CA2074075A1 - Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates/in accordance with this process prepared - Google Patents
Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates/in accordance with this process preparedInfo
- Publication number
- CA2074075A1 CA2074075A1 CA 2074075 CA2074075A CA2074075A1 CA 2074075 A1 CA2074075 A1 CA 2074075A1 CA 2074075 CA2074075 CA 2074075 CA 2074075 A CA2074075 A CA 2074075A CA 2074075 A1 CA2074075 A1 CA 2074075A1
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- CA
- Canada
- Prior art keywords
- phenyl
- ethyl
- preparing
- accordance
- glycidyl
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
Abstract
The present invention relates to a process for preparing S- and R-enantiomers of certain substituted 3-aryloxy-2-hydroxypropylamines used as beta blockers, and to the S- and R-enantiomers of certain intermediates used for this preparative stage.
Description
wosl/l0~2 PCT/SE91/00022 . -- 1 --2 ~ 7 ~ -Pr~cess for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process.
~he present invention relates to a process for preparing S- ànd R-enantiomers of substituted 3-aryloxy-2-hydroxypropylamines u~ed as beta-receptor-blocking ~ubstances (hereinaft~r call~d beta blockers~ and with the following respective formulae: .
~ U
~ 3 S-BETA ~LOCRERS
Oh' ~
o ~3 R-BETA ~LOCKERS
in which Ar2 = sub~tituted benzene or naphthalene radical and R3 = i~opropyl/
tertiary bu~yl, 2-~3,4-dimethox~phenyl)ethyl, 2-(2-methoxyphenoxy)ethyl, 2-(4-hydroxyphenylacetylamino)ethyl or a 2-(N-morpholinocarbonylamino)ethyl radical.
According to the i~vention, the~e beta blockers can be prepared ~ia in~ermediate~ in the form of the S- or R-enan~iomers of the amines defined below.
C~//~3 R~ ~ C~NR3R~
~q ~6 .
. - . .
- - . . . ..
... ;. . . . .. .. . . .
.. . . .- , . . .. ~ . .... . .
.
. .. . . . . .. . . .
:- ~ ~ , . . . .
WO 91tlO642 - 2 - PCT/SE~1/00022 ~ A/ R3 R~ ~/NR3 I~y ~3q 8b - f o r m Th~ abovementioned definitions for R3 apply here, while R~ will be hydrogen or a protecting group whi~h can be easily removed by means of hydrogenolysis, for example an optionally ~ubstituted benzyl radical with one or more identical or different substituents, for example methyl, alkyl, methoxy, alkoxy, hydroxyl or nitro, it being preferable, however, for the protecting group to consist of an unsubstituted benzyl radical.
The abovementioned intermediates designated 9a o~ 9b and 8a or 8b can in turn be obtained from other intermediates included in the invention and di~cussed lat~r in the text, with the following general formulae in their R- or S-forms.
~ 03~ ~ 03 S-/qr~
~0 or 706 or~ ~ fo~n and 03 ~-A rt or ~ ~ ~ 0 S~r~
5--f o~ fo r ~
in which Ax~ = substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character.
....
- ,, , ,, - . , :
., - . . . ., . . , . , : " . . . . . . . . .
.. : - .-. . . . . . : : .
WOgl/l0~2 3 PCT/SE91/~02t 2 ~
PRIOR ART
Beta blockers are used as drugs primarily f or cardiovascular ~iseases, such as hypertension, angina pectoris and c~rtain arrhythmia~, and for glaucoma (an ophthalmic disease). Most beta blockers consist of substituted 3-aryloxy-2-hydroxypropylamines. These have a chiral centre at carbon atom number 2, as a result of which each of them can exist as ~wo enantiomers, the R-form and t}.e S-form. Those substances consisting of equal parts of R-form and S-form will hereinafter be called racemic or racemate, and those which consist principally of one of these two forms will be called homochiral.
In the case of some beta blockers, it is known that it is their S-form which possesqes the pharmacological effect which is desirable in cardiovascular diseases, while the same beta blocker's R-form is virtually inactiYe. In contrast, both the enantiomers have been found to be approxLmately equally effective against glaucoma (Reates, E V, Stone, Rs Am J Ophthalmol 98, 73 (1984)). It has therefore ~een proposed to use these R-beta blockers again~t glaucoma in order to prevent any e~fect on the cardiova~cular syst~m, while the S-form should be used for cardiovascular diseases. There is therefore considerable interest in e~tabli~hing the simple~t possible synthesis route~ for preparing both khe S- and R-form~ of homochiral beta blockers.
Synthesi~ routes for prsparing certain homochiral beta blockers are deYcribe~ in the literature. Thus, it is already known, for example from US patent 4,408,063, that S- or R-propranolol can be prepared from S- or R~glycidyl 4-toluenesulphonate (la or lb) in accordance with the general Schemo I below (ln this and in ~ub~equent general formula ~chemes, ~teps and definitions obvious to the person skilled in the art have been omitted, to the extent that this has simplified the presentation. In many cases ~he text whîch follows also make3 direct reference ': .- .' " ,'' ' ", ' , ' . ~ .
.
..
.
WO 91/10642 ~ ~ 4 pcr/sEs1/ooo22 to th~ reference numbers given in the~e general formulae and schemes ) .
cheme I 4 o OæNS'~
S PROPRANOLOL
h 01 o~N~
R-PROPRANOLOL
g~ 3~g3 5(~ D ~
There are also other previously known beta blocXers which CQntain a substituted benzene radical instead of a subs~ituted naphthalene radical. For these be~a blockers too, the general designation Ar2 will there~ore be con-~idared, as earlier on page 1, as repre~enting bo~h tituted benzene and naphthalene radicals. Ç:B P~tent 1,269,7?5 da~cribes a me~hod for preparing such beta bloc3cer~ taking as a ~tarting point certain specific amines hereinafter designated 2a, 2b, 3a and 3b, in accordance with the general method defined below (Scheme II ) . Here, Rl = alkyl radical, R2 = hydroger or an alpha-arylalkyl radical and Z = a halogen atom, Scheme II shows on the one hand the product obtained when R2 ~ hydrogen and when the S- or R-beta blocker in question is obtained directly, and when R2 i8 not - hydrogen and when a product is obtained which is certsinly not the de~ ired product - .. . . .
- . . . .
.
WO 91/10642 5 2 ~ 7 ~ PCT~SE91/013022 but which can be converted ~o it by means of hydro-genolys is .
~
A P~_ 0~ + ~/1~, R2 ~ Ar~ /VRlRz~q~ ~/l ~a ~ S-6e~ 6/oc~c~
A~-~ ~NR~RZ~L~ ~Z=~ ~
3c~
~,e ~~
.......
\~ r2O~/vR~ 0~ R, b ~ , ~-~efcl 6~oc~4er O~f;, . . ~.
A~-O~lf~NRIR,~ ~Z~ ,?~ .
7 ~
Hitherto, it ha- only been possible for the above amines in question 2a, 2b, 3a and 3b, which include the amines 8a, 8b, 9a and ~b in que3tion on page 2, to be prepared in homochiral form from corre~ponding racemate~ by ~eparation via 8alt8 (so-called resolution of racemates).
It is also previously known, for example from SE-A-7414017-9 (425.971), corre~ponding to G~ Patents 14S8392 and 1458393, to prepare 5beta blockers a~cording to the general Scheme III below, from any of the starting substance~ de~ignated 4, S, 6 or 7, in which ~r2 has the same meaning as be~ore, and in which Y = An ~asily remo~abla protecting group, while Z1 ~ a substitutable radical.
.
. .
' W091/10542 ~r~ j'd - 6 - PCT/SE91/000~2 Scheme III 0~ C~
4r~0~oy ~~ Oh~
~ 6 /;~2 = ~
Ar,~,O~ N~Rf~l~O ~ ~/r~C I~G
S-BETA BLOCKER
DESCRIP~ON OF THE INVENTION
The present invention now includes, inter alia, a proces~
for preparing any desired enantiomers of amines 8a or 8b and 9a or 9b ~ ee page 2) from easily accessible raw materials. This involves S- or R-glycidyl esters of sulphonic acids (glycidyl sulphonate) initially being reacted with hydrogen chloride for converting the epoxy group c~ntained therein to a l,2-chlorohydrin group in order to give the corre~ponding chloropropanediol sulphonate which in turn i~ reacted with an amine to give the corresponding chloropropanolamine (9a or 9b, depend-ing on whieh enantiomer constituted the starting sub-stan~e), or alternatively by means of a further treatment with a ba3e, if appropriate in the presence of a phenol, completely or partially reacted to give the second ~mine (8a or 8b). The amines 9a, 9b, 8a and 8b are included in the general formulae for the amines 2 and 3 discussed earlier.
For preparing the glycidyl sulphonates which are used as intermediate3 in the proces~ according to the invention and which are de~ignated lOa and lOb in the for~ulae, the raw mat~rials which can be employed include commercially available substances ~uch as R- or 5-glycidol, or esters thereof, for example R-glycidyl butyrat~, which can be converted, ~y ~eans of techniques known to the person ~killed in the ar~, to lOa or lOb, respec~ively, accord-ing to the following scheme:
.
-.: . ; ~,,`~ , :' .' ` ' ' ' ' ' . ' ~091/10642 2 ~ '7 '1 ~ 7 ~
7 PCT/SE91t~022 Scheme A
p~O~C3~ ~o~ C~ O~ r~
O~o/~ ~2 ~r~ V
fi'--~Or~ ~/O~ ~--~r~
in which Ar1 is a su~stituted benzene or naph~halene radical in which at least one substituent is of an elect.ron-attracting character, for example one or more chlorine, bromine or iodine atoms, one or more nitroso~
nitro, cyano, trifluoromethyl, trichloromethyl or tri-bromomethyl groups, one or more optionally substi~uted sulphinyl, sulphonyl, phosphonyl, phosphoryl or carbonyl groups, or combinations of the~e atoms and groups, at any cho~en posit~ons on the benzene or naphthalene rings, it being prefsrable for Ar1 to be a subs~ituted benzene radical in which at leaAt one substituent is a nitro, an optionally ~ubstituted sulphonyl or an optionally sub-stituted carbonyl group at any cho~en position on the benzene rin~. In the mo~t interesting alternative, AI1 is a substituted benzehe radical in which at least one substituent i3 a nitro group at a~y chosen position on the benzene ring.
Alternatively, the glycidyl sulphonates lOa and lOb can be prepared starting from allyl alcohol which, by means of Qnantios~lective epoxidation r iS con~erted to S- or R-glycidol, which is then reacted to give lOa or lOb, respectively, again using the known technique (cf., for example, Rlunder, J M, ~o, S Y, Sharpless, R B: J Org Chem 5l, 3710 (l936)).
The prepar~tion of the amines 9a and 9b by reacting the glycidyl sulphonate~ lOa and lOb, ~espectively, with hydrogen chloride followed by treatment with an amine can be illustratsd a~ follows:
"
~ 8 - PCT/SE91/00022 Scheme V
035-~4r~~Q~S-Arl ~ R3f~f N~ J~ R R
~. fo.~ fo~ 9C~_ l~ 35~-'4r1 ~ ~o3~Ar1tR3R~
~0~ ~f6 ~ 9 5-~ ~~ ~~ f~ fo~~_ in which Arl, R3 and R4 have the same meanings as above.
As can be seen, R changes to S and S to R upon reaction with hydrogen chloride. We have cho~en to use references a and b to follow the chemistry, rather than the prefixes R and S which derive from nomenclature conventions.
The amines 9a and 9b can be completely or partially converted to amines 8a and 8b, re~pectively, by ~reatment wi~h a bsse, for oxample hydroxides, alkoxides or car-bonates of lithium, sodium, pota~sium, calcium.or magne-sium and optionally sub~tituted ammonia, it being prefer-able for the base to con~ist o~ sodium or potassium hydroxide or of sodium or potassium alkoxide, for ex~mple methoxide, ethoxide or tertia~y butoxide, optionally in the presence of a phenol, a~ i~ clear from the relevant part of Scheme V.
The advantage of the new procedure~ for preparing amines 8 and 9 in homochiral form is that they permi~ utiliza-tion of 10~% of the raw material, wher2as, with the earlier method, a maximum of 50~ of the employed raw material could be utilized, and also the earlier methods involve the use and recovery of a frequently ~xpen~ive homochiral salt-former.
As mentioned earlier, the inven~ion furthermore relates to new routes for the preparation of S- and R-beta blockers. Thase routes are via the amines 9a or 9b and 8a or 8b, for which reason the starting sub~tances for this part of the invention too are R- and S-glycidyl . ~ . . ' - - , ., . .
~ , . . ..... . .
- . . .. . , ,, , :, .: . , ~ : , ........... . .
.. . ~ ~ . , . .~ .. . . .
: ` ~..... : . , i . ... ... .
.. . . , . : . . . . - :. . .
,. .. -., .. , . - .. : . .. ' .. , ... , ,, .,,, . ' . . :, . , i~ , , ., ., ,. ,.: . . :.
WO91/10642 _ 9 ~ 2 ~ 7 ~ ~ i 3cr/sEg1/00022 e~ters of sulphonic acids (lOa or lOb) which are r~acted to give the amine~ 9a or 9b. These amines are then further treated in accordance with the following scheme.
Scheme V
~ =f/
Oh~ /~J ~Zf ~ r~ ~ ~4~3 J 6c~s 5- ~cf~ ~,~er +A~-O~
~he present invention relates to a process for preparing S- ànd R-enantiomers of substituted 3-aryloxy-2-hydroxypropylamines u~ed as beta-receptor-blocking ~ubstances (hereinaft~r call~d beta blockers~ and with the following respective formulae: .
~ U
~ 3 S-BETA ~LOCRERS
Oh' ~
o ~3 R-BETA ~LOCKERS
in which Ar2 = sub~tituted benzene or naphthalene radical and R3 = i~opropyl/
tertiary bu~yl, 2-~3,4-dimethox~phenyl)ethyl, 2-(2-methoxyphenoxy)ethyl, 2-(4-hydroxyphenylacetylamino)ethyl or a 2-(N-morpholinocarbonylamino)ethyl radical.
According to the i~vention, the~e beta blockers can be prepared ~ia in~ermediate~ in the form of the S- or R-enan~iomers of the amines defined below.
C~//~3 R~ ~ C~NR3R~
~q ~6 .
. - . .
- - . . . ..
... ;. . . . .. .. . . .
.. . . .- , . . .. ~ . .... . .
.
. .. . . . . .. . . .
:- ~ ~ , . . . .
WO 91tlO642 - 2 - PCT/SE~1/00022 ~ A/ R3 R~ ~/NR3 I~y ~3q 8b - f o r m Th~ abovementioned definitions for R3 apply here, while R~ will be hydrogen or a protecting group whi~h can be easily removed by means of hydrogenolysis, for example an optionally ~ubstituted benzyl radical with one or more identical or different substituents, for example methyl, alkyl, methoxy, alkoxy, hydroxyl or nitro, it being preferable, however, for the protecting group to consist of an unsubstituted benzyl radical.
The abovementioned intermediates designated 9a o~ 9b and 8a or 8b can in turn be obtained from other intermediates included in the invention and di~cussed lat~r in the text, with the following general formulae in their R- or S-forms.
~ 03~ ~ 03 S-/qr~
~0 or 706 or~ ~ fo~n and 03 ~-A rt or ~ ~ ~ 0 S~r~
5--f o~ fo r ~
in which Ax~ = substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character.
....
- ,, , ,, - . , :
., - . . . ., . . , . , : " . . . . . . . . .
.. : - .-. . . . . . : : .
WOgl/l0~2 3 PCT/SE91/~02t 2 ~
PRIOR ART
Beta blockers are used as drugs primarily f or cardiovascular ~iseases, such as hypertension, angina pectoris and c~rtain arrhythmia~, and for glaucoma (an ophthalmic disease). Most beta blockers consist of substituted 3-aryloxy-2-hydroxypropylamines. These have a chiral centre at carbon atom number 2, as a result of which each of them can exist as ~wo enantiomers, the R-form and t}.e S-form. Those substances consisting of equal parts of R-form and S-form will hereinafter be called racemic or racemate, and those which consist principally of one of these two forms will be called homochiral.
In the case of some beta blockers, it is known that it is their S-form which possesqes the pharmacological effect which is desirable in cardiovascular diseases, while the same beta blocker's R-form is virtually inactiYe. In contrast, both the enantiomers have been found to be approxLmately equally effective against glaucoma (Reates, E V, Stone, Rs Am J Ophthalmol 98, 73 (1984)). It has therefore ~een proposed to use these R-beta blockers again~t glaucoma in order to prevent any e~fect on the cardiova~cular syst~m, while the S-form should be used for cardiovascular diseases. There is therefore considerable interest in e~tabli~hing the simple~t possible synthesis route~ for preparing both khe S- and R-form~ of homochiral beta blockers.
Synthesi~ routes for prsparing certain homochiral beta blockers are deYcribe~ in the literature. Thus, it is already known, for example from US patent 4,408,063, that S- or R-propranolol can be prepared from S- or R~glycidyl 4-toluenesulphonate (la or lb) in accordance with the general Schemo I below (ln this and in ~ub~equent general formula ~chemes, ~teps and definitions obvious to the person skilled in the art have been omitted, to the extent that this has simplified the presentation. In many cases ~he text whîch follows also make3 direct reference ': .- .' " ,'' ' ", ' , ' . ~ .
.
..
.
WO 91/10642 ~ ~ 4 pcr/sEs1/ooo22 to th~ reference numbers given in the~e general formulae and schemes ) .
cheme I 4 o OæNS'~
S PROPRANOLOL
h 01 o~N~
R-PROPRANOLOL
g~ 3~g3 5(~ D ~
There are also other previously known beta blocXers which CQntain a substituted benzene radical instead of a subs~ituted naphthalene radical. For these be~a blockers too, the general designation Ar2 will there~ore be con-~idared, as earlier on page 1, as repre~enting bo~h tituted benzene and naphthalene radicals. Ç:B P~tent 1,269,7?5 da~cribes a me~hod for preparing such beta bloc3cer~ taking as a ~tarting point certain specific amines hereinafter designated 2a, 2b, 3a and 3b, in accordance with the general method defined below (Scheme II ) . Here, Rl = alkyl radical, R2 = hydroger or an alpha-arylalkyl radical and Z = a halogen atom, Scheme II shows on the one hand the product obtained when R2 ~ hydrogen and when the S- or R-beta blocker in question is obtained directly, and when R2 i8 not - hydrogen and when a product is obtained which is certsinly not the de~ ired product - .. . . .
- . . . .
.
WO 91/10642 5 2 ~ 7 ~ PCT~SE91/013022 but which can be converted ~o it by means of hydro-genolys is .
~
A P~_ 0~ + ~/1~, R2 ~ Ar~ /VRlRz~q~ ~/l ~a ~ S-6e~ 6/oc~c~
A~-~ ~NR~RZ~L~ ~Z=~ ~
3c~
~,e ~~
.......
\~ r2O~/vR~ 0~ R, b ~ , ~-~efcl 6~oc~4er O~f;, . . ~.
A~-O~lf~NRIR,~ ~Z~ ,?~ .
7 ~
Hitherto, it ha- only been possible for the above amines in question 2a, 2b, 3a and 3b, which include the amines 8a, 8b, 9a and ~b in que3tion on page 2, to be prepared in homochiral form from corre~ponding racemate~ by ~eparation via 8alt8 (so-called resolution of racemates).
It is also previously known, for example from SE-A-7414017-9 (425.971), corre~ponding to G~ Patents 14S8392 and 1458393, to prepare 5beta blockers a~cording to the general Scheme III below, from any of the starting substance~ de~ignated 4, S, 6 or 7, in which ~r2 has the same meaning as be~ore, and in which Y = An ~asily remo~abla protecting group, while Z1 ~ a substitutable radical.
.
. .
' W091/10542 ~r~ j'd - 6 - PCT/SE91/000~2 Scheme III 0~ C~
4r~0~oy ~~ Oh~
~ 6 /;~2 = ~
Ar,~,O~ N~Rf~l~O ~ ~/r~C I~G
S-BETA BLOCKER
DESCRIP~ON OF THE INVENTION
The present invention now includes, inter alia, a proces~
for preparing any desired enantiomers of amines 8a or 8b and 9a or 9b ~ ee page 2) from easily accessible raw materials. This involves S- or R-glycidyl esters of sulphonic acids (glycidyl sulphonate) initially being reacted with hydrogen chloride for converting the epoxy group c~ntained therein to a l,2-chlorohydrin group in order to give the corre~ponding chloropropanediol sulphonate which in turn i~ reacted with an amine to give the corresponding chloropropanolamine (9a or 9b, depend-ing on whieh enantiomer constituted the starting sub-stan~e), or alternatively by means of a further treatment with a ba3e, if appropriate in the presence of a phenol, completely or partially reacted to give the second ~mine (8a or 8b). The amines 9a, 9b, 8a and 8b are included in the general formulae for the amines 2 and 3 discussed earlier.
For preparing the glycidyl sulphonates which are used as intermediate3 in the proces~ according to the invention and which are de~ignated lOa and lOb in the for~ulae, the raw mat~rials which can be employed include commercially available substances ~uch as R- or 5-glycidol, or esters thereof, for example R-glycidyl butyrat~, which can be converted, ~y ~eans of techniques known to the person ~killed in the ar~, to lOa or lOb, respec~ively, accord-ing to the following scheme:
.
-.: . ; ~,,`~ , :' .' ` ' ' ' ' ' . ' ~091/10642 2 ~ '7 '1 ~ 7 ~
7 PCT/SE91t~022 Scheme A
p~O~C3~ ~o~ C~ O~ r~
O~o/~ ~2 ~r~ V
fi'--~Or~ ~/O~ ~--~r~
in which Ar1 is a su~stituted benzene or naph~halene radical in which at least one substituent is of an elect.ron-attracting character, for example one or more chlorine, bromine or iodine atoms, one or more nitroso~
nitro, cyano, trifluoromethyl, trichloromethyl or tri-bromomethyl groups, one or more optionally substi~uted sulphinyl, sulphonyl, phosphonyl, phosphoryl or carbonyl groups, or combinations of the~e atoms and groups, at any cho~en posit~ons on the benzene or naphthalene rings, it being prefsrable for Ar1 to be a subs~ituted benzene radical in which at leaAt one substituent is a nitro, an optionally ~ubstituted sulphonyl or an optionally sub-stituted carbonyl group at any cho~en position on the benzene rin~. In the mo~t interesting alternative, AI1 is a substituted benzehe radical in which at least one substituent i3 a nitro group at a~y chosen position on the benzene ring.
Alternatively, the glycidyl sulphonates lOa and lOb can be prepared starting from allyl alcohol which, by means of Qnantios~lective epoxidation r iS con~erted to S- or R-glycidol, which is then reacted to give lOa or lOb, respectively, again using the known technique (cf., for example, Rlunder, J M, ~o, S Y, Sharpless, R B: J Org Chem 5l, 3710 (l936)).
The prepar~tion of the amines 9a and 9b by reacting the glycidyl sulphonate~ lOa and lOb, ~espectively, with hydrogen chloride followed by treatment with an amine can be illustratsd a~ follows:
"
~ 8 - PCT/SE91/00022 Scheme V
035-~4r~~Q~S-Arl ~ R3f~f N~ J~ R R
~. fo.~ fo~ 9C~_ l~ 35~-'4r1 ~ ~o3~Ar1tR3R~
~0~ ~f6 ~ 9 5-~ ~~ ~~ f~ fo~~_ in which Arl, R3 and R4 have the same meanings as above.
As can be seen, R changes to S and S to R upon reaction with hydrogen chloride. We have cho~en to use references a and b to follow the chemistry, rather than the prefixes R and S which derive from nomenclature conventions.
The amines 9a and 9b can be completely or partially converted to amines 8a and 8b, re~pectively, by ~reatment wi~h a bsse, for oxample hydroxides, alkoxides or car-bonates of lithium, sodium, pota~sium, calcium.or magne-sium and optionally sub~tituted ammonia, it being prefer-able for the base to con~ist o~ sodium or potassium hydroxide or of sodium or potassium alkoxide, for ex~mple methoxide, ethoxide or tertia~y butoxide, optionally in the presence of a phenol, a~ i~ clear from the relevant part of Scheme V.
The advantage of the new procedure~ for preparing amines 8 and 9 in homochiral form is that they permi~ utiliza-tion of 10~% of the raw material, wher2as, with the earlier method, a maximum of 50~ of the employed raw material could be utilized, and also the earlier methods involve the use and recovery of a frequently ~xpen~ive homochiral salt-former.
As mentioned earlier, the inven~ion furthermore relates to new routes for the preparation of S- and R-beta blockers. Thase routes are via the amines 9a or 9b and 8a or 8b, for which reason the starting sub~tances for this part of the invention too are R- and S-glycidyl . ~ . . ' - - , ., . .
~ , . . ..... . .
- . . .. . , ,, , :, .: . , ~ : , ........... . .
.. . ~ ~ . , . .~ .. . . .
: ` ~..... : . , i . ... ... .
.. . . , . : . . . . - :. . .
,. .. -., .. , . - .. : . .. ' .. , ... , ,, .,,, . ' . . :, . , i~ , , ., ., ,. ,.: . . :.
WO91/10642 _ 9 ~ 2 ~ 7 ~ ~ i 3cr/sEg1/00022 e~ters of sulphonic acids (lOa or lOb) which are r~acted to give the amine~ 9a or 9b. These amines are then further treated in accordance with the following scheme.
Scheme V
~ =f/
Oh~ /~J ~Zf ~ r~ ~ ~4~3 J 6c~s 5- ~cf~ ~,~er +A~-O~
3~ ~ ~r~-O~ JrzO~A/f//~3 /46 ~ /O~er ;f' ~ ~ I
~/~3 ~ C4 e ~S ~ ~ .
~ /3 in which R3 and R4 have the ~ame meanings as above. When R3 iq i~opropyl, Ar2 i8 any one of the radicals given in ~able 1 below.
, : . . .
Wo9~ 2 ~ 5 - 10 - PCT~SE91/00022 Table 1 Order no. S- (15a) or without R- (15b) form of spec Radical ~ Ar2 (generic name) signif i-cance 1 2-acetyl-4-(butyrylamino)phenyl acebutolol 2 2-allylphenyl alprenolol 3 4-carbamoylmethylphenyl atenolol 4 4-(2-cyclopropylmethoxy-ethyl)phenyl betaxolol 4 (2-i~opropo~yethoxy-methyl)phenyl bisoprolol 6 4-(2-cyclopropylmethoxy-ethoxy)phenyl cicloprolol 7 2ace~yl-4-(acetylamino)phenyl diacetolol 8 2-methoxyphenyl levomoprolol 9 4-(2-methoxyethyl)phenyl metoprolol 8-(3-nitroxy)cromanyl nipradilol 11 2-allyloxyphenyl oxprenolol 12 4-indolyl pindolol 13 l-naphthyl propranolol 14 4-cyanomethylphenyl In addition, when R3 i tertiary butyl, Ar2 is any one of the radicals according to Table 2.
Table 2 ., _ . . _ . . . .
Order no. S- (lSa) or without R- (lSb) form of spec. Radical - Ar2 (g~neric name) sig~ifi-cance ~ . . _ 21 2-acetyl-4-(diethylcarbamoyl-amino)phenyl celiprolol 22 2-methylcarbamoylmethoxy-phenyl cet2molol 23 l-(5-oxo-5,6,7,8-tetrahydro-naphthyl) levobunolol 24 1-(cis-6,7-hydroxy-5,~,7,8-tetrahydronaphthyl) nadolol 2-cyclopentyl p~nbutolol 26 8~thiocromanyl tertatolol . - . ,- .. ,. - ,. . ,, , ,. ...... ,, ....... , .. , .. ~ . .. ..
,'` ''"." :- ' '.'.'.,, .''"'- ",,,',''',':'." ' ," , " .,'" ~ .' ' WO91/10642 ~ PCT/SE91/~OZ2 2~7~7~
~hen R3 is 2-(3~4-dimethoxyphenyl)ethyl Ar2 iS 3-methyl-phenyl or 4-(2-cyano-l-methylethenyl)phenyll when R3 = 2-(2-methoxyphenoxy)ethyl Arz is 4-carbazolyl, and when R3 is 2-(4-hydroxyphenylacetylamino)ethyl Ar2 is 2~cyano-phenyl, and finally when R3 is 2-(N-morpholinocarbonyl-amino)ethyl A12 is 4-hydroxyphenyl. Examples of the base shown in the scheme have already been mentioned above.
The S- or R-form of the beta blockers is thus obtained.
Of these, number 3, i.e. when Ar2 = 4-carbamoyl-methylphenyl (S- or R-form of atenolol), can also be obtained by hydrolysii~ of num~er 14 (Ar2 = 4-cyano-methylphenyl), for example by treating with aqueous acids or bases.
The procedures according to the invention for preparing, on the one hand, amines 8a and 9a or 8b and 9b and, on the other hand, S-beta blockers or R-be~a blockers consist, as has been partially described above, in the respective glycidyl sulphonate (lOa or lOb) being reacted with hydrogen chloride to give ~ chloropropanediol sul-phonate, which in turn i5 reacted with an amine, for example isopropylamine, to give the corresponding chloro-propanolamine 9a or 9b. By treating the chloropropanol-aminss thu~ obtained with a phenol 13, under the action of a ba3e illustrated above, ~ub~tances are obtained which~ when R4 represent3 hydrogen, are S- or R-beta blockers 15a or 15b but which, when R~ does not represent hydrogen, have the general structure 14a or 14b. ~he substances with structure 14~ or 14b are converted to corresponding S- or alternati~ely R-beta blockers (lSa or 15b) by being sub~ected to reaction condition~ which bring about hydrogenolysis, for example treatment with hydrogen gas in the presence of ~etal catalysts, for ex~mple pall~dium. Nhen treating the amine~ 9a or 9b with a phenol in the pre~ence of a ba~e, two parallel reac-tions take place. ~he one consists in direct conversion to 14a or 14b or 15a or 15b, the ~econd taking place ~ia previously mentioned amine 8a or 8b as intermediate . - - . . . . . ~ . . .
:... . . .
... , . ... . ~ . . ... . . . . . . .
. , . , ~. .. . . : . ,. .
.: . ........ ~: .: .: , .
WO91/l~Q~ 12 PCT/SE9ltO0022 product. If so de~ired, such an intermediate product 8a or 8b can be isolated by crystallisation or dis~illation.
The feature which essentially distinguishes the procedure according to the invention for the preparation of homo-chiral beta blockers from previously known procedures starting from homochiral glycidyl esters of sulphonic acids is that an extra reaction step is included in the synthesis sequence, in which an epo~y group is converted to a 1,2-chlorohydrin group ~conversion of lOa or lOb to lla or llb in Scheme IV~.
The advantage of adding this new reaction step i5 the following. The chloropropanediol ~ulphonates lla and llh h~ve been ~ound to give lcwer proportions of by-products, in the form of C3-aminated by-products, than corres-ponding glycidyl sulphonates lOa and lOb. This i~ very important since the presence of a C3-aminated impuri~y in amines 8a, 8b, 9a or 3b lead~ to formation of Lmpurities in the homochiral beta blo~kers prepared from the~e and consisting of the same beta blocker~ of the opposite chiral form tR beta blo~ker as an Lmpurity in an S-beta blocker or S- as an impurity in an R-). Impurities which are related to the ~ain component in thi~ way are generally difficult to remove.
The rea~on why, a~ has been mentioned above, Ar1 will contain at least one group of electron-attracting character is likewise that a lower proportion of C3-aminated by-product is in this way obtained.
As exampleR of some previou51y u~known ~ub~tances which can be u~ed in the procedure~ according to Schemes IV and V, the following may b~ mentioned.
R-glycidyl 4-nitrobenzenesulphonate, certain S or R-glycidyl esters of ~ulphonic acids of formulae lOa or lOb in which Arl has the meaning given earlier, and S- or R-3-chloro-1,2-propansdiol l-sulphonates of formulae lla WO91/10642 2 ~ 7 ~ ~ 7 ~ Pcr/SE91/00022 or llb, for example, S- or R-3-chloro-1,2-propanediol 1-(4-nitrobenzenesulphonate).
This means that the invention also includes intermediates of the following general formulae in their R- and S-forms:
~ 3 ~ 1 or ~ 03 S- J4rl ~q ~o~
/~~ /Or~ ~;- f or~
and 3 ~ ~ or ~ ~ 03 S ~rt 5~~or w h~ o r //~1 but with ~he exception of previou ly known substances, namely the ~-form in which Ar1 = 4-nitrophenyl and ~he R-and S-forms in which Ar1 = 2- or 3-nitrophenyl, 4-chloro-phenyl or 4-chloro-3 nitrophenyl.
In the reactions, described abo~e and forming part of the invention, of raw materials via intermediates to give desired final products and in the isolation of bo~h intermediate and final product, the choice of the chemi-cal conditions, such as ~ol~ents, concentrations, temper-atures, pre~ure etc. i~ not critical for those results which are the aLm of the invention to be achieved, and instead generally known practice in organic gynthesis can be used in each particular ca~e. The same applies of cour~e to the following e~amples in which the~e data ha~e for this rQa~on not alway~ been in~luded.
As exampl~s of some sol~ent3 which are suitable in connection with the proce~s according to the invention, mention may be made of dichloromethanel tetrahydrofuran, dimethyl sulphoxide, methanol, water, toluene and ethyl acetate. The concentrations are expediently chosen between about 0.1 M and the saturation concentrations in the reaction mixtures in questiQn, and the temperatures . , . ~ , . . . :
, , : : . . ., , ~ , . .
- :: . ,~ . . . : . . - .
.. .. . . .
W091/l~2 . ~ PCT/SE91/~022 are cho~en between about -20C and 150C and the preRsure between 0.01 and 20 bar.
The invention, which hAs been defined in the subsequent patent claims, will now be further illu-q~rated in its different parts in the following examples. In order to facilitate reading of the examples, these have in each particular case been provided with references to the relevant formula schemes, and at the same tLme there are also included ~ome of the reference numbers appearing in these formula sc~emes and relating to the various com-pounds and their enantiomers.
ExamEle l (Scheme IV!
60 g of R-glycidyl 3-nitrobenzenesulphonate (lOa; Arl =
3-nitrophenyl; > 99~ R-form) were dis301ved in 90 ml of dichloromethane in a glas~ fla~k, after which hydrogen chloride gas was introduced in~o the solution until high-pressure liquid chromatography (HPLC) ~howed that more than 99% of the benzene~ulphonate had been converted.
Removal of the exce~ HCl and the dichloromethane gave S-2-hydroxy-3-chloropropyl3-nitrobenzenesulphonate~lla;
Arl = 3-nitrophenyl) in the form of an oil which slowly crystallised. ~uclear magnetic resonance spectroscopy (N~R) with deutero~hloroform ~s solvent ga~e the follow-ing result:
~2.7 (1 H, singlet), 3.60 (2 H, doublet), 4.2 (1 H, multiplet), 4.24 (2 H, doublet), 7.80 (1 H, triplet), 8.24 ~ riplet of doublets), 8.50 (1 H, triplet of doublets), 8.74 (1 H, triplet) ppm.
Purity ac~ording to HPLC about 98%. ~he greatest Lmpurity may be a product formed by the opposite opening of ~he ~poxid~ ring.
Example 2 (Scheme IV
Carried out a~ in Example 1, but with 4 i~omer (lOa; Ar1 = 4-nitrophenyl;> 99~ R-form) instead of 3-i30mer, giving S-2-hydroxy-3-chloropropyl 4-nitrobenzene3ulphonate ,; .. . . .
'~ ' '''. ~ ' . ', '.
',' ~' ~ ' ~ , . ' ., ' ,'` .~.. ~ . ...
....
WO91/1~2 15 ~ 2 ~ 7 ~ ~ 7~ PCT/SE9l/~22 (lla; Ar~ = 4-nitrophenyl).
NMR: ~2.5 (l H, ~inglet), 3.61 (2 H, doublet), 4.2 (l H, multiplet), 4.26 (2 H, doublet), 8.12 (2 H, doublet), 8.41 t2 H, doublet) ppm.
Example 3 (Scheme IV!
Car~ied out as in Example 1, but with concentrated hydrochloric acid (200 ml) instead of hydrogen chloride gas and dichloromethane, which gave the same result.
Example 4 (Schemes IV and y~
Isopropylamine ~12; R3 = i~opropyl, R4 = H, 1.2 ml) and dichloromethane (0.35 ml) were added ~o S-2-hydroxy 3-chloropropyl 3-nitrobenzenesulphonate (lla; Ar~ = 3-nitrophenyl) prepared in accordance with Example 1 (O.20 g). The solution was allowed to stand for one hour at a~out 20C, af~er which ~olatile constituents were stripped of under reduced pre~sure. After di~solving in dimethyl sulphoxide (DMSO, 0.5 ml), a solution of 2-(4-hydroxyphenyl)acetamide (13; Ar2 = 4-carbamoyl-methylphenyl, 0.43 g) and potas-qium tert-butylate (0.68 g) in DMSO (1.3 ml) wa3 added. After two hours at 80C, HPLC (column: Chiral AGP~ ChromTech) on the reaction mixture showed that 4-(2-hydroxy 3-isopropylamino-propoxy)phsnylacetamide (l5a; Arz = 4-carbamoyl-methylphenyl, R3 = i~opropyl) had been formed and that the ratio between its S-form and R form was > 99:1.
Ex2mple 5 (withou~ conver~ion of epoxy group to 1,2-chlorohydrin group).
Carried out as in ~xEmple 4 but with R-glycidyl 3-nitro-benzene~ulphonate (lOa; Ar~ = 3-nitrophenyl) instead of S-2-hydro~y-3-chloropropyl3-nitrobenzenesulphonate(ll~;
Arl = 3-nitrophenyl). In this cas~ the ratio between the S- and R-forms of the product was 97:3.
Example 6 (Scheme~IV~
Isopropylamine (l2; R3 = isopropyl, R4 = H, 60 ml) and dichlorometh ne (lO ml) were added to S-2-hydroxy-3-, . .
- . . . .
. ~ . .
wo gl/10~2 ~ h ~ - 16 - PCT/SE91/00022 chloropropyl 3-nitrobenzenesulphonat~ (lla; AI1' 3-nitro-phenyl) prepared according to Example 1 (20 g). The solution was allowed to stand for ~wo hours at 30.
Removal of volatile constituents under reduced pressure gave a crystalline product (27 g). HPLC showed that it principally consisted of a mixture of 3-nitrobenzene-sulphonic acid salts of isopropylamine and S-2-hydroxy-3-chloropropylisopropylamine (9a; R3 = isopropyl, R4 =
H). ~s a rPference for identifyin~ the latter, a racemic product was used which was obtained by reacting epi-chlorohydrin with isopropylamine.
Example 7 (Sch.eme~
Carried out as in Example 6, but starting from 4-isomer (lla; Arl = 4-nitrophenyl) instead of 3-isomer. The crystalline product obtained in this case differed from that obtained in Example 6 only in that it consisted of 4- instead of 3-nitrobenzenesulphonic acid salts of isopropylamine and S-2-hydroxy-3-chloropropyl-isopropylamine (9a; R3 = isopropyl, R4 = H).
Example 8 (Scheme~I~
Stage A.
A solution of S-2-hydroxy-3-chloropropyl 3-nitro-benzenesulphonate (lla; Arl = 3-nitrophenyl) prepared according to ~xample-l (1.48 g) and benzyli~opropylamine (12~ R3 - i~opropyll R~ = benzyl, 1.16 g) in methanol (3.0 ml) was heated for five hours at 40C. The methanol was then stripped off under reduced pressure.
Stage B.
The product was chromatographed on sîlica gel with ethyl acetate/dichloromethane (1:9) a~ eluent. S-2-hydroxy-3-chloropropylbenzylisopropylamine (9a; R3 = isopropyl, R~ -= benzyl) in the form of a viscous oil tO.l g) was obtained in this Ca5e.
N~R: ~1.02 (6 H, two doublets), 2.55 (2 H, mul~iplet), 2.96 (1 H, sep~et), 3.2 (1 ~, broad singlet)~ 3.5 (5 ~, . , .
.. . .
: ` '" " : ., wvsl/10642 2 ~ 7 ~ ~ 7 ~ P~r/SE9l/00022 multiplet), 7.16 (5 H, ~ingl~t) ppm.
Exam~le 9 (Schem~ v) A product containing S 2-hydro~y-3-chlo~opropyl-isopropylamine (9a; R3 = isopropyl, R4 = H) prepared in accordance with Example 7 (46.1 g) was su~pended in methanol (22 ml), and a solution of potassium hydroxide (16.6 g) in methanol (95 ml) was added. After heating for one hour at 40~C, volatile constituents were stripped off, water was added, and the mixture was extracted with dichloromethane. The extract was evaporated, and this gave S-2,3-epoxypropylisopropylamine (8a; R3 = isopropyl, R~ = H) in the form of an oil which was purified by vacuum distillation (bp 38 at 1 torr). Identification was carried out by ~PLC, ~he reference used being a racemic product obtained by pota~sium tert-butylate-induced hydrogen chloride elLmina~ion from the reference used in Example 6.
Exam~le lO ~Scheme V) A product containing S-2-hydroxy-3-chloropropyl-isopropylamine (9a; R3 = i opropyl, R4 = H) prepared in accordance with ~xample 7 (46.1 g) was su~pended in methanol (22 ml), and a solution of 2~(4-hydroxy-phenyl)acetamide (13; Ar2 = 4-carbamoylmethylphenyl, 57.0 g) and pota~ium hydroxide (35.7 g) in methanol (195 ml) was added. After heating for two hours at 50~C, XPLC
showed that complete conversion had taken place, partially via 8a (R3 = isopropyl, R~ = H). Isobutanol was added, and the mixture was filtered and mo~t of the methanol stripped off from the filtrate. ~he solution which remained wa~ wa~hed with water after which ~he volatile co~stituents in th~ oxganic phase were stripped off. The product was recrystallised from i~opropyl alcohol, this giving S-4-(2-hydroxy-3-isopropylamino-propoxy)phenylacetamide (15a; AX2 = 4-carbamoylme~hyl-phenyl, R3 = isopropyl, 6.2 g). NMR identical with racemic reference. HPLC (column: Chiral AGP) showed that the ratio between S- and R~orm in the product wa~ > 99ol~
- , ~ . . , , . , , ~ , . .
: ' - : ~ ' ' , ' .. . .
- , . .
'' ,. ,,: - ': '.' ' . ~ ' ' . . .
WO9l/10642 ~ 18 - PCT/SE91/00022 Example 11 ~eme Vl Carried out as in Example 10, but with 1-naphthol (13;
Ar2 = 1-naphthyl, 54.4 g) instead of 2-(4-hydroxyphenyl)-acetamide. In this case S-1-(2-hydroxy-3-isopropylamino-propoxy)naphthalene (15a; Ar2 = 1-naphthyl, R3 isopropyl) was obtained~ the ratio between S- and R-form being > 99~.
Example 12 (Scheme V!
A product containing 5-2-hydroxy-3-chloropropylbenzyl-isopropylamine (9a; R3 - i~opropyl, R~ = benzyl) prepared in accordance with stage A in Example 8 ~6.7 g) was suspended in methanol (5 ml), and a solution of 2-(4-hydroxyphenyl)acetamide (13; ~r2 = 4-carbamoyl-methylphenyl, 5.7 g) and potassium hydroxide (3.6 g) in -~
methanol (20 ml) wa3 added. After heating for three hours at 60C, the mixture was filtered and the filtrate was evaporated. Water was added and the mixture was extracted with dichloromethane. After evaporation, the extract wa~
dissolved in methanol (50 ml), palladium/charcoal (10~, 0.21 g) was added, and the mixture was ctirred in a hydrogen gas atmo~phere. The reaction was discontinued when HPLC showed that all the startinq material had be~n consumed. The ~uspension was filtered and the methanol was stripped off. Recrystalli~ation from i~opropyl alcohol gave S-4-(2-hydroxy-3-isopropylaminopropoxy)-phenylacetamide (15a; Ar2 = carbamoylmethylphenyl, R3 = i~opropyl, 0.9 g)l NNR identical with racemic reference. HPLC (column: Chiral AGP) showed that the ratio between S- and R-form in the product was > 99:1 Example 13 (Scheme V) Carried out as in Ex~mple 10, but with 2-(4-hydroxy-phenyl)acetonitrile (13; Ar2 = 4-cyanomethylphenyl/ 50.2 g) instead of 2-(4-hydroxyphenyl)acetamide. In this ca e S-4-(2-hydroxy-3-isopropylaminopropoxy)phenylace~onitrile was obtained (15a; Ar2 = 4-cyanomethylphenyl, R3 isQp~opyl, 5.7 g).
." . . .
,. . ~
. : ~
, . .. .
W091/10~2 l9 PCT/SE91/~022 Example 14 2 ~ 3 S-4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetonitrile (15a; Ar2 - 4-cyanomethylphenyl, R3 = isopropyl) prepared in accordance with Example 13 (2.5 g) was stirred at 40 with concentrated hydrochloric acid (15 ml). After three hours, the mixture was cooled in an ice bath and the pH
was adjusted to 12 u~ing a solution of potassium hydroxide (lO~) in water. The mixture was saturated wi~h sodium chloride and was filtered. After recrys~allisation from isopropyl alcohol, S-~-(2 hydroxy-3-isopropyl-aminopropoxy)phenylacetamide (15a; Ar2 = 4-carbamoyl-methylphenyl, R3 = isopxopyl, l.5 g) was obtained, with identity and purity as in Example lO.
Example lS lScheme IV
Carried out as in Example 2, but with S-isomer (iOb; Ar = ~-nitrophenyl) instead of ~-isomer, giving R-~-hydroxy-3-chloropropyl 4-nitrobenzenesulphonate (llb; Ar1 = 4-nitrophenyl).
Example 16 (Scheme IV~
Carried out as in Example 7, but with R-isomer (llb; Ax = 4-nitrophenyl) prepared in accordance with Example 14 i~stead of S-isomer, giving 4-nitroben2ene~ulphonic acid salt of i~opropylamine and R-2-hydroxy-3-chloropropyl-isopropylamine (9b; R3 = isopropyl~ R4 = H).
Examl~he_Ll_L~ __me V~ -Carried out as in Example lO, but with R-isomer (gb; R3 = isopropyl, R~ - H) pxepared in accordance with Example lS instead of S~isomer, giving R-4-(2-hydroxy-3 iso-propylaminopropoxy)phenylacetaMide (lSb; A12 = 4-car-bamoylmethylphenyl, R3 = isopropyl). The ratio between R-and S-form was ~ 99:l.
. - :~' . . , '' .. :. ' :''' ' , .
~/~3 ~ C4 e ~S ~ ~ .
~ /3 in which R3 and R4 have the ~ame meanings as above. When R3 iq i~opropyl, Ar2 i8 any one of the radicals given in ~able 1 below.
, : . . .
Wo9~ 2 ~ 5 - 10 - PCT~SE91/00022 Table 1 Order no. S- (15a) or without R- (15b) form of spec Radical ~ Ar2 (generic name) signif i-cance 1 2-acetyl-4-(butyrylamino)phenyl acebutolol 2 2-allylphenyl alprenolol 3 4-carbamoylmethylphenyl atenolol 4 4-(2-cyclopropylmethoxy-ethyl)phenyl betaxolol 4 (2-i~opropo~yethoxy-methyl)phenyl bisoprolol 6 4-(2-cyclopropylmethoxy-ethoxy)phenyl cicloprolol 7 2ace~yl-4-(acetylamino)phenyl diacetolol 8 2-methoxyphenyl levomoprolol 9 4-(2-methoxyethyl)phenyl metoprolol 8-(3-nitroxy)cromanyl nipradilol 11 2-allyloxyphenyl oxprenolol 12 4-indolyl pindolol 13 l-naphthyl propranolol 14 4-cyanomethylphenyl In addition, when R3 i tertiary butyl, Ar2 is any one of the radicals according to Table 2.
Table 2 ., _ . . _ . . . .
Order no. S- (lSa) or without R- (lSb) form of spec. Radical - Ar2 (g~neric name) sig~ifi-cance ~ . . _ 21 2-acetyl-4-(diethylcarbamoyl-amino)phenyl celiprolol 22 2-methylcarbamoylmethoxy-phenyl cet2molol 23 l-(5-oxo-5,6,7,8-tetrahydro-naphthyl) levobunolol 24 1-(cis-6,7-hydroxy-5,~,7,8-tetrahydronaphthyl) nadolol 2-cyclopentyl p~nbutolol 26 8~thiocromanyl tertatolol . - . ,- .. ,. - ,. . ,, , ,. ...... ,, ....... , .. , .. ~ . .. ..
,'` ''"." :- ' '.'.'.,, .''"'- ",,,',''',':'." ' ," , " .,'" ~ .' ' WO91/10642 ~ PCT/SE91/~OZ2 2~7~7~
~hen R3 is 2-(3~4-dimethoxyphenyl)ethyl Ar2 iS 3-methyl-phenyl or 4-(2-cyano-l-methylethenyl)phenyll when R3 = 2-(2-methoxyphenoxy)ethyl Arz is 4-carbazolyl, and when R3 is 2-(4-hydroxyphenylacetylamino)ethyl Ar2 is 2~cyano-phenyl, and finally when R3 is 2-(N-morpholinocarbonyl-amino)ethyl A12 is 4-hydroxyphenyl. Examples of the base shown in the scheme have already been mentioned above.
The S- or R-form of the beta blockers is thus obtained.
Of these, number 3, i.e. when Ar2 = 4-carbamoyl-methylphenyl (S- or R-form of atenolol), can also be obtained by hydrolysii~ of num~er 14 (Ar2 = 4-cyano-methylphenyl), for example by treating with aqueous acids or bases.
The procedures according to the invention for preparing, on the one hand, amines 8a and 9a or 8b and 9b and, on the other hand, S-beta blockers or R-be~a blockers consist, as has been partially described above, in the respective glycidyl sulphonate (lOa or lOb) being reacted with hydrogen chloride to give ~ chloropropanediol sul-phonate, which in turn i5 reacted with an amine, for example isopropylamine, to give the corresponding chloro-propanolamine 9a or 9b. By treating the chloropropanol-aminss thu~ obtained with a phenol 13, under the action of a ba3e illustrated above, ~ub~tances are obtained which~ when R4 represent3 hydrogen, are S- or R-beta blockers 15a or 15b but which, when R~ does not represent hydrogen, have the general structure 14a or 14b. ~he substances with structure 14~ or 14b are converted to corresponding S- or alternati~ely R-beta blockers (lSa or 15b) by being sub~ected to reaction condition~ which bring about hydrogenolysis, for example treatment with hydrogen gas in the presence of ~etal catalysts, for ex~mple pall~dium. Nhen treating the amine~ 9a or 9b with a phenol in the pre~ence of a ba~e, two parallel reac-tions take place. ~he one consists in direct conversion to 14a or 14b or 15a or 15b, the ~econd taking place ~ia previously mentioned amine 8a or 8b as intermediate . - - . . . . . ~ . . .
:... . . .
... , . ... . ~ . . ... . . . . . . .
. , . , ~. .. . . : . ,. .
.: . ........ ~: .: .: , .
WO91/l~Q~ 12 PCT/SE9ltO0022 product. If so de~ired, such an intermediate product 8a or 8b can be isolated by crystallisation or dis~illation.
The feature which essentially distinguishes the procedure according to the invention for the preparation of homo-chiral beta blockers from previously known procedures starting from homochiral glycidyl esters of sulphonic acids is that an extra reaction step is included in the synthesis sequence, in which an epo~y group is converted to a 1,2-chlorohydrin group ~conversion of lOa or lOb to lla or llb in Scheme IV~.
The advantage of adding this new reaction step i5 the following. The chloropropanediol ~ulphonates lla and llh h~ve been ~ound to give lcwer proportions of by-products, in the form of C3-aminated by-products, than corres-ponding glycidyl sulphonates lOa and lOb. This i~ very important since the presence of a C3-aminated impuri~y in amines 8a, 8b, 9a or 3b lead~ to formation of Lmpurities in the homochiral beta blo~kers prepared from the~e and consisting of the same beta blocker~ of the opposite chiral form tR beta blo~ker as an Lmpurity in an S-beta blocker or S- as an impurity in an R-). Impurities which are related to the ~ain component in thi~ way are generally difficult to remove.
The rea~on why, a~ has been mentioned above, Ar1 will contain at least one group of electron-attracting character is likewise that a lower proportion of C3-aminated by-product is in this way obtained.
As exampleR of some previou51y u~known ~ub~tances which can be u~ed in the procedure~ according to Schemes IV and V, the following may b~ mentioned.
R-glycidyl 4-nitrobenzenesulphonate, certain S or R-glycidyl esters of ~ulphonic acids of formulae lOa or lOb in which Arl has the meaning given earlier, and S- or R-3-chloro-1,2-propansdiol l-sulphonates of formulae lla WO91/10642 2 ~ 7 ~ ~ 7 ~ Pcr/SE91/00022 or llb, for example, S- or R-3-chloro-1,2-propanediol 1-(4-nitrobenzenesulphonate).
This means that the invention also includes intermediates of the following general formulae in their R- and S-forms:
~ 3 ~ 1 or ~ 03 S- J4rl ~q ~o~
/~~ /Or~ ~;- f or~
and 3 ~ ~ or ~ ~ 03 S ~rt 5~~or w h~ o r //~1 but with ~he exception of previou ly known substances, namely the ~-form in which Ar1 = 4-nitrophenyl and ~he R-and S-forms in which Ar1 = 2- or 3-nitrophenyl, 4-chloro-phenyl or 4-chloro-3 nitrophenyl.
In the reactions, described abo~e and forming part of the invention, of raw materials via intermediates to give desired final products and in the isolation of bo~h intermediate and final product, the choice of the chemi-cal conditions, such as ~ol~ents, concentrations, temper-atures, pre~ure etc. i~ not critical for those results which are the aLm of the invention to be achieved, and instead generally known practice in organic gynthesis can be used in each particular ca~e. The same applies of cour~e to the following e~amples in which the~e data ha~e for this rQa~on not alway~ been in~luded.
As exampl~s of some sol~ent3 which are suitable in connection with the proce~s according to the invention, mention may be made of dichloromethanel tetrahydrofuran, dimethyl sulphoxide, methanol, water, toluene and ethyl acetate. The concentrations are expediently chosen between about 0.1 M and the saturation concentrations in the reaction mixtures in questiQn, and the temperatures . , . ~ , . . . :
, , : : . . ., , ~ , . .
- :: . ,~ . . . : . . - .
.. .. . . .
W091/l~2 . ~ PCT/SE91/~022 are cho~en between about -20C and 150C and the preRsure between 0.01 and 20 bar.
The invention, which hAs been defined in the subsequent patent claims, will now be further illu-q~rated in its different parts in the following examples. In order to facilitate reading of the examples, these have in each particular case been provided with references to the relevant formula schemes, and at the same tLme there are also included ~ome of the reference numbers appearing in these formula sc~emes and relating to the various com-pounds and their enantiomers.
ExamEle l (Scheme IV!
60 g of R-glycidyl 3-nitrobenzenesulphonate (lOa; Arl =
3-nitrophenyl; > 99~ R-form) were dis301ved in 90 ml of dichloromethane in a glas~ fla~k, after which hydrogen chloride gas was introduced in~o the solution until high-pressure liquid chromatography (HPLC) ~howed that more than 99% of the benzene~ulphonate had been converted.
Removal of the exce~ HCl and the dichloromethane gave S-2-hydroxy-3-chloropropyl3-nitrobenzenesulphonate~lla;
Arl = 3-nitrophenyl) in the form of an oil which slowly crystallised. ~uclear magnetic resonance spectroscopy (N~R) with deutero~hloroform ~s solvent ga~e the follow-ing result:
~2.7 (1 H, singlet), 3.60 (2 H, doublet), 4.2 (1 H, multiplet), 4.24 (2 H, doublet), 7.80 (1 H, triplet), 8.24 ~ riplet of doublets), 8.50 (1 H, triplet of doublets), 8.74 (1 H, triplet) ppm.
Purity ac~ording to HPLC about 98%. ~he greatest Lmpurity may be a product formed by the opposite opening of ~he ~poxid~ ring.
Example 2 (Scheme IV
Carried out a~ in Example 1, but with 4 i~omer (lOa; Ar1 = 4-nitrophenyl;> 99~ R-form) instead of 3-i30mer, giving S-2-hydroxy-3-chloropropyl 4-nitrobenzene3ulphonate ,; .. . . .
'~ ' '''. ~ ' . ', '.
',' ~' ~ ' ~ , . ' ., ' ,'` .~.. ~ . ...
....
WO91/1~2 15 ~ 2 ~ 7 ~ ~ 7~ PCT/SE9l/~22 (lla; Ar~ = 4-nitrophenyl).
NMR: ~2.5 (l H, ~inglet), 3.61 (2 H, doublet), 4.2 (l H, multiplet), 4.26 (2 H, doublet), 8.12 (2 H, doublet), 8.41 t2 H, doublet) ppm.
Example 3 (Scheme IV!
Car~ied out as in Example 1, but with concentrated hydrochloric acid (200 ml) instead of hydrogen chloride gas and dichloromethane, which gave the same result.
Example 4 (Schemes IV and y~
Isopropylamine ~12; R3 = i~opropyl, R4 = H, 1.2 ml) and dichloromethane (0.35 ml) were added ~o S-2-hydroxy 3-chloropropyl 3-nitrobenzenesulphonate (lla; Ar~ = 3-nitrophenyl) prepared in accordance with Example 1 (O.20 g). The solution was allowed to stand for one hour at a~out 20C, af~er which ~olatile constituents were stripped of under reduced pre~sure. After di~solving in dimethyl sulphoxide (DMSO, 0.5 ml), a solution of 2-(4-hydroxyphenyl)acetamide (13; Ar2 = 4-carbamoyl-methylphenyl, 0.43 g) and potas-qium tert-butylate (0.68 g) in DMSO (1.3 ml) wa3 added. After two hours at 80C, HPLC (column: Chiral AGP~ ChromTech) on the reaction mixture showed that 4-(2-hydroxy 3-isopropylamino-propoxy)phsnylacetamide (l5a; Arz = 4-carbamoyl-methylphenyl, R3 = i~opropyl) had been formed and that the ratio between its S-form and R form was > 99:1.
Ex2mple 5 (withou~ conver~ion of epoxy group to 1,2-chlorohydrin group).
Carried out as in ~xEmple 4 but with R-glycidyl 3-nitro-benzene~ulphonate (lOa; Ar~ = 3-nitrophenyl) instead of S-2-hydro~y-3-chloropropyl3-nitrobenzenesulphonate(ll~;
Arl = 3-nitrophenyl). In this cas~ the ratio between the S- and R-forms of the product was 97:3.
Example 6 (Scheme~IV~
Isopropylamine (l2; R3 = isopropyl, R4 = H, 60 ml) and dichlorometh ne (lO ml) were added to S-2-hydroxy-3-, . .
- . . . .
. ~ . .
wo gl/10~2 ~ h ~ - 16 - PCT/SE91/00022 chloropropyl 3-nitrobenzenesulphonat~ (lla; AI1' 3-nitro-phenyl) prepared according to Example 1 (20 g). The solution was allowed to stand for ~wo hours at 30.
Removal of volatile constituents under reduced pressure gave a crystalline product (27 g). HPLC showed that it principally consisted of a mixture of 3-nitrobenzene-sulphonic acid salts of isopropylamine and S-2-hydroxy-3-chloropropylisopropylamine (9a; R3 = isopropyl, R4 =
H). ~s a rPference for identifyin~ the latter, a racemic product was used which was obtained by reacting epi-chlorohydrin with isopropylamine.
Example 7 (Sch.eme~
Carried out as in Example 6, but starting from 4-isomer (lla; Arl = 4-nitrophenyl) instead of 3-isomer. The crystalline product obtained in this case differed from that obtained in Example 6 only in that it consisted of 4- instead of 3-nitrobenzenesulphonic acid salts of isopropylamine and S-2-hydroxy-3-chloropropyl-isopropylamine (9a; R3 = isopropyl, R4 = H).
Example 8 (Scheme~I~
Stage A.
A solution of S-2-hydroxy-3-chloropropyl 3-nitro-benzenesulphonate (lla; Arl = 3-nitrophenyl) prepared according to ~xample-l (1.48 g) and benzyli~opropylamine (12~ R3 - i~opropyll R~ = benzyl, 1.16 g) in methanol (3.0 ml) was heated for five hours at 40C. The methanol was then stripped off under reduced pressure.
Stage B.
The product was chromatographed on sîlica gel with ethyl acetate/dichloromethane (1:9) a~ eluent. S-2-hydroxy-3-chloropropylbenzylisopropylamine (9a; R3 = isopropyl, R~ -= benzyl) in the form of a viscous oil tO.l g) was obtained in this Ca5e.
N~R: ~1.02 (6 H, two doublets), 2.55 (2 H, mul~iplet), 2.96 (1 H, sep~et), 3.2 (1 ~, broad singlet)~ 3.5 (5 ~, . , .
.. . .
: ` '" " : ., wvsl/10642 2 ~ 7 ~ ~ 7 ~ P~r/SE9l/00022 multiplet), 7.16 (5 H, ~ingl~t) ppm.
Exam~le 9 (Schem~ v) A product containing S 2-hydro~y-3-chlo~opropyl-isopropylamine (9a; R3 = isopropyl, R4 = H) prepared in accordance with Example 7 (46.1 g) was su~pended in methanol (22 ml), and a solution of potassium hydroxide (16.6 g) in methanol (95 ml) was added. After heating for one hour at 40~C, volatile constituents were stripped off, water was added, and the mixture was extracted with dichloromethane. The extract was evaporated, and this gave S-2,3-epoxypropylisopropylamine (8a; R3 = isopropyl, R~ = H) in the form of an oil which was purified by vacuum distillation (bp 38 at 1 torr). Identification was carried out by ~PLC, ~he reference used being a racemic product obtained by pota~sium tert-butylate-induced hydrogen chloride elLmina~ion from the reference used in Example 6.
Exam~le lO ~Scheme V) A product containing S-2-hydroxy-3-chloropropyl-isopropylamine (9a; R3 = i opropyl, R4 = H) prepared in accordance with ~xample 7 (46.1 g) was su~pended in methanol (22 ml), and a solution of 2~(4-hydroxy-phenyl)acetamide (13; Ar2 = 4-carbamoylmethylphenyl, 57.0 g) and pota~ium hydroxide (35.7 g) in methanol (195 ml) was added. After heating for two hours at 50~C, XPLC
showed that complete conversion had taken place, partially via 8a (R3 = isopropyl, R~ = H). Isobutanol was added, and the mixture was filtered and mo~t of the methanol stripped off from the filtrate. ~he solution which remained wa~ wa~hed with water after which ~he volatile co~stituents in th~ oxganic phase were stripped off. The product was recrystallised from i~opropyl alcohol, this giving S-4-(2-hydroxy-3-isopropylamino-propoxy)phenylacetamide (15a; AX2 = 4-carbamoylme~hyl-phenyl, R3 = isopropyl, 6.2 g). NMR identical with racemic reference. HPLC (column: Chiral AGP) showed that the ratio between S- and R~orm in the product wa~ > 99ol~
- , ~ . . , , . , , ~ , . .
: ' - : ~ ' ' , ' .. . .
- , . .
'' ,. ,,: - ': '.' ' . ~ ' ' . . .
WO9l/10642 ~ 18 - PCT/SE91/00022 Example 11 ~eme Vl Carried out as in Example 10, but with 1-naphthol (13;
Ar2 = 1-naphthyl, 54.4 g) instead of 2-(4-hydroxyphenyl)-acetamide. In this case S-1-(2-hydroxy-3-isopropylamino-propoxy)naphthalene (15a; Ar2 = 1-naphthyl, R3 isopropyl) was obtained~ the ratio between S- and R-form being > 99~.
Example 12 (Scheme V!
A product containing 5-2-hydroxy-3-chloropropylbenzyl-isopropylamine (9a; R3 - i~opropyl, R~ = benzyl) prepared in accordance with stage A in Example 8 ~6.7 g) was suspended in methanol (5 ml), and a solution of 2-(4-hydroxyphenyl)acetamide (13; ~r2 = 4-carbamoyl-methylphenyl, 5.7 g) and potassium hydroxide (3.6 g) in -~
methanol (20 ml) wa3 added. After heating for three hours at 60C, the mixture was filtered and the filtrate was evaporated. Water was added and the mixture was extracted with dichloromethane. After evaporation, the extract wa~
dissolved in methanol (50 ml), palladium/charcoal (10~, 0.21 g) was added, and the mixture was ctirred in a hydrogen gas atmo~phere. The reaction was discontinued when HPLC showed that all the startinq material had be~n consumed. The ~uspension was filtered and the methanol was stripped off. Recrystalli~ation from i~opropyl alcohol gave S-4-(2-hydroxy-3-isopropylaminopropoxy)-phenylacetamide (15a; Ar2 = carbamoylmethylphenyl, R3 = i~opropyl, 0.9 g)l NNR identical with racemic reference. HPLC (column: Chiral AGP) showed that the ratio between S- and R-form in the product was > 99:1 Example 13 (Scheme V) Carried out as in Ex~mple 10, but with 2-(4-hydroxy-phenyl)acetonitrile (13; Ar2 = 4-cyanomethylphenyl/ 50.2 g) instead of 2-(4-hydroxyphenyl)acetamide. In this ca e S-4-(2-hydroxy-3-isopropylaminopropoxy)phenylace~onitrile was obtained (15a; Ar2 = 4-cyanomethylphenyl, R3 isQp~opyl, 5.7 g).
." . . .
,. . ~
. : ~
, . .. .
W091/10~2 l9 PCT/SE91/~022 Example 14 2 ~ 3 S-4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetonitrile (15a; Ar2 - 4-cyanomethylphenyl, R3 = isopropyl) prepared in accordance with Example 13 (2.5 g) was stirred at 40 with concentrated hydrochloric acid (15 ml). After three hours, the mixture was cooled in an ice bath and the pH
was adjusted to 12 u~ing a solution of potassium hydroxide (lO~) in water. The mixture was saturated wi~h sodium chloride and was filtered. After recrys~allisation from isopropyl alcohol, S-~-(2 hydroxy-3-isopropyl-aminopropoxy)phenylacetamide (15a; Ar2 = 4-carbamoyl-methylphenyl, R3 = isopxopyl, l.5 g) was obtained, with identity and purity as in Example lO.
Example lS lScheme IV
Carried out as in Example 2, but with S-isomer (iOb; Ar = ~-nitrophenyl) instead of ~-isomer, giving R-~-hydroxy-3-chloropropyl 4-nitrobenzenesulphonate (llb; Ar1 = 4-nitrophenyl).
Example 16 (Scheme IV~
Carried out as in Example 7, but with R-isomer (llb; Ax = 4-nitrophenyl) prepared in accordance with Example 14 i~stead of S-isomer, giving 4-nitroben2ene~ulphonic acid salt of i~opropylamine and R-2-hydroxy-3-chloropropyl-isopropylamine (9b; R3 = isopropyl~ R4 = H).
Examl~he_Ll_L~ __me V~ -Carried out as in Example lO, but with R-isomer (gb; R3 = isopropyl, R~ - H) pxepared in accordance with Example lS instead of S~isomer, giving R-4-(2-hydroxy-3 iso-propylaminopropoxy)phenylacetaMide (lSb; A12 = 4-car-bamoylmethylphenyl, R3 = isopropyl). The ratio between R-and S-form was ~ 99:l.
. - :~' . . , '' .. :. ' :''' ' , .
Claims (6)
1. Process for preparing S-and R-enantiomers of chloropropanolamines having the general formulae and (S-form) (R-form) respectively from R- and S-glycidyl esters of sulphonic acids (glycidyl sulphonate) with the formulae and (R-form) (S-form) in which Ar1 = substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character characterised in that the starting substance in the form of the respective glycidyl sulphonate is reacted with hydrogen chloride for converting the epoxy group con-tained therein to a 1,2-chlorohydrin group in order to give the corresponding chloropropanediol sulphonate which in turn is reacted with an amine of the general formula R3 R4NH in which R3 = isopropyl, tertiary butyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-methoxyphenoxy)ethyl, 2-(4-hydroxyphenylacetylamino)ethyl or a 2-(N-morpholinecarbonylamino)ethyl radical and R4 is hydrogen or a protecting group which can be easily removed by means of hydrogenolysis, to give the desired chloropropanolamine.
2. Process for preparing S- and R-enantiomers of 2,3-epoxypropylamines of the general formulae and S-form R-form from corresponding S- and R-chloropropanolamines prepared in accordance with Claim 1, characterised in that the starting substance is treated with a base optionally in the presence of a phenol.
3. Process for preparing S- and R-beta blockers starting from the S- or R-chloropropanolamines prepared in accordance with Claim 1, by treating these, in the presence of a base, with a phenol of the general formula Ar2OH
in which, when R3 = isopropyl, Ar2 will be a radical chosen from a group comprising 2-acetyl-4-(butyrylamino)phenyl, 2-allylphenyl, 4-carbamoylmethylphenyl, 4-(2-cyclopropylmethoxyethyl)phenyl, 4-(2-isopropoxyethoxymethyl)phenyl, 4-(2-cyclopropylmethoxyethoxy)phenyl, 2-acetyl-4-(acetylamino)phenyl, 2-methoxyphenyl, 4-(2-methoxyethyl)phenyl, 8-(3-nitroxy)chromanyl, 2-allyloxyphenyl, 4-indolyl, 1-naphthyl, 4-cyanomethylphenyl and, when R3 = tertiary butyl, Ar2 will be one of the radicals chosen from a group comprising 2-acetyl-4-(diethylcarbamoylamino)phenyl, 2-methylcarbamoylmethoxyphenyl, 1-(5-oxo-5,6,7,8-tetrahydronaphthyl), 1-(cis-6,7-hydroxy-5,6,7,8-tetrahydronaphthyl), 2-cyclopenthyl, 8-thiochromanyl and, when R3 is 2-(3,4-dimethoxyphenyl)ethyl, Ar2 will be 3-methylphenyl or 4-(2-cyano-1-methylethenyl)phenyl and, when R3 is 2-(2-methoxyphenoxy)ethyl, Ar2 will be 4-carbazolyl and, when R3 = 2-(N-morpholinocarbonylamino)ethyl, Ar2 will be 4-hydroxyphenyl and, when R3 = 2-(4-hydroxyphenylacetylamino)ethyl, Ar2 will be 2-cyanophenyl, after which the reaction product when required, i.e. when R4 is not identical to H, is subjected to those reaction conditions which result in hydrogenolysis and/or, when Ar2 = 4-cyanomethylphenyl, is optionally subjected to those reaction conditions which result in hydrolysis.
in which, when R3 = isopropyl, Ar2 will be a radical chosen from a group comprising 2-acetyl-4-(butyrylamino)phenyl, 2-allylphenyl, 4-carbamoylmethylphenyl, 4-(2-cyclopropylmethoxyethyl)phenyl, 4-(2-isopropoxyethoxymethyl)phenyl, 4-(2-cyclopropylmethoxyethoxy)phenyl, 2-acetyl-4-(acetylamino)phenyl, 2-methoxyphenyl, 4-(2-methoxyethyl)phenyl, 8-(3-nitroxy)chromanyl, 2-allyloxyphenyl, 4-indolyl, 1-naphthyl, 4-cyanomethylphenyl and, when R3 = tertiary butyl, Ar2 will be one of the radicals chosen from a group comprising 2-acetyl-4-(diethylcarbamoylamino)phenyl, 2-methylcarbamoylmethoxyphenyl, 1-(5-oxo-5,6,7,8-tetrahydronaphthyl), 1-(cis-6,7-hydroxy-5,6,7,8-tetrahydronaphthyl), 2-cyclopenthyl, 8-thiochromanyl and, when R3 is 2-(3,4-dimethoxyphenyl)ethyl, Ar2 will be 3-methylphenyl or 4-(2-cyano-1-methylethenyl)phenyl and, when R3 is 2-(2-methoxyphenoxy)ethyl, Ar2 will be 4-carbazolyl and, when R3 = 2-(N-morpholinocarbonylamino)ethyl, Ar2 will be 4-hydroxyphenyl and, when R3 = 2-(4-hydroxyphenylacetylamino)ethyl, Ar2 will be 2-cyanophenyl, after which the reaction product when required, i.e. when R4 is not identical to H, is subjected to those reaction conditions which result in hydrogenolysis and/or, when Ar2 = 4-cyanomethylphenyl, is optionally subjected to those reaction conditions which result in hydrolysis.
4. Process for preparing S- and R-beta blockers starting from the S- or R-2,3-epoxypropylamines prepared in accordance with Claim 2, by treating these, in the presence of a base, with a phenol of the general formula Ar2OH
in which, when R3 = isopropyl, Ar2 will be one of the radicals chosen from a group comprising 2-acetyl-4-(butyrylamino)phenyl 2-allylphenyl, 4-carbamoylmethylphenyl, 4-(2-cyclopropylmethoxyethyl)phenyl, 4-(2-isopropoxyethoxymethyl)phenyl, 4-(2-cyclopropylmethoxyethoxy)phenyl, 2-acetyl-4-(acetylamino)phenyl, 2-methoxyphenyl, 4-(2-methoxyethyl)phenyl, 8-(3-nitroxy)chromanyl, 2-allyloxyphenyl, 4-indolyl, 1-naphthyl, 4-cyanomethylphenyl and, when R3 = tertiary butyl, Ar2 will be one of the radicals chosen from a group comprising 2-acetyl-4-(diethylcarbomoylamino)phenyl, 2-methylcarbamoylmethoxyphenyl, 1-(5-oxo-5,6,7,8-tetrahydronaphthyl), 1-(cis-6,7-hydroxy-5,6,7,8-tetrahydronaphthyl), 2-cyclopenthyl, 8-thiochromanyl and, when R3 is 2-(3,4-dimethoxyphenyl)ethyl, Ar2 will be 3-methylphenyl or 4-(2-cyano-1-methylethenyl)phenyl and, when R3 is 2-(2-methoxyphenoxy)ethyl, Ar2 will be 4-carbazolyl and, when R3 = 2-(N-morpholinocarbonylamino)ethyl, Ar2 will be 4-hydroxyphenyl and, when R3 = 2-(4-hydroxyphenylacetylamino)ethyl, Ar2 will be 2-cyanophenyl, after which the reaction product when required, i.e. when R4 is not identical to H, is subjected to those reaction conditions which result in hydrogenolysis and/or, when Ar2 = 4-cyanomethylphenyl, is optionally subjected to those reaction conditions which result in hydrolysis.
in which, when R3 = isopropyl, Ar2 will be one of the radicals chosen from a group comprising 2-acetyl-4-(butyrylamino)phenyl 2-allylphenyl, 4-carbamoylmethylphenyl, 4-(2-cyclopropylmethoxyethyl)phenyl, 4-(2-isopropoxyethoxymethyl)phenyl, 4-(2-cyclopropylmethoxyethoxy)phenyl, 2-acetyl-4-(acetylamino)phenyl, 2-methoxyphenyl, 4-(2-methoxyethyl)phenyl, 8-(3-nitroxy)chromanyl, 2-allyloxyphenyl, 4-indolyl, 1-naphthyl, 4-cyanomethylphenyl and, when R3 = tertiary butyl, Ar2 will be one of the radicals chosen from a group comprising 2-acetyl-4-(diethylcarbomoylamino)phenyl, 2-methylcarbamoylmethoxyphenyl, 1-(5-oxo-5,6,7,8-tetrahydronaphthyl), 1-(cis-6,7-hydroxy-5,6,7,8-tetrahydronaphthyl), 2-cyclopenthyl, 8-thiochromanyl and, when R3 is 2-(3,4-dimethoxyphenyl)ethyl, Ar2 will be 3-methylphenyl or 4-(2-cyano-1-methylethenyl)phenyl and, when R3 is 2-(2-methoxyphenoxy)ethyl, Ar2 will be 4-carbazolyl and, when R3 = 2-(N-morpholinocarbonylamino)ethyl, Ar2 will be 4-hydroxyphenyl and, when R3 = 2-(4-hydroxyphenylacetylamino)ethyl, Ar2 will be 2-cyanophenyl, after which the reaction product when required, i.e. when R4 is not identical to H, is subjected to those reaction conditions which result in hydrogenolysis and/or, when Ar2 = 4-cyanomethylphenyl, is optionally subjected to those reaction conditions which result in hydrolysis.
5. Process for preparing S- and R-enantiomers of substituted 3-aryloxy-2-hydroxypropylamines used as beta blockers, with the following respective formulae:
S-BETA BLOCKERS
R-BETA BLOCKERS
in which Ar2 = substituted benzene or naphthalene radical and R3 = isopropyl, tertiary butyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-methoxyphenoxy)ethyl, 2-(4-hydroxyphenylacetylamino)ethyl or a 2-(N-morpholinocarbonylamino)ethyl radical, characterised in that a R- or S-glycidol or ester thereof is converted in accordance with the scheme below to the respective glycidyl sulphonate 10a R-form S-form R-form R-form 10b S-form in which Ar1 is a substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character, or alternatively the same glycidyl sulphonate is prepared from alkyl alcohol by enantioselective epoxidation, after which the glycidyl sulphonate thus obtained is reacted with hydrogen chloride and treated with an amine to give the corres-ponding chloropropanolamine according to the following scheme 10a R-form 11a S-form 9a S-form 10b S-form 11b R-form 9b R-form in which R4 is hydrogen or a protecting group easily removed by hydrogenolysis, and R3 and Ar1 have the mean-ings indicated above, after which the chloropropanolamine thus obtained is treated with a phenol under the action or a base in accordance with the following scheme 15a S-betablocker 15b R-betablocker
S-BETA BLOCKERS
R-BETA BLOCKERS
in which Ar2 = substituted benzene or naphthalene radical and R3 = isopropyl, tertiary butyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-methoxyphenoxy)ethyl, 2-(4-hydroxyphenylacetylamino)ethyl or a 2-(N-morpholinocarbonylamino)ethyl radical, characterised in that a R- or S-glycidol or ester thereof is converted in accordance with the scheme below to the respective glycidyl sulphonate 10a R-form S-form R-form R-form 10b S-form in which Ar1 is a substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character, or alternatively the same glycidyl sulphonate is prepared from alkyl alcohol by enantioselective epoxidation, after which the glycidyl sulphonate thus obtained is reacted with hydrogen chloride and treated with an amine to give the corres-ponding chloropropanolamine according to the following scheme 10a R-form 11a S-form 9a S-form 10b S-form 11b R-form 9b R-form in which R4 is hydrogen or a protecting group easily removed by hydrogenolysis, and R3 and Ar1 have the mean-ings indicated above, after which the chloropropanolamine thus obtained is treated with a phenol under the action or a base in accordance with the following scheme 15a S-betablocker 15b R-betablocker
6. Process according to Claim 5; characterised in that the chloropropanolamine obtained after hydrogen chloride reaction and treatment with the amine is first treated with a base and therearter with the phenol in accordance with the scheme below where the hydrogenolysis stage is carried out only when R4 is not identical to H and, when Ar2 = 4-cyanomethyl-phenyl, is optionally subjected to those reaction condi-tions which result in hydrolysis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9000206A SE468211B (en) | 1990-01-22 | 1990-01-22 | MULTIPLE-STEP PROCEDURE FOR THE PREPARATION OF HOMOCIRAL AMINES |
| SE9000206-4 | 1990-01-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2074075A1 true CA2074075A1 (en) | 1991-07-23 |
Family
ID=20378305
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2074075 Abandoned CA2074075A1 (en) | 1990-01-22 | 1991-01-15 | Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates/in accordance with this process prepared |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0512020A1 (en) |
| JP (1) | JPH05506008A (en) |
| AU (1) | AU638801B2 (en) |
| CA (1) | CA2074075A1 (en) |
| FI (1) | FI923305A (en) |
| SE (1) | SE468211B (en) |
| WO (1) | WO1991010642A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE222231T1 (en) * | 1996-09-18 | 2002-08-15 | Daiso Co Ltd | METHOD FOR PRODUCING 3-AMINO-2-HYDROXY-1-PROPYL ETHERS |
| AU3345599A (en) * | 1998-04-14 | 1999-11-01 | Samsung Fine Chemicals Co., Ltd. | A process for preparing chiral (s)-2,3-disubstituted-1-propylamine derivatives |
| CN103739512A (en) * | 2014-01-24 | 2014-04-23 | 南京工业大学 | Method for preparing (S)-atenolol |
| JP7108436B2 (en) * | 2018-03-22 | 2022-07-28 | 三井化学株式会社 | Method for producing epoxy compound containing biphenyl skeleton |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1269776A (en) * | 1968-08-29 | 1972-04-06 | Ici Ltd | Epoxides and halohydrins and conversion thereof to alkanolamine derivatives |
| GB1458392A (en) * | 1973-11-09 | 1976-12-15 | Ici Ltd | Optically-active 1-aryloxy-2,3-epoxypropane derivatives |
| US4408063A (en) * | 1978-06-27 | 1983-10-04 | Merck & Co., Inc. | Preparation of epihalohydrin enantiomers |
| WO1988000190A1 (en) * | 1986-06-25 | 1988-01-14 | Massachusetts Institute Of Technology | Optically active derivatives of glycidol |
-
1990
- 1990-01-22 SE SE9000206A patent/SE468211B/en not_active IP Right Cessation
-
1991
- 1991-01-15 JP JP91503496A patent/JPH05506008A/en active Pending
- 1991-01-15 EP EP19910903459 patent/EP0512020A1/en not_active Ceased
- 1991-01-15 AU AU72249/91A patent/AU638801B2/en not_active Ceased
- 1991-01-15 WO PCT/SE1991/000022 patent/WO1991010642A1/en not_active Application Discontinuation
- 1991-01-15 CA CA 2074075 patent/CA2074075A1/en not_active Abandoned
-
1992
- 1992-07-20 FI FI923305A patent/FI923305A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05506008A (en) | 1993-09-02 |
| SE9000206D0 (en) | 1990-01-22 |
| WO1991010642A1 (en) | 1991-07-25 |
| AU638801B2 (en) | 1993-07-08 |
| AU7224991A (en) | 1991-08-05 |
| SE468211B (en) | 1992-11-23 |
| SE9000206L (en) | 1991-07-23 |
| FI923305A0 (en) | 1992-07-20 |
| FI923305A (en) | 1992-07-20 |
| EP0512020A1 (en) | 1992-11-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |