WO1991010642A1 - Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process - Google Patents

Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process Download PDF

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Publication number
WO1991010642A1
WO1991010642A1 PCT/SE1991/000022 SE9100022W WO9110642A1 WO 1991010642 A1 WO1991010642 A1 WO 1991010642A1 SE 9100022 W SE9100022 W SE 9100022W WO 9110642 A1 WO9110642 A1 WO 9110642A1
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phenyl
ethyl
preparing
accordance
glycidyl
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PCT/SE1991/000022
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French (fr)
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Lars Westfelt
Aina Westfelt
Bo Birgersson
Lena Andersson
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Nobel Chemicals Ab
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Priority to NO922871A priority patent/NO922871D0/en

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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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

Process for preparing hoπtochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process.
The present invention relates to a process for preparing S- and R-enantiomers of substituted 3-aryloxy-2- hydroxypropylamines used as beta-receptor-blocking substances (hereinafter called beta blockers) and with the following respective formulae:
Figure imgf000003_0001
S-BETA BLOCKERS
Jr (J R-BETA BLOCKERS
Figure imgf000003_0002
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.
According to the invention, these beta blockers can be prepared via intermediates in the form of the S- or R-enantiomers of the amines defined below.
Figure imgf000003_0003
Figure imgf000004_0001
The abovementioned definitions for R3 apply here, while RA will be hydrogen or a protecting group which can be easily removed by means of hydrogenolysis, for example an optionally substituted 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 or 9b and 8a or 8b can in turn be obtained from other intermediates included in the invention and discussed later in the text, with the following general formulae in their R- or S-forms.
Figure imgf000004_0002
and
Figure imgf000004_0003
in which Arx = substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character. PRIOR ART
Beta blockers are used as drugs primarily for cardiovascular diseases, such as hypertension, angina pectoris and certain arrhythmias, 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 two enantiomers, the R-form and the 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 possesses the pharmacological effect which is desirable in cardiovascular diseases, while the same beta blocker's R-form is virtually inactive. In contrast, both the enantiomers have been found to be approximately equally effective against glaucoma (Keates, E U, Stone, R: Am J Ophthalmol 9_8, 73 (1984)). It has therefore been proposed to use these R-beta blockers against glaucoma in order to prevent any effect on the cardiovascular system, while the S-form should be used for cardiovascular diseases. There is therefore considerable interest in establishing the simplest possible synthesis routes for preparing both the S- and R-forms of homochiral beta blockers.
Synthesis routes for preparing certain homochiral beta blockers are described 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 Scheme I below (in this and in subsequent general formula schemes, steps 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 the text which follows also makes direct reference to the reference numbers given in these general formulae and schemes) .
Scheme I
Figure imgf000006_0001
Figure imgf000006_0003
Figure imgf000006_0002
There are also other previously known beta blockers which contain a substituted benzene radical instead of a substituted naphthalene radical. For these beta blockers too, the general designation Ar2 will therefore be con¬ sidered, as earlier on page 1, as representing both substituted benzene and naphthalene radicals. GB Patent 1,269,776 describes a method for preparing such beta blockers taking as a starting point certain specific amines hereinafter designated 2a, 2b, 3a and 3b, in accordance with the general method defined below (Scheme II). Here, R- = alkyl radical, R2 = hydrogen 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 is not = hydrogen and when a product is obtained which is certainly not the desired product but which can be converted to it by means of hydro- genolysis.
Figure imgf000007_0001
Figure imgf000007_0002
Hitherto, it h 3as6only been possible for the above amines in question 2a, 2b, 3a and 3b, which include the amines 8a, 8b, 9a and 9b in question on page 2, to be prepared in homochiral form from corresponding racemates by separation via salts (so-called resolution of racemates) .
It is also previously known, for example from SE-A-7414017-9 (425.971), corresponding to GB Patents 1458392 and 1458393, to prepare S-beta blockers according to the general Scheme III below, from any of the starting substances designated 4, 5, 6 or 7, in which Ar2 has the same meaning as before, and in which Y = an easily removable protecting group, while ' Z1 - a substitutable radical.
Figure imgf000008_0001
DESCRIPTION OF THE INVENTION
The present invention now includes, inter alia, a process for preparing any desired enantiomers of amines 8a or 8b and 9a or 9b (see 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 contained therein to a 1,2-chlorohydrin group in order to give the corresponding chloropropanediol sulphonate which in turn is reacted with an amine to give the corresponding chloropropanolamine (9a or 9b, depend¬ ing on which enantiomer constituted the starting sub¬ stance), or alternatively by means of a further treatment with a base, if appropriate in the presence of a phenol, completely or partially reacted to give the second amine (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 intermediates in the process according to the invention and which are designated 10a and 10b in the formulae, the raw materials which can be employed include commercially available substances such as R- or S-glycidol, or esters thereof, for example R-glycidyl butyrate, which can be converted, by means of techniques known to the person skilled in the art, to 10a or 10b, respectively, accord¬ ing to the following scheme:
Figure imgf000009_0001
in which Ar- is a substituted benzene or naphthalene radical in which at least one substituent is of an electron-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 substituted sulphinyl, sulphonyl, phosphonyl, phosphoryl or carbonyl groups, or combinations of these atoms and groups, at any chosen positions on the benzene or naphthalene rings, it being preferable for Arx to be a substituted benzene radical in which at least one substituent is a nitro, an optionally substituted sulphonyl or an optionally sub¬ stituted carbonyl group at any chosen position on the benzene ring. In the most interesting alternative, Arx is a substituted benzene radical in which at least one substituent is a nitro group at any chosen position on the benzene ring.
Alternatively, the glycidyl sulphonates 10a and 10b can be prepared starting from allyl alcohol which, by means of enantioselective epoxidation, is converted to S- or R-glycidol, which is then reacted to give 10a or 10b, respectively, again using the known technique (cf., for example, Klunder, J M, Ko, S Y, Sharpless, K B: J Org Chem 5i, 3710 (1986)).
The preparation of the amines 9a and 9b by reacting the glycidyl sulphonates 10a and 10b, respectively, with hydrogen chloride followed by treatment with an amine can be illustrated as follows:
Figure imgf000010_0001
Ma. //* Z 9 c,
Figure imgf000010_0002
/ έ 7U /£ ? , in which Arlf 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 chosen 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, respectively, by treatment with a base, for example hydroxides, alkoxides or car¬ bonates of lithium, sodium, potassium, calcium or magne¬ sium and optionally substituted ammonia, it being prefer¬ able for the base to consist of sodium or potassium hydroxide or of sodium or potassium alkoxide, for example methoxide, ethoxide or tertiary butoxide, optionally in the presence of a phenol, as is clear from the relevant part of Scheme V.
The advantage of the new procedures for preparing amines 8 and 9 in homochiral form is that they permit utiliza¬ tion of 100% of the raw material, whereas, 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 expensive homochiral salt-former.
As mentioned earlier, the invention furthermore relates to new routes for the preparation of S- and R-beta blockers. These routes are via the amines 9a or 9b and 8a or 8b, for which reason the starting substances for this part of the invention too are R- and S-glycidyl esters of sulphonic acids (10a or 10b) which are reacted to give the amines 9a or 9b. These amines are then further treated in accordance with the following scheme.
Scheme V
Figure imgf000011_0001
in which R3 and R4 have the same meanings as above. When R3 is isopropyl, Ar2 is any one of the radicals given in Table 1 below.
Figure imgf000012_0001
In addition, when R3 is tertiary butyl, Ar2 is any one of the radicals according to Table 2. Table 2
Order no. S- (15a) or without R- (15b) form of spec Radical = Ar, (generic name) signifi¬ cance
21 2-acetyl-4-(diethylcarbamoyl- araino) henyl celiprolol 22 2-methylcarbamoylmethoxy- phenyl cetamolol 23 1-(5-OXO-5,6,7,8-tetrahydro- naphthyl) levobunolol 24 l-(cis-6,7-hydroxy-5,6/7,8- tetrahydronaphthyl) nadolol
25 2-cyclopentyl penbutolol
26 8-thiocromanyl tertatolol When R3 is 2-(3,4-dimethoxyphenyl)ethyl Ar2 is 3-methyl- phenyl or 4-(2-cyano-l-methylethenyl)phenyl, when R3 = 2- (2-methoxyphenoxy)ethyl Ar2 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 Ar2 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 hydrolysis of number 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-beta blockers consist, as has been partially described above, in the respective glycidyl sulphonate (10a or 10b) being reacted with hydrogen chloride to give a chloropropanediol sul¬ phonate, which in turn is reacted with an amine, for example isopropylamine, to give the corresponding chloro- propanolamine 9a or 9b. By treating the chloropropanol- amines thus obtained with a phenol 13, under the action of a base illustrated above, substances are obtained which, when R represents hydrogen, are S- or R-beta blockers 15a or 15b but which, when R4 does not represent hydrogen, have the general structure 14a or 14b. The substances with structure 14a or 14b are converted to corresponding S- or alternatively R-beta blockers (15a or 15b) by being subjected to reaction conditions which bring about hydrogenolysis, for example treatment with hydrogen gas in the presence of metal catalysts, for example palladium. When treating the amines 9a or 9b with a phenol in the presence of a base, two parallel reac¬ tions take place. The one consists in direct conversion to 14a or 14b or 15a or 15b, the second taking place via previously mentioned amine 8a or 8b as intermediate product. If so desired, such an intermediate product 8a or 8b can be isolated by crystallisation or distillation.
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 epoxy group is converted to a 1,2-chlorohydrin group (conversion of 10a or 10b to 11a or lib in Scheme IV) .
The advantage of adding this new reaction step is the following. The chloropropanediol sulphonates 11a and lib have been found to give lower proportions of by-products, in the form of C3-aminated by-products, than corres¬ ponding glycidyl sulphonates 10a and 10b. This is very important since the presence of a C3-aminated impurity in amines 8a, 8b, 9a or 9b leads to formation of impurities in the homochiral beta blockers prepared from these and consisting of the same beta blockers of the opposite chiral form (R-beta blocker as an impurity in an S-beta blocker or S- as an impurity in an R-). Impurities which are related to the main component in this way are generally difficult to remove.
The reason why, as has been mentioned above, Ar. 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 examples of some previously unknown substances which can be used in the procedures according to Schemes IV and V, the following may be mentioned: ■
R-glycidyl 4-nitrobenzenesulphonate, certain S- or R-glycidyl esters of sulphonic acids of formulae 10a or 10b in which Arx has the meaning given earlier, and S- or R-3-chloro-l,2-propanediol 1-sulphonates of formulae 11a or lib, for example, S- or R-3-chloro-l,2-propanediol 1-(4-nitrobenzenesulphonate) .
This means that the invention also includes intermediates of the following general formulae in their R- and S-for s:
Figure imgf000015_0001
but with the exception of previously known substances, namely the S-form in which Arx = 4-nitrophenyl and the R- and S-forms in which Arx = 2- or 3-nitrophenyl, 4-chloro- phenyl or 4-chloro-3-nitrophenyl.
In the reactions, described above and forming part of the invention, of raw materials via intermediates to give desired final products and in the isolation of both intermediate and final product, the choice of the chemi¬ cal conditions, such as solvents, concentrations, temper¬ atures, pressure etc. is not critical for those results which are the aim of the invention to be achieved, and instead generally known practice in organic synthesis can be used in each particular case. The same applies of course to the following examples in which these data have for this reason not always been included.
As examples of some solvents which are suitable in connection with the process according to the invention, mention may be made of dichloromethane, 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 question, and the temperatures are chosen between about -20°C and 150βC and the pressure between 0.01 and 20 bar.
The invention, which has been defined in the subsequent patent claims, will now be further illustrated 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 time there are also included some of the reference numbers appearing in these formula schemes and relating to the various com¬ pounds and their enantiomers.
Example 1 (Scheme IV)
60 g of R-glycidyl 3-nitrobenzenesulphonate (10a; Arx = 3-nitrophenyl; > 99% R-form) were dissolved in 90 ml of dichloromethane in a glass flask, after which hydrogen chloride gas was introduced into the solution until high- pressure liquid chromatography (HPLC) showed that more than 99% of the benzenesulphonate had been converted. Removal of the excess HC1 and the dichloromethane gave S-2-hydroxy-3-chloropropyl3-nitrobenzenesulphonate (11a; Axx = 3-nitrophenyl) in the form of an oil which slowly crystallised. Nuclear magnetic resonance spectroscopy (NMR) with deuterochloroform as solvent gave the follow¬ ing result:
52.7 (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 (1 H, triplet of doublets), 8.50 (1 H, triplet of doublets), 8.74 (1 H, triplet) ppm.
Purity according to HPLC about 98%. The greatest impurity may be a product formed by the opposite opening of the epoxide ring.
Example 2 (Scheme IV)
Carried out as in Example 1, but with 4-isomer (10a; Arx = 4-nitrophenyl; > 99% R-form) instead of 3-isomer, giving S-2-hydroxy-3-chloropropyl 4-nitrobenzenesulphonate (11a; Ar- = 4-nitrophenyl) .
NMR: 82 .5 (1 H, singlet), 3.61 (2 H, doublet), 4.2 (1 H, ultiplet), 4.26 (2 H, doublet), 8.12 (2 H, doublet), 8.41 (2 H, doublet) ppm.
Example 3 (Scheme IV)
Carried 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 V)
Isopropylamine (12; R3 = isopropyl, R4 = H, 1.2 ml) and dichloromethane (0.35 ml) were added to S-2-hydroxy 3-chloropropyl 3-nitrobenzenesulphonate (11a; Arx = 3- nitrophenyl) prepared in accordance with Example 1 (0.20 g) . The solution was allowed to stand for one hour at about 20βC, after which volatile constituents were stripped of under reduced pressure. After dissolving in dimethyl sulphoxide (DMSO, 0.5 ml), a solution of 2-(4- hydroxyphenyl)acetamide (13; Ar2 = 4-carbamoyl- methylphenyl, 0.43 g) and potassium tert-butylate (0.68 g) in DMSO (1.3 ml) was added. After two hours at 80°C, HPLC (column: Chiral AGP, ChromTech) on the reaction mixture showed that 4-(2-hydroxy-3-iβopropylamino- propoxy)phenylacetamide (15a; Ar2 = 4-carbamoyl- methylphenyl, R3 » isopropyl) had been formed and that the ratio between its S-form and R-form was > 99:1.
Example 5 (without conversion of epoxy group to 1,2- chlorohydrin group) .
Carried out as in Example 4 but with R-glycidyl 3-nitro¬ benzenesulphonate (10a; Arx = 3-nitrophenyl) instead of S-2-hydroxy-3-chloropropyl3-nitrobenzenesulphonate (11a; Arx = 3-nitrophenyl) . In this case the ratio between the S- and R-forms of the product was 97:3.
Example 6 (Scheme IV)
Isopropylamine (12; R3 = isopropyl, RA = H, 60 ml) and dichloromethane (10 ml) were added to S-2-hydroxy-3- chloropropyl 3-nitrobenzenesulphonate (11a; Art = 3-nitro¬ phenyl) prepared according to Example 1 (20 g) . The solution was allowed to stand for two 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, R< = H) . As a reference for identifying the latter, a racemic product was used which was obtained by reacting epi- chlorohydrin with isopropylamine.
Example 7 (Scheme IV)
Carried out as in Example 6, but starting from 4-isomer (11a; Ei = 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, R = H) .
Example 8 (Scheme IV) Stage A.
A solution of S-2-hydroxy-3-chloropropyl 3-nitro¬ benzenesulphonate (11a; Ar- = 3-nitrophenyl) prepared according to Example 1 (1.48 g) and benzylisopropylamine (12; R3 = isopropyl, R4 = benzyl, 1.16 g) in methanol (3.0 ml) was heated for five hours at 40°C. The methanol was then stripped off under reduced pressure.
Stage B.
The product was chromatographed on silica gel with ethyl acetate/dichloromethane (1:9) as eluent. S-2-hydroxy-3- chloropropylbenzylisopropylamine (9a; R3 = isopropyl, R = benzyl) in the form of a viscous oil (0.1 g) was obtained in this case.
NMR: 51.02 (6 H, two doublets), 2.55 (2 H, multiplet), 2.96 (1 H, septet), 3.2 (1 H, broad singlet), 3.5 (5 H, multiplet) , 7.16 (5 H, singlet) ppm.
Example 9 (Scheme V)
A product containing S-2-hydroxy-3-chloroproρyl- isopropylamine (9a; R3 - isopropyl, R4 = H) prepared in accordance with Example 7 (46.1 g) was suspended 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 HPLC, the reference used being a racemic product obtained by potassium tert-butylate-induced hydrogen chloride elimination from the reference used in Example 6.
Example 10 (Scheme V)
A product containing S-2-hydroxy-3-chloropropyl- isopropylamine (9a; R3 = isopropyl, R4 = H) prepared in accordance with Example 7 (46.1 g) was suspended in methanol (22 ml), and a solution of 2-(4-hydroxy- phenyl)acetamide (13; Ar2 = 4-carbamoylmethylphenyl, 57.0 g) and potassium hydroxide (35.7 g) in methanol (195 ml) was added. After heating for two hours at 50βC, HPLC showed that complete conversion had taken place, partially via 8a (R3 = isopropyl, R4 = H) . Isobutanol was added, and the mixture was filtered and most of the methanol stripped off from the filtrate. The solution which remained was washed with water after which the volatile constituents in the organic phase were stripped off. The product was recrystallised from isopropyl alcohol, this giving S-4-(2-hydroxy-3-isopropylamino- propoxy)phenylacetamide (15a; Ar2 = 4-carbamoylmethyl¬ phenyl, R3 » isopropyl, 6.2 g) . NMR identical with racemic reference. HPLC (column: Chiral AGP) showed that the ratio between S- and R-form in the product was > 99:1. Example 11 (Scheme V)
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-l-(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 S-2-hydroxy-3-chloropropylbenzyl- isopropylamine (9a; R3 = isopropyl, R4 = 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; Ar2 = 4-carbamoyl- methylphenyl, 5.7 g) and potassium hydroxide (3.6 g) in methanol (20 ml) was added. After heating for three hours at 60βC, the mixture was filtered and the filtrate was evaporated. Water was added and the mixture was extracted with dichloromethane. After evaporation, the extract was dissolved in methanol (50 ml), palladium/charcoal (10%, 0.21 g) was added, and the mixture was stirred in a hydrogen gas atmosphere. The reaction was discontinued when HPLC showed that all the starting material had been consumed. The suspension was filtered and the methanol was stripped off. Recrystallisation from isopropyl alcohol gave S-4-(2-hydroxy-3-isopropylaminopropoxy)- phenylacetamide (15a; Ar2 = carbamoylmethylphenyl, R3 = isopropyl, 0.9 g) , NMR 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 Example 10, but with 2-(4-hydroxy¬ phenyl)acetonitrile (13; Ar2 = 4-cyanomethylphenyl, 50.2 g) instead of 2-(4-hydroxyphenyl)acetamide. In this case S-4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetonitrile was obtained (15a; Ar2 = 4-cyanomethylphenyl, R3 = isopropyl, 5.7 g) . Example 14
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 using a solution of potassium hydroxide (10%) in water. The mixture was saturated with sodium chloride and was filtered. After recrystallisation from isopropyl alcohol, S-4-(2-hydroxy-3-isopropyl- aminopropoxy)phenylacetamide (15a; Ar2 = 4-carbamoyl- methylphenyl, R3 = isopropyl, 1.5 g) was obtained, with identity and purity as in Example 10.
Example 15 (Scheme IV)
Carried out as in Example 2, but with S-isomer (10b; Ar. = 4-nitrophenyl) instead of R-isomer, giving R-2-hydroxy- 3-chloropropyl 4-nitrobenzenesulphonate (lib; Arx = 4- nitrophenyl) .
Example 16 (Scheme IV)
Carried out as in Example 7, but with R-isomer (lib; Arx = 4-nitrophenyl) prepared in accordance with Example 14 instead of S-isomer, giving 4-nitrobenzenesulphonic acid salt of isopropylamine and R-2-hydroxy-3-chloropropyl- isopropylamine (9b; R3 = isopropyl, R4 = H) .
Example 17 (Scheme V)
Carried out as in Example 10, but with R-isomer (9b; R3 = isopropyl, R = H) prepared in accordance with Example 15 instead of S-isomer, giving R-4-(2-hydroxy-3-iso- propylaminopropoxy)phenylacetamide (15b; Ar2 = 4-car- bamoylmethylphenyl, R3 = isopropyl). The ratio between R- and S-form was > 99:1.

Claims

PATENT CLAIMS
1. Process for preparing S-and R-enantiomers of chloropropanolamines having the general formulae
Figure imgf000022_0001
(S-fo m) (R-form)
respectively from R- and S-glycidyl esters of sulphonic acids (glycidyl sulphonate) with the formulae
Figure imgf000022_0002
(R-form) (S-form)
in which Arx = 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 RANH 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
Figure imgf000023_0001
S-form R-form from corresponding S- and R-chloropropanolamines prepared in accordance with Claim 1, characterised in that the starting stibstance 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-eyelopropylmethoxyethoxy)phenyl,
2-acetyl-4-(acetylamino)phenyl,
2-methoxyphenyl,
4-(2-methoxyethyl)phenyl,
8-(3-nitroxy)chromanyl, -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-(5-0x0-5,6,7,8-tetrahydronaphthyl) ,
1-(cis-6,7-hydroxy-5,6,7,8-tetrahydronaphthyl) ,
2-cyclopenthyl,
8-thiochromanyi
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
Ar20H
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-eyelopropylmethoxyethyl)phenyl,
4-(2-isopropoxyethoxymethyl)phenyl,
4-(2-eyelopropylmethoxyethoxy)phenyl,
2-acetyl-4-(acetylamino)phenyl, 2-methoxyphenyl,
4-(2-methoxyethyl)phenyl,
8-(3-nitroxy)chromanyl,
2-allyloxyphenyl,
4-indolyl,
1-naphthyl, -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-l-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
R 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. Intermediate for preparation of S- and R-enantiomers of chloropropanolamines, characterised in that it is represented by the following general formulae in its R- and S-forms respectively
Figure imgf000026_0001
in which Ar- = substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character, but with the exception of the S-form in which Ar., =
4-nitrophenyl and the R- and S-forms in which Ar. = 2- or
3-nitrophenyl, 4-chlorophenyl or 4-chloro-3-nitrophenyl.
6. Intermediate for preparation of S- and R-enantiomers of chloropropanolamines, characterised in that it is represented by the following general formulae in its R- and S-forms respectively
Figure imgf000026_0002
in which Arx = substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character.
7. Process for preparing S- and R-enantiomers of substituted 3-aryloxy-2-hydroxypropylamines used as beta blockers, with the following respective formulae:
0 μ fr 0 \/^/ Λ/ Y*Rj S-BETA BLOCKERS
R-BETA BLOCKERS
Figure imgf000026_0003
in which Ar2 = substituted benzene or naphthalene radical and R3 = isopropyl, tertiary butyl,
2-(3,4-dimethoxyphenyl)ethyl,
2-(2-methoxyphenoxy)ethyl,
2-( -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
Figure imgf000027_0001
in which Arx 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
Figure imgf000027_0002
T- /-__/»-_»-ι ?__j ,,
Figure imgf000027_0003
in which Rk is hydrogen or a protecting group easily removed by hydrogenolysis, and R3 and Arx have the mean¬ ings indicated above, after which the chloropropanolamine thus obtained is treated with a phenol under the action of a base in accordance with the following scheme
Figure imgf000028_0001
8. Process according to Claim 7, characterised in that the ehloropropanolamine obtained after hydrogen chloride reaction and treatment with the amine is first treated with a base and thereafter with the phenol in accordance with the scheme below
Figure imgf000028_0002
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.
PCT/SE1991/000022 1990-01-22 1991-01-15 Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process WO1991010642A1 (en)

Priority Applications (3)

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JP91503496A JPH05506008A (en) 1990-01-22 1991-01-15 A method for producing a homochiral amine, a method for producing an intermediate for producing the amine, and an intermediate produced according to the method
FI923305A FI923305A (en) 1990-01-22 1992-07-20 FOERFARANDE FOER FRAMSTAELLNING AV HOMOKIRALA AMINER, FOERFARANDE FOER FRAMSTAELLNING AV MELLANPRODUKTER SOM ANVAENDS DAERVID, SAMT GENOM FOERFARANDET FRAMSTAELLDA MELLANPRODUKTER.
NO922871A NO922871D0 (en) 1990-01-22 1992-07-20 PROCEDURE FOR THE MANUFACTURE OF HOMOCIRAL AMINES AND PROCEDURES FOR THE MANUFACTURE OF INTERMEDIATES FOR THE MANUFACTURING THEREOF, AND THE INTERMEDIATES PRODUCED UNDER THAT PROCEDURE

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999052855A1 (en) * 1998-04-14 1999-10-21 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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6057476A (en) * 1996-09-18 2000-05-02 Daiso Co., Ltd. Process for the preparation of 3-amino-2-hydroxy-1-propyl ethers
JP7108436B2 (en) * 2018-03-22 2022-07-28 三井化学株式会社 Method for producing epoxy compound containing biphenyl skeleton

Citations (4)

* Cited by examiner, † Cited by third party
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. Org. Chem., Vol. 51, 1986 JANICE M. KLUNDER et al.: "Asymmetric Epoxidation of Allyl Alcohol: Efficient Routes to Homochiral beta-Adrenergic Blocking Agents". *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999052855A1 (en) * 1998-04-14 1999-10-21 Samsung Fine Chemicals Co., Ltd. A process for preparing chiral (s)-2,3-disubstituted-1-propylamine derivatives
US6417403B1 (en) 1998-04-14 2002-07-09 Samsung Fine Chemicals Co., Ltd. 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

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