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CA1052790A - Process for the preparation of 2-amino-benzylamines - Google Patents

Process for the preparation of 2-amino-benzylamines

Info

Publication number
CA1052790A
CA1052790A CA205,312A CA205312A CA1052790A CA 1052790 A CA1052790 A CA 1052790A CA 205312 A CA205312 A CA 205312A CA 1052790 A CA1052790 A CA 1052790A
Authority
CA
Canada
Prior art keywords
acid
amino
formula
compound
trans
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
Application number
CA205,312A
Other languages
French (fr)
Other versions
CA205312S (en
Inventor
Johannes Keck
Gerd Kruger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE19732337363 external-priority patent/DE2337363A1/en
Priority claimed from DE19732337334 external-priority patent/DE2337334A1/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Application granted granted Critical
Publication of CA1052790A publication Critical patent/CA1052790A/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

2-amino-benzylamine ABSTRACT OF THE DISCLOSURE
The invention relates to a new process for the preparation of 2-amino-benzylamine derivatives having valuable pharmacological properties, in particular a secretolytic and/or antitussive activity. The process comprises the reaction of the corresponding 2-amino-benzyl alcohol with an appropriate amine, either the amino group being acylated or the reaction being performed in the presence of an organic acid. Examples of the proparation of certain 2-amino-benzylamine by means of the new process are given.

Description

`:
~ 105'~7~(~
The imention relates to a new process for the preparation of 2-amino-benzylamines havi~g interesting pharmacologici~l properties.
United States Patent Specifications Nos. 3,546~713 and 3,712,924 describe and claim inteI alia 2-amino-benzylamines of general formula 1 ~ N2 3 Ha i NH2 ,; . .

(wherein Hal represents a chlorine or bromine atom, Rl represents a hydrogen, chlorine or bromine atom, R2 represents a hydrogen atom or an alkyl group containing from I to 3 carbon atoms and R3~represents a hydroxy~
cyclohexyl or morpholin~GaIb~ethyl group) and physiologically compatible aoid addition sal~ts thereof, and also processes for their preparation.
In general the compounds of general formula I as hereinbefore defined and acid addition salts ~hereof ~`
possess valuable pharmacological properties~ in particular a secretolytic and/or antitussive activity.
It is an object of the present invention to provide ~ .
.
''.`'' ,' ~, .
.

~.05~7~ :
a new process for the preparation of compounds of general formula I (as hereinbefore defined and with the additional proviso that when R3 is a hydroxycyclohexyl group R2 is not an alkyl group) and acid addition salts thereof.
Thus according to the presen~ in~ention there is provided a process for the preparation of compounds o:F general formula I as hereinbefore defined, including the proviso that when R3 is a hydroxycyclohexyl group R2 is not an alkyl group, and pharmaceutically acceptable acid addition salts thereof which comprises reacting a compound of formula Rl ~ CH2H (II) Hal ~ N~-R4 , , .

~wherein Hal and Rl are as hereinbe~ore defined and R4 and R5, which may be the same or different, each represent a hydrogen atom or an organic acyl ~. :
group) with a compound of formula ,,~' 2 (III) :
H - N \ -`~
3 ~ .
Cwherein R2 and R3 are as hereinbefore defined) whereby a compound of formula I
i5 qbtained and if desired subsequently converting the compound of formula I
thereby produced into a pharmaceutically acceptable acid addition salt thereof.

Where R4 and R5 represent hydrogen atoms, ' ~ ' ~ ~ ~3- ~

;:. . .. . . i . . . . ,. . ~ . . . . ;.

~(~S~79(~
the reaction is carried out in the presence of an organic acid whereby the cdesired compound of formula I is obtained.
Using the process according to the invention we have prepared compounds of general formula I and acid addition salts thereof in good yield.
The reaction is preferably effected in the presence of a solvent~ usually a high boiling solvent such as tetraline or xylene. Alternatively an excess of the eompound of formula III and/or an excess of the organie aeid may be used to serve as solvent.
In general the reaetion is effeeted at temperatures from 100 to 220 C. If a compound o~ formula II wherein both R4 and R5 represent hydrogen atoms is used the reae~ion is preferably effeeted at temperatures from 140 to 180 C. If R4 and/or R5 in the eompound of formu]a II represent acyl groups the reaction is preferably effected at temperatures from 120 to 190C.
The organic acid when used is aclvantageously an aliphatie acid for example acetic acid, butyric aeid, valerie acid, trimethylacetie aeid or eapronie aeid~
Where the groups R~ and/or R5 in the eompound of formula II represent organie aeyl groups, these groups may for example be aeetyl, butyryl~ ben~oyl or p-ehlorobenzoyl groups.
The compounds of general formula I obtained may, i ,:
, - .; . .:

~ if desired, be subsequently convarted into their acid ; addition salts, preferably their physiologically compatible acid addition salts with inorganic or organic acids.
Suitable acids for this purpose include for example hydrochloric acid, hydrobromic acid~ sulfuric acid~ ;
.~ . . .
phosphoric acid~ lactic acid, citric acid and maleic acid.
The compounds of general formula II used as starting .,~ . ... ~ , .
materials may be prepared from the corresponding ben~yl alcohols~ which themselves may be conveni~ntly prepared by reduction of the corresponding aldehydydes with sodium borohydride. Compounds of general formula II wherein R~ and R5 represent hydrogen atoms may if desired be subsequently acylated by reaction with appropriate acyl halides in the presence of pyridine, the simultaneously formed esters being saponified under basic conditions.
. .
The s~arting materials of general formula II obtained ; may, if desired, be reacted without previous isolation.

It is surp~ising that the new process according to~t~e invention in general produces compounds of general formula I in such good yields since the analogous reaction .
of an unacylated ben~yl alcohol of formula II and an amine of formula III or the hydrochloride thereof in the absence of an organic acid does not yield the desired , .
product of formula I.

The following Examples serve to illustrate the . .. .

:~

~5Z~

new process according to the invention:
Example 1 ; ~ r benzylamine 5.8 g (0.018 mol) of 2-acetylamino-3,5-dibromo-benzyl alcohol were stirred with 2.3 g (0.020 mol~ of trans-4-amino-cyclohexanol in 20 ml of tetraline at 175C for 4 hours. Subsequently, the solution was evaporated in vacuo at 120C. The residue was dissolved in ether, extracted three times with water and the organic layer was dried with sodium sulfate and evaporated to dryness, The residue was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid to yield 2-amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride which was crystallized by addition of etherO
Yield: 4.4 g (59.0 % of theory3. After recrystallization from absolute ethanol the compound melted at 233-234.5 C
(decomp.).
Example 2 M.p.: 116 to 118 C
Prepared from 2-benzoylamino-6-chloro-benzyl alcohol and sarcosine morpholide analogously to Example 1
2-~mino-3,5-dibromo benz~lamine 1~:)5~

.. .
M~po of the hydrocholride: 233 to 234.5 C (decomp).
Prepared from 2-diacetylam:;no-3,S-dibromo-benzyl ; alcohol and trans-4-amino-cyclohexanol analogously to Example 1.
Example 4 ; .
.
506 g (0.02 mol) of 2-amino-3,5-dibromo-benzyl alcohol were stirred with 11.5 g (OolO mol of trans-4-amino-cyclohexanol and 8.8 g (OolO mol) of butyric acid at 165 C. The reaction solution was then taken up ln ether, extracted twice with water and the organic layer was dried with sodium sulfate and evaporated to dryness. The residue was dissolved in absolute ethanol and ether (1:1) and the solution was acidfied with e*hanolic hydrochloric acidO 1~5 g of a by-product first crystallized out and after further addition of ether, 3.5 g (42% of theory) of 2-amino-3~5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride ~-were obtained.
M.p.: 233 to 234 C (decomp.) - Example 5 2-Amino-6-chloro-N-methyl-N-morpholinocarbonylmeth~
benzyliamine M.p.: tl6 to lt8 C~
Prepared from 2-amino-6-chloro benzyl alcohol~
sarcosine morpholide and butyric acid analogously to ~xample 4 -`~ ~Q~ O
xample 6 2-Amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-butyrylam.Lno-3,5-dibromo-benzyl alcohol and trans-4-amino-cyclohexanol analogously to Example 1.
Example 7 10 ~
~I.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-p-chlorobenzoylamino-3,5-dibromo-benzyl alcohol and trans-4-amino-cyclohexanol analogously to Example 1.
Example _ , M.p. of the hydrochloride: 233 to 234.5 C (decomp.) Prepared from 2-amino-3~5-dibromo-benzyl alcohol~
20 trans-4-amino-cyclohexanol and acetic acid analogously to Example 4.
Example 9 2_~ml ~3, ~di~r~-N-(trans-4-hydroxy-cyclohexyl)-benzyl_~ine M.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-amino-3~5-dibromo-benzyl alcohol, _8- i . `, ` , . - , ` . , ~, - ' ' ' . , ' , ~ , ' ', ,` , ~, ., ' . - , . ` ' ' , . :
. . , ` , _ . . _ . .

~(~5~79~) trans-4-amino-cyclohexanol and valeric acid analogously to Example 4.
Example 10 2-Amino 325-dibromo-N-~trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-amino-3,5-dibromo-benzyl alcohol, trans-4-amino-cyclohexanol and capronic acid analogously to Example 4.
Example 11 ~-Amino-3?5-dibromo-N-~trans 4-hydroxy-ben~ylamine M.p. of the hydrochloride: 233 to 234.~ C (decomp.).
Prepared from 2-amino-3,5-dibromo-benzyl alcohol, trans-4-amino-cyclohexanol and trimethylacetic acid analogously to EKample 4.

~'' , .
,

Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY 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 atoms R2 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms and R3 represents a hydroxycyclohexyl or morpholinocarbonylmethyl group, with the proviso that when R3 is a hydroxy-cyclohexyl group R2 is not an alkyl group) and pharmaceutically acceptable acid addition salts thereof which comprises reacting a compound of formula (II) (wherein Hal and R1 are as hereinbefore defined and R4 and R5, which may be the same or different, each represent a hydrogen atom or an organic acyl group) with a compound of formula (III) (wherein R2 and R3 are as hereinbefore defined) whereby a compound of formula I is obtained and if desired subsequently converting the compound of formula I thereby produced into a pharmaceutically acceptable acid addition salt thereof.
2. A process as claimed in claim 1 wherein a compound of formula I is used in which both R4 and R5 represent hydrogen atoms and wherein the reaction is effected in the presence of an organic acid.
3. A process as claimed in claim 2 wherein the organic acid used is acetic acid, butyric acid, valeric acid, trimethy-lacetic acid or capronic acid.
4. A process as claimed in claim 1 wherein the reaction is effected in the presence of a solvent.
5. A process as claimed in claim 4 wherein an excess of the compound of formula III is used as solvent.
6. A process as claimed in claim 2 or claim 3 wherein an excess of the organic acid is used as solvent.
7. A process as claimed in claim 1 or claim 2 wherein the reaction is effected at temperatures from 100 to 200°C.
8. A process as claimed in claim 1 wherein the compound of formula II is prepared immediately prior to the reaction and is not isolated before use.
9. A process as claimed in claim 1 wherein the groups R4 and/or R5 in the compound of formula II represent acetyl, butyryl, benzoyl or p-chlorobenzoyl groups.
10. A process according to claim 1 in which Hal is a bromine atom in the 3-position and R1 is a bromine atom in the 5-position, R2 represents a hydrogen atom and R3 represents a trans-4-hydroxycyclohexyl group.
11. A process for the preparation of 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine and its hydrochloride which comprises reacting 2-acetylamino-3,5-dibromobenzyl alcohol or 2-diacetylamino-3,5-dibromobenzyl alcohol, 2-butyrylamino-3,5-dibromobenzyl alcohol or 2-p-chlorobenzoylamino-3,5-dibromobenzyl alcohol with trans-4-amino-cyclohexanol, and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
12. A process for the preparation of 2-amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)benzylamine and its hydrochloride which comprises reacting 2-amino-3,5-dibromobenzyl alcohol with trans-4-amino-cyclohexanol in the presence of butyric acid, acetic acid, valeric acid, capronic acid or trimethylacetic acid, and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
CA205,312A 1973-07-23 1974-07-22 Process for the preparation of 2-amino-benzylamines Expired CA1052790A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19732337363 DE2337363A1 (en) 1973-07-23 1973-07-23 Anti-tussive secretolytic 2-aminobenzylamines prepn. - by reaction of 2-acylaminobenzyl alcohols and amines
DE19732337334 DE2337334A1 (en) 1973-07-23 1973-07-23 Anti-tussive secretolytic 2-aminobenzylamines prepn. - by reaction of 2-acylaminobenzyl alcohols and amines

Publications (1)

Publication Number Publication Date
CA1052790A true CA1052790A (en) 1979-04-17

Family

ID=25765536

Family Applications (1)

Application Number Title Priority Date Filing Date
CA205,312A Expired CA1052790A (en) 1973-07-23 1974-07-22 Process for the preparation of 2-amino-benzylamines

Country Status (13)

Country Link
JP (1) JPS57303B2 (en)
AT (1) AT331779B (en)
CA (1) CA1052790A (en)
CH (2) CH605614A5 (en)
DK (1) DK137952C (en)
ES (1) ES427622A1 (en)
FI (1) FI61700C (en)
HU (1) HU168702B (en)
NL (1) NL7409043A (en)
NO (1) NO139085C (en)
PL (1) PL91508B1 (en)
SE (1) SE418178B (en)
YU (1) YU36917B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ307918B6 (en) * 2017-12-04 2019-08-21 Vysoká Škola Báňská-Technická Univerzita Ostrava Device for reducing the effects of the abrasive flow of bulk material

Also Published As

Publication number Publication date
PL91508B1 (en) 1977-02-28
FI61700B (en) 1982-05-31
CH605614A5 (en) 1978-09-29
NO742674L (en) 1975-02-17
SE7409535L (en) 1975-01-24
DK137952B (en) 1978-06-12
FI177374A (en) 1975-01-24
ES427622A1 (en) 1976-08-01
ATA510374A (en) 1975-12-15
JPS5047946A (en) 1975-04-28
JPS57303B2 (en) 1982-01-06
CH620668A5 (en) 1980-12-15
NO139085B (en) 1978-09-25
NL7409043A (en) 1975-01-27
NO139085C (en) 1979-01-03
YU36917B (en) 1984-08-31
HU168702B (en) 1976-06-28
FI61700C (en) 1982-09-10
YU170574A (en) 1982-06-18
AT331779B (en) 1976-08-25
DK394674A (en) 1975-03-10
DK137952C (en) 1978-11-06
SE418178B (en) 1981-05-11

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