CA1044699A - N,n'-bis(2-(3-substituted-4-hydroxyphenyl)-ethyl or -2-hydroxyethyl)-polymethylenediamines - Google Patents
N,n'-bis(2-(3-substituted-4-hydroxyphenyl)-ethyl or -2-hydroxyethyl)-polymethylenediaminesInfo
- Publication number
- CA1044699A CA1044699A CA143,419A CA143419A CA1044699A CA 1044699 A CA1044699 A CA 1044699A CA 143419 A CA143419 A CA 143419A CA 1044699 A CA1044699 A CA 1044699A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- give
- compound
- bis
- benzyloxy
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Polymethylenediamines are disclosed of the formula:
Polymethylenediamines are disclosed of the formula:
Description
1 This invention relates to novel N,N'-bis[2-(3-sub-stituted-4-hydroxyphenyl)-ethyl or -2-hydroxyethyl]-poly- ~-methylenediamines which have useful pharmacodynamic activityO
;. More specifically the compounds of thi8 invention have utility5 as ~-adrenergic stimulants with relatively greater activity on ~:
respiratory smooth mu~cle than on cardiac muscleO Therefore ~ :.
~hese compounds have direct bronchodilator action with mini-. mal cardiac stimulation.
,~ Two in vitro pharmacological te~t procedures used .: 10 for determining selective ~-stimulant activity are: (1) effecton ~pontaneous tone of guinea pig tracheal chain preparations : ~ a mea~ure of ~-~timulant (direct relaxant) effect on air- ~ -... . .
-; way smooth muscle, and (2~ effect on rate of spontaneously beating right atria of the guinea pig as a measure of ~-stimu-1 15 lant effect on cardiac muscleO Compounds having selective bronchodilating properties are active in (1) above at a dose -: lower than is required in (2) above resulting in a positive : ~-~i separation ra~io, The compound~ of this invention are represented by 20 the following general structural formula:
Y~cll-cN2Nll(c~2)n-Nlicll2cll~y l HO OH
? ..
, 25 FORMULA I
? in which:
n represents a positive whole integer of from 4 to ,? 8, pre~er bly 6;
`I Z represent3 hydrogen or hydroxy;
Y represents NH2J NHCHO, NHCOCH3 9 NHCONH2 9 NHS0 NHC02R, NHCONHR. NHS02NH2, NHS02N(CH3)2, CH2 ~ 2 2 CH2NHSQ2R, CH2NHCONH2 or CH2S02R; and .1 2 . .
.~ , . . .
. .
1 R represents lower alkyl of from 1 to 5 carbon atoms, strai~ht or branched chain, preferably methyl. In the above formula, each of the Y and Z terms are identical.
The compounds of this invention may be uised in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by -methods well known to the art, are formed with both inorganic -~
or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene~alicylic, methane-- 10 sulfonic, ethanedisulfonic, acetic, oxalic, propionic, tar-taric, salicylic, citric, gluconic, aspartic, stearic, pal-mitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsul-famic, phosphoric and nitric acids.
The compounds of formula I above in which Z is `
hydroxy may be present as diastereoisomers which may be re-solved into d, 1 optical isomers. Re801ution of the optical isomers may be conveniently accomplished by fractional cryfftallization of their salts with optically active acids such as, for example, tartaric, camphor-10-sulfonicJ 0,0-di~
il benzoyltartaric, 0,0-di(p-toluoyl)tartaric, menthyloxyacetic, camphoric, or 2-pyrrolidone-5-carboxylic acids or N-acetyl-tryptophane from appropriate solvents. Unless otherwise specified herein or in the claims, it is intended to include ~ ;
all isomer~, whether separated or mixtures thereof~
The compounds of this invention where Z is hydrogen , are conveniently prepared from intermediates of the following ; formula:
j 30 . ` ' .
., ', .
- 3 - ~
.:
1 ~ H2CH2NHCH2C6H5 Rl ~:
FORMnLA II
5 in which X is N02, C02CH3 or CH2S02R, R is as defined above and Rl is benzyl or methyl, by reaction with an appropriate polymethylene dihalide~ preferably dibromide, in the presence or absence of a solvent with the ratio of phenalkylamine to dihalide at least 20 lo Nonreactive organic solvents which 10 may be used are alcohols such as methanol, ethanol or i~opro-panol and hydrocarbon~ such as benzene, toluene or xylene. :.
The reaction i8 carried out at temperatures from about 20 to 150C~ and for about 2 to 12 hour~. The resulting polymethyl-, enediamines of the following formula: ;
15 .
., X~CH2CH~NI-~CH2~n-~cH2cH2~x R1 ~ CH2C6H5 CH2C6H5 ~ Rl FORMULA III
1 20 in which X, Rl and n are as defined above, are ~ubjected to -~ further operations to provide the desired benzene ring substi-tuents as set forth in formula I. For example, compounds of; ` :
l formula III wherein X i8 N2~ Rl i5 benzyl and n i9 4 to 8 .; are reduced with Raney nickel and hydrazine hydrate or 1 25 platinum oxide to give the amino compounds of ~he formula:
i,~
H2 ~ H2cH2Nl-(cH2) lcH2cH2 C6H5CH20~J CH2C6H5 CH2C6H5 ~OCH2C6H5 . .
FO~MULA IV
.
! :
.
; ' :
' ' ~' . : '. ' ' ~ -: ` .
l~ "
1 These key intermediate~ are (8) hydrogenated catalytlcally, preferably with palladium-on-carbon, to give the debenzylated . -:
phenethylamines of formula I wherein Y is NH2; (b) treated -~
with acetic anhydride or ethyl form~te to give the N-acyl ~ :
5 derivative~; (c) reacted with phosgene, then heated to give 1:~
the isocyanates which are reacted with ammonia or a monosub-stituted alkyl amine to yield the ureido derivatives, or ~-~
reacted with a lower alkanol to yleld the carboalkoxyamino :
derlv~tives; (d) reacted with an alkyl sulfonyl chloride to 10 give the ~ulfonamido derivatives; or (e) treated with sul~
- famyl chloride or N,N-dimethyl sulfamyl chloride to yield the corresponding sulfamoylamlno derivatives. The compounds :
prepared according to the procedures (b) through (e) above are subsequently debenzylated by catalytic hydrogenation, preferably with palladium-on-carbon, to furnish the phenethyl-1 amines of formula I wherein Y is NHCHO, NHCOCH3, NHCONH2, .! ~ 2R, NHS02R, NHS02NH2 and NHS02N(CH ) j respectively. .
. 1 , . . .
I Likewise, compounds of formula III above whexein X .-,~ 20 i8 C02CH3, Rl i8 methyl and n i8 4 to 8 are (a) treated with :~l hydrobromic acid to give the corresponding s~licylic acid . -I derivatives which are first debenzylated by catalytic hydro~
l genation, preferably with palladium-on-carbon, and then re-' duced with for example diborane to yield the phenethylamines ".
I 25 of formula I whereln Y is CH20H; or (b) treated with ammonia `1 to give the corresponding ~mide derivatives, followed by , reduction with for example lithium aluminum hydr~de to obtain :.l the aminomethyl compounds which in turn are demethylated with for example boron tribromide or sodium ethyl mercaptide and 30 then debenzylated by catalytic hydrogenation, preferably with ' :
palladium-on-carbon, to yield the phenethylamines of formula I .`
,' " ~
., .
:' . :
,, ;: ' .
. .
?~99 1 wherein Y is CH2NH2; or the aminomethyl compounds are first reacted with an alkyl sulfonyl chloride to give the sulfona-midomethyl derivatives or reacted with sodium cyanate in acid to obtain the ureidomethyl compounds, and subsequently de-; 5 methylated and debenzylated as described above to yield, respectively, the phenethylamines of formula I wherein Y is CH2NHSO2R and CH2NHCONH2.
~. . . .
; The compounds of this invention where Z is hydroxy .~ :-are conveniently prepared from intermediates of the following .~
10 formula: : -.:; y' ~ COCH2Br `
~ . 2 ~
:~: FORMULA V ;
~in which Y~ is NO2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, 2NH2' NHSO2N(CH3)2' CO2CH3' CH3C2CH2 or ;~
; CH2SO2R, R is as defined above and R2 is benzyl, acetyl or ~, ~ hydrogen, by reaction with an appropriate N,N'-dibenzyl poly~
.I methylenediamine in equimolar quantities, or with the bromo- j:
ketone being present in excess amount, and in the presence of a nreactive organic solvent such as acetonitrile at a .
temperature up to the boiling point of thé solvent employed ~}
for about 1 to 4 hours. Alternatively the reaction may be carried out in the presence of a condensing agent such as an alkali metal carbonate, for example potassium carbonate. The thus formed polymethylenediamines of the following formula: ~.
~., O O
Y' ~ H27 (C~2)n ~CH2C ~ Y . ~ :
R20~J CH2C6H5 CH2C6HS ~LOR2 ,, ,.~
FORMLnA VI
, . ~;J~ .
.,, . ,. , , .,. , .. - , ~ - . - .
:~ . ' '. .. ': : ~ '. : .
:
1 in which Y', R2 and n are as defined above, are reacted fur~
ther to furnish the phenethanolamine products of formula I.
,~ .
For example, compounds of formula VI wherein Y' i9 N2 ~ R2 i~
benzyl and n i8 4 to 8 are reduced with platinum oxide to .
give the corresponding aminoalcohols which are then hydrogena-ted catalytically, preferably with palladium-on-carbon, to ~-yield~the debenzylated phenethanolamine products of formula I -:.
. . ~ .
wherein Y is NH2. ~-The compounds of formula VI wherein Y' i8 NHCHO, -NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N-(CH3)2 or CH2SO2R,-R2 is benzyl and n is 4 to 8 are catalyti~
cally hydrogenated to reduce the ketone groups and remove the ~r , ,~
benzyl protective groups, preferably with palladium-on-carbon, :~
i or alternatively the ketone groups are first reduced with for 15 example sodium borohydride, followed by debenzylation by .
8imilar catalytic hydrogenation, to yield in each instance ;::
I the phenethanolamine products of fonmula I wherein Y i8 NHCHO, x .I NHCOCH3, NHCONH2, NNSO2R, NNCO2R, NHCONHR, NHSO2NH2, ~ .
; NHSO2N(CH3)2 and CH2SO2R- . :
~ 20 Compounds of formula VI abofe wherein Y' is j CN3CO2CH2,.R2 is acetyl and n is 4 to 8 are treated with a .;
mineral acid such as hydrochloric or hydrobromic acid to give .~ -the corresponding 3-hydroxymethyl-4-hydroxy derivatives which j.
are hydrogenated catalytically, preferably with palladium-on- ..
25 carbon to obtain the phenethanolamine products of formula I ~. ~
i~ wherein Y i8 CH20H. . ~ :: -!:~ m e compounds of formula VI wherein Y' i8 C02CN3, ' ~
~ R2 is hydrogen and n is 4 to 8 are treated with ammonia to ` -.
I give the amide derivatives of the formula: i~
' !
"''.`'''``
`'"
1~4~
o o o o H2NC ~ CcH2N-(cH2)n ICH2 ~ 2 HO ~ ~H2C6H5 CH2C6H5 ~ OH
FORMULR VII :~
These intermediates are ~a) reduced with for example lithium aluminum hydride to give the aminomethyl phenethanol deriva~ :
tives which are then debenzylated by catalytic hydrogenation, preferably with palladium-on-carbon, to yield the phenethanol-amine product~ of formula I wherein Y i8 CH2NH2; or (b) treated with benzyl chloride to give the benzyloxy protected compounds which are in turn reduced with for example lithium aluminum hydride to obtain the corre~ponding ben~yloxy aminomethyl phenethanol compounds and the latter are reacted with sodium cyanate in acid to yield the ureidomethyl derivatives or re~
acted with an alkyl sulfonyl chlor~de to give the sulfonamido-methyl derivativesJ subsequently debenzylated by catalytic hydrogenation, preferably with palladium-on-carbon, to furnish the phenethanolamine products of formula I wherein Y is CH2NHCONH2 and CH2NHS02R, respectively.
The starting materials used herein of formulas II
and V are either known or are prepared by methods well-known in the art from readily avsilable materials. Further it will be appreciated that the intermediates described hereinabove~
particularly those of formulas III, IV, VI and VII, are valuable intermediates and as such form a part of this inven-tion.
The compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets J capsules, in~ectables or the like, by incorporating the appropriate dose of a compound of formula I, with carriers ., , , : , " , ,.
. ,: , ;::, - " 1~4~
:' l according to accepted pharmaceutical practices. Preferably a compound or an acld addition salt thereof is administered or~lly to an animal organ~sm in a tablet or capsule comprising an amount ~ufficient to produce ~-adrenergic stimulant activity.
The pharmaceutical carrier employed may be, for :
example, either a solid or liquid. Exemplary of solid car~
riers are lactose, terra alba, sucro~e, talc, gelatin, agar, -pectin, acacia, magnesium stearate, stearic acid and the like.
Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent can in;~;
clude any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a . .: .
wax. ;
A wide variety of pharmaceutical forms can be em-ployed. Thus, if a solid carrier is used the preparation can be table~ed, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will 20 be about 25 mg n to about 1 g. If a liquid carrier i8 used, ~i the preparation will be in the form of a syrup, emulsion, sof~ gelatin capsule~ sterile injectable liquid such as an ampule, or an aqueous or nonaqueous liquid suspension.
of particular applicability is an aerosol dispensing 25 system wherein the active medicament is incorporated with ' ' - Freon (fluorohydrocarbon) or other inert propellant in an aerosol con~ainer. Such an aerosol system will deliver a metered dose, administered once or twice at a time as needed.
The foregoing is a general description of how to prepare the compounds of thi~ invention. The following exam~
ples illustrate the preparation of ~pecific compounds having .
_ g _ ..
~.
1~4~
' 1 ~-adrenergic stimulant activity. However this should not be construed as a limitation of the lnvention since appropriate variations In the starting materials will produce other pro- -ducts set forth hereinsbove.
EXAMPL~ 1 A solution of 17.1 g. (0.1 m.) of benzyl bromide in , 100 ml. of dimethylsulfoxide is added ~lowly to a stirred mixture of 18.2 g. (0.1 m.) of 4-hydroxyo3-nitrophenethylamine in 1 1. of dimethylsulfoxide and 60 ml. of 2N sodium hydroxide at 85C. After addition is complete the reaction mixture iB
stirred at 85C. or an additional two hours, poured into ice-water, saturated with sodium chloride and extracted with ethyl acetate. The organic extract is dried and concentrated , to give 4-benzyloxy-3-nitrophenethylamine. The latter i 15 (2.72 g., 0.01 m.) in 50 ml. of toluene is refluxed azeo-tropically with 1.27 g. (0.012 m.) of benzaldehyde until water formation i8 completed (about one hour). Solvent is removed by distillation to leave the crude imine~ Sodium borohydride (0.38 g., 0.01 m.) i~ then added to a solution of ~he above , 20 imine in 30 ml. of methanol over a period of 30 minutes and I sfter stirring for an additional hour the reaction mixture is evaporated. The residue i8 treated with 2N hydrochloric acid and ether. The solid obtained is filtered and washed to give N-benzyl-4-benzyloxy-3-nitrophenethylamine hydrochlorideO
A mixture of 145 g. (0.4 m.) of N-benzyl-4-benzyloxy-3-nitrophenethylamine (obtained from the above hydrochloride) and 24.4 g. (0.1 m.) of 1,6-dibromohexane is heated on a steam bath for three hours. The cooled reaction mixture is extracted with water to remove N-benzyl-4-benzyloxy-3-nitro-phenethylamine hydrobromide. The residue is dissolved in 10%
aque~us hydrochloric acid snd the acid solution is made basic ~, ., 4~f~99 .` `` ` .~' .
~- 1 with 40Z aqueous sodium hydroxide. Thi8 mixture i8 extrscted with ether and the dried ether extract i8 concentrated in vacuo to leave a residue of N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3~
nitrophenyl)-ethyl]-hexamethylenediamine. `
;; 5 A suspension of Raney nickel (approximately 25 g.) it in ethanol i8 added to a solution of 30.3 g. (0-0375 m.) of ~ the above prepared diamine in 500 ml. of ethanol and then ,~ 25 ml. of hydrazine hydrate is added dropwise. The resulting ~-mixture i8 heated at reflux for one hour, filtered and evap-orated to dryness. The residue i8 extracted with ether and the washed and dried extract is acidified with hydrochloric !j~ acid to precipitste the tetrahydrochloride salt of N,N'-,!~ dibenzyl-N,N'-bi812-(3-amino-4-benzyloxyphenyl)-ethyl]-hexa- ''~.,',.~ '.' methylenediamine. '``- ` ;
A solution of 9.7 g. (0.0109 m.) of the above pre- ;~ -~
pared tetrahydrochloride in 65 ml. of methanol and 25 ml. of -water is added to a suspension of 1.5 g. of 10% palladium-on-~ carbon in 10 ml. of water. The mixture is hydrogenated on 1~ the Parr apparatus at room temperature using an initial pressure of 60 psi of hydrogen. After four hours the mixture is filtered, an additional 1.5 g. of 10% palladium-on-carbon i8 dded and the hydrogenation is continued. After four ~:~
hours the reaction mixture is filtered and the filtrate is concentrated in vacuo to give N,N'-bis[2-(3-amino-4-hydroxy-phenyl)-ethyl~-hexamethylenediamine tetrahydrochloride.
3: Similarly, by employing 1,8-dibromooctane in the ;~
above condensation with N-benzyl~4-benzyloxy-3-nitrophenethyl-amine a~s described above there is obtained the corresponding N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-nitrophenyl)-ethyl octamethylenediamine which is carried through the same se-quence of reactions, namely reduction with Raney nickel and '~`'~`''~ .
~ 11 ~ ','' ' `
~I '`. .
fg9 :
1 hydrogenation with palladium-on-carbon, to yield N,N'-bis[2-(3-amino-4-hydroxyphenyl)-ethyl]-octamethylenedismine.
A mixture of 31.0 g. (0.0415 m.) of N,N'-dibenzyl- ~--N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexfi~methylene-diamine (from the tetrahydrochloride salt prepared as in Example 1) and 50 ml. of acetic anhydride i8 heated on the steam bath for one hour. The reaction mixture is concentrated .~ in vacuo, the residue i8 ~uspended in water and made alkaline with 10% sodium hydroxide. The product is extracted with methylene chloride and the dried extract is concentrated to glve N,N'-dibenzyl-N,N'-bis[2-(3-acetamido-4-benzyloxyphenyl)-l ethyl]-hexamethylenediamine.
; The above prepared compound is treated with ethereal hydrogen chloride to obtain the corre8ponding dihydrochloride.
, . ~
The latter (6.95 g., 0.0077 m.) with 1.0 g. of 10% palladium~
on-carbon in 30 ml. of water and 70 ml. of ethanol is hydro-genated on the Parr apparatus using an initial hydrogen pres-sure of 60 p8i at room temperature. After hydrogen uptake i8 ` 20 complete the reaction mixture i8 filtered and the filtrate t'i' concentrated Ln vacuo to yield N,N'-bis~2-(3-acetamido-4 JI hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrochlorideO
EXAMPLE 3 ~-,' A mixture of 31.0 g. (0.0415 m.) of N,N'-dibenzyl- -1 25 N,N'-bis~2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylene ;~;ii diamine in 230 ml. of ethyl formate is stirred and refluxed ,'~f for 24 hour~. The reactlon mixture i9 evaporated in vacuo ;',,f and the residue i8 dissolved in methylene chlor~de, then washed with dilute hydrochloric acid and saturated sodium f 30 chloride solution. The dried solution is evaporated in vacuo ;, ;
'. f to give N,N'-dibenæyl-N,N'-bis[2-(4-benzyloxy-3-formamido-phenyl)-ethyl]-hexamethylenediamine.
i, .. . .
,`'1' ',, :` ` ` 1S~44~'~9 1 The thus prepared compound is treated with ethereal -- -hydrogen chloride and the resulting dihydrochloride (2.75 g., 0.00314 m.) is hydrogenated in 70 ml. of ethsnol and 30 ml.
of water with 1.0 g. of palladium-on-carbon using 60 pBi of hydrogen at room temperature. The mixture is filtered and the filtrate evaporated to yield N,N'-bis[2-(3-formamido-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrochloride.
A stirred solution of 40 g. (0.41 m.) of pho~gene in 150 ml. of toluene is held at 25C. while a mixture of .. , ~ . .
39.3 g. (0.0525 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-amino-4- r"
benzyloxyphenyl)-ethyll~hexamethylenediamine and 300 mlO of toluene is added 810wly. The resulting mixture is heated to reflux and continued for 30 minutes. Concentration in vacuo -gives the bis isocyanate. The latter (40 g.) in 500 ml. of `
~!,, dry benzene i8 saturated with ammonia. After one hour, the ;l mixture is cooled to give N,N'-dibenzyl-N,N'-bis[2-(4- ;
. . .~ , .
benzyloxy-3-ureidophenyl~-ethyl]-hexamethylenediamine. ;~
The above prepared compound is treated with ethereal hydrogen chloride to yield the dihydrochloride. A solution .
l of 9.5 g. (0.0109 m.) of the dihydrochloride in 75 ml. of .l methanol and 25 ml. of water is added to a suspension of 1.5 g. of 10% palladium-on-carbon in 10 ml. of water. The m~xture is hydrogenated on the Parr apparatus at room tempera--ture, using an initial pressure of 60 psi of hydrogenO After four hours the mixture i8 filtered, an additional 1.5 g. of 10% palladium-on-carbon i5 added and the hydrogenation is con~
tinued. After three hours the mixture is filtered and the , filtrate is concentrated in vacuo to give N,N'-bis[2-(4~
: 30 hydroxy-3-ureidophenyl)-ethyl]-hexamethylenediamine dihydro-chloride.
... . .
, - 13 - ` ~
.
, . ., . . .. " , . . . . . ... . . .
~ 3 ` 1 Similarly, employing methyl amine, n-butylamine or .,.
i80propylamine in the initial reaction with the bis i~ocyanate and proceeding with the hydrogenation as described above yields the corresponding products, as follow8: N,NI-bis[2-(4-hydroxy-`~ 5 -3-N'-methylureidophenyl)-ethyl~-hexamethylenediamine, N,N5-:; bis~2-(3-N'~n~butylureido~4-hydroxyphenyl)-ethyl]-hexamethyl-enediamine and N,N'-bis[2-(4-hydroxy-3N'-isopropylureidoo phenyl)-ethyl]-hexamethylenediamine.
A solution of 12.5 g. of the bi8 isocyanate pre-,, pared from N,N'-dibenæyl~N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylenediamine as descrlbed in Example 4, in 200 ml. of ethanol i8 refluxed for two hours. The reaction mixture is concentrated to give N,N'-dibenzyl-N,N'-bis[2-(4-.~` 15 benzyloxy-3-carboethoxyaminophenyl)-ethyll-hexamethylene-diamine.
The dihydrochloride of the above prepared compound i~ (2.2 g., 0.0025 m.), 0.5 g. of 10% palladium-on-carbon and !' 100 ml. of ethanol is hydrogenated on the Parr apparatus at ,. .
room temperature, using an initial pressure of 60 psi of hydrogenO When hydrogen uptake i8 complete the reaction mix-ture is filtered and the filtrate i8 concentrated in vacuo to yield N,N'-bi~2~(3-carboethoxyamino-4-hydroxyphenyl)-~' ethyl]-hexamethylenediamine dihydrochloride. :~
Similarly, refluxing a solution of the bis iso-cyanate in methanol or isopropanol and continuing as described ~ above yields as final products N,N'-bis[2-(3-carbomethoxy~
:l amino~4-hydroxyphenyl)-ethyl]-hexamethylenediamine and N,N'-.~, bis[2-(3 carboisopropoxyamino-4-hydroxyphenyl)-ethylJ-;~ 30 hexamethylenediamine, respectively.
. ~., . , ~. .
~''' `'.~ ~ .
14 :b . ' . ' ,~' ' ''-' ,``' ~
' ' " ', ' ' ' ' ' ' . . ' ' : , . ' . ' i ' ' ., ', ~ ., ' ~ ' . . , ' ' . ' .. . . . . . . ..
' ~ 99 ,~
' 1 EXAMPLE 6 To a solution of 7.5 g. (0.01 m.) of N,N'-dibenzyl- ' N,N'-bis[2-(3~amino-4-benzyloxyphenyl)-ethyll-hexamethylene~
diamine in 30 ml. of pyridine iB added 2.5 g. of methanesul-fonyl chloride. The reaction mixture is allowed to stand atroom temperature overnight and i8 then added to excess water to yield N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy~3-methane~ul-fonamidophenyl)-ethyl]-hexamethylenediamine.
The dihydrochloride of the above prepared compound is hydrogenated as described in Example 1 to furnish the product N,N'-bis~2-(4-hydroxy-3-methanesulfonRmidophenyl)-ethyl]-hexamethylenediamine dihydrochloride. -: EXAMPLE 7 To a ~olution of 36.6 g. (0.049 m.) of N,N'-dibenzyl-N,N~-bis[2 (3-amino-4-benzyloxyphenyl)-ethyl~-hexamethylenedi~ ;r amine in 250 ml. of dry pyridine is added 28.6 g. (002 m.) of dimethylsulfamoyl chloride in 40 ml. of pyridine at OolOGo `
The reaction mixture i~ stirred in the cold overnight, then poured into water and extracted with ether. The ether ex-20 tract is washed with water and extracted with dilute aqueou~ -potassium hydroxide. The latter extract is washed with ether, acidified with hydrochlorlc acid and extracted with methylene chloride. The dried extract is evaporated in vacuo to give N,N'-dibenzyl-N,N'-bisr2-(4-benzyloxy-3-N,N-dimethylsulfamoyl-aminophenyl)-ethyll~hexamethylenediamine.
The dihydrochloride oi the thus prepared compound ~ (9.26 gO~ 0.01 m.) is hydrogenated in 30 ml. of water and ,~ 70 ml. of ethanol w~th 005 g. of palladium-on-carbon at room `~
temperature for two hours in the Parr apparatus. The reaction mixture is filtered, an additional 1 g. of pslladium-on-carbon ., ~ ', .
- .
:
:
` 1~ 4 ~9 ;l 18 added and the hydrogenation is continued for two hour8.
The mlxture i9 filtered and the filtrate evaporated to yield N,N'-bis[2-(3-N,N~dimethylsulfamoylamino-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrochloride.
To a stirred solution of 5.8 g. (0.05 m.) of sul-famyl chloride in 75 ml. of dry benzene at 10C. is added, in small portions, 37.4 gO (0005 m.) of N,NI-dibenzyl-N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylenediamine.
After the mix~ure i6 stirred at 10-20C. for 30 minutes, it i~ extracted with 5% aqueous sodium hydroxide. Adding dilute h~drochloric acid to the basic extract precipitates the product, N,N'-dibenzyl-NJN'-bis[2-(4-benzyloxy-3-suIfamoyl aminophenyl)ethyl]-hexamethylenediamine.
~; .
Proceeding as described in Example 7, namely ~`
h~drogenation of the corresponding dihydrochloride yields ~-~
j N,N'~bi8[2-(4 hydroxy-3-8ulfamoylaminophenyl)-ethyllhexa-methylenediamine dihydrochloride.
A solution of 2044 gO (0.01 m.) of 3-carbomethoxy-4-methoxyphenethylamine (prepared from 3-carbomethoxy-4-methoxybenzyl chloride by reaction with sodium cyanide fol-lowed by catalytic reduction of the resulting benzyl nitrile) in 25 ml. of toluene is refluxed azeotropically with 1.27 g.
,25 (0.012 m.~ of benzaldehyde for one hour, then the solution ' i8 concentrated to give the N-benzal derivative. Sodium borohydride (0.38 g., 0.01 m.) is then added to a solution ~'of the N-benzal derivative in 25 ml. of methanol over a period of 30 minutes. After being stirred for an additional ~30 hour at 25C. the reaction mixture i9 evaporated. The resi-'~due i8 treated with 2N hydrochloric acid and ether to i . .
~ - 16 -,,, , ~ .
~ 3 :
l precipitate N~benzyl-3-carbome~hoxy-4-methoxyphenethylamine hydrochloride.
A mixture of 119.5 g. (0.4 m.) of N-benzyl-3-carbo methoxy-4-methoxyphenethylamine (obtained from the above -hydrochloride) and 24.4 g. (0.1 m.) of 1,6-dibromohexane in 250 ml. of acetonitrile i9 refluxed for three hours. The cooled reaction mixture i8 diluted with ether to precipitate N-benzyl-3-carbomethoxy-4-methoxyphenethylamine hydrobromide.
; The mixture i8 filtered and the filtrate i8 concentrated ~-- lO in vacu to leave a residue of NJN'-dibenzyl-N,N'~bis[2-(3- -carbomethoxy-4-methoxyphenyl)-ethyl]-hexamethylenediamine. -~
A solution of 3.1 ~. (0.0041 m.) of the dihydro~ ~
chloride of the above prepared diamine in 30 ml. of methanol ;-~ ;
and 25 ml. of an aqueous solution of ammonia (d. 00880) is allowed to stand at room temperature about 20 hours~ The mixture i8 evaporated under reduced pre~sure to give a resi-rl due which with methanolic hydrochloric acid yields the `A,.
dihydrochloride of N,N'-dibenzyl-N,NI-bis[2-(3-carboxamido-4~ ;
~I methoxyphenyl)-ethyl]-hexamethylenediamine.
A solution of the above carboxamido free base ,~
liberated by aqueous ammonia from 3061 g. (0.005 m.~ of the dihydrochloride is added to a warm, stirred suspenslon of 1.5 g. of lithium aluminum hydride in 20 ml. of tetrahydro- '~'7,;," ' ~,~! ;` furan. After stirring at reflux for about 17 hours the cooled ,~ 25 reaction mixture is treated with 5 ml. of water, filtered and l the filtrate is evaporated. The residue is dissolved in ;;~i~ ethanol and ethereal hydrogen chloride is added to precipi tate the tetrahydrochloride of N,N'-dibenzyl-N,N'-bis[2-(3-j~ aminomethyl~4-methoxyphenyl)-ethyl]-hexamethylenediamine.
To a suspension of 12 g. (0.0177 m.) of the free ~ base derived from the above tetrahydrochloride in 75 ml. of ; -~
.', .', ' 1 methylene chloride i8 ~dded gradually 9.0 ml. of boron tri-bromide, with 8tirring in an ice bath. The ice bath i8 removed and the mixture is stirred for one hour. The reaction mixture i8 evapor~ted in vacuo, excess methanol i8 added gradually and the solution evaporated. The residue is dis-solved in water and the solution is neutralized with sodium bicarbonate to give N,N'-dibenzyl-N,N'-bis~2-(3-aminomethyl-4-hydroxyphenyl)-ethyl~-hexamethylenediamine.
A solution of 17.3 g. (0.0218 m.) of the tetrahydro chloride prepared from the above free ba~e in 75 ml. of methanol and 25 ml. of water is hydrogenated with palladium-on-carbon as described in Example 1 to give N,N'-bis[2-(3 aminomethyl-4-hydroxyphenyl~-ethyl]-hexamethylenediamine tetrahydrochloride.
.; , .... .
Following the procedure of Example 6, 2.5 g. of methanesulfonyl chloride is added to a solution of 6.78 g~
(0.01 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-aminomethyl-4 ;
methoxyphenyl) ethyl]-hexamethylenediamine in 30 ml~ of pyri~
dine and the mixture is allowed to stand at room temperature overnight to yield N,NI-dibenzyl-N,N'-bis[2-(3-methanesul-., ;;.
fonamidomethyl~4-methoxyphenyl)~ethyl]-hexamethylenediamine The latter as the dihydrochloride is demethylated and then debenzylated ~8 described in Example 9 to furnish the product N,N'-[2 (4-hydroxy-3--methanesulfonamidomethylphenyl) ethyl]-,. ' . .
hexamethylenediamine dihydrochloride. -~
., , ~ - .
A solution of 54.2 g. (0.08 m.) of N,N'-dibenzylo N,N'-bis~2-(3-aminomethyl-4-methoxyphenyl)-ethyl]~hexamethyl-enediamine in 500 ml. of acetic acid and 175 ml. of w~ter is ;;;
~tirred at 40C. while a slurry of 23.5 g. of 90% sodium ;
`"' ~.' .
- 18 - ~
' ~ :
' 4~ l';39 1cyanate (21.2 g., 0.32 m.) in 160 ml. of water i8 added in portions. The resulting mixture is stirred at 40C. for one hour, diluted with 1600 ml. of water and extracted with methylene chloride`. The extract i8 washed with sodium car- ~
5 bonate, dried and evaporated in vacuo to give N,N'-dibenzyl- ,-'!,.'' ' N,N'-bis[2-(4~methoxy-3-ureidomethylphenyl)-ethyl]-hexamethyl-enediamine. The latter as the dihydrochloride i8 demethylated i ;--and debenzylated as described in Example 9 to give N,N'~bis[2 (4-hydroxy-3-ureidomethylphenyl)-ethyll-hexamethylenediamine dihydrochloride, A mixture of 1.56 g. (0.0023 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-carbomethoxy-4-methoxyphenyl)-ethyll-hexàmethyl- ~i~
enediamine and 40 ml. of 48% aqueous hydrobromic acid is ~-refluxed for four hours. The cooled reaction mixture is fil-tered to give N,N'-dibenzyl-N,N'-bis[2-(3-carboxy-4-hydroxy-phenyl)-ethyll-hexamethylenediamine dihydrobromide. The ~-latter is hydrogenated with palladium-on-carbon as described in Example 1 to yield N,N'-bis[2-(3-carboxy-4-hydroxyphenyl)- `~
20 ethyl]-hexamethylenediamine dihydrobromide. The free base i obtained from this dihydrobromide (0.8 g., 0~0018 m.) is added to an ice cold solution of 40 ml. of lM borane in '--tetrahydrofuran (0.04 m.) while stirring under nitrogen. The temperature i8 maintained at 0C. for 20 hours, the solution ,~; 25 is then refluxed for one hour and concentrated in vacuo.
Several poxtions of methanol are added, the solution is con- -centrated and the residue is dissolved in ethanol and filtered.
l :; , ] Sulfuric acid i8 added to pH 2.0 to give N,NI-bis[2-(4-hydrcxy-3-hydroxymethylphenyl)~ethyll-hexamethylenediamine sulfateO
~ ; 30 EXAMPLE 13 !~ To a stirred solution of 5.42 g. (0.02 m.) of ~ 4-benzyloxy-3 nitroacetophenone in 100 ml. of chloroform is , . . .
,~ ~, 19 ~ 9 1 added 3.2 g. (0.02 m.) of bromlne. The mixture i8 ~tirred at room temperature for about 45 minutes and the solution i8 concentrated in vacuo at 25-30C. to leave 4-benzyloxy-a~
bromo-3-nitroacetophenone. The latter (35.0 g., 0.1 m.) in 250 ml. of acetonitrile is stirred at 25C. with 29.6 g.
(0.1 m.) of N,N'-dibenzyl-hexamethylenediamine for two hours.
The cooled reaction mixture i8 filtered to remove the dihydro-bromide of N,N'-dibenzyl-hexamethylenediamine. Acidification of the filtrate with ethereal hydrogen chloride gives N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-nitrophenyl)-2-oxoethyl]-hexamethylenediamine dihydrochloride.
The above prepared dihydrochloride i8 hydrogenated --in methanol ~olution with platinum oxide catalyst to obtain the dihydrochloride of N,N'-dibenzyl-N,N'-bis[2-(3-amino-4-15 benzy-loxyphenyl)-2-hydroxyethyl]-hexamethylenediamine. The `
latter i8 debenzylated as described in Example 1 with palladium-on-carbon and a methanolic solution of the product i8 treated with ethereal hydrogen chloride to yield N,N~-bis12- '~r;' ' ' ' ~3-amino-4-hydroxyphenyl)-2-hydroxyethyl]-hexamethylenediamine tetrahydrochloride, m.p, 202-205C.
A mixture of 20.0 g. (0.083 m.) of 3-amino-4-benzyl-oxyacetophenone and 50 ml. of acetic anhydride i8 heated on the steam bath for one hour. The resulting solution is con~
centrated in vacuo, the residu~l solid is suspended in water and the mixture made alkaline with 10% sodium hydroxide. The crystalline product is extracted with methylene chloride, and the dried extract is concentrated to give 3-acetamido-4-benzyloxyacetophenone, m.p. 132-134C.
To a stirred solution of 8.6 g. (0.03 m.) of 3-acetamido-4-benzyloxyacetophenone and 2.6 g. (0.03 m.) of 1 2-pyrrolidone in 300 ml. of tetrahydrofuran i8 added dropwise a solution of 1500 gO (0.03 m.) of pyrrolidone hydrotribromide in 300 mlO of tetrahydrofuran. The mixture is stirred a~ room temperature for 18 hours, filtered and the filtrate concen-trated in vacuo to yield 3-acetamido-4~benzyloxy-a-bromoaceto-phenone, m.pO 163-166C
A mixt~re of 3.48 gO (0.01 mO~ of 3-acetamido 4-benzyloxy-a-bromoacetophenone and 2096 g. (0~01 m.) of N,N'- ~-dibenzyl-hexame~hylenediamine in 50 mlO of acetonitrile i~
~tirred at 25Co for two hoursO The cooled reaction mixture is filtered and the filtrate acidified with ethereal hydrogen chloride to give N,N'-dibenzyl-N,N'-bis[2~3-acetamido-4 benzyloxyphenyl)-2-oxoethyl~-hexamethylenediamine dihydrochlor~
;' ideO The latter i8 hydrogenated with 10% palladium-on-carbon ~
I 15 to yield N,N'-bis[2-(3-acetamido-4-hydroxyphenyl~-2-hydroxy- -ethyl]-hexamethylenediamine dihydrochloride, m p. 218-219C do Similarly, equimolar amounts of 3-acetamido-4- ~ -benzyloxy-a-bromoacetophenone and N,N'-dibenzyl-tetramethylene-diamine are condensed as described above to give the N,N'-20 dibenzyl-N,N'-bis~2~3-acetamido-4-benzyloxyphenyl)-2-oxo- -ethyl]-tetramethylenediamine which is likewise hydrogenated to furnish N,N' bis~2~(3-acetamido-4-hydroxyphenyl)-2-hydroxy-ethyl]-tetramethylenediamine. -.
A solution of 20 g. (0.083 mO) of 3-amino-4-benzyl-oxyacetophenone in 230 ml. of ethyl formate is stirred and refluxed for 24 hours. The reaction mixture is evaporated in vacuo and the residue is dissolved in methylene chloride, then washed with dilute hydrochloric acid and saturated sodium chloride 301utionO The dried solution i8 evaporated in vacuo ;
' ~'' .
"; ~ . ' ': ~ . .' .' ' ' ' " ' ;
'f ~' , ~: ' ' ' , ' ' . ' ~ ' ,~"" " ' ',' : , .
~ 3~
1 to give a residue which upon trituration with ether give8 4-benzyloxy-3-formamidoacetophenone, m.p. 121-123 C.
To a solution of 17.5 g. (0.0648 m.) of 4-benzyloxy-3-formamidoacetophenone and 5.51 g. (0.0648 m.) of 2-pyrroli-done in 650 ml. of tetrahydrofuran, stirred at roQm tempera-ture, i8 added dropwise a solution of 32.2 g. (0.0648 m.) of pyrrolidone hydrotribromide in 650 ml. of tetrahydrofuran.
The mixture is stirred overnight at room temperature, filtered and the filtrate evaporated. The residue is dissolved in methylene chloride, washed with water, dried and evaporated to leave 4-benzyloxy-a-bromo-3-formamidoacetophenone, m.p 124-128C.
Following the procedure~ of Example 14, equimolar ;~ ~
amounts of 4-benzyloxy-a-bromo-3-formamidcacetophenone and ~ -N,N'-dibenzyl-hexamethylenediamine are stirred in acetonitrile at 25C. for two hours to give N,N'-dibenzyl-N,N'-bis[2-(4- ~-benzyloxy-3-formamidophenyl)-2-oxoethyl3-hexamethylenediamine which i8 similarly hydxogenated to furnish N,N'-bis[2-(3-formamido-4~hydroxyphenyl)-2-hydroxyethyl]-hexamethylenediamine. ~;~
A stirred solution of 40 g. (0.41 m.) of phosgene in 150 ml. of toluene i8 held at 25C. with a cooling bath -while a mixture of 25.2 g. (0.105 m.) of 3-amino-4-benzyloxy- ~ -acetophenone and 220 ml. of toluene are added ~lowly. The -25 mixture i8 heated to reflux and continued for 30 minutesO ~
Nitrogen is passed through the mixture and then concentrated ~ -in vacuo to give a crystalline isocyanate, m.p. 105-106C.
A stirred solution of the isocyanate (28.~0 g.) in 500 ml. of dry benzene is ~aturated with ammonia. Afeer one hour, the mixture is cooled to give the crystalline 4-benzyloxy-3~ureidoacetophenone, m.p. 184-186C.
1 To a stirred solution of 5.7 g. (a.o2 m.) of 4-benzyloxy-3-ureidoacetophenone in 100 ml. of chloroform is added 3.2 g. (0.02 mO) of bromine. The mixture i~ stirred at room temperature for about 45 minutes and the solution i~ con- ;
` 5 centrated in vacuo at 25-30C. to give 4-benzyloxy-a-bromo-3-ureidoacetophenone.
Following the procedures of Exa~ple 14, the above prepared acetophenone and N,N'-dibenzyl-hexamethylenediamine are refluxed in acetone for 12 hours and the resulting N,N'- ?7;. i , 10 dibenzyl-N,N'-bis[2-(4-benzyloxy-3-ureidophenyl)-2-oxoethyl~-; hexamethylenediamine i8 hydrogenated to yield N~N'-b~s~2-(4 hydroxy-3-ureidophenyl)-2-hydroxyethyl]-hexamethylenediamineO
Similarly, 4-benzyloxy-a-bromo-3-(N'-methylureido)-acetophenone, prepared from the above isocyanate by reacting with methyl amine followed by bromination as deæcribed above is refluxed in acetone for 12 hours with N,N'-dibenzyl-hexa-methylenediamine to give the corresponding N,N'-dibenzyl-N,N~
bis[2-(4~benzyloxy-3-N'-methylureidophenyl)-2-oxoethyl]-hexa- `;
methylenediamine which in turn is hydrogenated with palladium-on-carbon to furnish the product N,N'-bis[2-(4-hydroxy-3-N'-methylureidophenyl)-2-hydroxyethyl]-hexamethylenediamine. `-A solution of the isocyanate (12.5 g.), prepared as i in Exsmple 16, in 170 ml. of ethanol is refluxed for two hours.
The reaction mixture i~ concentrsted and the residue iæ tri-turated with hexane to give the crystalline 4-benzyloxy-3-carboethoxyaminoacetophenone, m.p. 84-86C.
To a stirred solution of 1.6 gO (0.005 m.) of 4-benzyloxy-3-carboethoxyaminoacetophenone in 20 mlO of chlorofrom and 0.2 g. of benzoyl peroxide is added 0.84 g.
`
1 (5% excess) of bromine in 2 mlO of chloroform. The mixture is stirred at room te~pera~ure for about 45 minutes in the presence of a spotlight and the solution i8 concentrated in vacuo at 35-45C~ to give 4-benzyloxy-a-bromo-3-carboethoxy-S aminoacetophenone, m.p. 98-100C.
By employing the procedure~ described in Example 14 ,~ ,.
the above prepared bromoketone and N,N~-dibenzyl-hexam~thylene- `~
diamine are stirred at 25Co in acetone for two hours to yield N,~'-dibenzyl N,N'-bis~2~(4-benzyloxy-8-carboethoxyaminophenyl)-- 10 2oxoethyl]-hexamethylenediamine which in turn is similarly `~
hydrogenated to give N,N'~bis~2-(3-carboethoxyamino-4-hydroxy-phenyl)-2~hydroxyethyl]-hexamethylenediamine; m.p. dihydro-chloride 227-228Cod ~
.EXAMI!LE 18 A mixture of 3098 g. (O o Ol mO) of 4-benzyloxy-3- ;
methanesulfonamido-a-bromoacetophenone ~UOSO Pa~ent NOD ,, 3,4789149~ and 2096 g. (OoOl m.) of N,N'-dibenzyl-hexamethyl-enediamine in 50 ml. of acetonitrile is stirred at 25C. for !,, ¦ two hoursO The cooled reaction mixture i8 filtered and the ?
~ 20 filtrate i~ acidified with ethereal hydrogen chloride to give .
N,N'-dibenzyl~N,N'-bisl2-~4-benzyloxy-3-methanesulfonamido-phenyl)-2~oxoethyl]-hexamethylenediamine dihydrochloride. The ~;~
::
latter is hydrogenated with 10% palladium-on~carbon to yield N,N'-bis[2(4-hydroxy-3-methanesulfonamidophenyl~-2-hydroxy-25 ethyl]-hexamethylenediamine dihydrochloride, m.p~ 194-195Co `
:~, .
j A solution of 23.6 g. ~0. 098 m.~ of 3~amino-4-benzyloxyacetophenone in 200 mlO of dry pyridine is treated with 28.6 g. (002 m.3 of dimethylsulfamoyl chloride in 40 ml.
of pyridine at 0-10C. The reaction mixture is stirred in the cold overnight, then poured into water and extracted with ether. The ether ex~ract is washed with water and extracted .. . . . .. .
,r~ ,, 4~99 1 with dilute aqueous potassium hydroxide. The latter extract f-- is washed with ether, acidified with hydrochloric acid and extracted with methylene chloride. The dried methylene `
chloride solution i8 evaporated in vacuo to give 4-benzyloxy- ~
3-(N,N-dimethyl~ulfamoylamino)-acetophenone, m.p. 108-109.5C. ;~ i To a stirred solution of 1.74 g. (0.005 m.) of 4-benzyloxy-3-(N,N-dimethylsulfamoylamino)-acetophenone in 25 ml. of chloroform is added a solution of 0.9 g. (0.0056 m.) of bromine in 25 ml. of chloroform. The mixture i8 stirred at room temperature for about 30 minutes and the solution is 1~ concentrated to leave 4-benzyloxy-a-bromo-3-(N,N-dimethyl-¦~ sulfamoylamino)-acetophenone, m.p. 80-85C.
Following the procedures of Example 14, the above prepared acetophenone is reacted with N,N'-dibenzyl-hexa-methylenediamine in acetonitrile at 25C. to give N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-N,N-dimethylsulfa ylaminophenyl)- `~
;. More specifically the compounds of thi8 invention have utility5 as ~-adrenergic stimulants with relatively greater activity on ~:
respiratory smooth mu~cle than on cardiac muscleO Therefore ~ :.
~hese compounds have direct bronchodilator action with mini-. mal cardiac stimulation.
,~ Two in vitro pharmacological te~t procedures used .: 10 for determining selective ~-stimulant activity are: (1) effecton ~pontaneous tone of guinea pig tracheal chain preparations : ~ a mea~ure of ~-~timulant (direct relaxant) effect on air- ~ -... . .
-; way smooth muscle, and (2~ effect on rate of spontaneously beating right atria of the guinea pig as a measure of ~-stimu-1 15 lant effect on cardiac muscleO Compounds having selective bronchodilating properties are active in (1) above at a dose -: lower than is required in (2) above resulting in a positive : ~-~i separation ra~io, The compound~ of this invention are represented by 20 the following general structural formula:
Y~cll-cN2Nll(c~2)n-Nlicll2cll~y l HO OH
? ..
, 25 FORMULA I
? in which:
n represents a positive whole integer of from 4 to ,? 8, pre~er bly 6;
`I Z represent3 hydrogen or hydroxy;
Y represents NH2J NHCHO, NHCOCH3 9 NHCONH2 9 NHS0 NHC02R, NHCONHR. NHS02NH2, NHS02N(CH3)2, CH2 ~ 2 2 CH2NHSQ2R, CH2NHCONH2 or CH2S02R; and .1 2 . .
.~ , . . .
. .
1 R represents lower alkyl of from 1 to 5 carbon atoms, strai~ht or branched chain, preferably methyl. In the above formula, each of the Y and Z terms are identical.
The compounds of this invention may be uised in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by -methods well known to the art, are formed with both inorganic -~
or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene~alicylic, methane-- 10 sulfonic, ethanedisulfonic, acetic, oxalic, propionic, tar-taric, salicylic, citric, gluconic, aspartic, stearic, pal-mitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsul-famic, phosphoric and nitric acids.
The compounds of formula I above in which Z is `
hydroxy may be present as diastereoisomers which may be re-solved into d, 1 optical isomers. Re801ution of the optical isomers may be conveniently accomplished by fractional cryfftallization of their salts with optically active acids such as, for example, tartaric, camphor-10-sulfonicJ 0,0-di~
il benzoyltartaric, 0,0-di(p-toluoyl)tartaric, menthyloxyacetic, camphoric, or 2-pyrrolidone-5-carboxylic acids or N-acetyl-tryptophane from appropriate solvents. Unless otherwise specified herein or in the claims, it is intended to include ~ ;
all isomer~, whether separated or mixtures thereof~
The compounds of this invention where Z is hydrogen , are conveniently prepared from intermediates of the following ; formula:
j 30 . ` ' .
., ', .
- 3 - ~
.:
1 ~ H2CH2NHCH2C6H5 Rl ~:
FORMnLA II
5 in which X is N02, C02CH3 or CH2S02R, R is as defined above and Rl is benzyl or methyl, by reaction with an appropriate polymethylene dihalide~ preferably dibromide, in the presence or absence of a solvent with the ratio of phenalkylamine to dihalide at least 20 lo Nonreactive organic solvents which 10 may be used are alcohols such as methanol, ethanol or i~opro-panol and hydrocarbon~ such as benzene, toluene or xylene. :.
The reaction i8 carried out at temperatures from about 20 to 150C~ and for about 2 to 12 hour~. The resulting polymethyl-, enediamines of the following formula: ;
15 .
., X~CH2CH~NI-~CH2~n-~cH2cH2~x R1 ~ CH2C6H5 CH2C6H5 ~ Rl FORMULA III
1 20 in which X, Rl and n are as defined above, are ~ubjected to -~ further operations to provide the desired benzene ring substi-tuents as set forth in formula I. For example, compounds of; ` :
l formula III wherein X i8 N2~ Rl i5 benzyl and n i9 4 to 8 .; are reduced with Raney nickel and hydrazine hydrate or 1 25 platinum oxide to give the amino compounds of ~he formula:
i,~
H2 ~ H2cH2Nl-(cH2) lcH2cH2 C6H5CH20~J CH2C6H5 CH2C6H5 ~OCH2C6H5 . .
FO~MULA IV
.
! :
.
; ' :
' ' ~' . : '. ' ' ~ -: ` .
l~ "
1 These key intermediate~ are (8) hydrogenated catalytlcally, preferably with palladium-on-carbon, to give the debenzylated . -:
phenethylamines of formula I wherein Y is NH2; (b) treated -~
with acetic anhydride or ethyl form~te to give the N-acyl ~ :
5 derivative~; (c) reacted with phosgene, then heated to give 1:~
the isocyanates which are reacted with ammonia or a monosub-stituted alkyl amine to yield the ureido derivatives, or ~-~
reacted with a lower alkanol to yleld the carboalkoxyamino :
derlv~tives; (d) reacted with an alkyl sulfonyl chloride to 10 give the ~ulfonamido derivatives; or (e) treated with sul~
- famyl chloride or N,N-dimethyl sulfamyl chloride to yield the corresponding sulfamoylamlno derivatives. The compounds :
prepared according to the procedures (b) through (e) above are subsequently debenzylated by catalytic hydrogenation, preferably with palladium-on-carbon, to furnish the phenethyl-1 amines of formula I wherein Y is NHCHO, NHCOCH3, NHCONH2, .! ~ 2R, NHS02R, NHS02NH2 and NHS02N(CH ) j respectively. .
. 1 , . . .
I Likewise, compounds of formula III above whexein X .-,~ 20 i8 C02CH3, Rl i8 methyl and n i8 4 to 8 are (a) treated with :~l hydrobromic acid to give the corresponding s~licylic acid . -I derivatives which are first debenzylated by catalytic hydro~
l genation, preferably with palladium-on-carbon, and then re-' duced with for example diborane to yield the phenethylamines ".
I 25 of formula I whereln Y is CH20H; or (b) treated with ammonia `1 to give the corresponding ~mide derivatives, followed by , reduction with for example lithium aluminum hydr~de to obtain :.l the aminomethyl compounds which in turn are demethylated with for example boron tribromide or sodium ethyl mercaptide and 30 then debenzylated by catalytic hydrogenation, preferably with ' :
palladium-on-carbon, to yield the phenethylamines of formula I .`
,' " ~
., .
:' . :
,, ;: ' .
. .
?~99 1 wherein Y is CH2NH2; or the aminomethyl compounds are first reacted with an alkyl sulfonyl chloride to give the sulfona-midomethyl derivatives or reacted with sodium cyanate in acid to obtain the ureidomethyl compounds, and subsequently de-; 5 methylated and debenzylated as described above to yield, respectively, the phenethylamines of formula I wherein Y is CH2NHSO2R and CH2NHCONH2.
~. . . .
; The compounds of this invention where Z is hydroxy .~ :-are conveniently prepared from intermediates of the following .~
10 formula: : -.:; y' ~ COCH2Br `
~ . 2 ~
:~: FORMULA V ;
~in which Y~ is NO2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, 2NH2' NHSO2N(CH3)2' CO2CH3' CH3C2CH2 or ;~
; CH2SO2R, R is as defined above and R2 is benzyl, acetyl or ~, ~ hydrogen, by reaction with an appropriate N,N'-dibenzyl poly~
.I methylenediamine in equimolar quantities, or with the bromo- j:
ketone being present in excess amount, and in the presence of a nreactive organic solvent such as acetonitrile at a .
temperature up to the boiling point of thé solvent employed ~}
for about 1 to 4 hours. Alternatively the reaction may be carried out in the presence of a condensing agent such as an alkali metal carbonate, for example potassium carbonate. The thus formed polymethylenediamines of the following formula: ~.
~., O O
Y' ~ H27 (C~2)n ~CH2C ~ Y . ~ :
R20~J CH2C6H5 CH2C6HS ~LOR2 ,, ,.~
FORMLnA VI
, . ~;J~ .
.,, . ,. , , .,. , .. - , ~ - . - .
:~ . ' '. .. ': : ~ '. : .
:
1 in which Y', R2 and n are as defined above, are reacted fur~
ther to furnish the phenethanolamine products of formula I.
,~ .
For example, compounds of formula VI wherein Y' i9 N2 ~ R2 i~
benzyl and n i8 4 to 8 are reduced with platinum oxide to .
give the corresponding aminoalcohols which are then hydrogena-ted catalytically, preferably with palladium-on-carbon, to ~-yield~the debenzylated phenethanolamine products of formula I -:.
. . ~ .
wherein Y is NH2. ~-The compounds of formula VI wherein Y' i8 NHCHO, -NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N-(CH3)2 or CH2SO2R,-R2 is benzyl and n is 4 to 8 are catalyti~
cally hydrogenated to reduce the ketone groups and remove the ~r , ,~
benzyl protective groups, preferably with palladium-on-carbon, :~
i or alternatively the ketone groups are first reduced with for 15 example sodium borohydride, followed by debenzylation by .
8imilar catalytic hydrogenation, to yield in each instance ;::
I the phenethanolamine products of fonmula I wherein Y i8 NHCHO, x .I NHCOCH3, NHCONH2, NNSO2R, NNCO2R, NHCONHR, NHSO2NH2, ~ .
; NHSO2N(CH3)2 and CH2SO2R- . :
~ 20 Compounds of formula VI abofe wherein Y' is j CN3CO2CH2,.R2 is acetyl and n is 4 to 8 are treated with a .;
mineral acid such as hydrochloric or hydrobromic acid to give .~ -the corresponding 3-hydroxymethyl-4-hydroxy derivatives which j.
are hydrogenated catalytically, preferably with palladium-on- ..
25 carbon to obtain the phenethanolamine products of formula I ~. ~
i~ wherein Y i8 CH20H. . ~ :: -!:~ m e compounds of formula VI wherein Y' i8 C02CN3, ' ~
~ R2 is hydrogen and n is 4 to 8 are treated with ammonia to ` -.
I give the amide derivatives of the formula: i~
' !
"''.`'''``
`'"
1~4~
o o o o H2NC ~ CcH2N-(cH2)n ICH2 ~ 2 HO ~ ~H2C6H5 CH2C6H5 ~ OH
FORMULR VII :~
These intermediates are ~a) reduced with for example lithium aluminum hydride to give the aminomethyl phenethanol deriva~ :
tives which are then debenzylated by catalytic hydrogenation, preferably with palladium-on-carbon, to yield the phenethanol-amine product~ of formula I wherein Y i8 CH2NH2; or (b) treated with benzyl chloride to give the benzyloxy protected compounds which are in turn reduced with for example lithium aluminum hydride to obtain the corre~ponding ben~yloxy aminomethyl phenethanol compounds and the latter are reacted with sodium cyanate in acid to yield the ureidomethyl derivatives or re~
acted with an alkyl sulfonyl chlor~de to give the sulfonamido-methyl derivativesJ subsequently debenzylated by catalytic hydrogenation, preferably with palladium-on-carbon, to furnish the phenethanolamine products of formula I wherein Y is CH2NHCONH2 and CH2NHS02R, respectively.
The starting materials used herein of formulas II
and V are either known or are prepared by methods well-known in the art from readily avsilable materials. Further it will be appreciated that the intermediates described hereinabove~
particularly those of formulas III, IV, VI and VII, are valuable intermediates and as such form a part of this inven-tion.
The compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets J capsules, in~ectables or the like, by incorporating the appropriate dose of a compound of formula I, with carriers ., , , : , " , ,.
. ,: , ;::, - " 1~4~
:' l according to accepted pharmaceutical practices. Preferably a compound or an acld addition salt thereof is administered or~lly to an animal organ~sm in a tablet or capsule comprising an amount ~ufficient to produce ~-adrenergic stimulant activity.
The pharmaceutical carrier employed may be, for :
example, either a solid or liquid. Exemplary of solid car~
riers are lactose, terra alba, sucro~e, talc, gelatin, agar, -pectin, acacia, magnesium stearate, stearic acid and the like.
Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent can in;~;
clude any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a . .: .
wax. ;
A wide variety of pharmaceutical forms can be em-ployed. Thus, if a solid carrier is used the preparation can be table~ed, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will 20 be about 25 mg n to about 1 g. If a liquid carrier i8 used, ~i the preparation will be in the form of a syrup, emulsion, sof~ gelatin capsule~ sterile injectable liquid such as an ampule, or an aqueous or nonaqueous liquid suspension.
of particular applicability is an aerosol dispensing 25 system wherein the active medicament is incorporated with ' ' - Freon (fluorohydrocarbon) or other inert propellant in an aerosol con~ainer. Such an aerosol system will deliver a metered dose, administered once or twice at a time as needed.
The foregoing is a general description of how to prepare the compounds of thi~ invention. The following exam~
ples illustrate the preparation of ~pecific compounds having .
_ g _ ..
~.
1~4~
' 1 ~-adrenergic stimulant activity. However this should not be construed as a limitation of the lnvention since appropriate variations In the starting materials will produce other pro- -ducts set forth hereinsbove.
EXAMPL~ 1 A solution of 17.1 g. (0.1 m.) of benzyl bromide in , 100 ml. of dimethylsulfoxide is added ~lowly to a stirred mixture of 18.2 g. (0.1 m.) of 4-hydroxyo3-nitrophenethylamine in 1 1. of dimethylsulfoxide and 60 ml. of 2N sodium hydroxide at 85C. After addition is complete the reaction mixture iB
stirred at 85C. or an additional two hours, poured into ice-water, saturated with sodium chloride and extracted with ethyl acetate. The organic extract is dried and concentrated , to give 4-benzyloxy-3-nitrophenethylamine. The latter i 15 (2.72 g., 0.01 m.) in 50 ml. of toluene is refluxed azeo-tropically with 1.27 g. (0.012 m.) of benzaldehyde until water formation i8 completed (about one hour). Solvent is removed by distillation to leave the crude imine~ Sodium borohydride (0.38 g., 0.01 m.) i~ then added to a solution of ~he above , 20 imine in 30 ml. of methanol over a period of 30 minutes and I sfter stirring for an additional hour the reaction mixture is evaporated. The residue i8 treated with 2N hydrochloric acid and ether. The solid obtained is filtered and washed to give N-benzyl-4-benzyloxy-3-nitrophenethylamine hydrochlorideO
A mixture of 145 g. (0.4 m.) of N-benzyl-4-benzyloxy-3-nitrophenethylamine (obtained from the above hydrochloride) and 24.4 g. (0.1 m.) of 1,6-dibromohexane is heated on a steam bath for three hours. The cooled reaction mixture is extracted with water to remove N-benzyl-4-benzyloxy-3-nitro-phenethylamine hydrobromide. The residue is dissolved in 10%
aque~us hydrochloric acid snd the acid solution is made basic ~, ., 4~f~99 .` `` ` .~' .
~- 1 with 40Z aqueous sodium hydroxide. Thi8 mixture i8 extrscted with ether and the dried ether extract i8 concentrated in vacuo to leave a residue of N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3~
nitrophenyl)-ethyl]-hexamethylenediamine. `
;; 5 A suspension of Raney nickel (approximately 25 g.) it in ethanol i8 added to a solution of 30.3 g. (0-0375 m.) of ~ the above prepared diamine in 500 ml. of ethanol and then ,~ 25 ml. of hydrazine hydrate is added dropwise. The resulting ~-mixture i8 heated at reflux for one hour, filtered and evap-orated to dryness. The residue i8 extracted with ether and the washed and dried extract is acidified with hydrochloric !j~ acid to precipitste the tetrahydrochloride salt of N,N'-,!~ dibenzyl-N,N'-bi812-(3-amino-4-benzyloxyphenyl)-ethyl]-hexa- ''~.,',.~ '.' methylenediamine. '``- ` ;
A solution of 9.7 g. (0.0109 m.) of the above pre- ;~ -~
pared tetrahydrochloride in 65 ml. of methanol and 25 ml. of -water is added to a suspension of 1.5 g. of 10% palladium-on-~ carbon in 10 ml. of water. The mixture is hydrogenated on 1~ the Parr apparatus at room temperature using an initial pressure of 60 psi of hydrogen. After four hours the mixture is filtered, an additional 1.5 g. of 10% palladium-on-carbon i8 dded and the hydrogenation is continued. After four ~:~
hours the reaction mixture is filtered and the filtrate is concentrated in vacuo to give N,N'-bis[2-(3-amino-4-hydroxy-phenyl)-ethyl~-hexamethylenediamine tetrahydrochloride.
3: Similarly, by employing 1,8-dibromooctane in the ;~
above condensation with N-benzyl~4-benzyloxy-3-nitrophenethyl-amine a~s described above there is obtained the corresponding N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-nitrophenyl)-ethyl octamethylenediamine which is carried through the same se-quence of reactions, namely reduction with Raney nickel and '~`'~`''~ .
~ 11 ~ ','' ' `
~I '`. .
fg9 :
1 hydrogenation with palladium-on-carbon, to yield N,N'-bis[2-(3-amino-4-hydroxyphenyl)-ethyl]-octamethylenedismine.
A mixture of 31.0 g. (0.0415 m.) of N,N'-dibenzyl- ~--N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexfi~methylene-diamine (from the tetrahydrochloride salt prepared as in Example 1) and 50 ml. of acetic anhydride i8 heated on the steam bath for one hour. The reaction mixture is concentrated .~ in vacuo, the residue i8 ~uspended in water and made alkaline with 10% sodium hydroxide. The product is extracted with methylene chloride and the dried extract is concentrated to glve N,N'-dibenzyl-N,N'-bis[2-(3-acetamido-4-benzyloxyphenyl)-l ethyl]-hexamethylenediamine.
; The above prepared compound is treated with ethereal hydrogen chloride to obtain the corre8ponding dihydrochloride.
, . ~
The latter (6.95 g., 0.0077 m.) with 1.0 g. of 10% palladium~
on-carbon in 30 ml. of water and 70 ml. of ethanol is hydro-genated on the Parr apparatus using an initial hydrogen pres-sure of 60 p8i at room temperature. After hydrogen uptake i8 ` 20 complete the reaction mixture i8 filtered and the filtrate t'i' concentrated Ln vacuo to yield N,N'-bis~2-(3-acetamido-4 JI hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrochlorideO
EXAMPLE 3 ~-,' A mixture of 31.0 g. (0.0415 m.) of N,N'-dibenzyl- -1 25 N,N'-bis~2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylene ;~;ii diamine in 230 ml. of ethyl formate is stirred and refluxed ,'~f for 24 hour~. The reactlon mixture i9 evaporated in vacuo ;',,f and the residue i8 dissolved in methylene chlor~de, then washed with dilute hydrochloric acid and saturated sodium f 30 chloride solution. The dried solution is evaporated in vacuo ;, ;
'. f to give N,N'-dibenæyl-N,N'-bis[2-(4-benzyloxy-3-formamido-phenyl)-ethyl]-hexamethylenediamine.
i, .. . .
,`'1' ',, :` ` ` 1S~44~'~9 1 The thus prepared compound is treated with ethereal -- -hydrogen chloride and the resulting dihydrochloride (2.75 g., 0.00314 m.) is hydrogenated in 70 ml. of ethsnol and 30 ml.
of water with 1.0 g. of palladium-on-carbon using 60 pBi of hydrogen at room temperature. The mixture is filtered and the filtrate evaporated to yield N,N'-bis[2-(3-formamido-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrochloride.
A stirred solution of 40 g. (0.41 m.) of pho~gene in 150 ml. of toluene is held at 25C. while a mixture of .. , ~ . .
39.3 g. (0.0525 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-amino-4- r"
benzyloxyphenyl)-ethyll~hexamethylenediamine and 300 mlO of toluene is added 810wly. The resulting mixture is heated to reflux and continued for 30 minutes. Concentration in vacuo -gives the bis isocyanate. The latter (40 g.) in 500 ml. of `
~!,, dry benzene i8 saturated with ammonia. After one hour, the ;l mixture is cooled to give N,N'-dibenzyl-N,N'-bis[2-(4- ;
. . .~ , .
benzyloxy-3-ureidophenyl~-ethyl]-hexamethylenediamine. ;~
The above prepared compound is treated with ethereal hydrogen chloride to yield the dihydrochloride. A solution .
l of 9.5 g. (0.0109 m.) of the dihydrochloride in 75 ml. of .l methanol and 25 ml. of water is added to a suspension of 1.5 g. of 10% palladium-on-carbon in 10 ml. of water. The m~xture is hydrogenated on the Parr apparatus at room tempera--ture, using an initial pressure of 60 psi of hydrogenO After four hours the mixture i8 filtered, an additional 1.5 g. of 10% palladium-on-carbon i5 added and the hydrogenation is con~
tinued. After three hours the mixture is filtered and the , filtrate is concentrated in vacuo to give N,N'-bis[2-(4~
: 30 hydroxy-3-ureidophenyl)-ethyl]-hexamethylenediamine dihydro-chloride.
... . .
, - 13 - ` ~
.
, . ., . . .. " , . . . . . ... . . .
~ 3 ` 1 Similarly, employing methyl amine, n-butylamine or .,.
i80propylamine in the initial reaction with the bis i~ocyanate and proceeding with the hydrogenation as described above yields the corresponding products, as follow8: N,NI-bis[2-(4-hydroxy-`~ 5 -3-N'-methylureidophenyl)-ethyl~-hexamethylenediamine, N,N5-:; bis~2-(3-N'~n~butylureido~4-hydroxyphenyl)-ethyl]-hexamethyl-enediamine and N,N'-bis[2-(4-hydroxy-3N'-isopropylureidoo phenyl)-ethyl]-hexamethylenediamine.
A solution of 12.5 g. of the bi8 isocyanate pre-,, pared from N,N'-dibenæyl~N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylenediamine as descrlbed in Example 4, in 200 ml. of ethanol i8 refluxed for two hours. The reaction mixture is concentrated to give N,N'-dibenzyl-N,N'-bis[2-(4-.~` 15 benzyloxy-3-carboethoxyaminophenyl)-ethyll-hexamethylene-diamine.
The dihydrochloride of the above prepared compound i~ (2.2 g., 0.0025 m.), 0.5 g. of 10% palladium-on-carbon and !' 100 ml. of ethanol is hydrogenated on the Parr apparatus at ,. .
room temperature, using an initial pressure of 60 psi of hydrogenO When hydrogen uptake i8 complete the reaction mix-ture is filtered and the filtrate i8 concentrated in vacuo to yield N,N'-bi~2~(3-carboethoxyamino-4-hydroxyphenyl)-~' ethyl]-hexamethylenediamine dihydrochloride. :~
Similarly, refluxing a solution of the bis iso-cyanate in methanol or isopropanol and continuing as described ~ above yields as final products N,N'-bis[2-(3-carbomethoxy~
:l amino~4-hydroxyphenyl)-ethyl]-hexamethylenediamine and N,N'-.~, bis[2-(3 carboisopropoxyamino-4-hydroxyphenyl)-ethylJ-;~ 30 hexamethylenediamine, respectively.
. ~., . , ~. .
~''' `'.~ ~ .
14 :b . ' . ' ,~' ' ''-' ,``' ~
' ' " ', ' ' ' ' ' ' . . ' ' : , . ' . ' i ' ' ., ', ~ ., ' ~ ' . . , ' ' . ' .. . . . . . . ..
' ~ 99 ,~
' 1 EXAMPLE 6 To a solution of 7.5 g. (0.01 m.) of N,N'-dibenzyl- ' N,N'-bis[2-(3~amino-4-benzyloxyphenyl)-ethyll-hexamethylene~
diamine in 30 ml. of pyridine iB added 2.5 g. of methanesul-fonyl chloride. The reaction mixture is allowed to stand atroom temperature overnight and i8 then added to excess water to yield N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy~3-methane~ul-fonamidophenyl)-ethyl]-hexamethylenediamine.
The dihydrochloride of the above prepared compound is hydrogenated as described in Example 1 to furnish the product N,N'-bis~2-(4-hydroxy-3-methanesulfonRmidophenyl)-ethyl]-hexamethylenediamine dihydrochloride. -: EXAMPLE 7 To a ~olution of 36.6 g. (0.049 m.) of N,N'-dibenzyl-N,N~-bis[2 (3-amino-4-benzyloxyphenyl)-ethyl~-hexamethylenedi~ ;r amine in 250 ml. of dry pyridine is added 28.6 g. (002 m.) of dimethylsulfamoyl chloride in 40 ml. of pyridine at OolOGo `
The reaction mixture i~ stirred in the cold overnight, then poured into water and extracted with ether. The ether ex-20 tract is washed with water and extracted with dilute aqueou~ -potassium hydroxide. The latter extract is washed with ether, acidified with hydrochlorlc acid and extracted with methylene chloride. The dried extract is evaporated in vacuo to give N,N'-dibenzyl-N,N'-bisr2-(4-benzyloxy-3-N,N-dimethylsulfamoyl-aminophenyl)-ethyll~hexamethylenediamine.
The dihydrochloride oi the thus prepared compound ~ (9.26 gO~ 0.01 m.) is hydrogenated in 30 ml. of water and ,~ 70 ml. of ethanol w~th 005 g. of palladium-on-carbon at room `~
temperature for two hours in the Parr apparatus. The reaction mixture is filtered, an additional 1 g. of pslladium-on-carbon ., ~ ', .
- .
:
:
` 1~ 4 ~9 ;l 18 added and the hydrogenation is continued for two hour8.
The mlxture i9 filtered and the filtrate evaporated to yield N,N'-bis[2-(3-N,N~dimethylsulfamoylamino-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrochloride.
To a stirred solution of 5.8 g. (0.05 m.) of sul-famyl chloride in 75 ml. of dry benzene at 10C. is added, in small portions, 37.4 gO (0005 m.) of N,NI-dibenzyl-N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylenediamine.
After the mix~ure i6 stirred at 10-20C. for 30 minutes, it i~ extracted with 5% aqueous sodium hydroxide. Adding dilute h~drochloric acid to the basic extract precipitates the product, N,N'-dibenzyl-NJN'-bis[2-(4-benzyloxy-3-suIfamoyl aminophenyl)ethyl]-hexamethylenediamine.
~; .
Proceeding as described in Example 7, namely ~`
h~drogenation of the corresponding dihydrochloride yields ~-~
j N,N'~bi8[2-(4 hydroxy-3-8ulfamoylaminophenyl)-ethyllhexa-methylenediamine dihydrochloride.
A solution of 2044 gO (0.01 m.) of 3-carbomethoxy-4-methoxyphenethylamine (prepared from 3-carbomethoxy-4-methoxybenzyl chloride by reaction with sodium cyanide fol-lowed by catalytic reduction of the resulting benzyl nitrile) in 25 ml. of toluene is refluxed azeotropically with 1.27 g.
,25 (0.012 m.~ of benzaldehyde for one hour, then the solution ' i8 concentrated to give the N-benzal derivative. Sodium borohydride (0.38 g., 0.01 m.) is then added to a solution ~'of the N-benzal derivative in 25 ml. of methanol over a period of 30 minutes. After being stirred for an additional ~30 hour at 25C. the reaction mixture i9 evaporated. The resi-'~due i8 treated with 2N hydrochloric acid and ether to i . .
~ - 16 -,,, , ~ .
~ 3 :
l precipitate N~benzyl-3-carbome~hoxy-4-methoxyphenethylamine hydrochloride.
A mixture of 119.5 g. (0.4 m.) of N-benzyl-3-carbo methoxy-4-methoxyphenethylamine (obtained from the above -hydrochloride) and 24.4 g. (0.1 m.) of 1,6-dibromohexane in 250 ml. of acetonitrile i9 refluxed for three hours. The cooled reaction mixture i8 diluted with ether to precipitate N-benzyl-3-carbomethoxy-4-methoxyphenethylamine hydrobromide.
; The mixture i8 filtered and the filtrate i8 concentrated ~-- lO in vacu to leave a residue of NJN'-dibenzyl-N,N'~bis[2-(3- -carbomethoxy-4-methoxyphenyl)-ethyl]-hexamethylenediamine. -~
A solution of 3.1 ~. (0.0041 m.) of the dihydro~ ~
chloride of the above prepared diamine in 30 ml. of methanol ;-~ ;
and 25 ml. of an aqueous solution of ammonia (d. 00880) is allowed to stand at room temperature about 20 hours~ The mixture i8 evaporated under reduced pre~sure to give a resi-rl due which with methanolic hydrochloric acid yields the `A,.
dihydrochloride of N,N'-dibenzyl-N,NI-bis[2-(3-carboxamido-4~ ;
~I methoxyphenyl)-ethyl]-hexamethylenediamine.
A solution of the above carboxamido free base ,~
liberated by aqueous ammonia from 3061 g. (0.005 m.~ of the dihydrochloride is added to a warm, stirred suspenslon of 1.5 g. of lithium aluminum hydride in 20 ml. of tetrahydro- '~'7,;," ' ~,~! ;` furan. After stirring at reflux for about 17 hours the cooled ,~ 25 reaction mixture is treated with 5 ml. of water, filtered and l the filtrate is evaporated. The residue is dissolved in ;;~i~ ethanol and ethereal hydrogen chloride is added to precipi tate the tetrahydrochloride of N,N'-dibenzyl-N,N'-bis[2-(3-j~ aminomethyl~4-methoxyphenyl)-ethyl]-hexamethylenediamine.
To a suspension of 12 g. (0.0177 m.) of the free ~ base derived from the above tetrahydrochloride in 75 ml. of ; -~
.', .', ' 1 methylene chloride i8 ~dded gradually 9.0 ml. of boron tri-bromide, with 8tirring in an ice bath. The ice bath i8 removed and the mixture is stirred for one hour. The reaction mixture i8 evapor~ted in vacuo, excess methanol i8 added gradually and the solution evaporated. The residue is dis-solved in water and the solution is neutralized with sodium bicarbonate to give N,N'-dibenzyl-N,N'-bis~2-(3-aminomethyl-4-hydroxyphenyl)-ethyl~-hexamethylenediamine.
A solution of 17.3 g. (0.0218 m.) of the tetrahydro chloride prepared from the above free ba~e in 75 ml. of methanol and 25 ml. of water is hydrogenated with palladium-on-carbon as described in Example 1 to give N,N'-bis[2-(3 aminomethyl-4-hydroxyphenyl~-ethyl]-hexamethylenediamine tetrahydrochloride.
.; , .... .
Following the procedure of Example 6, 2.5 g. of methanesulfonyl chloride is added to a solution of 6.78 g~
(0.01 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-aminomethyl-4 ;
methoxyphenyl) ethyl]-hexamethylenediamine in 30 ml~ of pyri~
dine and the mixture is allowed to stand at room temperature overnight to yield N,NI-dibenzyl-N,N'-bis[2-(3-methanesul-., ;;.
fonamidomethyl~4-methoxyphenyl)~ethyl]-hexamethylenediamine The latter as the dihydrochloride is demethylated and then debenzylated ~8 described in Example 9 to furnish the product N,N'-[2 (4-hydroxy-3--methanesulfonamidomethylphenyl) ethyl]-,. ' . .
hexamethylenediamine dihydrochloride. -~
., , ~ - .
A solution of 54.2 g. (0.08 m.) of N,N'-dibenzylo N,N'-bis~2-(3-aminomethyl-4-methoxyphenyl)-ethyl]~hexamethyl-enediamine in 500 ml. of acetic acid and 175 ml. of w~ter is ;;;
~tirred at 40C. while a slurry of 23.5 g. of 90% sodium ;
`"' ~.' .
- 18 - ~
' ~ :
' 4~ l';39 1cyanate (21.2 g., 0.32 m.) in 160 ml. of water i8 added in portions. The resulting mixture is stirred at 40C. for one hour, diluted with 1600 ml. of water and extracted with methylene chloride`. The extract i8 washed with sodium car- ~
5 bonate, dried and evaporated in vacuo to give N,N'-dibenzyl- ,-'!,.'' ' N,N'-bis[2-(4~methoxy-3-ureidomethylphenyl)-ethyl]-hexamethyl-enediamine. The latter as the dihydrochloride i8 demethylated i ;--and debenzylated as described in Example 9 to give N,N'~bis[2 (4-hydroxy-3-ureidomethylphenyl)-ethyll-hexamethylenediamine dihydrochloride, A mixture of 1.56 g. (0.0023 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-carbomethoxy-4-methoxyphenyl)-ethyll-hexàmethyl- ~i~
enediamine and 40 ml. of 48% aqueous hydrobromic acid is ~-refluxed for four hours. The cooled reaction mixture is fil-tered to give N,N'-dibenzyl-N,N'-bis[2-(3-carboxy-4-hydroxy-phenyl)-ethyll-hexamethylenediamine dihydrobromide. The ~-latter is hydrogenated with palladium-on-carbon as described in Example 1 to yield N,N'-bis[2-(3-carboxy-4-hydroxyphenyl)- `~
20 ethyl]-hexamethylenediamine dihydrobromide. The free base i obtained from this dihydrobromide (0.8 g., 0~0018 m.) is added to an ice cold solution of 40 ml. of lM borane in '--tetrahydrofuran (0.04 m.) while stirring under nitrogen. The temperature i8 maintained at 0C. for 20 hours, the solution ,~; 25 is then refluxed for one hour and concentrated in vacuo.
Several poxtions of methanol are added, the solution is con- -centrated and the residue is dissolved in ethanol and filtered.
l :; , ] Sulfuric acid i8 added to pH 2.0 to give N,NI-bis[2-(4-hydrcxy-3-hydroxymethylphenyl)~ethyll-hexamethylenediamine sulfateO
~ ; 30 EXAMPLE 13 !~ To a stirred solution of 5.42 g. (0.02 m.) of ~ 4-benzyloxy-3 nitroacetophenone in 100 ml. of chloroform is , . . .
,~ ~, 19 ~ 9 1 added 3.2 g. (0.02 m.) of bromlne. The mixture i8 ~tirred at room temperature for about 45 minutes and the solution i8 concentrated in vacuo at 25-30C. to leave 4-benzyloxy-a~
bromo-3-nitroacetophenone. The latter (35.0 g., 0.1 m.) in 250 ml. of acetonitrile is stirred at 25C. with 29.6 g.
(0.1 m.) of N,N'-dibenzyl-hexamethylenediamine for two hours.
The cooled reaction mixture i8 filtered to remove the dihydro-bromide of N,N'-dibenzyl-hexamethylenediamine. Acidification of the filtrate with ethereal hydrogen chloride gives N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-nitrophenyl)-2-oxoethyl]-hexamethylenediamine dihydrochloride.
The above prepared dihydrochloride i8 hydrogenated --in methanol ~olution with platinum oxide catalyst to obtain the dihydrochloride of N,N'-dibenzyl-N,N'-bis[2-(3-amino-4-15 benzy-loxyphenyl)-2-hydroxyethyl]-hexamethylenediamine. The `
latter i8 debenzylated as described in Example 1 with palladium-on-carbon and a methanolic solution of the product i8 treated with ethereal hydrogen chloride to yield N,N~-bis12- '~r;' ' ' ' ~3-amino-4-hydroxyphenyl)-2-hydroxyethyl]-hexamethylenediamine tetrahydrochloride, m.p, 202-205C.
A mixture of 20.0 g. (0.083 m.) of 3-amino-4-benzyl-oxyacetophenone and 50 ml. of acetic anhydride i8 heated on the steam bath for one hour. The resulting solution is con~
centrated in vacuo, the residu~l solid is suspended in water and the mixture made alkaline with 10% sodium hydroxide. The crystalline product is extracted with methylene chloride, and the dried extract is concentrated to give 3-acetamido-4-benzyloxyacetophenone, m.p. 132-134C.
To a stirred solution of 8.6 g. (0.03 m.) of 3-acetamido-4-benzyloxyacetophenone and 2.6 g. (0.03 m.) of 1 2-pyrrolidone in 300 ml. of tetrahydrofuran i8 added dropwise a solution of 1500 gO (0.03 m.) of pyrrolidone hydrotribromide in 300 mlO of tetrahydrofuran. The mixture is stirred a~ room temperature for 18 hours, filtered and the filtrate concen-trated in vacuo to yield 3-acetamido-4~benzyloxy-a-bromoaceto-phenone, m.pO 163-166C
A mixt~re of 3.48 gO (0.01 mO~ of 3-acetamido 4-benzyloxy-a-bromoacetophenone and 2096 g. (0~01 m.) of N,N'- ~-dibenzyl-hexame~hylenediamine in 50 mlO of acetonitrile i~
~tirred at 25Co for two hoursO The cooled reaction mixture is filtered and the filtrate acidified with ethereal hydrogen chloride to give N,N'-dibenzyl-N,N'-bis[2~3-acetamido-4 benzyloxyphenyl)-2-oxoethyl~-hexamethylenediamine dihydrochlor~
;' ideO The latter i8 hydrogenated with 10% palladium-on-carbon ~
I 15 to yield N,N'-bis[2-(3-acetamido-4-hydroxyphenyl~-2-hydroxy- -ethyl]-hexamethylenediamine dihydrochloride, m p. 218-219C do Similarly, equimolar amounts of 3-acetamido-4- ~ -benzyloxy-a-bromoacetophenone and N,N'-dibenzyl-tetramethylene-diamine are condensed as described above to give the N,N'-20 dibenzyl-N,N'-bis~2~3-acetamido-4-benzyloxyphenyl)-2-oxo- -ethyl]-tetramethylenediamine which is likewise hydrogenated to furnish N,N' bis~2~(3-acetamido-4-hydroxyphenyl)-2-hydroxy-ethyl]-tetramethylenediamine. -.
A solution of 20 g. (0.083 mO) of 3-amino-4-benzyl-oxyacetophenone in 230 ml. of ethyl formate is stirred and refluxed for 24 hours. The reaction mixture is evaporated in vacuo and the residue is dissolved in methylene chloride, then washed with dilute hydrochloric acid and saturated sodium chloride 301utionO The dried solution i8 evaporated in vacuo ;
' ~'' .
"; ~ . ' ': ~ . .' .' ' ' ' " ' ;
'f ~' , ~: ' ' ' , ' ' . ' ~ ' ,~"" " ' ',' : , .
~ 3~
1 to give a residue which upon trituration with ether give8 4-benzyloxy-3-formamidoacetophenone, m.p. 121-123 C.
To a solution of 17.5 g. (0.0648 m.) of 4-benzyloxy-3-formamidoacetophenone and 5.51 g. (0.0648 m.) of 2-pyrroli-done in 650 ml. of tetrahydrofuran, stirred at roQm tempera-ture, i8 added dropwise a solution of 32.2 g. (0.0648 m.) of pyrrolidone hydrotribromide in 650 ml. of tetrahydrofuran.
The mixture is stirred overnight at room temperature, filtered and the filtrate evaporated. The residue is dissolved in methylene chloride, washed with water, dried and evaporated to leave 4-benzyloxy-a-bromo-3-formamidoacetophenone, m.p 124-128C.
Following the procedure~ of Example 14, equimolar ;~ ~
amounts of 4-benzyloxy-a-bromo-3-formamidcacetophenone and ~ -N,N'-dibenzyl-hexamethylenediamine are stirred in acetonitrile at 25C. for two hours to give N,N'-dibenzyl-N,N'-bis[2-(4- ~-benzyloxy-3-formamidophenyl)-2-oxoethyl3-hexamethylenediamine which i8 similarly hydxogenated to furnish N,N'-bis[2-(3-formamido-4~hydroxyphenyl)-2-hydroxyethyl]-hexamethylenediamine. ~;~
A stirred solution of 40 g. (0.41 m.) of phosgene in 150 ml. of toluene i8 held at 25C. with a cooling bath -while a mixture of 25.2 g. (0.105 m.) of 3-amino-4-benzyloxy- ~ -acetophenone and 220 ml. of toluene are added ~lowly. The -25 mixture i8 heated to reflux and continued for 30 minutesO ~
Nitrogen is passed through the mixture and then concentrated ~ -in vacuo to give a crystalline isocyanate, m.p. 105-106C.
A stirred solution of the isocyanate (28.~0 g.) in 500 ml. of dry benzene is ~aturated with ammonia. Afeer one hour, the mixture is cooled to give the crystalline 4-benzyloxy-3~ureidoacetophenone, m.p. 184-186C.
1 To a stirred solution of 5.7 g. (a.o2 m.) of 4-benzyloxy-3-ureidoacetophenone in 100 ml. of chloroform is added 3.2 g. (0.02 mO) of bromine. The mixture i~ stirred at room temperature for about 45 minutes and the solution i~ con- ;
` 5 centrated in vacuo at 25-30C. to give 4-benzyloxy-a-bromo-3-ureidoacetophenone.
Following the procedures of Exa~ple 14, the above prepared acetophenone and N,N'-dibenzyl-hexamethylenediamine are refluxed in acetone for 12 hours and the resulting N,N'- ?7;. i , 10 dibenzyl-N,N'-bis[2-(4-benzyloxy-3-ureidophenyl)-2-oxoethyl~-; hexamethylenediamine i8 hydrogenated to yield N~N'-b~s~2-(4 hydroxy-3-ureidophenyl)-2-hydroxyethyl]-hexamethylenediamineO
Similarly, 4-benzyloxy-a-bromo-3-(N'-methylureido)-acetophenone, prepared from the above isocyanate by reacting with methyl amine followed by bromination as deæcribed above is refluxed in acetone for 12 hours with N,N'-dibenzyl-hexa-methylenediamine to give the corresponding N,N'-dibenzyl-N,N~
bis[2-(4~benzyloxy-3-N'-methylureidophenyl)-2-oxoethyl]-hexa- `;
methylenediamine which in turn is hydrogenated with palladium-on-carbon to furnish the product N,N'-bis[2-(4-hydroxy-3-N'-methylureidophenyl)-2-hydroxyethyl]-hexamethylenediamine. `-A solution of the isocyanate (12.5 g.), prepared as i in Exsmple 16, in 170 ml. of ethanol is refluxed for two hours.
The reaction mixture i~ concentrsted and the residue iæ tri-turated with hexane to give the crystalline 4-benzyloxy-3-carboethoxyaminoacetophenone, m.p. 84-86C.
To a stirred solution of 1.6 gO (0.005 m.) of 4-benzyloxy-3-carboethoxyaminoacetophenone in 20 mlO of chlorofrom and 0.2 g. of benzoyl peroxide is added 0.84 g.
`
1 (5% excess) of bromine in 2 mlO of chloroform. The mixture is stirred at room te~pera~ure for about 45 minutes in the presence of a spotlight and the solution i8 concentrated in vacuo at 35-45C~ to give 4-benzyloxy-a-bromo-3-carboethoxy-S aminoacetophenone, m.p. 98-100C.
By employing the procedure~ described in Example 14 ,~ ,.
the above prepared bromoketone and N,N~-dibenzyl-hexam~thylene- `~
diamine are stirred at 25Co in acetone for two hours to yield N,~'-dibenzyl N,N'-bis~2~(4-benzyloxy-8-carboethoxyaminophenyl)-- 10 2oxoethyl]-hexamethylenediamine which in turn is similarly `~
hydrogenated to give N,N'~bis~2-(3-carboethoxyamino-4-hydroxy-phenyl)-2~hydroxyethyl]-hexamethylenediamine; m.p. dihydro-chloride 227-228Cod ~
.EXAMI!LE 18 A mixture of 3098 g. (O o Ol mO) of 4-benzyloxy-3- ;
methanesulfonamido-a-bromoacetophenone ~UOSO Pa~ent NOD ,, 3,4789149~ and 2096 g. (OoOl m.) of N,N'-dibenzyl-hexamethyl-enediamine in 50 ml. of acetonitrile is stirred at 25C. for !,, ¦ two hoursO The cooled reaction mixture i8 filtered and the ?
~ 20 filtrate i~ acidified with ethereal hydrogen chloride to give .
N,N'-dibenzyl~N,N'-bisl2-~4-benzyloxy-3-methanesulfonamido-phenyl)-2~oxoethyl]-hexamethylenediamine dihydrochloride. The ~;~
::
latter is hydrogenated with 10% palladium-on~carbon to yield N,N'-bis[2(4-hydroxy-3-methanesulfonamidophenyl~-2-hydroxy-25 ethyl]-hexamethylenediamine dihydrochloride, m.p~ 194-195Co `
:~, .
j A solution of 23.6 g. ~0. 098 m.~ of 3~amino-4-benzyloxyacetophenone in 200 mlO of dry pyridine is treated with 28.6 g. (002 m.3 of dimethylsulfamoyl chloride in 40 ml.
of pyridine at 0-10C. The reaction mixture is stirred in the cold overnight, then poured into water and extracted with ether. The ether ex~ract is washed with water and extracted .. . . . .. .
,r~ ,, 4~99 1 with dilute aqueous potassium hydroxide. The latter extract f-- is washed with ether, acidified with hydrochloric acid and extracted with methylene chloride. The dried methylene `
chloride solution i8 evaporated in vacuo to give 4-benzyloxy- ~
3-(N,N-dimethyl~ulfamoylamino)-acetophenone, m.p. 108-109.5C. ;~ i To a stirred solution of 1.74 g. (0.005 m.) of 4-benzyloxy-3-(N,N-dimethylsulfamoylamino)-acetophenone in 25 ml. of chloroform is added a solution of 0.9 g. (0.0056 m.) of bromine in 25 ml. of chloroform. The mixture i8 stirred at room temperature for about 30 minutes and the solution is 1~ concentrated to leave 4-benzyloxy-a-bromo-3-(N,N-dimethyl-¦~ sulfamoylamino)-acetophenone, m.p. 80-85C.
Following the procedures of Example 14, the above prepared acetophenone is reacted with N,N'-dibenzyl-hexa-methylenediamine in acetonitrile at 25C. to give N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-N,N-dimethylsulfa ylaminophenyl)- `~
2-oxoethyl]-hexamethylenediamine which i~ similarly hydrogenated to yield N,N'-bisr2-(3-N,N-dimethylsulfamoylamino-4-hydroxy-~ phenyl)-20hydroxyethyl]-hexamethylenediamine.
¦~ 20 Similarly, 4-benzyloxy-a-bromo-3-sulfamoyl-mino~
acetonephenone, prepared from 3-amino-4-benzyloxyacetophenone by reac~ing with sulfamyl chloride in dry benzene at 10-20C.
followed by bromination as described above, is refluxed in acetone for 12 hours with N,N'-dibenzyl-hexamethylenediamine to give N,N'-dibenzyl-N,N'-bist2-(4-benzyloxy-3-sulfamoyl~
aminophenyl)-2-oxoethyll-hexamethylenediamine which is then ;~ hydrogenated with palladium-on-carbon to yield N,N'-bis[2O
(4-hydroxy-3~sulfamoylaminophenyl)-2-hydroxyethyl]-hexa-methylenediamine.
~: '`'.~ .
25 ~ ;
,;~,.. l .
.,.~, . . .
`:
" . , , ~ . . . . .. .
` 1 ~XA~L~ 20 A mixture of 3029 g. (OoOl mO) of 4-acetoxy-3-acetoxymethyl-a-bromoacetophenone (South Arican Patent NoO -67/5591) and 2096 gO (OoOl m.~ of N,N!-dibenzyl-hexamethylene-diamine in 50 mlO of acetonitrile i8 stirred at 25Co for two .: ~... ..
;~ hoursO The cooled reaction mixture is filtered, the filtrate is acidified with concentrated hydrochloric acid and the solution is allowed to stand for 18 hours to precipitate N,N'~ ~ ;
dibenzyl-N,N'-bis[2~(4~hydroxy-3-hydroxymethylphenyl~2~ ;
oxoethyl]-hexamethylenediamine dihydrochlorideO The latter is hydrogenated with 10% palladium~on-carbon to yield N,N'-bis~2-~4-hydroxy-3~hydroxymethylphenyl~-2~hydroxyethyl]-hexa-; methylenediamine dihydrochloride, m.pO 155-160C~ d. ~
; 15 A mixture of 2073 g. (OoOl m.) of 3-carbomethoxy-4-.. . .
hydroxy-a-bromoacetophenone (South African Patent NoO 67/5591~ :
and 2096 g. (OoOl mO) o N,N~dibenzyl-hexamethylenediamine in 50 ml~ of acetonitrile is stirred at 25C~ for two hours. The .
cooled reaction mixture i8 filtered and the filtrate is acidified with ethereal hydrogen chloride to give N,N'-di-', benzyl-N,N'-bis[2-(3~carbomethoxy-4Qhydroxyphenyl)-2-oxoethyl]-, hexamethylenediamine dihydrochloride. ;
:, ...
A solution of 15 g. ~0.02 m.) of the above prepared dihydrochloride in 125 ml~ of methanol and 125 ml. of aqueous ammonia ~d~ 0.880) is allowed to ætand in a stoppered flask for 8iX days~ The mixture is then evaporated to dryness and the residue is extracted with ether. Treatment of the ~
ethereal mixture with hydrogen chloride gives N,N'-dibenzyl- !` - ' N,N'-bis[2(3-carboxamido4-hydroxyphenyl)-2-oxoethyll-hexa- .~
30 methylenediamine dihydrochloride. -.. .
., ~ .
.,: .
.: . . -1~4~
1 Following the procedure outlined in Example 9, a solution of the above carboxamido free base liberated by aqueous ammonia from 0.0025 m. of the dihydrochloride is added to a suspension of 1.5 g. of lithium aluminum hydride to yield after treating the product with ethereal hydrogen chloride the tetrahydrochloride of N,N'-dibenzyl-N,N'~bis[2-(3-aminomethyl-4-hydroxyphenyl)-2~hydroxyethyl]-hexamethylenediamineO ~ -Hydrogenation with palladium-on~carbon gives N,N'-bis[2w(3 aminomethyl-4-hydroxyphenyl)-2-hydroxyethyl]-hexamethylene~
diamine tetrahydrochloride, A mixture of 28.7 g. of N,N'-dibenzyl-N,N'-bis~2-(3-carboxamido-4-hydroxyphenyl)-2-oxoethyl]-hexamethylenedi~
amine (obtained from the dihydrochloride as prepared in Example 21)9 12.0 g~ of potassium carbonate, 3.0 gO of sodium iodide and 9.1 ml. of benzyl chloride in 50 ml. of methyl-ethylketone i9 heated at reflux for four hours. The cooled reaction mixture is filtered and the filtrate i8 evaporated to dryness to leave N,N~dibenzyl~N,N' bis[2-(4-benzyloxy~3-carboxamidophenyl)~2-oxoethyl] hexamethylenediamine.
A mixture of 15 g. (0.0175 m.) of the above carboxa~
mido compound and 6 g. of lithium aluminum hydride in 400 ml.
of tetrahydrofuran i8 heated at reflux for 22 hours. After water i5 addedg the reaction mixture is evaporated to dryness and the residue is partitioned between ether and water. The ether extract is treated with hydrogen chloride to give the ;~
tetrahydrochloride of N9N' dibenzyl-N,N'-bis[2~(3~aminomethyl-4~benzyloxyphenyl)~2~hydroxyethyl]~hexamethylènediamineO
A solution of 3 . 9 g . (O . 004 m.) of the above tetra-hydrochloride in 50 ml. of ethanol containing 2.3 g. of - . . : .
1~4~j9~
'. :' '.
1 potassium cyanate is heated for two hours. The reaction mix~
ture is evaporated to dryness and the residue is partitioned ,,5'' ~.
between ether and aqueous sodium carbonate. The ether extract is washed with water, dried and evaporated to yield N,N'-di- -5 benzyl-N,N'-bis[2-(4-benzyloxy-3~ureidomethylphenyl)-2-hydroxymethyl~-hexamethylenediamine. The latter, as the dihydrochloride, is hydrogenated with 10% palladium-on-carbon to give N,N'-bis[2-(4-hydroxy-3-ureidome~hylphenyl)-2~hydroxy-ethyl]-hexamethylenediamine dihydrochloride.
~; ~ -- .: .
~ ,".!~
To a solution of 9~35 gO of N,N'-dibenzyl-N,N'-bis[2-~3-aminomethyl-4-benzyloxyphenyl)-2-hydroxyethyl]-hexa-methylenediamine in 50 mlO of pyridine is added 2O5 mlO of methanesulfonyl chloride at room temperatureO After 18 hours 15 the reaction mixture is added to an excess of 2N hydrochloric acid and extracted with chloroform. The extract i8 neutralized with sodium bicarbonate, washed, dried and evaporated to give ~ -N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methanesulfonamido- -methylphenyl)-2Ohydroxyethyll-hexamethylenediamine. The ;~
2Q latter, a~ the dihydrochloride, i8 hydrogenated with palladium- ,~
on-carbon to yield N,N'-bis[2-(4-hydroxy-3-methanesulfonamido- `~
methylphenyl)o2-hydroxyethyl]-hexamethylenediamine dihydro ''!' chlorideO .. '~ , '. -,. i.::
To a mixture of 260 ccO of 37% formaldehyde and 1800 cc. of concentrated hydrochloric acid is added 400 gO of p-hydroxyacetophenone at a temperature of about 45Co The mixture is maintained at 50Co for two hours, filteredJ and washed with water to give 3-chloromethyl~4-hydroxyaceto- ;~
30 phenone, mOpO 154C. dec. - ~
~." , ~ ' .
`':"' 1~4~9 ; `
,.:,, .
1 A mixture of 40 gO of 3-chloromethyl-4-hydroxy-acetophenone and 26 g. of magnesium methyl sulfinate in ;~
~ -500 mlO of ethanol i9 refluxed with stirrin8 for 3 hours.
The reaction mixture i8 then concentrated in vacuo. The re- -sultant oil i9 redissolved in chloroform and wa~hed with waterO The chloroform is dried and evaporated to give 4-hydroxy-3-methyl-sulfonylmethylacetophenone, m.pO 206.5- - :
208. 5C o A mixture of 1400 gO of 4-hydroxy-3-methylsulfonyl- ~~
1 10 methylacetophenone, 903 g. of potassium carbonate, 7.8 mlO of benzyl chloride and a catalytic amount of sodium iodide in t~.' ~-, 250 mlO of acetone and 250 ml. of water is refluxed with stirrine for 16 hours. The acetone is removed and the aqueous phase ~8 extracted with chloroform, washed with water, dried 15 and evaporated to yield an oil which is recrystallized in ,.. ... .
isopropyl alcohol to give crystalline 4-benzyloxy-3-methyl- ~,',,'t sulfonylmethylacetophenone, m.p O 94-97Co -To a stirred ~olution of 707 gO of 4-benzyloxy-3 methylsulfonylmethylacetophenone and 2015 g. of 2-pyrrolidone in 300 ml. of tetrahydrofuran is added 12~5 g. of pyrrolidone hydrotribromide (PHT) and the ~tirring is continued for 56 hours at room temperature. The mixture is filtered and the .. . .
filtrate concentrated in vacuo to give an oil which crystal- '~-~
; lizes upon standing. The crystals are redissolved in chloro-25 form. The chloroform-solution is washed with water, dried ~' ;
and concentrated to yield a solid which is recrystallized ~ . ... .
from scetonitrile to give 4-benzyloxy-a-bromo-3-methylsul-fonylmethylacetophenone, m~p. 143-144C. ~`
Following the procedures of Example 14, equimolar amount8 of 4-benzyloxyoa-bromo-3~methylsulfonylmethylaceto-.
.. , `,.
~ . . . . . . . . . .
1 phenone and N,N'~dibenzyl-hexamethylenediamine are stirred in acetonitrile at 25Co for two hours to give N,N'-dibenzyl-N, N'-bis[2-(4-benzyloxy-3~methylsulfonylmethylphenyl)2-oxo- ,::
ethyl]-hexamethylenediamine which is similarly hydrogenated ;~
to furnish NJN'-bis[2-(4-hydroxy-3-methylsulfonylmethylphenyl)-2-hydroxyethyl]-hexamethylenediamine; m.pO dihydrochloride 177-179C.
~ ,'; ~ :A solution of lOoO gO (0.0252 m.) of 4-benzyloxy-a-bromo-3-methylsulfonylmethylacetophenone in 50 mlO of dimethyl- ;~
sulfoxide is allowed to stand for 40 hours and then i9 poured into waterO The mixture is extracted with chloroform and the ...
extract is washed with water, dried and evaporated to give 4-benzyloxy~3-methylsulfonylmethylphenyl glyoxal, m.pO
1080110Co To a warm slurry of 3.32 gO (0.01 m.) of the above prepared phenyl glyoxal in 40 mlO of methanol i8 added a solution of 0058 g. (0~005 m.~ of 1,6-diaminohexane in ~...... .
methanolO After warming for 20 minutes the reaction mixture s 20 is filtered to give N,N'-blsl2-~4-benzyloxy-3-methylsulfonyl- ~ ;
methylphenyl) 2-oxoethylidene]~hexamethylenediamine, mOp. -162-163Co ~`.
The above diamine is slurried in absolute ethanol and 1.0 gO of sodium borohydride is added. The mixture is 25 refluxed for two hours and filtered hot to yield N,N'-bis120 (4-benzyloxyo3-methylsulfonylmethylphenyl~-2-hydroxyethyl]-hexamethylenediamine, m.pO 146~148.5C.
This bis aminoalcohol (2 0 g., 000027 mO) is hydro-genated as a slurry in methanol on a Parr shaker over 1.0 g.
30 of palladiumon-carbon for about five hour80 The reaction , . .
1 mixture is filtered, evaporated and the residue in methanol is treated with ethereal-hydrogen chloride to give N,N'-bis[2-(4-hydroxy-3-methyl8ulfonylmethylphenyl)-2-hydroxyethyll-hexa-methylenediamine dihydrochloride, mOp. 177-179C.
.
.''' ,."", ~"
; .
. -~:
.... . .
:
... ,~,., ~ :
.
-;
. .
. .
, , - : - . .
.. .
¦~ 20 Similarly, 4-benzyloxy-a-bromo-3-sulfamoyl-mino~
acetonephenone, prepared from 3-amino-4-benzyloxyacetophenone by reac~ing with sulfamyl chloride in dry benzene at 10-20C.
followed by bromination as described above, is refluxed in acetone for 12 hours with N,N'-dibenzyl-hexamethylenediamine to give N,N'-dibenzyl-N,N'-bist2-(4-benzyloxy-3-sulfamoyl~
aminophenyl)-2-oxoethyll-hexamethylenediamine which is then ;~ hydrogenated with palladium-on-carbon to yield N,N'-bis[2O
(4-hydroxy-3~sulfamoylaminophenyl)-2-hydroxyethyl]-hexa-methylenediamine.
~: '`'.~ .
25 ~ ;
,;~,.. l .
.,.~, . . .
`:
" . , , ~ . . . . .. .
` 1 ~XA~L~ 20 A mixture of 3029 g. (OoOl mO) of 4-acetoxy-3-acetoxymethyl-a-bromoacetophenone (South Arican Patent NoO -67/5591) and 2096 gO (OoOl m.~ of N,N!-dibenzyl-hexamethylene-diamine in 50 mlO of acetonitrile i8 stirred at 25Co for two .: ~... ..
;~ hoursO The cooled reaction mixture is filtered, the filtrate is acidified with concentrated hydrochloric acid and the solution is allowed to stand for 18 hours to precipitate N,N'~ ~ ;
dibenzyl-N,N'-bis[2~(4~hydroxy-3-hydroxymethylphenyl~2~ ;
oxoethyl]-hexamethylenediamine dihydrochlorideO The latter is hydrogenated with 10% palladium~on-carbon to yield N,N'-bis~2-~4-hydroxy-3~hydroxymethylphenyl~-2~hydroxyethyl]-hexa-; methylenediamine dihydrochloride, m.pO 155-160C~ d. ~
; 15 A mixture of 2073 g. (OoOl m.) of 3-carbomethoxy-4-.. . .
hydroxy-a-bromoacetophenone (South African Patent NoO 67/5591~ :
and 2096 g. (OoOl mO) o N,N~dibenzyl-hexamethylenediamine in 50 ml~ of acetonitrile is stirred at 25C~ for two hours. The .
cooled reaction mixture i8 filtered and the filtrate is acidified with ethereal hydrogen chloride to give N,N'-di-', benzyl-N,N'-bis[2-(3~carbomethoxy-4Qhydroxyphenyl)-2-oxoethyl]-, hexamethylenediamine dihydrochloride. ;
:, ...
A solution of 15 g. ~0.02 m.) of the above prepared dihydrochloride in 125 ml~ of methanol and 125 ml. of aqueous ammonia ~d~ 0.880) is allowed to ætand in a stoppered flask for 8iX days~ The mixture is then evaporated to dryness and the residue is extracted with ether. Treatment of the ~
ethereal mixture with hydrogen chloride gives N,N'-dibenzyl- !` - ' N,N'-bis[2(3-carboxamido4-hydroxyphenyl)-2-oxoethyll-hexa- .~
30 methylenediamine dihydrochloride. -.. .
., ~ .
.,: .
.: . . -1~4~
1 Following the procedure outlined in Example 9, a solution of the above carboxamido free base liberated by aqueous ammonia from 0.0025 m. of the dihydrochloride is added to a suspension of 1.5 g. of lithium aluminum hydride to yield after treating the product with ethereal hydrogen chloride the tetrahydrochloride of N,N'-dibenzyl-N,N'~bis[2-(3-aminomethyl-4-hydroxyphenyl)-2~hydroxyethyl]-hexamethylenediamineO ~ -Hydrogenation with palladium-on~carbon gives N,N'-bis[2w(3 aminomethyl-4-hydroxyphenyl)-2-hydroxyethyl]-hexamethylene~
diamine tetrahydrochloride, A mixture of 28.7 g. of N,N'-dibenzyl-N,N'-bis~2-(3-carboxamido-4-hydroxyphenyl)-2-oxoethyl]-hexamethylenedi~
amine (obtained from the dihydrochloride as prepared in Example 21)9 12.0 g~ of potassium carbonate, 3.0 gO of sodium iodide and 9.1 ml. of benzyl chloride in 50 ml. of methyl-ethylketone i9 heated at reflux for four hours. The cooled reaction mixture is filtered and the filtrate i8 evaporated to dryness to leave N,N~dibenzyl~N,N' bis[2-(4-benzyloxy~3-carboxamidophenyl)~2-oxoethyl] hexamethylenediamine.
A mixture of 15 g. (0.0175 m.) of the above carboxa~
mido compound and 6 g. of lithium aluminum hydride in 400 ml.
of tetrahydrofuran i8 heated at reflux for 22 hours. After water i5 addedg the reaction mixture is evaporated to dryness and the residue is partitioned between ether and water. The ether extract is treated with hydrogen chloride to give the ;~
tetrahydrochloride of N9N' dibenzyl-N,N'-bis[2~(3~aminomethyl-4~benzyloxyphenyl)~2~hydroxyethyl]~hexamethylènediamineO
A solution of 3 . 9 g . (O . 004 m.) of the above tetra-hydrochloride in 50 ml. of ethanol containing 2.3 g. of - . . : .
1~4~j9~
'. :' '.
1 potassium cyanate is heated for two hours. The reaction mix~
ture is evaporated to dryness and the residue is partitioned ,,5'' ~.
between ether and aqueous sodium carbonate. The ether extract is washed with water, dried and evaporated to yield N,N'-di- -5 benzyl-N,N'-bis[2-(4-benzyloxy-3~ureidomethylphenyl)-2-hydroxymethyl~-hexamethylenediamine. The latter, as the dihydrochloride, is hydrogenated with 10% palladium-on-carbon to give N,N'-bis[2-(4-hydroxy-3-ureidome~hylphenyl)-2~hydroxy-ethyl]-hexamethylenediamine dihydrochloride.
~; ~ -- .: .
~ ,".!~
To a solution of 9~35 gO of N,N'-dibenzyl-N,N'-bis[2-~3-aminomethyl-4-benzyloxyphenyl)-2-hydroxyethyl]-hexa-methylenediamine in 50 mlO of pyridine is added 2O5 mlO of methanesulfonyl chloride at room temperatureO After 18 hours 15 the reaction mixture is added to an excess of 2N hydrochloric acid and extracted with chloroform. The extract i8 neutralized with sodium bicarbonate, washed, dried and evaporated to give ~ -N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methanesulfonamido- -methylphenyl)-2Ohydroxyethyll-hexamethylenediamine. The ;~
2Q latter, a~ the dihydrochloride, i8 hydrogenated with palladium- ,~
on-carbon to yield N,N'-bis[2-(4-hydroxy-3-methanesulfonamido- `~
methylphenyl)o2-hydroxyethyl]-hexamethylenediamine dihydro ''!' chlorideO .. '~ , '. -,. i.::
To a mixture of 260 ccO of 37% formaldehyde and 1800 cc. of concentrated hydrochloric acid is added 400 gO of p-hydroxyacetophenone at a temperature of about 45Co The mixture is maintained at 50Co for two hours, filteredJ and washed with water to give 3-chloromethyl~4-hydroxyaceto- ;~
30 phenone, mOpO 154C. dec. - ~
~." , ~ ' .
`':"' 1~4~9 ; `
,.:,, .
1 A mixture of 40 gO of 3-chloromethyl-4-hydroxy-acetophenone and 26 g. of magnesium methyl sulfinate in ;~
~ -500 mlO of ethanol i9 refluxed with stirrin8 for 3 hours.
The reaction mixture i8 then concentrated in vacuo. The re- -sultant oil i9 redissolved in chloroform and wa~hed with waterO The chloroform is dried and evaporated to give 4-hydroxy-3-methyl-sulfonylmethylacetophenone, m.pO 206.5- - :
208. 5C o A mixture of 1400 gO of 4-hydroxy-3-methylsulfonyl- ~~
1 10 methylacetophenone, 903 g. of potassium carbonate, 7.8 mlO of benzyl chloride and a catalytic amount of sodium iodide in t~.' ~-, 250 mlO of acetone and 250 ml. of water is refluxed with stirrine for 16 hours. The acetone is removed and the aqueous phase ~8 extracted with chloroform, washed with water, dried 15 and evaporated to yield an oil which is recrystallized in ,.. ... .
isopropyl alcohol to give crystalline 4-benzyloxy-3-methyl- ~,',,'t sulfonylmethylacetophenone, m.p O 94-97Co -To a stirred ~olution of 707 gO of 4-benzyloxy-3 methylsulfonylmethylacetophenone and 2015 g. of 2-pyrrolidone in 300 ml. of tetrahydrofuran is added 12~5 g. of pyrrolidone hydrotribromide (PHT) and the ~tirring is continued for 56 hours at room temperature. The mixture is filtered and the .. . .
filtrate concentrated in vacuo to give an oil which crystal- '~-~
; lizes upon standing. The crystals are redissolved in chloro-25 form. The chloroform-solution is washed with water, dried ~' ;
and concentrated to yield a solid which is recrystallized ~ . ... .
from scetonitrile to give 4-benzyloxy-a-bromo-3-methylsul-fonylmethylacetophenone, m~p. 143-144C. ~`
Following the procedures of Example 14, equimolar amount8 of 4-benzyloxyoa-bromo-3~methylsulfonylmethylaceto-.
.. , `,.
~ . . . . . . . . . .
1 phenone and N,N'~dibenzyl-hexamethylenediamine are stirred in acetonitrile at 25Co for two hours to give N,N'-dibenzyl-N, N'-bis[2-(4-benzyloxy-3~methylsulfonylmethylphenyl)2-oxo- ,::
ethyl]-hexamethylenediamine which is similarly hydrogenated ;~
to furnish NJN'-bis[2-(4-hydroxy-3-methylsulfonylmethylphenyl)-2-hydroxyethyl]-hexamethylenediamine; m.pO dihydrochloride 177-179C.
~ ,'; ~ :A solution of lOoO gO (0.0252 m.) of 4-benzyloxy-a-bromo-3-methylsulfonylmethylacetophenone in 50 mlO of dimethyl- ;~
sulfoxide is allowed to stand for 40 hours and then i9 poured into waterO The mixture is extracted with chloroform and the ...
extract is washed with water, dried and evaporated to give 4-benzyloxy~3-methylsulfonylmethylphenyl glyoxal, m.pO
1080110Co To a warm slurry of 3.32 gO (0.01 m.) of the above prepared phenyl glyoxal in 40 mlO of methanol i8 added a solution of 0058 g. (0~005 m.~ of 1,6-diaminohexane in ~...... .
methanolO After warming for 20 minutes the reaction mixture s 20 is filtered to give N,N'-blsl2-~4-benzyloxy-3-methylsulfonyl- ~ ;
methylphenyl) 2-oxoethylidene]~hexamethylenediamine, mOp. -162-163Co ~`.
The above diamine is slurried in absolute ethanol and 1.0 gO of sodium borohydride is added. The mixture is 25 refluxed for two hours and filtered hot to yield N,N'-bis120 (4-benzyloxyo3-methylsulfonylmethylphenyl~-2-hydroxyethyl]-hexamethylenediamine, m.pO 146~148.5C.
This bis aminoalcohol (2 0 g., 000027 mO) is hydro-genated as a slurry in methanol on a Parr shaker over 1.0 g.
30 of palladiumon-carbon for about five hour80 The reaction , . .
1 mixture is filtered, evaporated and the residue in methanol is treated with ethereal-hydrogen chloride to give N,N'-bis[2-(4-hydroxy-3-methyl8ulfonylmethylphenyl)-2-hydroxyethyll-hexa-methylenediamine dihydrochloride, mOp. 177-179C.
.
.''' ,."", ~"
; .
. -~:
.... . .
:
... ,~,., ~ :
.
-;
. .
. .
, , - : - . .
.. .
Claims (14)
1. A process for the preparation of compounds having the formula:
in which:
n is a positive whole integer of from 4 to 8;
Y is NH2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR NHSO2NH2, NHSO2N(CH3)2, CH2OH, CH2NH2, CH2NHSO2R, CH2NHCONH2 or CH2SO2R; and R is lower alkyl of from 1 to 5 carbon atoms, straight or branched chain, which comprises condensing an N,N'-dibenzyl polymethylene-diamine with a bromoketone of the formula:
in which Y' is NO2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2, CO2CH3, CH3CO2CH2 or CH2SO2R, R is as defined above and R2 is benzyl, acetyl or hydrogen, to give a polymethylenediamine of the formula:
in which Y', R2 are n are as defined above, and reacting said polymethylenediamine as follows:
(a) when Y' is NO2, R2 is benzyl and n is 4 to 8, reducing with platinum oxide to give the corresponding amino-alcohols and debenzylating by catalytic hydrogenation;
(b) when Y' is NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3) or CH2SO2R, R2 is benzyl nnd n is 4 to 8, hydrogenating catalytically to reduce the ketone groups and debenzylate, or reducing the ketone groups with sodium borohydride and debenzylating by catalytic hydrogenation;
(c) when Y' is CH3CO2CH2, R2 is acetyl and n is 4 to 8, treating with a mineral acid to give the corresponding 3-hydroxymethyl-4-hydroxy derivatives and hydrogenating catalytically; and (d) when Y' is CO2CH3, R2 is hydrogen and n is 4 to 8, treating with ammonia to give the amide derivatives of the formula:
and (i) reducing with lithium aluminum hydride to give the corresponding aminomethyl derivatives and debenzylating by catalytic hydrogenation, or (ii) treating with benzyl chloride to give the benzyloxy protected compounds, reducing with lithium aluminum hydride to obtain the corresponding benzyloxy aminomethyl derivatives, reacting with sodium cyanate in acid to yield the ureidomethyl derivatives or reacting with an alkyl sulfonyl chloride to give the sulfonamidomethyl deriva-tives, and debenzylating by catalytic hydrogenation.
in which:
n is a positive whole integer of from 4 to 8;
Y is NH2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR NHSO2NH2, NHSO2N(CH3)2, CH2OH, CH2NH2, CH2NHSO2R, CH2NHCONH2 or CH2SO2R; and R is lower alkyl of from 1 to 5 carbon atoms, straight or branched chain, which comprises condensing an N,N'-dibenzyl polymethylene-diamine with a bromoketone of the formula:
in which Y' is NO2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2, CO2CH3, CH3CO2CH2 or CH2SO2R, R is as defined above and R2 is benzyl, acetyl or hydrogen, to give a polymethylenediamine of the formula:
in which Y', R2 are n are as defined above, and reacting said polymethylenediamine as follows:
(a) when Y' is NO2, R2 is benzyl and n is 4 to 8, reducing with platinum oxide to give the corresponding amino-alcohols and debenzylating by catalytic hydrogenation;
(b) when Y' is NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3) or CH2SO2R, R2 is benzyl nnd n is 4 to 8, hydrogenating catalytically to reduce the ketone groups and debenzylate, or reducing the ketone groups with sodium borohydride and debenzylating by catalytic hydrogenation;
(c) when Y' is CH3CO2CH2, R2 is acetyl and n is 4 to 8, treating with a mineral acid to give the corresponding 3-hydroxymethyl-4-hydroxy derivatives and hydrogenating catalytically; and (d) when Y' is CO2CH3, R2 is hydrogen and n is 4 to 8, treating with ammonia to give the amide derivatives of the formula:
and (i) reducing with lithium aluminum hydride to give the corresponding aminomethyl derivatives and debenzylating by catalytic hydrogenation, or (ii) treating with benzyl chloride to give the benzyloxy protected compounds, reducing with lithium aluminum hydride to obtain the corresponding benzyloxy aminomethyl derivatives, reacting with sodium cyanate in acid to yield the ureidomethyl derivatives or reacting with an alkyl sulfonyl chloride to give the sulfonamidomethyl deriva-tives, and debenzylating by catalytic hydrogenation.
2. A process for the preparation of compounds having the formula:
in which:
is a positive whole integer of from 4 to 8;
Y is NH2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHR, NHSO2NH2, NHSO2N(CH3)2, CH2OH, CH2NH2, CH2NHSO2R, CH2NHCONH2 or CH2SO2R; and R is lower alkyl of from 1 to 5 carbon atoms, straight or branched chain, which comprises reacting a polymethylenediamine of the formula:
in which Y' is NO2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2, CO2CH3, CH3CO2CH2, or CH2SO2R, R2 is benzyl, acetyl or hydrogen, and R and an n are as defined above, as follows:
(a) when Y' is NO2, R2 is benzyl and n is 4 to 8, reducing with platinum oxide to give the corresponding amino-alcohols and debenzylating by catalytic hydrogenation;
(b) when Y' is NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2 or CH2SO2R, R2 benzyl and n is 4 to 8, hydrogenating catalytically to reduce the ketone groups and debenzylate, or reducing the ketone groups with sodium borohydride and debenzylating the catalytic hydrogenation;
(c) when Y' is CH3CO2CH2, R2 is acetyl and n is 4 to 8, treating with a mineral acid to give the corresponding 3-hydroxymethyl-4-hydroxy derivatives and hydrogenating catalytically; and (d) when Y' is CO2CH3, R2 is hydrogen and n is 4 to 8, treating with ammonia to give the amide derivatives of the formula:
and (i) reducing with lithium aluminum hydride to give the corresponding aminomethyl derivatives and debenzylating by catalytic hydrogenation, or (ii) treating with benzyl chloride to give the benzyloxy protected compounds, reducing with lithium aluminum hydride to obtain the corresponding benzyloxy aminomethyl derivatives, reacting with sodium cyanate in acid to yield the ureidomethyl derivatives or reacting with an alkyl sulfonyl chloride to give the sulfonamidomethyl deriva-tives, and debenzylating by catalytic hydrogenation.
in which:
is a positive whole integer of from 4 to 8;
Y is NH2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHR, NHSO2NH2, NHSO2N(CH3)2, CH2OH, CH2NH2, CH2NHSO2R, CH2NHCONH2 or CH2SO2R; and R is lower alkyl of from 1 to 5 carbon atoms, straight or branched chain, which comprises reacting a polymethylenediamine of the formula:
in which Y' is NO2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2, CO2CH3, CH3CO2CH2, or CH2SO2R, R2 is benzyl, acetyl or hydrogen, and R and an n are as defined above, as follows:
(a) when Y' is NO2, R2 is benzyl and n is 4 to 8, reducing with platinum oxide to give the corresponding amino-alcohols and debenzylating by catalytic hydrogenation;
(b) when Y' is NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2 or CH2SO2R, R2 benzyl and n is 4 to 8, hydrogenating catalytically to reduce the ketone groups and debenzylate, or reducing the ketone groups with sodium borohydride and debenzylating the catalytic hydrogenation;
(c) when Y' is CH3CO2CH2, R2 is acetyl and n is 4 to 8, treating with a mineral acid to give the corresponding 3-hydroxymethyl-4-hydroxy derivatives and hydrogenating catalytically; and (d) when Y' is CO2CH3, R2 is hydrogen and n is 4 to 8, treating with ammonia to give the amide derivatives of the formula:
and (i) reducing with lithium aluminum hydride to give the corresponding aminomethyl derivatives and debenzylating by catalytic hydrogenation, or (ii) treating with benzyl chloride to give the benzyloxy protected compounds, reducing with lithium aluminum hydride to obtain the corresponding benzyloxy aminomethyl derivatives, reacting with sodium cyanate in acid to yield the ureidomethyl derivatives or reacting with an alkyl sulfonyl chloride to give the sulfonamidomethyl deriva-tives, and debenzylating by catalytic hydrogenation.
3. The process in accordance with claim 1 charac-terized in that the bromoketone and polymethylenediamine are condensed in acetonitrile for from 1 to 4 hours.
4. The process in accordance with claim 1 charac-terized in that catalytic hydrogenation is carried out with palladium-on-carbon.
5. The process in accordance with claim 1 charac-terized in that the product obtained is converted to a pharmaceutically acceptable acid addition salt.
6. The process for the preparatlon of N,N'-bis[2-(4-hydroxy-3-methylsulfonylmethylphenyl)-2-hydroxyethyl]-hexamethylenediamine which comprises condensing 4-benzyloxy-.alpha.-bromo-3-methylsulfonylmethylacetophenone and N,N'-dibenzyl-hexamethylenediamine to give N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methylsulfonylmethylphenyl)-2-oxoethyll-hexa-methylenediamine and hydrogenating the latter with 10%
palladium-on-carbon.
palladium-on-carbon.
7. A compound having the formula:
in which:
n is a positive whole integer of from 4 to 8;
Y is NH2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2, CH2OH, CH2NH2, CH2NHSO2R, CH2NHCONH2 or CH2SO2R; and R is lower alkyl of from 1 to 5 carbon atoms, straight or branched chain, whenever said compound is pre-pared by the process of claim 1 or an obvious chemical equivalent thereof.
in which:
n is a positive whole integer of from 4 to 8;
Y is NH2, NHCHO, NHCOCH3, NHCONH2, NHSO2R, NHCO2R, NHCONHR, NHSO2NH2, NHSO2N(CH3)2, CH2OH, CH2NH2, CH2NHSO2R, CH2NHCONH2 or CH2SO2R; and R is lower alkyl of from 1 to 5 carbon atoms, straight or branched chain, whenever said compound is pre-pared by the process of claim 1 or an obvious chemical equivalent thereof.
8. N,N'-Bis[2-(4-hydroxy-3-methylsulfonylmethyl-phenyl)-2-hydroxyethyl]-hexamethylenediamine, whenever prepared by the process of claim 6 or an obvious chemical equivalent thereof.
9. A process for the preparation of a compound of the formula (i) (i) in which R1 represents a hydrogen atom or a lower acyl group R2 represents CH2OH, NHCHO, NHCOCH3, CH2NHCONH2, NHSO2R3, NHSO2N(CH3)2, CH2NHSO2R3 R3 represents alkyl of 1 to 5 carbon atoms n is an integer of 4 to 8 and pharmaceutically acceptable acid addition salts thereof which comprises either (a) the hydrolysis, hydrogenolysis or alcoholysis of a compound of the formula (ii) (ii) in which R1, R2, R3 and n are as defined above and in which any phenolic hydroxy groups present are either free or protected by a hydrolytically, alcoholytically or hydrogen-olytically removable protecting group and R4 represents a hydrogen atom or a hydrogen-olytically removable amine or imine protecting group with the proviso that the compound of the formula (ii) contains at least one such removable protecting group, or an acid addition salt thereof, whereby the protected compound of formula (ii) is converted into a compound of formula (i) or a pharmaceutically acceptable acid addition salt thereof or (b) the reduction of a compound of the formula (iii) (iii) in which R1, R2, R3 and n are as defined above, or an acid addition salt thereof with a reagent serving to reduce a keto group to a secondary alcohol group or (c) the reduction of a compound of the formula (iv) ( iV) in which R1, R2, R3, R4 and n are as defined above and in which any phenolic hydroxy groups present are either free or protected by a hydrolytically, alcoholytically or hydrogen-olytically removable protecting group, or an acid addition salt thereof, and subsequently removing the protecting group(s) present, whereby a compound of formula (i) is obtained; and wherein the process may include the additional step of converting a base of formula (i) into a corresponding pharmaceutically acceptable acid addition salt.
10. A compound of the formula (i) as defined in claim 9 or a pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
11. A process for the preparation of a compound of the the formula (v) (V) n which R represents NHCHO, NHCOCH3, CH2NHCONH2, NHSO2R3, NHSO2N(CH3)2, CH2NHSO2R3 R3 represents alkyl of 1 to 5 carbon atoms R5 represents benzyl, acetyl or hydrogen n is an integer of 4 to 8 which comprises condensing an N,N'-dibenzyl polymethylene diamine of the formula (vi) (vi) in which n is as defined above, with a bromoketone of the formula (vii) (vii) in which R2, R3 and R5 are as defined above.
12. A process as claimed in claim 9 for the preparation of a compound of the formula (viii) (viii) in which R1 represents a hydrogen atom or a lower acyl group and in which, in the reactants R2 represents CH2OH.
13. A process as claimed in claim 9 for the preparation of a compound of the formula (ix) ( ix) in which R1 represents a hydrogen atom or a lower acyl group and in which, in the reactants R2 represents NHSO2CH3.
14. A process as claimed in claim 9 for the preparation of a compound of the formula (X) (X) in which, R1 represents a hydrogen atom or a lower acyl group and in which, in the reactants R2 represents NHCOCH3.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14891271A | 1971-06-01 | 1971-06-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1044699A true CA1044699A (en) | 1978-12-19 |
Family
ID=22527996
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA143,419A Expired CA1044699A (en) | 1971-06-01 | 1972-05-30 | N,n'-bis(2-(3-substituted-4-hydroxyphenyl)-ethyl or -2-hydroxyethyl)-polymethylenediamines |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5614656B1 (en) |
| AU (1) | AU474656B2 (en) |
| BE (1) | BE784105A (en) |
| CA (1) | CA1044699A (en) |
| DE (1) | DE2227022C2 (en) |
| FR (1) | FR2140149B1 (en) |
| GB (3) | GB1370066A (en) |
| ZA (1) | ZA723611B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1386029A (en) * | 1972-03-20 | 1975-03-05 | Smithkline Corp | Alpha-benzylamino-4-benzyloxy-3-alkylsulphonylmethyl phenones |
| EP0142283B1 (en) * | 1983-10-25 | 1991-01-30 | FISONS plc | Phenylethylamines, process for their preparation and compositions containing them |
| JPH01163553U (en) * | 1988-04-30 | 1989-11-15 | ||
| JPH04106659U (en) * | 1991-02-20 | 1992-09-14 | 本田技研工業株式会社 | electrostatic coating equipment |
| US6713651B1 (en) | 1999-06-07 | 2004-03-30 | Theravance, Inc. | β2-adrenergic receptor agonists |
| US6362371B1 (en) | 1998-06-08 | 2002-03-26 | Advanced Medicine, Inc. | β2- adrenergic receptor agonists |
| FR2788768B1 (en) | 1999-01-21 | 2001-02-16 | Oreal | NEW CATIONIC 2-ACYLAMINOPHENOLS, THEIR USE AS COUPLER FOR OXIDATION DYEING, COMPOSITIONS COMPRISING THEM, AND DYEING METHODS |
| US6683115B2 (en) | 1999-06-02 | 2004-01-27 | Theravance, Inc. | β2-adrenergic receptor agonists |
| UA73965C2 (en) | 1999-12-08 | 2005-10-17 | Theravance Inc | b2 ADRENERGIC RECEPTOR ANTAGONISTS |
-
1972
- 1972-05-26 ZA ZA723611A patent/ZA723611B/en unknown
- 1972-05-29 BE BE784105A patent/BE784105A/en not_active IP Right Cessation
- 1972-05-30 GB GB2526972A patent/GB1370066A/en not_active Expired
- 1972-05-30 CA CA143,419A patent/CA1044699A/en not_active Expired
- 1972-05-30 GB GB1482574A patent/GB1370068A/en not_active Expired
- 1972-05-30 GB GB1482474A patent/GB1370067A/en not_active Expired
- 1972-05-31 AU AU42965/72A patent/AU474656B2/en not_active Expired
- 1972-06-01 FR FR7219677A patent/FR2140149B1/fr not_active Expired
- 1972-06-01 JP JP5500372A patent/JPS5614656B1/ja active Pending
- 1972-06-02 DE DE2227022A patent/DE2227022C2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2140149A1 (en) | 1973-01-12 |
| GB1370068A (en) | 1974-10-09 |
| GB1370066A (en) | 1974-10-09 |
| GB1370067A (en) | 1974-10-09 |
| AU4296572A (en) | 1973-12-06 |
| AU474656B2 (en) | 1976-07-29 |
| DE2227022A1 (en) | 1972-12-14 |
| ZA723611B (en) | 1973-03-28 |
| FR2140149B1 (en) | 1976-03-05 |
| JPS5614656B1 (en) | 1981-04-06 |
| DE2227022C2 (en) | 1983-01-13 |
| BE784105A (en) | 1972-11-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3928412A (en) | 1-Aryloxy-3-ureidoalkylamino-2-propanols | |
| CA1044699A (en) | N,n'-bis(2-(3-substituted-4-hydroxyphenyl)-ethyl or -2-hydroxyethyl)-polymethylenediamines | |
| US5914349A (en) | Compositions containing and methods of using 1-aminoindan and derivatives thereof and process for preparing optically active 1-aminoindan derivatives | |
| US3689524A (en) | Phenethylamine derivatives | |
| FI85692B (en) | FOERFARANDE FOER FRAMSTAELLNING AV FENYLETANOLAMINTETRALINER MED LIPOLYTISK AKTIVITET. | |
| US3933911A (en) | 1-Aryl-2-amidoalkylaminoethanol derivatives | |
| JPS5912113B2 (en) | Process for producing ethanolamine derivatives or acid addition salts thereof | |
| WO1996021640A1 (en) | Optically active aminoindane derivatives and preparation thereof | |
| GB2133788A (en) | Phenethylamine derivatives | |
| US3933913A (en) | N,N'-bis[3-substituted-4-hydroxypheyl)-2-hydroxyethyl)]-polymethylenediamines | |
| US3117160A (en) | Aralkylamines | |
| US3875233A (en) | Bis-P-hydroxy-phenethyl amines | |
| AU2003229734B2 (en) | Hydroxy tetrahydro-naphthalenylurea derivatives | |
| IE63650B1 (en) | Process for the preparation of n-methyl-3-(p-trifluoro-methyl-phenoxy)-3phenyl-propylamine and its salts | |
| GB2029407A (en) | Phenethanolamines | |
| MURASE et al. | New β-Adrenoreceptor Stimulants. Studies on 3-Acylamino-4-hydroxy-α-(N-substituted aminomethyl) benzyl Alcohols | |
| EP0185814A2 (en) | Phenylserine derivatives and processes for their preparation | |
| US2879293A (en) | Benzylamine derivatives | |
| US3763232A (en) | Alpha-aminoalkyl-4-hydroxy-3-ureidobenzyl alcohols | |
| US3803230A (en) | 5-(2-((1-methyl-3-phenylpropyl)amino)ethyl)salicylamide hydrochloride | |
| US4024281A (en) | N,N-bis[2-(3-substituted-4-hydroxyphenyl)-ethyl or -2-hydroxyethyl]-polymethylenediamines | |
| US3657319A (en) | Alpha-aminoalkyl-4-hydroxy-3-carboalkoxyaminobenzyl alcohols | |
| US3957870A (en) | Organic compounds | |
| US2538763A (en) | Phenylaminopropandiols | |
| US4041074A (en) | 1-Hydroxyaryl-2-amidoalkylaminoethanol derivatives |