GB1598667A - 1,3-dioxolane derivatives and their use in the preparation of 1-amino-3-aryloxy-2-propanols - Google Patents

1,3-dioxolane derivatives and their use in the preparation of 1-amino-3-aryloxy-2-propanols Download PDF

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GB1598667A
GB1598667A GB11113/78A GB1111378A GB1598667A GB 1598667 A GB1598667 A GB 1598667A GB 11113/78 A GB11113/78 A GB 11113/78A GB 1111378 A GB1111378 A GB 1111378A GB 1598667 A GB1598667 A GB 1598667A
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isopropyl
indol
oxazolidinone
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07C217/38—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 being part of a condensed ring system containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/93—Spiro compounds
    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Abstract

Process for preparing the compounds of the formula II, <IMAGE> in which R represents a group which is stable during a reductive amination, Ra denotes a group which is eliminated during an intramolecular oxazolidinone formation, in racemic or optically active form, by eliminating the isopropylidene radical from corresponding compounds of the formula III, <IMAGE> which, for their part, can be obtained by introducing the group -CORa into corresponding compounds of the formula IV <IMAGE> The compounds of the formula II are intermediates for the preparation of valuable drugs having a beta -adrenozepto-blocking effect.

Description

(54) NOVEL 1,3-DIOXOLANE DERIVATIVES AND THEIR USE IN THE PREPARATION OF l-AMINO-3 A RYLOXY-2-PROPANOLS (71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to intermediates which may be used for, inter alia, the production of 1 - amino - 3 - aryloxy - 2 propanols, which may bear a substituent on the amino group and the hydroxy group of which may be esterified. One such intermediate is a compound of formula I
wherein R1 is an inert group, and X is oxygen or sulphur.
R1 may, for example, be hydrogen.
Alternatively R1 may be an alkyl group attached to a side chain nitrogen atom of a - - alkylamino - 3 - aryloxy - 2 - propanol beta - blocking, anti- hypertensive or anti - arrhythmic agent. R1 may be aliphatic alkyl of 3 to 7 carbon atoms, especially branched in the a-position, such as isopropyl or tert-butyl. Alternatively R1 may be a substituted alkyl group, e.g.
phenylalkyl, phenoxyalkyl or phenylthioalkyl of 8 to 11 carbon atoms wherein the phenyl ring is separated from the nitrogen atom by at least 2 carbon atoms, such as phenoxyethyl or phenethyl.
The phenyl ring may bear one, two or more substituents, e.g. alkyl (C1.4), alkoxy (C14), halogen (Cl, Br, F), cyano or amido, as in e.g. 3,4 - dimethoxyphenethyl. R1 may alternatively be alkyl (C1 4) cycloalkyl 3-6 B).
A compound of formula I may be produced by intramolecularly cyclizing a compound of formula II HOCH2 . CH(OH) . CH2 . NR1 . C(=X). R2 II wherein R1 and X are as defined above and R2 is a leaving group.
The process may be effected in conventional manner for such intramolecular cyclizations, e.g. of urethanes. Conventiently X is oxygen. R2 is conveniently alkoxy (C1~4), haloalkoxy (C1 4), or phenoxy or benzyloxy unsubstituted or substituted by halogen, alkyl (C14) or alkoxy (C14) (halogen is preferably fluorine, bromine or especially chlorine). Preferred examples of R2 include 2,2,2 trichloroethoxy, and especially methoxy, ethoxy, and unsubstituted benzoxy or phenoxy.
The reaction is conventiently effected under basic conditions, e.g. in the presence of sodium hydroxide, pyridine or triethylamine.
Suitable reaction temperatures may be from 0 to SOOC, e.g. room temperature.
Suitable solvents include tetrahydrofuran, dioxane, ethanol or methanol, or water.
The present invention provides a process for the production of a compound of formula II by splitting off the protecting group A from a compound of formula III
wherein A is a protecting group, and R1, R2 and X are as defined above.
The reaction may be effected in conventional manner for deprotecting a 1.2 - diol without splitting off the moiety C(=X). R2. The protecting group A is conveniently a hydrophobic group and may, as will be appreciated from the reactions described hereinafter, for example be a base-stable group. For example A may be alkylidene, e.g. of 1 to 5 carbon atoms, which is preferably symmetrical, e.g.
methylene or preferably isopropylidene.
Alternatively A may be a cycloalkylidene, e.g. such as cyclohexylidene or cyclopentylidene, or a benzylidene group which may be substituted in the ring, e.g. by nitro.
The reaction may be effected with an organic acid, e.g. aqueous acetic acid, or preferably with a mineral acid such as aqueous hydrochloric acid. An appropriate solvent such as methanol may be present.
Suitable temperatures are between 0 and 50"C, e.g. 100C.
It is to be appreciated that the resultant compound of formula II may be further converted into a compound for formula I directly without purification.
The present invention also provides a process for the production of compound of formula III by reacting a compound of formula IV
wherein A and R1 are as defined above with a compound of formula V Y.C(=X).R2 V wherein R2 and X are as defined above and Y is a group capable of being split off with the hydrogen of an amine.
The reaction may be effected in -conventional manner, e.g. for a Schotten Baumann reaction. Y is, for example, chlorine. Alternatively Y may be alkoxy (which may conveniently be the same as R2 when this is alkoxy). The reaction may be effected at a temperature of from 0 to 200C.
A compound of formula IV may be obtained by reductively aminating a compound of formula VI
which, according to needs, can be of the R, S, or racemic form.
The above process is therefore applicable not only to the production of racemic compounds, but also, and preferably, to the production of optically active compounds in R and S form, because the configuration of the 2-carbon of the propyl moiety is maintained in the above reactions.
Compounds of formula I are, by virtue of e.g. the hydroxy group, useful intermediates for the production of pharmaceutically active compounds and are particularly useful in the production of optically active and racemic I - amino - 3 - aryloxy 2 - propanols, e.g. of formula VII Ar. OCH2 . CH(OH) . CH2 . NHR, VII wherein Ar is an aryl group and R1 is as defined above.
Such agents are well-known in the art.
Aryl may be, for example, a monocyclic or bicyclic moiety e.g. of up to 10 carbon atoms, e.g. phenyl or naphthyl, and may contain one or two heteroatoms, e.g.
nitrogen as in indolyl or nitrogen and/or sulphur as in thiazolyl. The aryl moiety may also have ring substituents.
The aryl moiety may also have an alkyl chain between two adjacent carbon atoms thereby forming a saturated ring. For example, the aryl moiety nucleus may be tetralone or tetraline.
Conveniently the aryl radical does not contain a group sensitive to reactions under basic conditions, or else the group is temporarily protected.
Suitable aryl radicals Ar are: a) 4 - Indolyl, optionally substituted in position 2 by methyl; b) Phenyl optionally substituted, e.g. by carbamoylmethyl, allyl in position 2,3 or 4,2 - allyloxy, 2 - cyano, 2 - chloro - 5 methyl, 2 - chloro, 3,4 - dichloro, 2.5 dichloro, 2 - ethinyl, 2 - - chloroallyl, 2 cis - y - chloroallyl, methyl in position 2,3 or 4, 2,3 - dimethyl, 3,5 - dimethyl, 2 bromo, 2 - propinyloxy, 2 - hydroxymethyl, 2 - methyl - 3 - nitro, 2 - phenoxy, methoxy in position 2, 3 or 4, methanesulphonamido, 3 - cyclo hexylureido, 2 - methylthio, 2 - or 3 tetrahydrofurfuryloxy, 3 - n - butinyloxy, 2- cyclopropyl, 2- cyclopentyl, 4 methoxyethyl c) 2,3 - dimethyl - 4 - benzo[b]furyl; d) 1 - naphthyl or 5,8 - dihydro - 1 naphthyl; e) 1, 2, 3,4 - tetrahydro - 1,4 - ethano 5 - naphthyl; f) 8 - thiochromanyl; g) 4 - indanyl; h) 7 - indenyl; i) 2,3 - dihydro - 1 - (2H) - oxo - 5 naphthyl; j) Cis - 2,3 - dihydroxy - l,2,3A - tetrahydro - 8 - naphthyl, and k) I' - oxo - 4 - spiro (cyclohexane 1,2' - indanyl).
Particularly preferred aryl radicals Ar are 4 - indolyl and 2 - methyl - 4 - indolyl.
Compounds of the following formula IX and their use in the production of the compounds of formula VII, wherein Ar is indol - 4 - yl or 2 - methylindole - 4 - yl and R1 is isopropyl or tert-butyl, and esters thereof, is claimed in Divisional Application No. 8020036 (Patent Specification No.
1598668).
A compound of formula VII may, for example, be obtained by a process which comprises a) either (i) condensing a compound of formula I as defined above with a compound of formula VIII At 7' VIII wherein Ar is an aryl radical and Z' is a leaving group to produce a compound of formula IX
wherein Ar is as defined above and X and R1 are as defined above, or (ii) introducing a leaving group Z" into a compound of formula I as defined above to form a compound of formula X
wherein R1 and X are as defined above and Z" is a leaving group, which is then condensed with a compound of formula XI Ar-OH XI wherein Ar is as defined above, to produce a compound of formula IX defined above, and b) splitting off the group
from the resulting compound of formula IX.
Step a) may be effected in conventional manner. It is to be appreciated that Z' and Z" will be appropriately chosen bearing in mind the nature of the compounds used in step i) and step ii) respectively. Z' and Z" may be, for example, chloro, bromo or iodo or especially mesyloxy or tosyloxy. Z' may alternatively be fluoro, or iodosyl. Z' may be nitro when Ar is an aryl radical activated by another nitro substituent. If desired the compound VIII may be alternatively an aryl-diazonium salt.
Step b) defined above may be effected in conventional manner, e.g. under basic conditions, e.g. with an alkali metal hydroxide. Alternatively strong acidic or reductive conditions, where appropriate, may be used.
If desired the hydroxy group of the resultant 1 - amino - 3 - aryloxy - 2propanol may be esterified, e.g. by an aryl carboxylic acid, an aliphatic carboxylic acid or an alicyclic carboxylic acid of, e.g., up to 10 carbon atoms.
It is also to be appreciated that if desired a radical R1 may be interconverted into another radical R1. For example a compound of formula VII or IX wherein R1 is hydrogen may be alkylated to produce a compound of formula VII or IX wherein R is alkyl.
The above process steps, in general, may lead to high yields of optically active or racemic products with the formation of few side products, or side products which may be easily removed using conventional purification procedures, e.g. cyrstallization, chromatography or distillation.
Naturally two or more of the above steps may be effected without isolating and/or purifying the intermediate product(s). It is, however, particularly convenient to isolate and purify the compounds of formula I, and to use directly without purification the compounds of formulae II, IX and X.
A particular advantage of this process is that when A is a hydrophobic group, then the intermediates of formulae III and IV are less water soluble than the corresponding diols with the result that working up of the reaction mixtures using extraction of aqueous solutions with organic solvents or washing of organic solutions with aqueous solvents is more efficient than with the corresponding diols. Such an advantage is particularly useful when the intermediates of formula III and IV are oils at room temperatures.
As indicated above the process is particularly useful for the production of optically active compounds. Thus 2S - I alkylamino - 3 - aryloxy - 2 - propanols, which in general are the more active optical isomers as regards beta - blocking activity may be produced in which case the intermediates have the following configuration:
Additionally a further advantage of the process when applied to the production of - - amino - 3 - aryloxy - 2 - propanols is that the last step, namely the splitting of the oxazolidinone or thiazolidinone, may be effected under a wide range of conditions, e.g. acidic, basic or reduction conditions.
In so far as the production of any compounds is not particularly described then this is known or may be prepared according to conventional methods.
The compounds of formula III above which are new form part of the present invention.
In the following examples all temperatures are in degrees Centigrade and are uncorrected. Unless otherwise mentioned all optical rotations are expressed as a 1% (w/v) solution in methanol. Examples 3 to 5, which do not fall under the scope of the present application, but fall under the scope of Divisional application No. 8020036, serve to illustrate the invention. Serial No. 1598668.
EXAMPLE 1 (5S)-5-Hydroxymethyl-3-isopropyl-2- oxazolidinone (Optically active compound of formula I wherein R1 is isopropyl and X is O) a) (4S)-4-Isopropylaminomethyl-2,2 dimethyl-1,3-dioxolane [Compound of for formula IV] 52.5 g of (4R) - 2,2 - dimethyl - 1,3 dioxolane - 4 - carbaldehyde in 400 ml methanol [obtained by treating 1,2,5,6 - diiso - propylidene - D - mannitol with lead tetracetatel are added dropwise to a suspension of 5.25 g of 10% palladium on - charcoal, 150 mil of methanol and 86 ml of isopropylamine in the presence of hydrogen over 2 hours. The mixture is hydrogenated overnight at 1 atmosphere.
The catalyst is filtered off and the methanol is distilled off. The residue is stirred for five minutes with a solution of 95 g of NazCO3 in 500 ml of water and is extracted thrice with methylene chloride. The organic phases are dried with Na2SO4 and the filtrate is concentrated by evaporation. The yellowish oil is subsequently distilled at 420 (0.1 mm Hg) to give the heading compound. [Ct]DO -7.2" (2% methanol).
b) N-[(4S)-2,2-Dimethyl-1,3-dioxolan-4- ylmethyll-N-isopropyl-carbamic acid ethyl ester [Compound of formula III] 150 g of (45) - 4 isopropylaminomethyl - 2,2 - dimethyl 1,3 - dioxolane are dissolved in 1.5 1 of methylene chloride and are cooled to 00. To this solution there are added dropwise during the course of one hour simultaneously 92 ml of ethyl chloroformate and 240 ml of 4N sodium hydroxide and the suspension is thoroughly stirred for 30 minutes at 00. The suspension is then made acid with cold 10% tartaric acid, the phases are separated and the aqueous phase is extracted thrice with methylene chloride.
The combined organic phases are shaken twice with cold 2N NaOH, washed with water, dried over Na2SO4 and concentrated by evaporation. Distillation of the residue yields pure N- [(4S)- 2,2 - dimethyl 1,3 - dioxolan - 4- ylmethyll - Nisopropylcarbamic acid ethyl ester B.P. 96" (0.6 mm Hg). [(r]0-19.2".
c) (2S)-N-(2,3-Dihydroxypropyl)-Nisopropylcarbamic acid ethyl ester [Compound of formula II] 115.7 g of N - [(4S) - 2,2 - dimethyl - 1,3 dioxolan - 4 - ylmethyl] - N isopropylcarbamic acid ethyl ester are stirred in 500 ml of methanol and 115 ml of 4N HCI for two hours at 10 and are concentrated by evaporation in a vacuum.
(2S)- N- (2,3 - dihydroxypropyl) - N isopropylcarbamic acid ethyl ester is obtained, [a]0-19.9", which is further reacted in crude form.
d) (5S?-5-Hydroxymethyl-3-isopropyl-2- oxazolidinone 4N NaOH are added to 98.7 g of crude (2S)- N- (2,3 - dihydroxypropyl) - N - isopropylcarbamic acid ethyl ester until the pH is 13. The mixture is allowed to stand for 2 hours at 200 and then extracted thrice with methylene chloride. The organic phases are washed with 6M NaCI, dried over Na2SO4 and the solvent is distilled off.
The title compound is obtained (M.P. 56 590 - from methylene chloride/ether). [al020 + 491" Instead of ethyl chloroformate, either benzyl chloroformate or phenyl chloroformate may be used in step b) to produce the corresponding benzyl ester of formula III B.P. 130--133" (0.03 mm Hg) [a]020 20.10 (2% methanol) or phenyl ester of formula III B.P. 123--125" (0.1 mm Hg) [al020 -33.70, respectively, which may be further reacted according to steps c) and d) to produce the title compound of formula I.
EXAMPLE 2 (5S)-3-tert-Butyl-5-hydroxymethyl-2- oxazolidinone (Optically active compound of formula I wherein R, is tert-butyl and X is O).
In analogous manner to that described in example I the corresponding tert-butyl compound is made. Physical characteristics of products are:- step a) product B.P. 45 (0.1 mmHg). [&alpha;]D20 8.70; b) product [ethyl ester] B.P. 60 (0.1 mm Hg); [al20 1 ; c) product directly worked up d) product, M.P. 82--830 llo20 ±33.70.
EXAMPLE 3 (2S)- I -(indol-4-yloxy)-3-isopropylamino-2 propanol (Compound of formula VII) a) (SS)-3-isopropyl-5-tosyloxymethyl-2- oxazolidinone (Compound of formula X) 32.8 g of p - toluenesulphonyl chloride are added over 30 minutes to a solution of 24.8 g of (5S)- 5 - hydroxymethyl - 3 isopropyl - 2 - oxazolidinone in 60 ml of pyridine at -5 and are kept overnight at 00.
The mixture is poured onto ice, the oil is extracted with methylene chloride and the organic phases are washed with 2N HCI and water. After the phases have been dried over Na2SO4 the methylene chloride is removed and the residue is crystallized from methylene chloride/ether. (5S)- 3 Isopropyl- 5 - tosyloxymethyl- 2 oxazolidinone is obtained (M.P. 77-79 [a]20 +51.80.
b) (5S)-5-(Indol-4-yloxymethyl)-3-isopropyl- 2-oxazolidinone (Compound of formula IX) A solution of 17.4 g of 4 - hydroxyindole in 100 ml of N,N - dimethylformamide is added dropwise during one hour to a suspension of 6.3 g of sodium hydride (50% dispersion) and 50 ml of N,N dimethylformamide under argon. The temperature is kept below 35 . The suspension is stirred for 1.5 hours at room temperature, 41 g (5S) - 3 - isopropyl - 5 tosyloxymethyl - 2 - oxazolidinone in 50 ml of N,N - dimethylformamide are added dropwise and stirred at 800 overnight under argon. The suspension is poured onto ice and shaken with methylene chloride. The organic phases are washed with 2N NaOH and water, dried over Na2SO4 and concentrated by evaporation. The residue is crystallized from methylene chloride/ether.
(5S) - 5 - (Indol - 4 - yloxymethyl) - 3 isopropyl - 2 - oxazolidinone is obtained (M.P. 139-142 - from CH2CI2/ether).
[Q#]D +56.70.
c) (2S)-l -(1 ndol-4-yloxy)-3-isopropylamino- 2-propanol A suspension of 19.5 g of (5S) - 5 (Indol - 4 - yloxymethyl) - 3 isopropyl - 2 - oxazolidinone, 200 ml of ethanol and 180 ml of 4N NaOH are heated at reflux overnight, the solvent is distilled off and the residue is taken up in methylene chloride/water. The aqueous phase is extracted with methylene chloride. The combined organic phases are washed neutral with water, dried over Na2SO4 and concentrated by evaporation. The residue is crystallized from benzene. The title compound is obtained (M.P. 93-94.5 ).
[a]:L -7.8 (1% CHCl2). [a]2% 4.80 (1% methanol).
EXAMPLE 4 In analogous manner to that described in Example 1, 4S - 2,2 - dimethyl - 1,3 dioxolane - 4- carbaldehyde may be converted into (5R) - 5 - hydroxymethyl 3 - isopropyl - 2 - oxazolidinone which in turn may be converted in analogous manner to that described in Example 3 into (2R) I - (Indol - 4 - yloxy) - 3 isopropylamino - 2 - propanol. M.P. 93 95 ; []546 +7.7 (1% CHCl3). [a]54260 +4.8 (1, methanol).
EXAMPLE 5 In analogous manner to that described in Example 4, racemic 2,2 - dimethyl - 1,3 dioxolane - 4- carbaldehyde may be converted into racemic 1 - (Indol - 4yloxy)- 3 - isopropyl - amino - 2propanol. M.P. 171-173 (from ethanol).
EXAMPLE 6 In analogous manner to that described in Example 3, (5S)- 3 - tert - butyl- 5hydroxymethyl - 2 - oxazolidinone may be reacted with p- toluene- sulphonyl chloride to produce the tosylate thereof (M.P. 117-I 190) which is then reacted with 4' - hydroxy - spiro(cyclohexane - 1,2' indan) - 1' - one to produce at the product of step c) (2S) - 4' - (3 - tert - butylamino 2- hydroxypropoxy)spiro(cyclohexane 1,2' - indan) - 1' - one M.P. 64-66 (hydrogen maleate solvate salt form, from ethanol/ether); [&alpha;]D20 -12.0 (2% in CHCl3).
WHAT WE CLAIM IS: 1. A process for the production of a compound of formula II HO . CM2. CH(OH) . CM2. NR1 . C(=X) . R2 II wherein R, is inert group, X is oxygen or sulphur, and R2 is a leaving group.
which comprises splitting off the protecting group A from a compound of formula III
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (32)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    of products are:- step a) product B.P. 45 (0.1 mmHg). [&alpha;]D20 8.70; b) product [ethyl ester] B.P. 60 (0.1 mm Hg); [al20 1 ;
    c) product directly worked up d) product, M.P. 82--830 llo20 ±33.70.
    EXAMPLE 3 (2S)- I -(indol-4-yloxy)-3-isopropylamino-2 propanol (Compound of formula VII) a) (SS)-3-isopropyl-5-tosyloxymethyl-2- oxazolidinone (Compound of formula X) 32.8 g of p - toluenesulphonyl chloride are added over 30 minutes to a solution of 24.8 g of (5S)- 5 - hydroxymethyl - 3 isopropyl - 2 - oxazolidinone in 60 ml of pyridine at -5 and are kept overnight at 00.
    The mixture is poured onto ice, the oil is extracted with methylene chloride and the organic phases are washed with 2N HCI and water. After the phases have been dried over Na2SO4 the methylene chloride is removed and the residue is crystallized from methylene chloride/ether. (5S)- 3 Isopropyl- 5 - tosyloxymethyl- 2 oxazolidinone is obtained (M.P. 77-79 [a]20 +51.80.
    b) (5S)-5-(Indol-4-yloxymethyl)-3-isopropyl- 2-oxazolidinone (Compound of formula IX) A solution of 17.4 g of 4 - hydroxyindole in 100 ml of N,N - dimethylformamide is added dropwise during one hour to a suspension of 6.3 g of sodium hydride (50% dispersion) and 50 ml of N,N dimethylformamide under argon. The temperature is kept below 35 . The suspension is stirred for 1.5 hours at room temperature, 41 g (5S) - 3 - isopropyl - 5 tosyloxymethyl - 2 - oxazolidinone in 50 ml of N,N - dimethylformamide are added dropwise and stirred at 800 overnight under argon. The suspension is poured onto ice and shaken with methylene chloride. The organic phases are washed with 2N NaOH and water, dried over Na2SO4 and concentrated by evaporation. The residue is crystallized from methylene chloride/ether.
    (5S) - 5 - (Indol - 4 - yloxymethyl) - 3 isopropyl - 2 - oxazolidinone is obtained (M.P. 139-142 - from CH2CI2/ether).
    [Q#]D +56.70.
    c) (2S)-l -(1 ndol-4-yloxy)-3-isopropylamino- 2-propanol A suspension of 19.5 g of (5S) - 5 (Indol - 4 - yloxymethyl) - 3 isopropyl - 2 - oxazolidinone, 200 ml of ethanol and 180 ml of 4N NaOH are heated at reflux overnight, the solvent is distilled off and the residue is taken up in methylene chloride/water. The aqueous phase is extracted with methylene chloride. The combined organic phases are washed neutral with water, dried over Na2SO4 and concentrated by evaporation. The residue is crystallized from benzene. The title compound is obtained (M.P. 93-94.5 ).
    [a]:L -7.8 (1% CHCl2). [a]2% 4.80 (1% methanol).
    EXAMPLE 4 In analogous manner to that described in Example 1, 4S - 2,2 - dimethyl - 1,3 dioxolane - 4- carbaldehyde may be converted into (5R) - 5 - hydroxymethyl 3 - isopropyl - 2 - oxazolidinone which in turn may be converted in analogous manner to that described in Example 3 into (2R) I - (Indol - 4 - yloxy) - 3 isopropylamino - 2 - propanol. M.P. 93 95 ; []546 +7.7 (1% CHCl3). [a]54260 +4.8 (1, methanol).
    EXAMPLE 5 In analogous manner to that described in Example 4, racemic 2,2 - dimethyl - 1,3 dioxolane - 4- carbaldehyde may be converted into racemic 1 - (Indol - 4yloxy)- 3 - isopropyl - amino - 2propanol. M.P. 171-173 (from ethanol).
    EXAMPLE 6 In analogous manner to that described in Example 3, (5S)- 3 - tert - butyl- 5hydroxymethyl - 2 - oxazolidinone may be reacted with p- toluene- sulphonyl chloride to produce the tosylate thereof (M.P. 117-I 190) which is then reacted with 4' - hydroxy - spiro(cyclohexane - 1,2' indan) - 1' - one to produce at the product of step c) (2S) - 4' - (3 - tert - butylamino 2- hydroxypropoxy)spiro(cyclohexane 1,2' - indan) - 1' - one M.P. 64-66 (hydrogen maleate solvate salt form, from ethanol/ether); [&alpha;]D20 -12.0 (2% in CHCl3).
    WHAT WE CLAIM IS: 1. A process for the production of a compound of formula II HO . CM2. CH(OH) . CM2. NR1 . C(=X) . R2 II wherein R, is inert group, X is oxygen or sulphur, and R2 is a leaving group.
    which comprises splitting off the protecting group A from a compound of formula III
    wherein A is protecting group, and Rl, R2 and X as defined above.
  2. 2. A process for the production of a compound of formula III
    wherein A is protecting group, and R1, R2 and X are as defined in claim 1 which comprises reacting a compound of formula IV
    wherein A and R, are as defined in claim 1 with compound of formula V Y.C(=X).R2 V wherein R2 and X are as defined in claim 1 and Y is a group capable of being split off with the hydrogen of an amine.
  3. 3. A process according to claim 2 wherein the compound of formula IV is obtained by reductively aminating a compound of formula VI
    wherein A is as defined in claim 1.
  4. 4. A process according to any one of claims 1 to 3 wherein A is isopropylidene.
  5. 5. A process according to any one of the preceding claims wherein X is O.
  6. 6. A process according to any one of claims 1 to 4, wherein X is S.
  7. 7. A process according to any one of the preceding claims wherein R1 is alkyl (C3.7) or phenyalkyl, phenoxyalkyl or phenylthioalkyl of 8 to 11 carbon atoms wherein the phenyl ring is separated from the nitrogen atom by at least 2 carbon atoms.
  8. 8. A process according to any one of the preceding claims wherein R1 is isopropyl.
  9. 9. A process according to any one of claims 1 to 7 wherein R1 is tert-butyl.
  10. 10. A process according to any one of the preceding claims wherein the compound produced is in optically active form containing the moiety:
  11. 11. A process for the production of a compound of formula II as defined in claim 1 substantially as hereinbefore described with reference to Example 1.
  12. 12. A process for the production of a compound of formula III as defined in claim 2 substantially as hereinbefore described with reference to Example I.
  13. 13. A compound of formula II when obtained by a process of any one of (i) claim 1, (ii) claim 4 to 10 when dependent directly or indirectly upon claim 1, and (iii) claim 11.
  14. 14. A compound for formula III when obtained by a process of any one of (i) claim 2, and (ii) claims 3 to 10 when dependent directly or indirectly upon claim 2, and (iii) claim 12.
  15. 15. A process for the production of a compound of formula I
    wherein X and R1 are as defined in claim 1 which includes the step of intramolecularly cyclizing a compound of formula II as claimed in claim 13.
  16. 16. A compound of formula I whenever prepared by a process according to claim 15.
  17. 17. A compound of formula I
    wherein X and R1 are as defined in claim I whenever prepared using as an intermediate a compound of formula III as defined in claim 1.
  18. 18. A compound of formula I
    wherein X and R1 are as defined in claim 1 whenever prepared using as an intermediate a compound of formula III as defined in claim 14.
  19. 19. A process for the production of a 1 amino - 3 - aryloxy - 2 propanol other than a compound of formula Ara-OCII2CH(OH)CH2NH-Ra wherein Ara is indol-4-yl or 2-methylindol-4-yl and Ra is isopropyl or tert-butyl, which comprises A) splitting off the protecting group A from a compound of formula III
    wherein A, X, R1 and R2 are as defined in claim 1 to produce a compound of formula ii HO . CH2. CH(OH) . CH2. NR1. .C(=X). R2 II wherein X, R1 and R2 are as defined in claim I, B) intramolecularly cyclizing a compound of formula II so obtained to produce a compound of formula I
    wherein X and R1 are as defined in claim 1, C) either (i) condensing the so obtained compound of formula I with a compound of formula VIII Ar-Z' III wherein Ar is an aryl radical other than indol-4-yl or 2-methylindol-4-yl when R1 is isopropyl or tert-butyl and Z' is a leaving group to produce a compound of formula IX
    wherein Ar is as defined above and X and R1 are as defined in claim 1, or (ii) introducing a leaving group Z" into the so obtained compound of formula I to form a compound of formula X
    wherein R1, and X are as defined above, and Z" is a leaving group, which is then condensed with a compound of formula XI Ar-OH wherein Ar is as defined above, to produce a compound of formula IX defined above, and D) splitting off the group
    from the resulting compound of formula IX.
  20. 20. A process according to claim 19 wherein the aryl group is 1 - oxo - 4spiro(cyclohexane - 1,2 - indanyl), 2,3 - dihydro - I(2H) - oxo - 5 - naphthyl, 1 naphthyl, or 5,8 - dihydro - 1 - naphthyl.
  21. 21. A process for the production of a I amino - 3 - aryloxy - 2 - propanol other than a compound of formula AraOCH2CH(OH)CH2NHRnx wherein Ara is indol - 4 - yl or 2 - methylindol 4 - yl and Ra is isopropyl or tert-butyl, substantially as hereinbefore described with reference to Example 6.
  22. 22. A 1 - amino - 3 - aryloxy - 2propanol other than a compound of formula Ara-OCH2CH(OH)CH2NH-Ra, wherein Ara is indol - 4 - yl or 2 - methylindol 4 - yl and Ra is isopropyl or tert-butyl, whenever produced by a process according to any one of claims 19 to 21.
  23. 23. A compound of formula IX whenever prepared by process step C as set forth in claim 19.
  24. 24. A compound of formula III
    wherein A, R1, R2 and X are as defined in claim 1.
  25. 25. A compound of claim 24 wherein X is 0.
  26. 26. A compound of claim 24 or 25 wherein R1 is isopropyl or tert-butyl.
  27. 27. A compound of claim 24, 25 or 26 wherein A is alkylidene (C1-C5).
  28. 28. A compound of claim 24, 25, 26 and 27 wherein R2 is alkoxy (C1-C4),
  29. 29. A compound of any one of claims 22 to 28 in optically active form containing the configuration:
  30. 30. A 1 - amino - 3 - aryloxy - 2 - propanol other than a compound of formula Ara-OCH2CH(OH)CH2NH-Ra wherein Ar is indol - 4 - yl or 2 - methylindol 4 - y! and Ra is isopropyl or tert-butyl, obtained using a compound of any one of claims 23 to 28.
  31. 31. An esterified 1 - amino - 3 aryloxy - 2 - propanol other than an ester of a compound of formula Ar8-OCH2CH(OH)CH2NH-Ra, wherein Ara is indol - 4 - yl or 2 - methylindol 4 - yl and Ra is isopropyl or tert-butyl, whenever obtained by esterifying the hydroxy group of a corresponding 1 - amino - 3 - aryloxy - 2 - propanol of claims 22 or 30.
  32. 32. A compound of claims 30 or 31 having the 2S - configuration.
GB11113/78A 1977-03-24 1978-03-21 1,3-dioxolane derivatives and their use in the preparation of 1-amino-3-aryloxy-2-propanols Expired GB1598667A (en)

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CH375477A CH635573A5 (en) 1977-03-24 1977-03-24 Process for preparing novel 1,2-dihydroxypropane derivatives

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GB11113/78A Expired GB1598667A (en) 1977-03-24 1978-03-21 1,3-dioxolane derivatives and their use in the preparation of 1-amino-3-aryloxy-2-propanols

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US4777293A (en) * 1984-08-13 1988-10-11 Aktiebolaget Hassle Method for the synthesis of pharmacologically active compounds and intermediates for such synthesis

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JPS577465A (en) * 1980-06-13 1982-01-14 Paamakemu Asia:Kk Preparation of indole derivative
JPS574969A (en) * 1980-06-13 1982-01-11 Paamakemu Asia:Kk Preparation of indole derivative
JPS5973223U (en) * 1982-11-06 1984-05-18 ブラザー工業株式会社 Jusa
JPS59227238A (en) * 1983-06-06 1984-12-20 Tetsuya Nishikura Rot-proof paste food and its preparation
DE3330005A1 (en) * 1983-08-19 1985-02-28 Wolfgang Dr. Graz Lindner TONIC ACID MONOESTERS OF OPTICALLY ACTIVE ALKANOLAMINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE
JPS60261586A (en) * 1984-06-09 1985-12-24 Fuiruton Internatl Kk Method for removing metal, metallic ion, and organic chlorine from water
JPS61192268A (en) * 1985-02-19 1986-08-26 Yagira Suisan:Kk Preparation of boiled fish paste having taste and flavor of sushi
CH674843A5 (en) * 1988-01-26 1990-07-31 Lonza Ag
SE8801518D0 (en) * 1988-04-22 1988-04-22 Astra Pharma Prod A NOVEL PROCESS
US7390825B1 (en) * 2001-10-18 2008-06-24 Board Of Trustees Of Michigan State University Process for the preparation of oxazolidinones and method of use thereof

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CH572924A5 (en) * 1972-04-19 1976-02-27 Frosst & Co Charles E Thiadiazole derivs - for treating angina pectoris
GB1435276A (en) * 1974-04-10 1976-05-12 Pfizer Ltd Oxazolidines and conversion to propanolamines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4777293A (en) * 1984-08-13 1988-10-11 Aktiebolaget Hassle Method for the synthesis of pharmacologically active compounds and intermediates for such synthesis

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FR2401148A1 (en) 1979-03-23
CH639953A5 (en) 1983-12-15
JPS579781A (en) 1982-01-19
IT1104182B (en) 1985-10-21
JPS5716853A (en) 1982-01-28
GB1598668A (en) 1981-09-23
NL7802986A (en) 1978-09-26
DE2810732A1 (en) 1978-09-28
CH635573A5 (en) 1983-04-15
CH642646A5 (en) 1984-04-30
BE865201A (en) 1978-09-22
FR2401148B1 (en) 1983-01-28

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