridinium group with a compound of formula:
wherein R2 and R4 are as defined above, and if desired converting the com-pound of formula I to a pharmacologically acceptable acid addition salt thereof.
butyl or tert.pentyl group, R4 may be a hydrogen atom, and acid addition salts thereof which comprises reacting at a temperature in the range of from 0 to 180°C a compound of formula:
(II) wherein R1 and Hal are as hereinbefore defined and R6 represents an amino, a (lower alkyl)amino, a di-(lower alkyl)amino, a tri-(lower alkyl)alkyl-ammonium or pyridinium group with a compound of formula:
wherein R2 and R4 are as defined above, and if desired converting the com-pound of formula I to a pharmacologically acceptable acid addition salt thereof.
2. A process as claimed in claim 1 wherein a compound of formula II as defined in claim 1 wherein R6 represents a dimethylamino, trimethyl-ammonium or pyridinium group is reacted with a compound of formula III as defined in claim 1.
3. A process as claimed in claim 1 wherein the reaction is effected in the presence of an excess of the compound of formula III which excess serves as solvent.
4. A process as claimed in claim 1 wherein the reaction is effected at temperatures from 100 to 160°C.
5. Compounds of general formula I as defined in claim 1 and pharma-ceutically acceptable acid addition salts thereof whenever prepared by a process as claimed in claim 1 or any obvious chemical equivalent thereof.
6. A process according to claim 1 wherein R1 represents a bromine atom in the 5- position, Hal represents a bromine atom in the 3- position and the hydroxyl group is in the 2- position on the benzene nucleus,,R2 is a trans-4-hydroxycyclohexyl group and R4 is hydrogen.
7. A process according to claim 1 for producing 3, 5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine and its hydrochloride which comprises reacting 3, 5-dibromo-N,N-dimethyl-2-hydroxy-benzylamine hydrochloride with excess trans-4-amino-cyclohexanol, and if the hydro-chloride is required reacting the base so obtained with hydrogen chloride.
8. A process according to claim 1 for producing 3, 5-dibromo-2-hydroxy?N-(trans-4-hydroxy-cyclohexyl)-benzylamine and its hydrochloride which comprises reacting N-(3, 5-dibromo-2-hydroxy-benzyl)-trimethyl-ammonium iodide with excess trans-4-amino-cyclohexanol, and if the hydrochloride is required reacting the base so obtained with hydrogen chloride.
9. A process according to claim 1 for producing 3, 5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine and its hydrochloride which comprises reacting N-(3, 5-dibromo-2-hydroxy-benzyl)-pyridinium bromide with excess trans-4-amino cyclohexanol, and if the hydrochloride is required reacting the base so obtained with hydrogen chloride.
10. 3, 5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)benzylamine when made by a process according to claim 7, 8 or 9 or an obvious chemical equivalent thereof.
11. A process according to claim 1 wherein R1 represents a bromine atom in the 5- position, Hal represents a bromine atom in the 3- position and the hydroxyl group is in the 2-position on the benzene nucleus, R2 is a trans-cyclohexyl group and R4 is an ethyl group.
12. A process according to claim 1 for producing N-ethyl-N-cyclo-hexyl-3,5-dibromo-2-hydroxy-benzylamine and its hydrochloride which comprises reacting 3,5-dibromo-N,N-dimethyl-2-hydroxy-benzylamine hydrochloride with excess N-ethyl-cyclohexylamine and if the hydrochloride is required reacting the base so obtained with hydrogen chloride.
13. A process according to claim 1 for producing N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine and its hydrochloride which comprises reacting N-(3,5-dibromo-2-hydroxy-benzyl)-pyridinium bromide with excess N-ethyl-cyclohexylamine and if the hydrochloride is required reacting the base so obtained with hydrogen chloride.
14. N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine when made by a process according to claim 12 or 13 or an obvious chemical equivalent thereof.
15. A process according to claim 1 wherein R1 represents a bromine atom in the 5-position, Hal represents a bromine atom in the 3-position and the hydroxyl group is in the 4-position on the benzene nucleus, R2 is a cis-3-hydroxycyclohexyl group and R4 is a hydrogen atom.
16. A process according to claim 1 for producing 3, 5-dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine and its hydrochloride which comprises reacting 3,5-dibromo-N,N-dimethyl-4-hydroxy-benzylamine hydro-chloride with excess cis-3-amino-cyclohexanol and if the hydrochloride is required reacting the base so obtained with hydrogen chloride.
17. A process according to claim 1 for producing 3,5-dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine and its hydrochloride which comprises reacting N-(3,5-dibromo-4-hydroxy-benzyl)-pyridinium bromide with excess cis-3-amino-cyclohexanol and if the hydrochloride is required reacting the base so obtained with hydrogen chloride.
18. 3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine when prepared by a process according to claim 16 or 17 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2403511A DE2403511A1 (en) | 1974-01-25 | 1974-01-25 | NEW PROCESS FOR PRODUCING BENZYLAMINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1048547A true CA1048547A (en) | 1979-02-13 |
Family
ID=5905656
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA74197924A Expired CA1048547A (en) | 1974-01-25 | 1974-04-22 | Process for the preparation of benzylamines |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5922695B2 (en) |
| AT (1) | AT329537B (en) |
| BG (1) | BG24227A4 (en) |
| CA (1) | CA1048547A (en) |
| CH (1) | CH609039A5 (en) |
| CS (1) | CS187455B2 (en) |
| DD (1) | DD119412A6 (en) |
| DE (1) | DE2403511A1 (en) |
| DK (1) | DK153139C (en) |
| FI (1) | FI63215C (en) |
| HU (1) | HU169632B (en) |
| NL (1) | NL7500844A (en) |
| NO (1) | NO139478C (en) |
| PL (1) | PL93723B1 (en) |
| RO (1) | RO68643A (en) |
| SE (1) | SE418741B (en) |
| SU (1) | SU520034A3 (en) |
| YU (1) | YU40110B (en) |
-
1974
- 1974-01-25 DE DE2403511A patent/DE2403511A1/en not_active Withdrawn
- 1974-03-22 FI FI888/74A patent/FI63215C/en active
- 1974-04-19 NO NO741416A patent/NO139478C/en unknown
- 1974-04-19 DK DK217874A patent/DK153139C/en not_active IP Right Cessation
- 1974-04-19 SE SE7405323A patent/SE418741B/en not_active IP Right Cessation
- 1974-04-22 CA CA74197924A patent/CA1048547A/en not_active Expired
- 1974-11-13 AT AT906674A patent/AT329537B/en not_active IP Right Cessation
- 1974-11-20 BG BG028241A patent/BG24227A4/en unknown
- 1974-12-19 DD DD183210A patent/DD119412A6/xx unknown
-
1975
- 1975-01-03 CS CS7569A patent/CS187455B2/en unknown
- 1975-01-14 RO RO7581107A patent/RO68643A/en unknown
- 1975-01-20 YU YU130/75A patent/YU40110B/en unknown
- 1975-01-21 JP JP50009207A patent/JPS5922695B2/en not_active Expired
- 1975-01-23 HU HUTO994A patent/HU169632B/hu not_active IP Right Cessation
- 1975-01-23 CH CH79375A patent/CH609039A5/en not_active IP Right Cessation
- 1975-01-23 SU SU2100973A patent/SU520034A3/en active
- 1975-01-24 PL PL1975177523A patent/PL93723B1/pl unknown
- 1975-01-24 NL NL7500844A patent/NL7500844A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PL93723B1 (en) | 1977-06-30 |
| CS187455B2 (en) | 1979-01-31 |
| HU169632B (en) | 1976-12-28 |
| FI88874A (en) | 1975-07-26 |
| JPS5922695B2 (en) | 1984-05-28 |
| YU13075A (en) | 1982-02-28 |
| NO741416L (en) | 1975-08-18 |
| NL7500844A (en) | 1975-07-29 |
| DK153139B (en) | 1988-06-20 |
| SE418741B (en) | 1981-06-22 |
| JPS50106932A (en) | 1975-08-22 |
| YU40110B (en) | 1985-08-31 |
| CH609039A5 (en) | 1979-02-15 |
| FI63215C (en) | 1983-05-10 |
| BG24227A4 (en) | 1978-01-10 |
| NO139478B (en) | 1978-12-11 |
| DK153139C (en) | 1988-10-31 |
| NO139478C (en) | 1979-03-21 |
| DK217874A (en) | 1975-10-13 |
| AT329537B (en) | 1976-05-10 |
| DE2403511A1 (en) | 1975-08-14 |
| SU520034A3 (en) | 1976-06-30 |
| RO68643A (en) | 1983-02-01 |
| FI63215B (en) | 1983-01-31 |
| ATA906674A (en) | 1975-08-15 |
| SE7405323L (en) | 1975-07-28 |
| DD119412A6 (en) | 1976-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW304193B (en) | ||
| JPS6026782B2 (en) | Method for producing novel arylpiperidine derivatives | |
| JPS584752A (en) | Carboxyamide derivative, manufacture and central nervous system trouble remedy | |
| TW200424171A (en) | Indole derivatives useful for the treatment of diseases | |
| TW201725207A (en) | Crystalline form of BTK kinase inhibitor and a preparation method thereof | |
| TWI485147B (en) | Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives | |
| KR100747425B1 (en) | Substituted N-benzyl-indol-3-yl glyoxylic acid derivatives having an anti-tumoral effect | |
| TW509678B (en) | Method for the synthesis of quinoline derivatives | |
| CA1048547A (en) | Process for the preparation of benzylamines | |
| EA003941B1 (en) | 2-aminopyridines containing fused ring substituents | |
| JP2001501217A (en) | N- (Benzothiazol-2-yl) -1-piperidineethanamine derivatives, their preparation and therapeutic applications | |
| US4576953A (en) | Quinoline derivatives | |
| JP3045354B2 (en) | Thioxanthenones and their antitumor agents | |
| US11242332B2 (en) | Method for producing benzimidazole derivative | |
| PT87433B (en) | PROCESS FOR THE PREPARATION OF NEW SUBSTITUTED SILIL-ALKYLENE-AMINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
| US6172078B1 (en) | Quinolinomorphinane derivatives and medicinal use thereof | |
| JPH10511641A (en) | Diarylethylene metallocene derivative, process for producing the same, and pharmaceutical composition containing the derivative | |
| JPS6015616B2 (en) | Method for producing N-2-(pyrrolidinylmethyl)-substituted benzamide derivative or salts thereof | |
| JPH0124793B2 (en) | ||
| US2798072A (en) | Substituted benzamidopiperidinopropanes | |
| JPH03294277A (en) | Piperidine derivative | |
| CA1050023A (en) | Process for the preparation of benzylamines | |
| JPH0319228B2 (en) | ||
| JPH0357896B2 (en) | ||
| JPH02145572A (en) | N-substituted amide |