GB2162517A - Process for the preparation of 3-substituted derivatives of 1- amino2-hydroxy-propane - Google Patents

Process for the preparation of 3-substituted derivatives of 1- amino2-hydroxy-propane Download PDF

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GB2162517A
GB2162517A GB08517095A GB8517095A GB2162517A GB 2162517 A GB2162517 A GB 2162517A GB 08517095 A GB08517095 A GB 08517095A GB 8517095 A GB8517095 A GB 8517095A GB 2162517 A GB2162517 A GB 2162517A
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formula
compound
obtaining
propane
diastereoisomer
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Piero Melloni
Arturo Della Torre
Ettore Lazzari
Giuseppe Mazzini
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Single diastereoisomers of 3-substituted derivatives of 1-amino-2-hydroxy-propane of formula (I): <IMAGE> wherein R is C1-C6 alkoxy or tri-halomethyl, are prepared by: (a) epoxidizing trans-cinnamic alcohol, so obtaining the compound of formula (II> <IMAGE> (b) reacting the compound of formula (II) with a phenol derivative of formula (III> <IMAGE> wherein R is as defined above, so obtaining a 3-substituted-1,2-dihydroxy propane derivative of formula (IV> wherein R is as defined above; and either (c) esterifying a compound of formula (IV) with a sulfonic acid, or a reactive derivative thereof, so obtaining a monoester of formula (V> <IMAGE> wherein R is as defined above and R1 is the residue of a sulfonic acid, and then reacting a compound of formula (V) with ammonia so obtaining one diastereoisomer of formula (I); or, in alternative, (d) esterifying a compound of formula (IV) with a carboxylic acid, or a reactive derivative thereof, so obtaining a compound of formula (VI> <IMAGE> wherein R2 is the residue of a carboxylic acid and R is as defined above; (e) esterifying a compound of formula (VI) with a sulfonic acid, or a reactive derivative thereof, so obtaining a diester of formula (VII> <IMAGE> wherein R, R1 and R2 are as defined above; (f) making an epoxide from a compound of formula (VII), so obtaining a compound of formula (VIII> <IMAGE> wherein R is as defined above, and then reacting a compound of formula (VIII) with ammonia, so obtaining the other diastereoisomer of formula (I).

Description

SPECIFICATION Process for the preparation of 3-substituted derivatives of 1-amino-2-hydroxy-propane The present invention relates to a new process for the preparation of 3-substituted derivatives of 1-amino-2-hydroxy-propane in the form of single diastereoisomers, to certain of these diastereoisomers, and to compounds which are intermediates in the new process of the invention.
According to the invention, single diastereoisomers of 3-substituted derivatives of 1-amino-2hydroxy-propane of the following formula (I)
wherein R is C,-C6 alkoxy or tri-halomethyl, are prepared by a process comprising: (a) epoxidizing transcinnamic alcohol, so obtaining the compound of formula (II)
(b) reacting the compound of formula (II) with a phenol derivative of formula (III)
wherein R is as defined above, so obtaining a 3-substituted-l ,2-dihydroxy propane derivative of formula (IV)
wherein R is as defined above; and either (c) esterifying a compound of formula (IV) with a sulfonic acid, or a reactive derivative thereof, so obtaining a monoester of formula (V)
wherein R is as defined above and Rl is the residue of a sulfonic acid, and then reacting a compound of formula (V) with ammonia so obtaining one diastereoisomer of formula (I); or, in alternative, (d) esterifying a compound of formula (IV) with a carboxylic acid, or a reactive derivative thereof, so obtaining a compound of formula (VI)
wherein R2 is the residue of a carboxylic acid and R is as defined above; (e) esterifying a compound of formula (VI) with a sulfonic acid, or a reactive derivative thereof, so obtaining a diester of formula (VII)
wherein R, Rl and R2 are as defined above; (f) making an epoxide from a compound of formula (VII), so obtaining a compound of formula (VIII)
wherein R is as defined above, and then reacting a compound of formula (VIII) with ammonia, so obtaining the other diastereoisomer of formula (I).
In the above formulae, when R is C,-C6 alkoxy preferred groups are methoxy and ethoxy, in particular ethoxy. When R is tri-halo-methyl, trifluoromethyl is preferred. Preferably R is an ethoxy group in the ortho-position of the benzene ring.
A sulfonic acid is, for example, methanesulfonic acid or p-toluenesulfonic acid.
A carboxylic acid may be either aliphatic or aromatic. An aliphatic carboxylic acid may be, for example, a C2-C6 carboxylic acid such as, for instance, acetic acid or propionic acid.
An aromatic carboxylic acid is, for instance, an optionally substituted benzoic acid, such as, e.g., benzoic acid and pnitro-benzoic acid.
A reactive derivative of a either sulfonic or carboxylic acid may be, for example, a corresponding halide, e.g. the chloride, or the corresponding anhydride or a mixed anhydride.
Thus, for example, the R, residue of a sulfonic acid, in the above formulae (V) and (VII) is, e.g., methanesulfonyl or ptoluenesulfonyl; preferably R1 is ptoluenesulfonyl in formula (V) and methanesulfonyl in formula (VII).
Similarly the R2 residue of a carboxylic acid in the above formulae (VI) and (VII) is, e.g., acetyl, propionyl, benzoyl or p-nitro-benzoyl.
As already said, the new process of the invention allows to obtain compounds of formula (I) in the form of single diastereoisomers: these, in accordance with IUPAC, Nomenclature of Organic Chemistry Sections A, B, C, D, E, F and H, 1979 Edition, can be referred to as (RS,RS) and, respectively, (RS,SR) diastereoisomers, each diastereoisomer involving, as is known, a couple of enantiomers. Accordingly, a (RS,RS) diastereoisomer is intended to be a racemate of (R,R) and (S,S) enantiomers, and a (RS,SR) diastereoisomer is intended to be a racemate of (R,S) and (S,R) enantiomers.
When the new process of the invention is carried out through the steps (a), (b) and (c), a (RS,SR) diastereoisomer is obtained; when the process is carried out through the steps (a), (b), (d), (e) and (f), then a (RS,RS) diastereoisomer is obtained.
The epoxidation of the transcinnamic alcohol to give the epoxide of formula (II) may be carried out by the use of a suitable oxidizing agent, for instance with vanadic anhydride and hydrogen peroxide, or with a peroxy acid such as, e.g., perbenzoic, mchloroperbenzoic, peracetic, mono- or di-peroxy-phthalic, or peroxytrifluoroacetic acid.
The reaction may be carried out at any suitable temperature between room temperature and the boiling point of the used solvent, preferably at room temperature, in an appropriate solvent which may be, for example, an optionally halogenated hydrocarbon, e.g. benzene, chloroform or methylene chloride, or a linear or cyclic ether, e.g. dioxane, or also acetic acid.
The reaction between a compound of formula (II) and a compound of formula (III) is preferably carried out by heating at a temperature between about 60"C and about 1 20 C, in the presence of a base such as, e.g., aqueous sodium or potassium hydroxide, preferably in the absence of any other solvent.
The esterification of a compound of formula (IV) to give a compound of formula (V) is preferably carried out with a reactive derivative of a sulfonic acid, preferably a sulfonic acid halide, in particular the chloride, e.g. methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of an acid acceptor which may be, for instance, an organic base such as, e.g., triethylamine or pyridine.
The reaction is preferably performed under cooling, e.g., at - 10" to + 50"C, in particular at - 10" to 0 C, in a suitable anhydrous solvent such as, e.g., benzene, toluene or pyridine: when pyridine is used as solvent, it also acts as a base. The reaction of a compound of formula (V) with ammonia to give one, (RS,SR), diastereoisomer of formula (I) is preferably carried out at a temperature between about O"C and the room temperature, in particular at room temperature, with 30-32% aqueous ammonia in a suitable solvent which may be, for instance, dimethylacetamide or an aliphatic alcohol, e.g. methanol or ethanol.
The esterification of a compound of formula (IV) to give a compound of formula (VI) is preferably performed with a reactive derivative of a carboxylic acid, preferably a carboxylic acid halide, in particular chloride, operating under cooling, e.g. at 10 to + 50"C, in particular at about - 10" to 0 C or at room temperature, in an anhydrous organic solvent, e.g. benzene or toluene, in the presence of a base which may be, for example, an organic base such as, e.g., triethylamine or pyridine: according to a preferred procedure, pyridine is used as solvent in absence of any other base.
The subsequent esterification of a compound of formula (VI) to give a compound of formula (VII) is carried out using reaction conditions similar to those described hereabove for the conversion of a compound of formula (IV) into a compound of formula (V).
The transformation of a compound of formula (VII) into a compound of formula (VIII), is carried out by reaction with a suitable base, preferably an inorganic base such as, e.g., an alkali metal or alkaline-earth metal hydroxide, preferably sodium or potassium hydroxide.
Preferably the reaction is carried out at a temperature between about O"C and about 50"C, in particular atroom temperature, in an aqueous organic solvent such as, e.g., dioxane or dimethylformaide.
The subsequent reaction of the epoxide of formula (Vlil) with ammonia, to give the other, (RS,RS), diastereoisomer of formula (I), may be performed using conditions similar to those reported above for the analogous reaction on a compound of formula (V).
The compounds of formula (II) and the compounds of formula (III) are known, commercially available products. While diastereoisomeric mixtures of compounds of formula (I) are known (U.K. Patent Specification 2,014,981B), compounds of formula (I) in the form of single diastereoisomers are only partially known.
The invention provides, therefore, as a further object, compounds of the above formula (I) wherein R is ethoxy or trifluoromethyl, in the form of the single diastereoisomers.
Object of the invention are also single diastereoisomers of the compounds having the above reported formulae (IV), (V), (VI), (VII) and (VIII).
Following known methods, e.g. same step sequences as those described in U.K. patent specification 2,014,981 B, single (RS,RS) or (RS,SR) diastereoisomers of formula (I) obtained by the new process of the invention may be converted into corresponding single (RS,RS) or, respectively, (RS,SR) morpholine diastereoisomers: the latter are described too in U.K. patent specification 2,014,981 B and are therein reported as being very useful antidepressant agents.
The following examples illustrate but do not limit the invention.
Example 1 To a solution of transcinnamic alcohol (20 g) in methylene chloride (550 ml), cooled to 0-5"C, 77% aqueous m-chloro-perbenzoic acid (36 g) was added in a period of 75 minutes.
The reaction mixture was left to rise to room temperature and stirring was continued for 2.5 hours.
The formed mchloro-benzoic acid was filtered under vacuum and washed with fresh methylene chloride. The organic phase was washed with sodium metabisulfite aqueous solution, with 20% aqueous Na2CO3, and then with a saturated NaCI aqueous solution; finally it was dried over Na2SO4 and filtered and the solvent was removed under reduced pressure with external temperature of 35"C, to give trans-3-phenyl-2-hydroxymethyl-oxirane (20.7 g) as a clear oil, NMR (CDCl3) 90 MHz 8:: 2.70 (1 H, br) 3.22 (1H, dt) 3.95 (1H, d) 3.76 (1H, dd) 4.04 (1 H, dd) 7.32 (5H, bs)
J J=2.1 Hz Example 2 To a solution of NaOH pellets (2.66 g) in water (10 ml) 2-ethoxy-phenol (27.6 g) was added dropwise under vigorous stirring and inert gas atmosphere, and with an external bath at 70"C.
The solid which formed during the addition dissolved in 15-30 minutes and then trans-3phenyl-2-hydroxymethyl-oxirane (11.76 g) was added.
The reaction mixture was stirred 2.5 hours at 70"C then poured into 1 N aqueous NaOH (250 ml), keeping the temperature at 10-15"C with an external water bath, and finally extracted with methylene chloride. The organic phase was washed with NaCI saturated aqueous solution, dried over Na2 SO4, filtered and the solvent was removed under vacuum keeping the external temperature at 35"C. The oily residue was treated with n-hexane to give 1.72 g of 1,2 dihydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane, m. p. 68-70 'C, as RS,SR diastereoisomer.
Example 3 To a solution of (RS,SR)-1 ,2-dihydroxy-3-(2-ethoxyphenoxy)-3-phenyl-propane (5 g) in anhydrous pyridine (50 ml), cooled to - 1 0'C, a solution of p-nitro-benzoylchloride (3.22 9) in anhydrous pyridine (50 ml) was added dropwise in 1.5 hours. After 30 minutes stirring at - 10'C, the reaction mixture was poured into 2M aqueous HCI (1 I) and ice (600 g), then extracted with ethylacetate.
The organic phase was successively washed with water (400 ml), a 5% aqueous NaHCO3 solution (400 ml) and a saturated aqueous NaCI solution, and finally dried over Na2SO4 and filtered. Evaporation of the solvent under vacuum led to an oil which, upon treatment with nhexane, was converted to 1-(4-nitrobenzoyloxy)-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-pro- pane as a solid product (4.5 g), m.p. 90-92"C (RS,SR diastereoisomer).
Example 4 To a solution of (RS,S R)-l -(4-nitro-benzoyloxy)-2-hyd roxy-3-(2-ethoxy-phenoxy)-3-phenyl-pro- pane (4 g) in methylene chloride (45 ml) and triethylamine (1.93 ml), cooled to - 5"C, methanesulfonyl chloride (0.77 ml) was added dropwise. After 1 hour stirring at - 5"C, the reaction mixture was diluted with methylene chloride and successively washed with 10% aqueous HCI (50 ml), water (50 ml), a 5% aqueous solution of NaHCO3 (50 ml) and saturated aqueous NaCI (50 ml).The separated organic phase was then dried over Na2SO4 and filtered and the solvent was evaporated under vacuum to give an oily residue which, upon treatment with isopropyl ether (30 ml), led to 3.95 g of solid 1-(4-nitro-benzoyloxy)-2-methanesulfonyloxy- 3-(2-ethoxy-phenoxy)-3-phenyl-propane, m.p. 89-90 'C as RS,SR diastereoisomer.
Example 5 To a solution of (R S,S R)- 1 -(4-n itro-benzoyloxy)-2-methanesu lfonyloxy-3-(2-ethoxy-phenoxy)-3phenyl-propane (3.95 g) in dioxane (40 ml) 2N aqueous NaOH (16 ml) was added. After 4 hours stirring at room temperature the reaction mixture was poured in iced water (200 ml) and then extracted with ethyl acetate (200 ml). The organic phase was successively washed with 5% aqueous NaHCO3 (75 ml) and saturated aqueous NaCI solution (3 X 75 ml), and then dried over Na2SO4 and filtered. Evaporation of the solvent under vacuum with external temperature of 35"C led to 2.05 g of (RS,RS)-a-(2-ethoxy-phenoxy)-benzyl-oxirane with a chromatographic title of 97%, NMR (CDCl3) 90 MHz 6:1.4 (3H, t); 2.70 (2H, m); 3.25 (H, m); 4.03 (3H, q); 4.75 (H, d); 6.85 (4H, m); 7.30 (5H, bs).
Example 6 To a solution of (RS,RS) a-(2-ethoxy-phenoxy)-benzyl-oxirane (4.9 g) in methanol (50 ml), 32% aqueous ammonia (50 ml) was added. The reaction mixture was then stirred for 6 hours at room temperature in an hermetically sealed vessel. The reaction mixture was then concentrated under vacuum and the residue taken up with 99% ethanol (2 x 50 ml) and then with benzene (50 ml), each time evaporating the solvent to dryness. Crystallization of the residue with ethyl acetate led to 1-amino-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane as single RS,RS diastereoisomer, m.p. 105-107"C.
In analogous fashion, starting from suitable intermediates prepared according to the procedures described in the examples 1 to 5, the compound 1-amino-2-hydroxy-3-(4-trifluoromethyl- phenoxy)-3-phenyl-propane was obtained as single RS,RS diastereoisomer.
Example 7 To a solution of (RS,SR) 1,2-dihydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane (5 g) in pyridine (50 ml), cooled to - 10"C, a solution of ptoluenesulfonyl chloride (3.9 g) in pyridine (50 ml) was added dropwise in 1.5 hours.
The reaction mixture was stirred at 10 C for 30 minutes then was left to reach the room temperature, stirred for further 3 hours and finally poured into a mixture of 2N aqueous HCI (1 I) and ice (650 g).
After extraction with ethyl acetate, the organic phase was successively washed with water (400 ml), 5% aqueous NaHCO3 (400 ml) and saturated aqueous NaCI, dried over Na2SO4 and filtered.
Evaporation of the solvent under vacuum led to a residue which was purified on chromatographic column (toluene: acetone 190:7.5 as eluant) to give 4.3 g of (RS,SR)-1 -(ptoluene- sulfonyloxy)-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane, NMR (CDCl3) 90 MHz, 8: 1.41 (3H, t); 2.42 (3H, s); 3.13 (1H, br); 4.04 (2H, q); 4.0-4.3 (3H, m); 5.01 (1H, d); 6.6-7.8 (13H, m).
Example 8 To a solution of (RS, SR)- 1 -(p-toluenesulfonyloxy)-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl- propane (4.3 g) in dimethylacetamide (125 ml), 30% aqueous ammonia (125 ml) was added and the reaction mixture was kept for 1 2 hours at room temperature in an hermetically sealed vessel. The mixture was then concentrated under vacuum to a small volume, poured into water, saturated with NaCI, and extracted with ethylacetate. The organic phase was washed with water, dried over Na2SO4, filtered, and the solvent evaporated under vacuum. The obtained oily residue was purified on chromatographic column (CHCl3:CH3OH:NH4OH 180:20:2 as eluant), to give 1,1 g of 1 -amino-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane as single RS,SR diastereoisomer, m.p. 115-117"C.
In analogous fashion, using appropriate starting compounds prepared according to the procedure described in the example 1, 2 and 7, the compound 1-amino-2-hydroxy-3-(4- trifluoromethyl-phenoxy)-3-phenyl-propane was obtained as single RS,SR diastereoisomer, m.p.
120-122"C.

Claims (14)

1. Process for the preparation of single diastereoisomers of 3-substituted derivatives of 1amino-2-hydroxy-propane of the following formula (I)
wherein R is C1 -C6 alkoxy or tri-halomethyl, the process comprising: (a) epoxidizing transcinnamic alcohol, so obtaining the compound of formula (II)
(b) reacting the compound of formula (II) with a phenol derivative of formula (III)
wherein R is as defined above, so obtaining a 3-substituted-1,2-dihydroxy propane derivative of formula (IV)
wherein R is as defined above; and either (c) esterifying a compound of formula (IV) with a sulfonic acid, or a reactive derivative thereof, so obtaining a monoester of formula (V)
wherein R is as defined above and R1 is the residue of a sulfonic acid, and then reacting a compound of formula (V) with ammonia so obtaining one diastereoisomer of formula (I); or, in alternative, (d) esterifying a compound of formula (IV) with a carboxylic acid, or a reactive derivative thereof, so obtaining a compound of formula (VI)
wherein R2 is the residue of a carboxylic acid and R is as defined above; (e) esterifying a compound of formula (VI) with a sulfonic acid, or a reactive derivative thereof, so obtaining a diester of formula (VII)
wherein R, R1 and R2 are as defined above; (f) making an epoxide from a compound of formula (VII), so obtaining a compound of formula (VIII)
wherein R is as defined above, and then reacting a compound of formula (VIII) with ammonia, so obtaining the other diastereosiomer of formula (I).
2. A compound having the formula (VIII) reported in claim 1, as a RS,RS diastereoisomer.
3. Process for the preparation of a compound of formula (VIII) according to claim 2, the process comprising making an epoxide from a RS,SR compound having the formula (VII) reported in claim 1.
4. A compound having the formula (VII) reported in claim 1, as a RS,SR diastereoisomer.
5. A compound having the formula (VI) reported in claim 1, as a RS,SR diastereoisomer.
6. A compound having the formula (V) reported in claim 1, as a RS,SR diastereoisomer.
7. A compound having the formula (IV) reported in claim 1, as a RS,SR diastereoisomer.
8. A compound having the formula (I) reported in claim 1, wherein R is ethoxy or trifluoromethyl, as a single diastereoisomer.
9. A process for the preparation of a compound of formula (i) as defined in claim 1 in the form of a (RS,RS) diastereoisomer, said process being substantially as hereinbefore described in Examples 1 to 6 together.
10. A process for the preparation of a compound of formula (I) as defined in claim 1 in the form of a (RS,SR) diasteroisomer, said process being substantially as hereinbefore described in Examples 1, 2, 7 and 8 together.
11. (RS, SR)-1 ,2-dihydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane.
1 2. (RS, SR)- 1 -(4-nitrobenzoyloxy)-2-hyd roxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane.
1 3. (RS,SR)-1-(4-nitrobenzoyloxy)-2-methanesulfonyloxy-3-(2-ethoxy-phenoxy)-3-phenyl-pro- pane.
14. (RS, RS)-alpha-(2-ethoxy-phenoxy)-benzyl-oxirane.
1 5. (RS,RS)- or (RS,S R)- 1 -amino-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane.
1 6. (RS,SR)-1 -(p-toluenesulfonyloxy)-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane.
1 7. (RS,RS)- or (RS, SR)-1 -amino-2-hydroxy-3-(4-trifluoromethyl-phenoxy)-3-phenyl-propane.
GB08517095A 1984-08-01 1985-07-05 Process for the preparation of 3-substituted derivatives of 1-amino-2-hydroxy-propane Expired GB2162517B (en)

Applications Claiming Priority (2)

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GB848419658A GB8419658D0 (en) 1984-08-01 1984-08-01 Nitrogen containing heterocyclic compounds
GB848419683A GB8419683D0 (en) 1984-08-02 1984-08-02 3-substituted derivatives of 1-amino-2-hydroxy-propane

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GB2162517A true GB2162517A (en) 1986-02-05
GB2162517B GB2162517B (en) 1988-04-27

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2014981A (en) * 1978-01-20 1979-09-05 Erba Farmitalia Substituted propanolamine and morpholine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2014981A (en) * 1978-01-20 1979-09-05 Erba Farmitalia Substituted propanolamine and morpholine derivatives

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GB2162517B (en) 1988-04-27

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