CA1105041A - 1-aryloxy-2,3-epoxy-propanes and process for the production thereof - Google Patents

Abstract

Abstract of the disclosure:

Compounds of the formula wherein R1 and R1' are the same or different and represent hydrogen, an alkyl or alkoxy radical having 1 - 4 carbon atoms, the allyl radical, halogen or the nitro group and R2 represents an acrylic acid radical or acrylic acid nitrile radical of the formulae or

Description

The presen~ invcntion relate~ to new l-aryloxy-2, 3 epoxy propanss of the formula I

R Rl I

CN2-C~I-CH2 1' wherein R and R are the same or dlffererlt and represen~ hydro-gen9 an alkyl or alkoxy radical having 1 - 1, carbon atom~, the 5 allyl radical, halogen or ~he nitro gro~p and R repr~sents an acryllc acid radical or acryl~ c acid nitrile radlcal, o~ the ~ormulae _(~ = C _ C - OR or -C = C-CN
~t O

L~
.

.

` . . . .

s~

wh~rein R represents hydrogen, a (C~ - C5) alkyl radlcal, an un~ubstituted aryl or aryl- lower alkyl radical or an aryl or aryl lo~er alkyl radical substituted by lower alkyl or lower alkoxy, R represents hydrogen or a ~Cl - C~)-alkyl radical, and R5 represents hydrogen, a lower alkyl or aryl- lower alkyl radical, as well as a proce~s for the production of comp-~unds of formula I, tha~ i5 charac~eri~ed in that a ~ a compound of formula II

O\ I I
~ ocH -CH-CH2 wherein R and R ha~e the meanlngs given for fo~mula I and R
represents a radical o~ the formula O , whereln R7 repre3ents -C -R
hydrogen, a Cl - C5-alkyl radical or the ben~yl radical~ is reacted according to Wittlg with a triphenylphosphinemethylene of formula III
(C6H5) 3P CHR8 III
~, wherein R~ represents a cyano group or a carbalkoxy group of the formula -C-oR5. wherein R has the meanlng given above, or o . ..
.
.. . : ~ .
~' . ~' . ' ., .. , ' ' b) a compound of form~lla II i~ reacted according to ~Jittig-Horner with a carbanion of diphenylphosphine oxides of f ormula IV or a phosphonate carbarlion of formula V
o e 0 Q
t 6 5 ) 2 IV (RO) P-~-R8 v wherein R4 and R have the meanings given abo~e and R represents 10 a lower alkyl group or a phenyl group, or c ~ a hyclroxycinammic acid ester or nitrile o~ fo~nula VI

C--R

OH VI

R
whereirl R , R , R3, R4 and R hav~ the meanings given abov~
20 reacted wlth epichlorohydrin.
Of the radicals mentioned for the rad~cals R , R , R3, R 4 and ~ , the following are preferred:
For Rl and R : hydrogen, a~}cyl and alkoxy radicals having 1 - 3 carbon atoms, :fluorine, chlor~n2 as well as the nitro group.
25 For R3: hydrogen, unbranched Cl ~ C4-alkyl, in particular the methyl, ethyl and phenyl radicals.

~' .
.
..
, . , , . . .. . :

: : . .
- ~. . . -~ 5~
For R . hydrogen, Cl - C4-alkyl.
~or R : C ~ C4-alkyl, in par~icular the methyl, ethyl and tert.-butyl radicals as well a~ ~he benzyl radical.
Triphenylphosphinecarb~lethoxy_ or triphenylphosphinec~rbethoxy-methylenes or also triphenylphosphinecyanomethylen~s are preferably used for the reaction of a compound of ormula II with phosphoranes of formula III.
Suitable reaction media are iner~ organic sol~ents, such as~
e.g~, diethyl ether, tetrahydrofuran, dioxan, glycol dimethyl ether, dimethyl sul~oxide, dimethylformamide, aromatic or aliphatic hydrocarbon~, such as, e.g., ben~ene, toluene, ketone, or alcohols, such as msthanol, ethanol, tert.-butanol or also mixtures of these solvents~ In order to carry out the reaction, a solution of a compound of formula II is advantageously reacted with 1 - lO mol equ~alents, preferably 1 - 3 mol equivalents, of pho~phorane under ~ nitroge~ atmosphere for 1 - 4~ hours, preferably 1 - 16 hours, at temperatures botween 0C and the boiling temperatures of the solvents used.
In order to effect the sy~thesis of 1-~ryloxy~2,3-epoxy-pro-pane~ of formula I according to process variant b) the compounds of formula II are reacted preferably with carbalkoxymothyldialkyl or cyanomethyldialkyl phosphonates in the presence o~ anhydrous bases in in~rt organic solvents~ Preferably, carbmethoxymethyl-, carbethoxymethyl-, carbbenzoxymethyl , dimethyl- or diethyl- pho~-phonates, [-methyl-earbethoxy-methyl]-diethyl phosphonate, cyanomethyldlmethyl- or diethyl phosphonate, [-methyl-cy~nomethyl]-diethyl phosphonate are useA as phosphonates.

'~

.

.

s~
The phosphonates uaed ~ay be produced, e.g.9 aceording to the method described in G. M. I~osolapo~t "Organophosphorus Compounds" (~lley and Song, Inc., New York, N.Y~ (1950), chap, 7) by reactions of the alkyl radicals9 correspondingly halogenated in ~he ~-posi~ion, with triethyl phosph~te. There are mainly used as bases alkali metal and alkaline ear~h metal hydrides and amides a~; well as alkali metal and alkaline earth m~ oholate~, preferably sodium or potassium hydride but also sodium or potassium amide and sodlum or potassium tert.-butylate.
Suitable inert solvents are alcohols, hydrocarbons, but preferably aprotic solvents, such a~, for example, ethers (tetra-hydrofuran, dioxa~, dimethoxy glycol, dig~ym), dimethylformamide, dimethyl sulfoxide or mixtures o~ the solvents mentioned.
In order to effect ~he process, 1 mol equivalent of a com pound of formula II is dissolved or suspended in one of the sol-vents indicated, preferably in a non-prototropic solvent~ 1 - 10, preferably 1 - ~, mol equivalents of the alkali metal or alkaline earth metal compound o~ one of the phosphonates indicated are then added to one of the solvents indicated, preferably in a ~0 non-prototropic solvent, at 0 - 30OC, while cooling if necessary.
The alkali metal o~ alkaline earth metal phosphonates are prepared according to known methods. In a particularly advantageous embodimentg a stoichiometric quantity of sodium hydride ~n one Or the aprotic solYents indicated, ~or example~ in tetrahydro~uran or dioxan, and one of the phosphonates mentioned {s added dropwise until the sodium hydride dissolves or ~ltil the evolution of H2 is co~plete.

,~ :
?

.
. , - " , ' ' . ' :.' . ' ' ' ' ' "

': '' ' ' . ' . ' .
" ~ , ~ ' ~' ' ' , ' :
.. .

The reac~ion solution is then stirred at a temperature between -I~OoC and ~he boil~ng point of the solvent used, preferably at temperatures between OoC and 500C. The reaction times may be between 1 minute and approximately 72 hours but the reaction is 5 generally complete after between 30 minutes and 7 hours.
The procedure may also be reversed, the solution or sus~
pension of ~he compound of formula II being added to the solu~i~n of the alkali metal or alkaline earth metal phosphonate. However, the procedurs may al90 be such that the base, preferably an alkali metal hydride or amide, is suspended in the solution or suspension of the compound of ~ormula II in one of the aprotic solvents indicated~ preferably i~ an ether, and the phosphonate is then added and the reaction mlxture further treated as usual.
Th* dissolution, occurring later in thi3 case, of the alkal~
metal hydride or amide and th~ H~ evolution connected therewith, do not impair the olefination reaction.
The process products are i~olated according to normal methods of operation. After the react~on has terminated the reaction mixture~ are added to salt-containing water and9 where t~ere is suf~clent lipoid solubility of the process products, these are precip~tated in solid or oily form~ Water-soluble process products thereby largely di~solve. In 90 far as the pro-cess products cannot be separated by filtering o~f~ they are isolated in the normal manner by extraction with a w3ter-insoluble solvent, for example, chloroform or methylene chloride, to which a small quantity o~ a lower alcohol is advantageously added.
After the solvents hav~ been drawn off~ the process products result ~;
A

"'' ' ~ " ' ,' " '' , ' . ' . ' , ' ', . , . ' ~ , ' ' ' ~
,, . , , ' I
`' ' " ~ . ' . ~ ' ' ~ "
' " ' ' ~ 5 ~ ~

in solid or oily form. They can generally be obtained in a pure state in crys~allized or amorphous form by recrystallizing or dissolving and reprec~pita~ing from suitable organic sol~ents.
The process products can also be ob~ained in a pure ~orm by 5 normal chromatography.
The reactlon of hydroxycinnamic acid esters or ni~rile~ of formula VI takes place in a manner known per se by reacting the alkali metal phenolates of the compounds of formula VI, which are obtained also in s~u by adding alkali metal hydroxide~ in ~he presence of absence of sol~ents, e.g9, alcohols~ with l - lOQ
mol equivalen~ of epichlorohydrin at Oo to ~0 for ~ - 4~ hours.
The starting compounds of formula II can be produced accor-ding to normal methods by react~ng a correspondingly substltutad hydroxybenzene derivative9 having a keto function in the o-, m-or ~-posi~ion, with epichlorohydrin~
The hydroxycinnam1c acid esters or nitriles of formula VI are likewise produced according to normal methods by reacting the compounds mentioned with a dialkylcyanoalkyl phosphonate instead of with ~pichlorohydrin.
The compounds according to the invention are valuable inter-mediate products for the production of l-aryloxy-2-hydroxy-3-amino-propanes that are u~ed as medicaments for the treatment of heart diseases.
The l-aryloxy-2-hydroxy-3-amino-propanes c~n be produced from the compound~ of the invention according to Canadian Patsnt Applicatlon Serial No. 27$,974, flled May 24, 1977.
The ~ollowing Examples illustrste khe invention.

~, - .
. . .
. . , . . -, . . : . - ~, . :
.

... ... ~ . ~ . . ...

Exam~le l_a:
,~opoxy ) -phenyl] -c~o__Id Ai~r~l~
73 ml of die~hyl cyanomethylphosphonate are added dropw~ ~e to a suspension of g . ~ g of sodium hydride in 750 ml of absolute 5 tetrahydrofuran wh~le stirring and cooling to approxO 0 - 30 internal temperature. When the evolution of H2 has etld~ a mixture o 70 g of o-(293-epoxy-propoxy)~acetophenone and 70 ml of absolute tetrahydrofuran is added to the now clear reaction solu~ion at O - 30~
A~ter stirr1ng for 2 hours at 5 - 10 ) the reaction mix~ure is ~tirred into 5 li~ers of waterD Subsequently, extraction is carrled out with mQthylene chloride, the organ~c phase i~ dried o~er sodium sulfa~e and eoncentrated in YaCUo to drynes~.
The resulting oil is uniform in the thin layer chromatogram.
The following signals wero measured in the NMR spectrum:
H-NMR ~= 2.47 ppm (3H,s); 2.5-2.9 (2~,m) ; 3.1_3.4 (lH,m);
3,~-4.22 (2H,m~; 5.5 ilH.s)i 6.~-7.2 (4H,m).
The o~l2~3-epoxY-propoxy)-acetophenone used in Example 1 as starting material may ad~rantageously be obtained as described in the ~ollowing. A solution vr 26.6 g o~ sodium hydroxide in 50 ml of water is added dropwisa in the course of 30 minut~s and whilst st~rring vigorously to a solution of ~.6 g oP o~hydroxyacetophenone irl 21~5 ml Or epiehlorohydr~n which ~s boiling urlder reflux on a water ~eparator ~bath temperature about 150o)~ The mixture i~ then boiled under reflux while 3tlrring on th~ water separator for a ~urther one hour. After fi1tering off precipitated sodlum chloride and washlng the filter residue with a little methylene chloride, the i1trate is concentrated ~n vacuo and then subjected twice to fract10nal d~ stlllation a~ Bp 0.7 = I35-13B

. . .
, .
.

, : " ~ . ~ ' .
.
..

and at Bp O . 3 115 ~ o .
The yleld is '70~3 g with a melting point of 46 - 47.
F,xampl e 1 b [D,L]~ [2_(2,3_epoxy propoxy)-4-methoxyphenyl]-crotonic acid 5 nitrile

2 . 2 g of sodium hydr~de in 150 ml of absolute te~rahydro~lran are reacted in the usual manner (see Example 1~ with 20 ml of diethyl cyanomethylphosphonate and subsequently with a solution of 19.~ g of ~2~3-ox~do-propoxy)-2-acetyl_5 methoxyben~ene in 100 ml of absolute tetrahydrofuran . ~or the re~ operation is carried out as in Example 2a.
Yi eld: 1~ o 2 g of~ [D,L]-3-~2l3-oxido-propoxy)-4-methoxyphenyl]-crotonic acid nitrile having a melting point of 75 - 770.
(2,3-epoxy propoxy)-2-acetyl-5-methoxybenzene is advantageously obtained in the usual manner by reacting 25.0 g of paeonol in 250 ml of epichlorohydrin with 6.o g of sodium h~drox~de in lS
ml of water, and after the same working!up as described in Example 2a, is recry~tallized from t sopropanol/hexane and isopropanol.
Yield : 20.5 g having a mel~ing point of 53 - 5~o.
~ L__~

nitrile

3.3 g Or sodlum hydride in 200 ml of absolute tetrahydrofuran ara reacted and worked up in the usual manner (see Example 13 2s with 36~0 ml of diethylcyanomethyl phosphonate and then, a~
described in Example 2 c~ but with ~tirring continued for 1 hour at 0 (in~tead of 200), reacted and wor~ed up with 20.5 ~ of (293-oxido_propoxy)-2-acetyl-5-rluoroben~ene in 60 ml of absolut~
tetrahydrofuran.

.. 10 - - . , , . - . , , . - . . .
. . . , -, . ,., .. . ~ . . ~ ~
.. . . . . . . . .
~: : , - -~ ?S~
2701 g of [D,L~ 3-[2-(2S3-~poxy-propoxy) 4-fluoro-phenyl]-crotonic acld ni~rile having a meltlng point of 66 to S~o are obtained.
The (2,3-epoxy_propoxy)-2_acetyl-5-fluoroben~ene used as starting material is advantageously prepared from ~6.2 g of 2~
acetyl~5-fluorophenol in 500 ml of eplchlorohydrin, and 12 g of sodium hydroxide ~n 20 ml of water, as describ~d l~ Example 2 a.
The crude product is recrystalli3ed ~rom isopropanol and once a~ain ~rom ethanol.
20~5 g having a melting point of 71 - 720 are ob~ained.
~xample 1 d :

3.2 g of sodium hydride in 200 ml of absolu~e te~rahydrofuran are reacted in the usual manner (see Example 1) with 25~5 ml of diethyl cyanomethylphosphona~e. At 0~ 27.0 g of (2,3-epoxy_ propoxy) 2~acet,yl-4-fluoroben~ene in 60 ml of absolute tetra-hydrofuran are added dropwise to the cl~ar ylide solution.
Stirring is ~hen carried out for 2 hours at 200. After the usual ~ working up (see Example 1), 37.0 g of ~D,~]_3_[2-(2,3_epoxy-propoxy~-5.-fluorophenyl]-crotonic acid nltrile are obtained as a uniform oil ~ccording to thin layer chromatography which has characteristic IR bands at 2230, 1660~ 1562, 14~2, 1245 and 730 cm The ~2,3-epoxy-propoxy)-2-acetyl-4 fluorobenzone used as start~ng matarial ~s advantageously obtained as follows :
13.9 g of epichIorohydrin are added dropwise to a mixture of 15.4 g of 2-acetyl-4 fluorophenol and 150 ml of water that contains 5 g of sodium hydrox~de, and the whol~ is stirred for lS hours at 20 - 25~ The precipitate depo~ited is suctioned off, washed wlkh some water, and dried in aCuQ. h~ter r~crystallization ~'` .

,, . . , , , :.
, . ~ ., , , . ~ . "
., - ., : .

. . . " :
:

5¢~
from isopropanoll 9.0 g havlng a melting point of 60 - 61 are obtain~d.
Example 2 a :
~D,L]-~-[~(2~-epoxy_propoxy~~phenyl]_~crotonic acid _itrile A suspension of 6.0 g of sodiwn hydride in 500 ml of absolute tetrahydro~uran is caused to react, as described in ~xample 1 with ~0 ml of diethyl cyanomethylpho~phona~e, and ~hen ~ith a solution of ~B g o~ p-(2,3 epoxy-propoxy)-acetophenone in 50 ml of tetrahydrofuran~
After the usual working up, the resulting crud~
[D,L]-3-[~-(253-epox~-propGxy)-phenyl]-croton~c acid nitrile i~ recrystallized for purification from toluene/petroleum ether, and than recrystallized once again from ethanol. 40.9 g o~
[D,L]-3-[4-(2,3-epoxy-propoxy)-phenyl~-crotonic acid nitrile having a melting point of 77 - 77. 50 are obtained~
The ~-(2,3-epoxy-propoxy)-acetophenon0 used as star~ing matarial in example 2 may ad~antageously be obtained as described in the following: A solution of loBo ~ g of p-hydroxy-ace~ophenone in 500 ml of epichlorohydrin is caused to reac~ with a solution of 32 g of ~odium hydroxide in 6~ ml of water, as described in Example 1.
After the usual working up, the crude product is sub~ect~d twice to fractionakion in a high ~acuum. 1~5 g f ~a-(2,3-epoxy-propoxy)-acetophenone were obtained as peak ractlon having a boiling point o~ 154 - 1600 (00~ mm). ~ -Exampla 2 b :

n~ e 3.6 g of sodi~m hydride in 150 ml of absolute tetrahydrofuran are reacted, in the usual manner (ses Example 1) with 17.3 ml of ~ ~, ~ ~ 12 ...
... ... . ...
....

, ~ , , .

~s~
d~ethyl cyanomethylphosphonate and ~hen with a solution of 17.~ g of (2,3_epoxy_propoxy)-3_methoxy_~-acetylbenzene in 60 ml of absolute tetrahydrofuran. After stirring for 5 hours at 200, working up is continued as usual . After crystalll zation from isopropanol/hexane, 10.2 g of [D,L]-3-[2-methoxy-4-(2~3-epo~y-propoxy)-phenyl]-crotonic acid nitrile having a melting point of 6~ - 690 are obtained.
The (2,3-epoxy-propoxy)-3-methoxy-4-acetylbenzene used in Example 2 a may advantageousl~ be obtained as descri~ed in the lo following : 21.7 g of isopaeonol in 200 ml of epichlorohydrin are reacted in the usual manner ~;ee Example 1) with ~.6 g o~
pota3sium hydroxide in 20 ml o~ wa~er" Filtration is then c~rried out, the filtrate is sub~ected to rotary evaporation in ~acuo, and once again evaporated on a rotary evaporator.
Recry~talllzation is from ethanol/hexane and ethanol (second fraction)~
Yield~ g having a melting point of 57 - 59 .
~:

nitr~ile 2.5 g of sodium hydrid~ in 150 ml of absolute t~trahydro-furan ara reacted as usual (see Example 1) with 22.0 ml of diethyl cyanomethylphosphonate and then with 16.5 g Or ~2,3~poxy-propoxy)-2-chloro_4_acetylben~ene in 100 ml o~ absolute tetrahydrofuran.
Arter stirring for one hour at ~0, wor~ing up is carried out in the usual manner~ ( see ~xample 2)~ After crystallization from sopropanol, 1~ . 6 g 0.~ [ n, L]-3-[3-chloro-4-(2,3-epuxy-propoxy)-phenyl]-crotonic acid.nitrile having a melting point of ~5 - B60 are obtained.

" ' ' ~ ' .,' . , ':

- , ~ .

(2,3-epoxy-propoxy~_2-chloro 4-acetyl-benzene is advantag-eously obtained by reacting 17.1 g of 2-chloro-4~acetylphenol in 200 ml of epichlorohydrin w~th ~ g of sodium hydroxide in 10 ~1 of water, (as described in Example 2 a).
~ E~
~D,L]-3-[~-fluoro-nltrile 5.5 g of sodium hydride in 350 ml of absolu~e tetrahy~rofuran are reacted in the usual manner (see Example 1~ with ~O ml of 10 diethyl cyanomethylphosphonate and then with 35 g of ~2,3-epoxy-propoxy)~2-~luoro-~-acetylbenzene ~n 100 ml o absolute tetrahydrofuran ~but th~s time at -10 internal temperature on the addition o~ the latter solu~ion). Stirring is continued ~or 1 hour at 2û and ther~after 4 li'Gsrs of water contain~ng 15 ml 15 of glacial acetic acid are stirred in. Extr~ction i9 carried out with toluene/acetic ester. The dried extract is sub~ected to rotary evaporation in vacuo and the residue is recrys~allized from i~opropanol. 32.~ g o~ [D,L]-3-[3-fluoro-~-(2,3-epoxy-propoxy)-phen~}]-crotonic acld nitrile hydrochloride having a meltlng point of B7 - ~ ar~ obtained. The (2~3-oxido_propoxy)-2-fluoro_4_acetyl benzene i5 advantageously prepared from 46~2 g Or 2-fluoro-4-acetylphenol in 500 ml of epichlorohydrin and 12 g of sodium hydroxide in 20 ml Or water, a~ described in Example 2 a. The o~ly crude product is distilled~ Bp. 0~5 = 1~5 - 150. -.
35.5 g having a melting point of 56 - 59 are obtained.
ExamJ~Le 2 e :
. . .
[D LJ-3-~3-methoxy~4-(2,3-epoxy-propo ~)-pheny11-crotonlc acid n1trlle - 11, - .
!, ~`

, . . :, ,: , .
, ' , ', , , ~ ' 3.2 g of sodium hydride in 200 ml of absolute tetrahrdroruran are reacted in the usual manner with ~5~5 ml of diethyl cyanomethyl-phosphonate (see Example 1). At -10, 29 g o~ (2,3-epoxy-propoxy)-2-methoxy_4_acetylbenzene ~n 60 ml of absolute tetra~
hydrofuran are stirred dropw~se into the clear ylide solution~
Stirring is then carried ou~ for 1 hour at Oo 9 2~ hours at 20 and for a f~rther 1 hour at 35 - 400 0 The reaction mixture is pour~d into 1.5 liters of water, extracted with ~oluen~/acetic ester~ dried, subjected to ro~ary evaporation and ~he residue lo i~ recrystalllzed from ethanol~ Yield : 2~.3 g of ~D,L]-3 [3-methoxy ~-(2,3~epoxy-propoxy~_phenyl]_crotonic acid nitrile having a melting point of 117 - llB.50 ~
The ~2j3-epoxy-propoxy)-2-me~hoxy-~acetylben~ene used as starting material ~s advantageously prepared by react~ng ~9.~ g of 2-methoxy-~_acetylphenol in ~00 ml of epichlorohydrin with 12~0 g of sodium hydroxide in 20 ml of water, as de~cribed in Example 2 a. The crud~ product ~s distilled for purification ~Bp.~ ~ 156 - 165), and the distillate is recrystalli~ed from ~sopropanol Yield~ 2903 g ha~ing a melt~ng point of 59 - 61.~.

A suspension of 7 g of sodium hydride in 200 ml o~ absolute tetrahydrofuran is r~acted~ as described in Example 1, with 60 ml Of diethyl cyanomethylphosphonate.
At room temparatura 50 g of o-acetoxybenzaldehyde in 250 ml o.~ absolut~ tetrahydrofuran are stirred into thi~ reaction mixture .

.

~ ~5}~
and stirring :I s carried out for 4~ hours at 60 . The ma,~ority of the tetrahydrofurarl i~3 distilled o.t`f ln Yacuo, the di~tlllation residue ls poured into 400 ml of ice water and weakly acidi~ied wi~h acetic acid. Extraction i5 carried out twlce w~t~ m~thylene chloride, the extract is washed ~wice ~ith water, dried and concentrate~ to dryness in vacuo. The resulting 50 g o~ oil~
distilla~ion residu~ are eluted on a column comprising 1 kg of sil~ca gel with 3 x 500 ml of methylene chloride. 15 g o~ crude 3- ( o-hydroxyphenyl ) -acrylic acid nitrile are obtained~ The crude product is digested wi~h 50 ml of 16 % strength sodlum hydroxide ~olu~ion for 15 minutes~ the resul~ing solut~on is suctioned O~r over active charcoal, washed with wa~er, and the filtrate is acidified with 2N hydrochloric acid. The crystals precip1t~ted are filtered Ofr, washed with a little water and 1.S dried. The 6.2 g of 3-(o-hydroxyphenyl)-acrylic acid nitrile thus obtained are dissolved in 50 ml of methanol, and reacted with 14.3 ml of epichlorohydrin and a solution of 1.46 g of sodium hydroxide in 6.5 ml of water. After stirring for 14 hours a~ room temperatur~, the mi~ture i9 concentrat~d to dryness ~n vacuo and the dis~illation res~due is taken up in methylene chlor~de/waterO The organic phase is washed until ~eutral with water~ dried over Na2504 and evaporated to dryness i vacuo, 6.~ g of ~D,L]-3-~2-(2,3-epoxy_propoxy)-phenyl],-acrylic acid nitrile ar~ o~ta~ned as an oil. The compound has characterist~c IR bands at ~200, 1600, 1590, 1565~ 14~09 ~240 and 740 cm~l.

[D~L]-.3-[2~ epoxy-~roE~xy)-phen~-acr~lic acid tert -butyl - ~ . .
:, ~ , . . .. . .
- . . :
.' . ' : . : ,.: . ..
, . . .. .

~3 ~5~

sster.
W~ile cool~ng at 5 - 16, a ~olution oî 126.0 g of dimethyl tert.-bu~oxycarbonylmethylphosphonate in 125 ml of absolute te~rahydrofuran is stirred ~nto a suspension Or 10.0 g Or sodium hydride in ~00 ml o~ absolute tetrahydrofuran within 5 . the cours2 of 5 minut~s, After stirring for 3~ hours at 15 - 20~
all the sodium hydride has gone into solution. A solution of 71.0 g of o-(2,3-epoxy-propoxy~-benæaldehyd~ in 70 ml of absolute ketrahydrofuran i~ then stirred in during the cour~e o~ 30 minut~s while coo~ing with ice. St~rring is then continued for a ~urther 1 hour wh~le cooling with lce and the rsaction m~xture is pourod into 5 liters of wa~er. Extrac~ion i~ carried out to exhaustion wi~h methylene chloride, the purified methylene chloride extract is washed with water, dried over sodium sulfate and concen-tra~ed to dryness in ~acuo. 150 g o.~ lD,L]-3-~2-(2,3~oxido-propoxy) 15 -phenyl ] -acryll.c acid ter'c .-butyl ester are obtained as an oil wh~ch is uniform accordlng to thin layer chromatography.
The characteristic IR bands are at 169~ ".625, 1593, 1573, 14~0 ~- a~d 74~ cm 1.
The o~(2,3-epoxy-propoxy)-ben~aldehyde used in Example 4 as starting material may advantageously be ob~ained as follows : A
solution of ~4 g of salicylaldehydei~ 500 ml of ep~chlorohydrin is, as described in Example 1, reacted with a solution o~ 32 g of ~od~m hydroxide in 6~ ml o~ water. Tha crude o-(2,3-epoxy-propoxy)-benzaldehyde obtained after the usual working up procedure ~s ~S su~iciently pure for the above reaction so that fractional dis-tillation can be dispensed w~th here.
~ .
: - 17 _ .. ~ ' '' .

.

~ ~ 5 Example 5 propox~ henyll=acrylic acid tert.-butyl ~ster __ Whilst cooling at 200, a solutlon oP 7~ g o~ diethyl tert.-butoxycarbonylmethylphosphona~e in lO0 ml of dimethoxyethane isstirred into a suspension o~ 6.7 g of sodium hydrid~ in 560 ml of absolute dimethoxyekhane. Stirring is then~continu~d for 30 minutes at 25, until all the sodium hydride has gone ~nto solutionO Then, with~n the cour~e o~ lO minutes~ a solution of

4-9 . 3 g of ~ ~ 2, 3-epoxy-pxopoxy~-ben~aldehyde in 100 ml of dimeth-ox~ethane i~ ~tirred ~n, whilst sl~ghkly cooling the mix~ure, such ~hat the temperature does not rise above 25~ A~ter ~tirring has continued for 30 minutes the reaction m~x~ure i~ poured on~o 3 liters of ice. The crystals prec~pitated aft~r the mixture has stood ~or a ~Ihi~e are suctioned of~, and recry~tallized from metha-nol. 41 g Or [D~L]-3-l4-(2,3-epox~propoxy)-phenyl]-acrylic acid tert.-bu~yl e~tsr ha~ing a melting point o~ ~6 - ~7 (Kofler melt~ng block) ~re obtained.
: Th~ ~-t2,3,-epoxy-propoxy?-benzaldehyde used as startin~
materi~l can b~ obtained in a ~anner analogous to the preparation, described in Example ~, of th~ o-(2,3-epoxy_propoxy)-benzaldehyde~
le 6 a :
[ D,L]~[2-(2,~epox~r-eropoxyj-phenylL ;~ a~y_ic acid nitrile 25. A suspension of 3 . ~5 g Or 50dium hydride in 400 ml of absolute ketrahydrofuran i~ reacted as described in Example 1 wikh 36.0 g oiE diethyl cyanom~thylphosphonate. While cooling .
~1 . . . . ... : ~ : ... . .. . .

` \ J

with ice, a solution of ~0~5 g of o_(2,3-epoxy-propoxy)-benzophe_ none ~n 50 ml of absolute tetrahydro~uran ~s st-lrred into the reaction mixture and stlrring i9 continued at room temperatùre - for 20 hours.
Af~er the usual worklng up (as described in ~xample 1) after the recrystallisation from i~opropanol/petroleum ether, 15.~ g of [D,L]-3-[2-i2,3-epoxy-propoxy)-phenyl]-3_phenyl_aeryllc acid n~trile having a melting point of g~ are obt~in~d.
The o-(2,3_epoxy propoxy~-benzophenone used as starting material can be obtained in a manner analogous to that descr~b~d in ~he preceding Examples~ by reacting, for example, 49.7 g of o-hydroxybenzophenonè in 200 ml of epichlorohydrin with 10.2 g of sodium hydroxide in 20 ml of water. After the usual working up, the crude product ls sub~eoted to fractional distillation.
41.6 g of o-(2,3-epoxy-propoxy)-benzophenone having a boiling point at 0 4 mm Or 1~4 - 1~6 were obtained.
Example 6 b :
~D,L~-3-L4-(2,3-epo,~ propo~=
n~trile A suspension Or 7.25 g of sodium hydride in 750 ml o.f ab~olute tetrahydrofuran is reacted, as described in Example 1, with 6~.0 g of d~ethyl cyanomethylpho~phonate. While cooling with icel a ~olut~on of 76,0 g of ~-(2,3-epoxy_propoxy)_ben~ophenone in 100 ml of tetrahydrofuran is stirred into ~he re~ction mixture.
A~ter stirring for a further 4 hours at 25O~ work~ng up is e~fected in the usual manner (see Example 1). ~2 g of ~D,L]-3-[~_(2~3-epoxy_propoxy~phenyl~ ~3-phenyl-acrylic acld ni~rlle ara - 19 _ .

;: ,- - : .
, ~.. . ' ' ' . . ' ' ~' . .
. . , . ~
- -. ' ~ .. . .' . " `
..

obtained as an oil which i3 un~form accordîng to thin layer chromatography, and has character~stic IR bands at 2205, 1640, 1595 ) 1503, 1242, B92, 755 and 690 cm ExamPle ?:

5 ~D,Ll -3- r4-(2,3-epoxy-propox~-phenyl] -acrylic acid ethyl es~er.
A suspen~ion of 2 . 5 g of sodium hydride in 50 ml of absolute tetrahydrofuran is~ as described in Example 5, reacted with 25 ml Or diethyl ethoxycarbonylmethylphosphonate in 30 ml of tP~rahydro-~uran~ The reaction mixture is, as described in Exampl~ ~ allowed 10 to react with a solution of 20 g OI P-t2,3-epoxY-propoxy)-benzal-dehyde in lûO ml of absolute tetrahydrofuran. After stirring has cont~nued for 2 hours, working up is carried out in the usual manner. 1~. 3 g of [D,L]~3-[4-~2,3-epoxy-propoxy)-phenyl]-acrylic acid ethyl ester are obtained ha~ring characteristic IR bands at 1695, 1592, 1497, 1277, 1~45 and ~23 cm 1.
: , .. .
[D,~ -3-[ 2-(?.~ ac~d e~ esterO
W~thin the cour~e of 15 minutes, a solution of 1004 g Or 2U ~odium hydroxide in 2.2 ml of water is added dropwis~ to a solution of 5 g of o-hydroxycirlarmnlc acid ethyl ester in 30 ml of epichlorohydr~n bo~l.ing on a water separator under reflux.
Heating at the boil under reflux is continued for a f`urther 1~ hours a~ a bath temperature of 1~0~ on the water separator.
Further working up is effected as descr~bed in ~xample 1 ~n the preparation Or the o-(2~3--epoxy-propoxy3-ac~tophenone.
The f~raction hav~ng a bolling poin~ of 0 7 167 - 170 !~, , , :' . : ' . ' ' ' . . " ; ' '`'' ' . '' '' ' ' '' . , ~'; . ' . . ' ." , ~ ', , . . . ' . . ' ' ' ' ~ ' .
- '' . ' . . '. ~ . ' .

5~

yield~ 3.6 g of [D,L]-3 [~_(2,3-epoxy-propoxy)-pherlyl]-acrylic acid ethyl ester.
Example 9:
-I~,L~- 3 - ~4- ( ? . 3 epoxy- propox~ 3-phenyll~-ethyl-aGrylic acid nitrile A susp~nsion of 7.~ g o~ sodium hydride in 600 ml of absolute tetrahydrofuran is, as described in Example 6, allow~d to react with 63~7 g of diethyl cyanomethylphosphonate and then wi~h g o~ p (2~3-epoxy_propoxy3_p~op~ophenone in 60 ml of absolute ~etrahydrofuran. After ~he usual working up (see Example 4)~
lo 65.2 g of [D,E]-3- [4-~2,3-epoxy-propoxy~-phenyl~-3-ethyl-acrylic acid n~trile are obtained as an o~l which is uniform according to thin layer chromatography and has characterist~c I~ bands at 2200, 1590, 150~, 12~5~ ~30, ~10 and 757 cm~l, The ~-(2,3-epoxy-propoxy)-propiophenone used as starting material may ~e obtained a~ follows:
A solution of 9~0 g of p-hydroxypropiophenon~ in 300 ml of epichlorohydrin i9, as described in ~xample 1, reacted with a solution of 26.0 ~ o~ sodium hydroxide in 50 ml Or water.
After the usual working up by recrystallization from ethanclt 75.5 g of p~(2,3_epoxy_propoxy)_prop~ophenone having a melting point of 6B - 690 are obtained.
, ~:
~- [~-(2,~-e~o~ propoxy)-phen~ crotonic acid ethyl ester.
.
A su~pen3ion of 17.3 g of ~odium hydride in 750 ml of absolute tetrahydrofuran is ~eacted at 0 - 10, but otherw~se in the manner described in Example 1, with 105.0 g of diethyl ethoxycarbon-ylmethylphosphonate. The reaction mix~e ~s, a~ de~cribed in Example 5~ treated with a solution of 76.5 g of ~ 21 _ ..

S¢~

o_(2,3-epoxy-propoxy) acetophenone in 100 ml of absolute tetra-hydrofuran. After stirring for 25 hours at 15, working up ls carried out in the usual manner ( see Example 13 . 129.5 g oï
[D,L]-3-[2-(2,3-epoxy-propoxy)-phenyl]-crotonic ~cid ethyl e~ter 5 were obtained as an oil which is unifor~ according ~o thin layer chromatography and has characteristic IR bands at 1705, 1625, 1~92, 14 g2, 115~ 9 1025 and 74~ cm~l .
xample 10 b:

1~ 7.2 g Or sodium hydride in 700 ml of absolu~e tetr~hydrofuran are reacted as described ~ n Example 1() with ~5 .0 g of diethyl methoxycarbonglmethylphosphonate. The reaction mixture is as describ~d ~n Exampl~ 5, but at 10 - 150 internal temperature, treated with a solution of 57.6 g of p-~2~3-epoxy-propoxy~-15 acetophenone in 60 ml of' absolute tetrahydrofuran. After stirring for 3 days a~ room temperature, the mlxture is worked up in the usual manner (se= Example 1). 9Q.1 g of [D,L]-3-[~-(2,3-epox~-propoxy) --phenyl ]-crotonic acld methyl ester are obtained as an oil which is uniform according to thin layer chromato~sr~phy and ha~ characteristîc IR ~ands at 1704, 1626, 1594, 14~3 and 1150 cm Example 11 :
~D,L]-3-[3-(2~3-epoxy~ropoxy)-pheny~-acr~lic~ L~
A ~olution o~ lZ g o~ m~hydroxycinnamic acid nitrile in a mixture consisting of 2~ ml of eplchlorohydrin and 100 ml of .
methanol i9 stirred for 14 hour~ a~ter the addi~ion of 2.~2 g o~ sodium hydroxide in 1~ ml of water. I~ is then mixed with .

. - 2~ - .

, ':
.

, ' , , . ~.

~1~5~
500 ml of H 0 and extracted wlth ~ethylen~ chloride~ Th~ extrac~
is washed with water, dried and concen~rated to dryness in vacuo.
15.3 g of [D9L~_3-[3_(2,3_epoxy_propoxy)-phenyl]-acrylic acid n~trile are obtained as an oil which is u~iform according to thin layer chromatography and has characteristic IR band~ at 2110 1610t 1570, 14~09 773 and 677 cm The m-hydroxycinnamic acid nitrile used as starting ma~er~al may advantageously ~e ob~ained a~ follows:
A ~u~pension of 2.~ g of sodium hydride in 50 ml of absolut2 lo ~etrahydrofuran is reacted, as des¢ribed in Example 1 with 24 ml of diethyl cyanQmethylphosphonate ~n 20 ml of absolu~e tetrahydro-furan and then wlth a solution of 20 g Or m-acetoxybenzaldehyd~
ln 100 ml of absolute te'crahydrofuran.
Subsequen~ly the mixture i~ st~rred lnto 5OO ml of wate:r and weakly acidifled.
After the usual working up, 1~.92 ~ o~ m-hydroxycinnamic acid ni~rile which is un~form according to thin layer chromato-graphy are obtained.

- A solution of 12 g o~ 3-(m-hydroxyph~ny~)-crotonic acid nitrile ln a mlxture consi~ting of ~lOO ml o~ methanol wikh 2g ~1 of epichlorohydrin, is reacted, as describ~d in Example 11, w~th a solutlon of 2.~2 g Or sodiu~ hydroxide in 13 ml of water. A~ter the usual working up, 15.~ g of [DjL]-3-[3~(2,3_epoxy-propoxy)-phenrl]-crotonic acid nltrile are obtained as an oil which i3 : uniform according to thin layer chromatography and has characteristic . ~ - 23 _ ,,~. . ; :

- : ,. ,: . . - . . ~, . : . , :

- . ' ..... . ~ . , ~. . .... . ~ . .

IR bands at 2195, 16543 1423, 1255 and 1025 cm .
The 3- (m-hydroxyphenyl ) -crotonic acid nitrile u3ed as starting mat~rial can be obtained as follows: A ~3uspenslon of 2.~`g oX sodiwn hydride in 50 ml of absolute tetrahydrofllran is, as described in Example 1, reacted with 21~ ml of` diethyl 5 cyanomethylphosphonate in 20 ml of absolute tetrahydrofuran and subsequently with a solution of 20 g oï m~aeetoxy-ace~ophenone ln 100 ml of absolute te~rahydrofuran. qlhe mixtllre is then poured into water and ~lightly acidi~ied. After the usual working up, 1~.35 g of 3-(m-hydroxyphenyl)-crotonic acid nitr~le ar~ obta~ned.
10 ~
[D~LL-3-[3-¦2,3-epox~-propoxy) phenyl]-acrylic acid ethyl ester.
A suspension o~ ~.g g Or sodium hydr~de in ~O0 ml of tetra-hydrofuran is reacted, as described in Example 5, with 54.O g of diethyl e~hoxycarbonylmethylphosphc)nate in lOO ml Or tetrahydro-furan. h 901ut~0n of ~2 g of m (2,3-epoxy propoxy)-benzaldehyde in 50 ml of tetrahydrofuran is added dropwise while stirring, ~t oo, to the resulting reac~ion mixture. The reaction mixture i9 then stirred into 5 llters of water, extracted with toluens, the toluene extract is dried over sodium sulfate, clarif~ed wlt,h carbon, and freed from sol~ents ln _ uo.
5~ g of ~,L~3-~3-(2,3-epoxy-propoxy)-phenyll-acrylic acld ethyl ester are obtained as an oil whlch is uniform accordlng to thin layer ehromatography and ha~ character~stic IR bands at 1702, lb30, 15~5, 14~0, 1360, 1170, 1027 and 670 cm .
The m-(2,3-epoxy-propoxy)-ben~aldehyde used as starting material can be obtained as ~ollows: .

. ~ .
2~

100 g of m-hydroxybenzaldehyde in ~00 ml of epichlorohydrin are, as descrlbed in Example 1, raacted w1~h 30.5 g of ~odium hydroxide in 50 ml of water. The crude aldehyde obtained af~er the usual working up may, as described in Example 1" be u3ed for 5 further reaction without pre~r~ous distillation.
Example 11~:
[D,L] 2~phenyl 3- ~4-l2,3-epoxy~ropoxy)-phenyll-acryl c_~
ester ___ - 16.0 g of 2-phenyl-3-(1~-hydroxyphenyl)-acryliG acld me~hyl 10 ester in 90 ml of epichlorohydrin are, as des~ribed in Example 1~7 reacted with 2~51 g of ~odium hydroxide in 5.3 ml OI water.
Further working up is carried out as described in Example 1.
The fraction having a boiling point of o 2 155 - 1600 yields after recry3tallization from methanol, 15.05 g of [D,L]-2-phenyl-3_[4_~2~3_epoxy_propoxy)-phenyl]-acrylic acid methyl ester.
:, :

.' ' ' , ~ .
, .
- 25 _ .
'`, .

- .
.

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula I

I

wherein R1 and R1' are the same or different and represent hydro-gen, an alkyl or alkoxy radical having 1-4 carbon atoms, the allyl radical, halogen or the nitro group, and R2 represents an acrylic acid radical or acrylic acid nitrile radical of the formulae or wherein R3 represents hydrogen, a (C1-C5)-alkyl radical, an unsubstituted aryl or aryl- lower alkyl radical or an aryl or aryl- lower alkyl radical substituted by lower alkyl or lower alkoxy, R4 represents hydrogen or a (C1-C8)-alkyl radical, and R5 represents hydrogen, a lower alkyl or aryl- lower alkyl radical, in which (a) a compound of the formula II

II

wherein R1 and R1' are as defined above and R6 represents a radical of the formula ? , wherein R7 represents hydrogen, a C1-C5-alkyl radical of the benzyl radical, is reacted according to Wittig with a triphenylphosphinemethylene of formula III

(C6H5)3?-?HR8 III

wherein R8 represents a cyano group or a carbalkoxy group of the formula -?-OR5, wherein R5 has the meaning given above, or (b) a compound of the formula II is reacted according to Wittig-Horner with a carbanion of a diphenylphosphine oxide of the formula IV or a phosphonate carbanion of formula V

IV V

wherein R4 and R8 have the meanings given above and R represents a lower alkyl group or a phenyl group, or (c) a hydroxycinammic acid ester or nitrile of the formula VI

VI

wherein R1, R1', R3, R4 and R8 have the meanings given above, is reacted with epichlorohydrin.

2. A process as claimed in claim 1 in which the preparation is carried out according to reaction (a) in an inert organic solvent under an inert atmosphere and at a temperature between 0°C and the boiling point of the solvent used.

3. A process as claimed in claim 1 in which the preparation is carried out according to reaction (b) in the presence of an anhydrous base in an inert organic solvent.

4. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.

5. A process as claimed in claim 1 in which the preparation is carried out according to reaction (c).

6. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.

7. A process as claimed in claim 1 for the preparation of [D,L]-3-[2-(2,3-epoxy-propoxy)-phenyl]-crotonic acid nitrile in which diethyl cyanomethylphosphonate is added dropwise to a suspension of sodium hydride in absolute tetrahydrofuran, hydrogen evolution is allowed to proceed to completion, o-(2,3-epoxy-propoxy)-acetophenone in solution in tetrahydrofuran is added to the mixture, the mixture is reacted with stirring for 2 hours at 5 to 10°C and the resultant product is isolated.

8. [D,L]-3-[2-(2,3-epoxy-propoxy)-phenyl]-crotonic acid nitrile whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.

9. A process as claimed in claim 1 for the preparation of [D,L]-3-[4-(2,3-epoxy-propoxy)-phenyl]-crotonic acid nitrile in which diethyl cyanomethylphosphonate is added dropwise to a suspension of sodium hydride in absolute tetrahydrofuran, hydrogen evolution is allowed to proceed to completion, p-(2,3-epoxy-propoxy)-acetophenone in tetrahydrofuran is added to the mixture, the mixture is reacted with stirring and the resultant product is isolated.

10. [D,L]-3-[4-(2,3-epoxy-propoxy)-phenyl]-crotonic acid nitrile, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.