AU6774987A

AU6774987A - Synthesis of aryloxypropanolamines and arylethanolamines

Info

Publication number: AU6774987A
Application number: AU67749/87A
Authority: AU
Inventors: Khuong H.X. Mai; William L. Matier; Ghanshyam Patil
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1985-12-04
Filing date: 1986-11-14
Publication date: 1987-06-30
Anticipated expiration: 2006-11-14
Also published as: AU5756290A; EP0248879A4; AU631433B2; AU604005B2; CA1282787C; WO1987003583A1; EP0248879A1; JPS63502585A; ZA868713B

Description

SYNTHESIS OF ARYLOXYPROPANOLAMINES AND ARYLETHANOLAMINES

BACKGROUND OF THE INVENTION

Aryloxypropanolamines and arylethanolamines are widely used therapeuttc agents, particularly those compounds possessing potent betaadrenergic receptor blocking activity. These beta-adrenergic blocking agents are widely used for a number of cardiovascular therapeutic indications, such as hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction and more recently in the treatment of glaucoma. In addition, certain ary loxypropanolamines possess potent beta-adrenergic stimulating properties and such compounds are used as cardiac stimulants.

Among beta-blocker oxypropanolamines, the R isomers are less active or essentially devoid of beta-blocking activity as compared to their counterpart S isomers. Similarly, the R-isomer beta-agonists are more potent agents than their S-isomer counterparts.

Conventional methods for preparing such compounds util ize the nonselective mesylation or tosylation of the diol 3 followed by the separation of monomesyIate or monotosylate 4a from the undesirable dimesylate or ditosylate 4b. Subsequently, the monomesylate or tosylate is transformed into an epoxide which is then treated with the corresponding amine to provide the desired beta-blocker in separate stages. Such a procedure is described by Tsuda et al. in CHEM. PHARM. BULL. 29 (12) 3593-3600 (1981). In such a procedure, to prepare monotosylate, p-toluenesufonyI chloride (p-TsCI) is used, which is not a very selective reagent and significant quantities of undesirable ditosylate are also formed. This considerably reduces the yield of the desired monotosylate and, generally, extensive purification of the mixture is required in order to obtain the monotosylate. Frequently this is not possible in a large scale manufacturing process and this process is uneconomical as a means to obtain isomers. An efficient and an economical process for preparing the separate isomers is therefore highly desirable.

4a, R=Ms or Ts, R¹=H 4b, R=R¹ = Ms or Ts

SUMMARY OF THE INVENTION

In accordance with the present invention, disclosed is a process for preparing a racemic or chiral aryloxypropanolamine (1) or arylethanolamine (2) of the formula

wherein Ar is aryl, substituted aryl, heteroaryl, or aralkyl and R is alkyl, substituted alkyl, aralkyl, or WB wherein W is a straight or branched chain alkylene of from 1 to about 6 carbon atoms and wherein B is -NR₂COR₃, -NR₂CONR₃R₄, -NR₂SO₂R₃, -NR₂SO₂NR₃R₄, or -NR₂COOR₅, where R₂, R₃, R₄, and R₅ may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R₃ and R₅ are not hydrogen when B is -NR₂SO₂R₃ or -NR₂COOR₅, or R₃ and R₄ may together with N form a 5- to 7-membered heterocycl ic group.

As an example, the method involves the utilization of trisubstituted phosphonlum hal ides such as R₃P/CCI₄ as selective chlorinating agents to provide the monochloro derivative 5.

The chlorohydrin 5 is then converted into the aryloxypropanolamine 2 in the same reaction vessel or in separate steps as desired. It is noted that the undesirable dichloro intermediate 6 is not formed or formed in insignificant amounts in this reaction. The method does not cause racemization of the optically active intermediate or final product and produces high purity chiral products. No complex separation steps are required to isolate a particular isomer. the three consecutive steps in the process may be performed in a single reaction vessel if desired. This makes the process much more efficient. Moreover, the method allows the use of economical starting materials.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, disclosed is a process for preparing optically active ary loxypropanolamines (1) or aryIethanolamines (2) of the formula

wherein Ar is aryl, substituted aryl, heteroaryl or aralkyl and R is alkyl, substituted alkyl, aralkyl, or WB wherein W ts a straight or branched chain alkylene of from 1 to about 6 carbon atoms and wherein B represents -NR₂COR₃, -NR₂CONR₃R₄, -NR₂SO₂R₃, -NR₂SO₂NR₃R₄, or -NR₂COOR₅ wherein R₂, R₃, R₄ and R₅ may be the same or different and may be hydrogen, alkyl of from 1 to about 10 carbon atoms and preferably from 1 to about 6 carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to about 10 carbon atoms and preferably fron 1 to about 6 carbon atoms; cycloalkyl of from 3 to about 8 carbon atoms, alkenyl of from 3 to about 10 carbon atoms, alkoxyaryl wherein the alkyl group contains from 1 to about 6 carbon atoms, alkynyl of from 3 to about 10 carbon atoms, aryl which includes substituted or unsubstituted monocyclic or polycyclic aromatic or heterocyclic ring systems of from 6 to about 10 carbon atoms such as phenyl, thienyl, imidazole, oxazole, indole, and the I ike, or aralkyl wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion represents substituted or unsubstituted monocyclic or polycyclic aromatic or heterocyclic ring systems of from 2 to about 10 carbon atoms such as benzyl, phenethyl, 3,4-dimethoxyphenethyl, 1,1-dimethyl-2-(3-lndolyl)ethyI and the like; except that R₃ and R₅ are not hydrogen when B is -NR₂SO₂R₃ or -NR₂COOR₅, or R₃ and R₄ may together with N form a 5- to 7-membered heterocycl ic group such as pyrrolidine, piperidine, piperazine, morpholine, or thiomorpholine.

As used herein, the term "aryl" represents a phenyl or naphthyl group which may be unsubstituted or substituted with alkyl of from 1 to about 6 carbon atoms, alkenyl of from 2 to about 6 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms, halo, acetamido, amino, amido, nitro, alkyIamino of from 1 to about 6 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about 6 carbon atoms, cyano or aryIalkoxy wherein the alkyl group contains form 1 to about 6 carbon atoms and the aryl group is substituted or unsubstituted phenyl.

The term "heteroaryI" as used herein represents pyridine, pyrazine, pyrrole, pyrazole, piperazine, thiophene, benzothiophene, furan, benzofuran, Imldazole, oxazole, indole, carbazole, thiazole, thiadiazole, benzothiadiazole, triazole, tetrazole, azepine, 1, 2-diazepine, or 1,4-thiazepine. Preferably, the heteroaryl is selected from the group consisting of pyridine, pyrazine, thiophene, benzothfophene, benzofuran, indole, carbazole, thiadiazole or benzothiadiazole, with the most preferred being pyrazine, indole, 1,2, 5-thiadiazole, or benzofuran. The term "heterocyclic" as used herein represents pyrrolidine, piperidine, morphol ine, or thiomorphol ine.

In the term "aralkyl" as used herein, the alkyl group contains from about 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstltuted monocyclic or polycyclic aromatic or heterocycl ic ring systems of from 5 to about 10 carbon atoms, such as benzyl, phenethyl, 3,4-dimethoxyphenethyl, 1,1-dimethyl-2-(3-indolyl)-ethyI and the l ike. Aromatic (Ar) substituents may include lower alkyl of from 1 to about 10 carbons atoms, alkenyl of from 2 to about 10 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 to about 10 carbon atoms, halo, acetamido, amino, nitro, alkyIamino of from 1 to about 10 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about 10 carbon atoms, cyano, aryIalkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstituted phenyl and groups of the formula

R₄-O-C-A wherein R₄ is lower alkyl, aryl or aralkyl and A is a direct bond, alkylene of from 1 to about 10 carbon atoms or alkenylene of from 2 to about 10 carbon atoms.

The term "cycloalkyl" as used herein refers to cycl ic saturated al iphatic radicals containing 3 to 6 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyI.

The method involves the utilization of trisubstituted phosphonium hal ide, namely the R₃P/CX₄ complex as selective halogenating agents, an example being the use of Ph₃P/CCl₄ as selective chlorinating agents to provide the monochloro derivative, which is then converted into the aryloxypropanolamine. The complete process can be performed in one reaction vessel to avoid having to isolate and purify intermediates, or can be performed stepwise. The method can be used in the synthesis of beta agonists or beta-bIockers or any halohydrin intermediate. In the R₃-phosphines, as used herein R represents alkyl, aryl, cycloalkyl, alkylamino, aminoalkyl, cycloalkyl, amino or amino cycloakyl. X represents halo, namely chloro, bromo or iodo.

The arylethanolamines can be prepared as follows, all in a single reaction vessel. Aryl 1,2-ethanediol can be converted to the corresponding chlorohydrln by reacting it with Ph₃P and CCI₄ in acetonitriIe. The resulting chlorohydrin then can be cycl ized to an epoxide by treating it with one equivalent of sodium methoxlde. The aryiethanolamine can then be obtained by treating the epoxide with one equivalent of amine.

The following reaction schemes summarize the process of the present invention.

Referring to Scheme 1, the racemic, the (R)-(+) or S-(-) 3-(aryloxy)-1,2- propanediol (1) can be made by known methods. For example, the S-enantiomer can be prepared readily by reacting an appropriate phenoxide with R-(-)-2,2-dimethyl-4-(hydroxymethyl)-1,3- dioxolane methanesulfonate or p-toluene-sulfonate, followed by acid hydrolysis of the ketal.

The aryloxypropanolamine (4) can be made by mixing in the same reaction vessel, in the following named order, the 3-(aryloxy)-1,2- propanediol (1) with a trisubstituted phosphonium hal ide to prepare the aryl substituted halohydrin (2) which, unless desired, need not be isolated. A suitable base is then added to prepare the epoxide which, likewise, need not be isolated. A selected amine is then added to prepare the desired aryloxypropanolamine.

A suitable base for reaction with the halohydrin would be a metal alkoxide, metal hydroxide, metal hydride, metal carbonate or metal bicarbonate wherein the metal is sodium, potassium or calcium, or an ammonium hydroxide or a suitable organic base. Preferred organic bases are pyridine, dlmethylaminopyridine, dimethylaniI ine, quinol ine,

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4,3.0]non- 5-ene (DBN) or tertiary alkyIamines. Preferred bases are sodium or potassium methoxide, ethoxide or t-butoxide or a tertiary alkyl amine.

The following beta-adrenergic blocking agents, beta-agonists and partial agonists are representative of the compounds that can be made using the described process:

_°

Compound

Bevantolol

Bisprolol

Bometolol

Bornaprolol

Bucindolol

Bucumolol

Bufetolol Compound

Bunitrolol

Bunalol

Bupranolol

Butocrolol

Butofilolol

Carazolol

Carteolol

Carvedilol Compound

Celiprolol

Cetamolol

Chinoin-103

Cidoprolol

Cloranolol

Diacetolol

Exaprolol Compound IPS-339

Indenolol

Indopanolol

Isoxaprolol

Levobunolol

Mepindolol

Metipranolol Compound nvJ Metoprolol

Moprolol

Nadolol

Nafetolol

Oxprenolol

P^acrinolol

Pafenolol Pamatolol Compound

Pargolol

Penbutolol

Pindolol

Pirepolol

Practolol

Prenalterol

Prizidilol

Procinolol Compound

Propranolol

Spirendolol

Teoprolol

Tertatolol

Timolol

Tiprenolol

Tolamolol

Xibenolol

Xamoterol Miscellaneous Beta-Blockers Compound

Arotinolol

Bopindolol

In order to illustrate the manner in which the above compounds may be made, reference is made to the following examples, which, however, are not meant to Iimit or restrict the scope of the invention in any respect.

EXAMPLE 1

Preparation of (S)-(-) Methyl 3-[4-[[2-hydroxy-3(isopropylamine)propoxy]phenyl]propionate Hydrochloride

A mixture of (S)-(-)MethyI 3-[4-(2,3-dIhydroxypropoxy)phenyl] propionate (74 g, 0.29 mole), triphenyIphosphine (85 g, 1.1 mole) and carbon tetrachIoride (140 mL) in 400 mL acetonitrile was stirred at 22° C for 16 hours. Another 8.5 g of triphenylphosphine was added and stirring was continued for another 3 hours. If desired, the product 2 can be isolated at this stage. The clear solution was cooled in an iceisopropanol bath and to this was added dropwise 62.8 gms. of 25% sodium methoxide solution in methanol over 30 minutes. The Ice bath was removed and the solution was stirred at 22° C for 20 hours. To this solution was added 50 mL of isopropylamine and the mixture was refluxed for 4 hours. The reaction mixture was evaporated to dryness. The sol Idlf ted mixture was liquified, treated with 1000 mL ether, and filtered over eel Ite. The filtrate was treated with hydrogen chloride for 5 minutes (pH = 2) and immediately the oil began to separate. This oil was isolated by decanting the ethereal layer. This process was repeated three times using 250 mL ether and the oil was solidified. The solid was recrystaiIized from methyl ethyl ketone (MEK)/ether (200 mL/35 mL) to give white crystalline product (28.6 g, 29.7%), mp 91-94° C, -19.1 (C 1, MeOH).

Anal. Cal. for C₁₆H₂₆CINO₄ Cal : C, 57.91; H, 7.90; N, 4.22

Found: C, 57.98; H, 7.91; N. 4.13

EXAMPLE 2

Preparation of S-(+)-Methyl 3-[4-(2.3-epoxypropoxy)phenyl]propIonate

A mixture of S-(-)-Methyl 3-[4-2,3-dIhydroxypropoxy)phenyl]propionate (50.8 g, 0.2 mole), triphenyIphosphine (58 g, 0.22 mole), and carbon tetrachloride (100 g, 0.65 mole) In 500 mL acetonltrlle was stirred at 22° C for 24 hours. To the solution was added anhydrous potassium carbonate (40 g, 0.3 mole) and the mixture was refluxed with stirring for 48 hours. The mixture was evaporated to dryness to give an oil, which was sol idified immediately. To this was added 600 mL hexane and the mixture was refluxed with vigorous stirring for 10 minutes and decanted while It was hot. This procedure was repeated four times. The decanted solution was cooled to 22º C and trlphenyIphosphine oxide was filtered off. The hexane solution was evaporated to give an oil (29 g) which was distilled under reduced pressure to give 22.5 g (47.3%) of the titled compound as a clear oil, b.p. 150° (0.1 mm Hg), +7.9 (C 0.66, MeOH). EXAMPLE 3

Preparation of (SW-)-Methyl 3-[4-2-hydroxy-3igopropylaιtιine)propoxy]phenyl]propIonate Hydrochlorida

A solution of (S)-(+)-MethyI 3-[4-(2,3-epoxypropoxy)pheny Gproplonate (22 g, 92.7 mmole) and isopropylamine (50 mL) in 50 mL methanol was refluxed for 2 hours and evaporated to dryness. The oily residue was redissolved in 100 mL methanol and the solution was evaporated. This procedure was repeated twice to el iminate traces of isopropylamine. The clear oil was dissolved in 200 mL methyl ethyl ketone, acified with hydrogen chloride, treated with 100 mL ether, seeded and allowed to stand at 22° C for 16 hours. The white crystalIine sol id was filtered, washed with ether followed by hexane and air dried to yield 21.6 g (70%) of the titled product, mp 91-95° C, -19.3 (C 1, MeOH).

Anal. for C₁₆H₂₆CINO₄ Cal: C, 57.91; H, 7.90; N, 4.22

Found: C, 57.99; H, 7.79; N, 4.14 EXAMPLE 4

Preparation of levo-Propranolol HCI or (S)- (-)[(3-Isopropylamino-2chIoro)propoxy]napthaIene HydrochIoride

(1) Ph₃P/CCl₄/CH₃CN (2) NaOCH₃/CH₃OH

(3) H₂N

(4) HCI

A solution of (S)-(-)-1-(2,3-dihydroxypropoxy)-napthalene (10.9 g, 0.05 mole), triphenyIphosphine (14.4 g, 0.055 mole) and carbon tetrachloride (10.5 mL, 2.2 equiv.) in dry acetonitrile (dried over 3A Mol-sieve) was stirred at 22° C. Within 5 minutes this mixture became a clear, homogenous solution. Stirring was continued for 20 hours at 22° C and the mixture was then placed in an ice bath. To this was added 11.4 mL of 25% solution of sodium methoxide in methanol and the ice bath was removed and stirring continued for 16 hours at 22° C. The resulting mixture was diluted with 100 mL ethanol and treated with isopropylamine (10 mL, 2.4 equiv.) and refluxed for 2 hours. The reaction mixture was evaporated to dryness. The oily residue was taken up with ether (200 mL) and washed with water (2 x 200 mL) and then extracted with 1N hydrochloric acid (1 x 500 mL). The aqueous layer was washed with ether (1 x 200 mL), basified with 2N sodium hydroxide (pH = 10) and extracted with ether (2 x 200 mL). The ethereal layers were combined and acidified with hydrogen chloride until a pH of 2 was obtained. The precipitated crystalline mass was filtered, washed with ether and air dried to give 14.1 g (95.6%) of crude levo-propranolol. The crude product was recrystaiIized from isopropanol (200 mL) to give 6.62 g (44.9%) of crystalline product, mp

190-191° C (Lit. 189-190° C), -26.5 (C1, EtOH) (Lit: -25.5

(C1, EtOH)). Th e mother I iquor was treated with 200 mL ether to give 1.62 g (10%, mp 189-190° C) of more crystalline Ievo-propranolol. The above products were combined to give 55.9% yield from the diol.

NMR data:

Anal, for C₁₆H₂₀NO₂·HCI Cal: C, 65.17; H, 7.18; N, 4.75

Found: C, 64.87; H, 7.21; N, 4.81

EXAMPLE 5

Preparation of (R)-[(3-Chloro-2-hydroxy)propoxy]napthalene

A solution of (S)-(-)-1-(2,3-dihydroxypropoxy)-naphthalene (5.45 g.,

0.025 mole), 4-(diisopropylaminomethyl]triphenyIphosphine (10 g, 0.0226 mole), carbon tetrachloride (5 mL) in acetonitrile (100 mL) was stirred at 22° C for 18 hours. This clear yellow solution was passed through a dry silica gel pad (1.5 cm x 2 cm, 30 g) and eluted with acetonitrile (50 mL). The eluent was evaporated to give a yellow oil. This was treated with ispropyl ether (50 mL) and stirred for 15 minutes. The top layer was decanted and evaporated under reduced pressure to give the titled chlorohydrin as a clear oil (4.66 g, 78.8%). EXAMPLE 6

Preparation of (R)-Ethyl 3-[[(3-Chloro-2-hydroxy)propoxy] 1.2.5thiadiazol-4-yl]propionate

A solution of S-(-) ethyl 3-[3-(2,3-dihydroxy-propoxy) 1,2,5thiadiazol-4-yI]propionate (6.51 g, 0.025 mole), 4-(diisopropyIamtnomethyl) trlphenyIphosphine (10g, 0.0266 mole), carbon tetrachloride (5 mL) and acetonitrile (100 mL) was stirred at 22° C for 18 hours. This clear solution was passed through a dry siliea-gel pad (1.5 cm x 2 cm, 30 g) and eluted with acetonitrile (50 mL). The eluent was evaporated to give a yellow oil. This was then treated with isopropyl ether (50 mL) an the top layer was separated and evaporated under reduced pressure to give the titled product as a clear oil (5.56 g., 79.7%), Rf 0.38 (SiO₂, EtOAC: Hexane, 3:7), a single homogeneous spot. EXAMPLE 7

Preparation of (S)-(+)-EthyI 3-[3-(2.3-epoxypropoxy)-1.2.5-thiadlazol4-yl]propionate

A mixture of (S)-(-)-EthyI 3-C(2,3-dthydroxypropoxy)-1,2,5thiadiazoI-4-yl] proptonate (6.7g, 24,2 mmole), triphenyIphosphine (8.26 g, 1.3 equv.) and carbon tetrachloride (60 mL) was heated under reflux for 16 hours, and evaporated to dryness. The residue was mixed with methyl ethyl ketone (60 mL) and anhydrous potassium carbonate (7.0 g). This mixture was heated under reflux with vigorous stirring for 36 hours, cooled to 22° C and filtered. The filtrate was evaporated under reduced pressure and the residue was stirred vigorously in hexane (200 mL) for 15 minutes and the hexane layer was then decanted. This process was repeated twice; the organic layers were combined and evaporated under reduced pressure. The crude oil was distilled in vacuo to yield 1.9g (30.8%) of the titled esterepoxtde, b.p. 118-122° C (0.2 mm Hg), a²⁵ +25.3 (C 1.5, EtOH), Rf 0.45

(SI02, 1% MeOH in CH₂CI₂).

Claims

What is claimed is:

1. A method of preparing a racemic or chiral aryloxypropanolamine (1) or chiral aryIethanolamine (2) of the formula

wherein Ar is aryl, substituted aryl, heteroaryl, or aralkyl and R is alkyl, aryl, aralkyl, or WB wherein W is a straight or branched chain alkylene of from 1 to about 6 carbon atoms and wherein B is -NR₂COR₃, -NR₂CONR₃R₄, -NR₂SO₂R₃, -NR₂SO₂NR₃R₄, or -NR₂COOR₅, where R₂, R₃, R₄, and R₅ may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyi, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R₃ and R₅ are not hydrogen when B is -NR₂SO₂R₃ or -NR₂COOR₅, or R₃ and R₄ may together with N form a 5- to 7-membered heterocycl ic group, which method comprises:

mixing, in the named order, in a single reaction vessel, a selected racemic or chiral 3-(aryloxy)-1,2-propanediol or chiral aryl 1,2- ethanediol and trisubstituted phosphonium halide to prepare an aryl substituted halohydrin; a suitable base, to prepare an epoxide; and a selected amine to thereby prepare the desired aryloxypropanolamine or aryl ethanolamine.

2. A method of preparing an aryIoxy-2,3-epoxypropane or 1,2-epoxyethane which method comprises reacting a selected aryl substituted halohydrin with a base selected from the group consisting of metal alkoxtdes, metal hydroxides, metal hydrides, metal carbonates and metal bicarbonates wherein the metal is sodium, potassium or calcium, or ammonium hydroxide or suitable organic base.

3. The method of Claim 2 wherein the base is selected from the group consisting of metal alkoxldes, metal hydroxides, metal hydrides or tertiary alkyl amines.

4. The method of Claim 3 wherein the base is sodium or potassium methoxide, ethoxide or t-butoxide or a tertiary alkyl amine.

5. The method of Claim 3 wherein the base is sodium or potassium methoxide, ethoxide or t-butoxide or a tertiary alkyl amine.

6. The method of Claim 5 wherein the aryloxy-2,3-epoxy propane is alkyl 3-[4-[(2,3-epoxy) propoxy] pheny] proprlonate.

7. The method of Claim 6 wherein the aryloxy-2,3-epoxy propane is methyl 3-[4-[(2,3-epoxy) propoxy] pheny] proplonate.

8. A method of preparing an aryl substituted halohydrin which method comprises reacting a selected racemic or chiral 3-(aryloxy)-1,2- propanediol with a trisubstituted phosphonium hal ide.

9. The method of Claim 1 wherein the trisubstituted phosphonium hal ide comprises the R₃P/CX₄ complex wherein R represents alkyl, aryl, cycloalkyl, alkylamino, aminoalkyl, cycloalkyi, amino or amino cycloalkyl and X represents chloro, bromo or iodo.

10. The method of Claim 2 wherein the R₃P/CX₄ complex comprises triphenyIphosphine/carbon tetrachIoride.

11. The method of Claim 3 wherein the aryl substituted halohydrin is (R)-alkyl 3-[-4-[(2-hydroxy-3-chloro) propoxy] phenyl] proptonate and the propanediol is alkyl 3-[4-[2,3-(dihydroxy propoxy)] pheny] proptonate.

12. The method of Claim 4 wherein the halohydrln is methyl 3-[4-[(2-hydroxy-3-chloro) propoxy] pheny] proptonate and the propanediol is methyl 3-[4-[2,3-(dthydroxy propoxy)] phenyl] proprtonate.