IE53457B1 - Allyl derivatives - Google Patents

Description

This invention relates to novel chemical intermediates in the production of allyl amine MAO inhibitors.

We have disclosed and claimed in our Patent 5 Specification No. 1246/82 pharmacologically active compounds of the formula: F R I I c = c ι I Y CHgNHR^ F I or C I Y A - R I Ϊ CH2NHR1 II 34 a 7 wherein: R la 3,4-methylenedloxyphenyl; phenyl; phenyl monoaubstituted, dlsubstituted, or trlaubstltuted by (C^-Cg) alkyl, (Cχ-Cg)alkoxy, (Cj^-CgJalkylcarbony5 loxy, hydroxy, chlorine, bromine, iodine, fluorine, trifluoromethyl, (C^-Cgialkylcarbonyl, benzoyl, or phenyl; 1- or 2-naphthyl; 1-, 2-, or 3indenyl; 1-, 2-, or 9-fluorenyl; 2-pyridlnyl; 1-, 2-, or 3-piperidinyl; 2- or 3-pyrrolyl; 2- or 310 thienyl; 2- or 3-furanyl; 2- or 3-indolyl; 2- or 3thianaphthenyl; or 2- or 3-benzofuranyl; R ls hydrogen, (C,-Ce)alkyl, benzyl, or phenethyl; X IB Ϊ is hydrogen or .fluorine; and IS Ale a divalent radical of the formula: ι2 “^H2^mCH^CH2^i“’ wherein Rg is hydrogen, methyl, or ethyl, and m and n, Independently, are o or an integer from 1 to 4, provided.that m + n cannot be greater than 4; -(CHg)p-D-(CH2)q-, wherein D ls oxygen or sulfur, p is an integer from 2 to 4, and q is 0 or an integer from 1 to 2 provided that p + q cannot be greater than 4; or ~(CH2)rCH»CH(Ci^ )g-, wherein r is an integer from 1 to 3 aad a is 0 or an integer from 1 to 2, provided that r -t- s cannot be greater than 3; or a non-toxic, pharmaceutically acceptable acid 5 addition salt thereof; provided that when each of X and Y in Formula I is hydrogen, R cannot be phenyl.

The compounds of Formula I and XI are pharmacologically active, being capable of inhibiting MAO in vitro and in vivo. The compounds of Formula I and II are useful for the treatment of psychiatric disorders, in particular depression, which are known to be responsive to MAO inhibitor therapy. For the treatment of depression, the compounds can be employed in a manner similar to that of the known clinically active MAO inhibitors, such as phenelzine and tranylcypromine.

Certain compounds of Formula I or II are capable of preferentially inhibiting the B form of MAO in vitro and, at suitable low dosages in vivo, such compounds will inhibit MAO-B without substantially inhibiting MAO-A. At dosage levels where such compounds exert a selective effect on MAO-B, the compounds will not produce a marked cheese effect . »3457 Hence, as with L-deprenyl, a known selective Inhibitor of MAO-B, such compounds can be employed at suitable dosages for the treatment of depression, or for the potentiation of L-DOPA in the treatment of Parkinsonism, with a significantly decreased risk of producing side effects, such as the cheese effect The preferred compounds of Formula I or II showing selective Inhibition of MAO-B are (E)-2—(4*— methoxyphenyl)-3-fluoroallyl-amine and (E)-2-(3',4'10 dimethoxyphenyl)-3-fluoro-allylamlne.

In its composition of matter aspect, the present invention comprehends chemical compounds of the Formula; F R f A - R II II C « c or C « C II I I Y CHgRg Y CH^l3 III IV wherein Y, R, and A have the meanings defined supra with respect to Formula I or II; except that R cannot be mono -, di-, or tri-hydroxyphenylj and R2 is hydroxy or a leaving group. The compounds of »3457 Formula Ill or IV are intermediates for the preparation of the pharmacologically active compounds of Formula 1 and II, respectively. Preferred examples of leaving groups as defined by R are: chlorine, bromine, tosyloxy, or mesyloxy. Other suitable leaving groups will be apparent to those skilled in the art of chemistry.

As employed herein, the term alkyl contemplates both straight- and branched-chain alkyl groups. Straight-chain alkyl groups are preferred.

Illustrative examples of (C -C ) alkyl groups are 1 6 methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, and n-oetyl. Methyl and ethyl are most preferred. The term alkoxy contemplates both straight- and branchedchain alkoxy groups. Straight-chain alkoxy groups are preferred. Illustrative examples of (C -C )alkoxy 1 8 groups are methoxy, ethoxy, n-propoxy, iso-propoxy. n-butoxy, iso-butoxy. tert-butoxy, n-pentyloxy, n20 hexyloxy, n-heptyloxy, and n-octyloxy. Methoxy and ethoxy are most preferred. The term alkylcarbonyloxy contemplates both straight- and branched alkylcarbonyloxy groups. Straight-chain groups are preferred. Illustrative (C -C )alkylcarbonyloxy groups 1 6 are acetoxy, propionyloxy, n-butyroyloxy. Acetoxy is 83457 most preferred. The term alkylcarbonyl contemplates both straight- and branched-chain alkylcarbonyl groups. Straight-chain alkylcarbonyl groups are preferred. Illustrative (Cj^-Cg)5 alkylcarbonyl groups are acetyl, propionyl, and nbutyryl. Acetyl is most preferred. The term 11 monosubstituted as used herein in the definition of R In Formula I or II means that the phenyl ring is substituted by one substituent group which can be located at any of the available positions in the ring (i.e. in the ortho. para, or meta positions). The term disubstituted 11 means that the phenyl ring is substituted by two substituents groups which may be located at any of the available positions in the ring IS or oriented in any manner with respect to each other. The term trisubstituted means that the phenyl ring is substituted by three substituents groups which may be located at any of the available positions in the ring or oriented in any manner with respect to each other. When R in Formula I or II represents a di- or tri-substituted phenyl group, the groups substituted on the phenyl ring may be the same or they may be different.

Illustrative examples of divalent groups represented by A are -CHg-,’ -(CH2)2-, -(CH2)3-, -CCH2)4-, -(CH2)5-, -CH2S(CH2)2-, -CH2O(CH2)2-, and -CH«CH-CH2-. Methylene is preferred.

It will be apparent to those skilled in the art that, because the compounds of Formula I, II, III, or IV contain a double bond, depending on the meanings given to Y, geometric isomerism is possible. In naming the compounds of Formula I, II, III, or IV herein, the prefixes (E) and (Z) are used in the conventional manner to indicate the stereo10 chemistry at the double bond. If no stereochemical designation is given, both the substantially pure isomers, or mixtures thereof, are meant.

Preferred compounds of Formula III or IV are those wherein R is phenyl or phenyl mono, di-, or tri-substituted by (Ci-Cg)alkyl, (Ci-Cg)alkoxy, (Cj-Cg)alkylcarbonyloxy, chlorine, bromine, iodine, fluorine, trifluoromethyl, nitro, (C^-Cg)alkylcarbonyl, benzoyl, or phenyl. Moat preferred compounds of Formula III or IV are those wherein R is phenyl, (Cj-Cg)alkoxyphenyl, e.g. methoxyphenyl or ethoxyphenyl, di(C-C )alkoxyphenyl, e.g. 8 dimethoxyphenyl or diethoxyphenyl, (C^-Cg)alkylphenyl chlorophenyl, trifluoromethylphenyl, 1-naphthyl, or 2-naphthyl. Most preferred compounds of Formula IV are those wherein A is methylene.

Illustrative embodiments of Formula III or IV are: 2-phenyl-3-fluoroallyl alcohol, 2-benzyl-3-fluoroallyl alcohol, 2-(2'-methoxy)phenyl-3-fluoroallyl alcohol, 2-(3'-methoxy)phenyl-3-fluoroallyl alcohol, 2-(4'-methoxy)phenyl-3-fluoroallyl alcohol, 2—(2',3'-dlmethoxy)phenyl-3-fluoroallyl alcohol, 2-(2' ,4'-dimethoxy)phenyl-3-fluoroallyl alcohol,' 2-(21,5*-dimethoxy)phenyl-3-fluoroallyl alcohol, 2-(2·,6'-dimethoxy)phenyl-3-fluoroallyl alcohol, 2-(31,41-dimethoxy)phenyl-3-fluoroallyl alcohol, 2-(3',5'-dimethoxy)phenyl-3-fluoroallyl alcohol, 2-(21-me thoxy)benzyl-3-fluoroally1 alcohol, 2-(3'-methoxy)benzyl-3-fluoroallyl alcohol, 2-(4'-methoxy)benzyl-3-fluoroallyl alcohol, 2-(21,3'-dimethoxy)benzyl-3-fluoroallyl alcohol, 2-(21,4'-dimethoxy)benzyl-3-fluoroallyl alcohol, 2-(2·,S'-dimethoxy)benzyl-3-fluoroallyl alcohol, 2-(2',6'-dimethoxy)benzyl-3-fluoroallyl alcohol, 2-(3·,4'-dimethoxy)benzyl-3-fluoroallyl alcohol, 2-(3',5'-dimethoxy)benzyl-3-fluoroallyl alcohol, 2-(1-naphthyl)-3-fluoroallyl alcohol, 2-(2-naphthyl)-3-fluoroallyl alcohol, 2-(2'-methyl)phenyl-3-fluoroallyl alcohol, 2-(3'-methyl)phenyl-3-fluoroallyl alcohol, 2-(4'-methyl)phenyl-3-fluoroallyl alcohol, 2-(2'-chloro)phenyl-3-fluoroallyl alcohol, 2-(3’-chloro)phenyl-3-fluoroallyl alcohol, 2-(4*-chloro)phenyl-3-fluoroallyl alcohol, 2-(21-trifluoFomethyl)phenyl-3-fluoroallyl alcohol, 2-(3'-trifluoromethyl)phenyl-3-fluoroallyl alcohol, 2-(4'-trifluoromethyl)phenyl-3-fluoroallyl alcohol, 2-(21-methyl)benzyl-3-fluoroallyl alcohol, 2-(3'-methyl)benzyl-3-fluoroallyl alcohol, 2-(4’-methyl)benzyl-3-fluoroallyl alcohol, 2-(2'-chloro)benzyl-3-fluoroallyl alcohol, 2-(31-chloro)benzyl-3-fluoroallyl alcohol, 2-(4’-chloro)benzyl-3-fluoroallyl alcohol, 2-(2'-trifluoromethyl)benzyl-3-fluoroallyl alcohol, 2-(3'-trifluoromethyl)benzyl-3-fluoroallyl alcohol, 2-(4'-trifluoromethyl)bfenzyl-3-fluoroallyl alcohol.

The manner and process for preparing the compounds of Formula 1 or II will now be discussed with reference to the DRAWINGS. The compounds of Formula I and II can be prepared in general by the process steps depicted in SCHEME I of the DRAWINGS. In SCHEME I, the symbols Ra, Rp. Rc/ K^, Kc, B, Q, Y, W, and Z in the various formula have the following meanings: Ra is R- or R-A- wherein R and A have the meanings defined with respect to Formula I and II; Rb is tert-butyl, benzyl, diphenylmethyl, or triphenylmethyl; Rc is (C1-C4) straight-chain alkyl, tert-butyl, benzyl, diphenylmethyl, or triphenylmethyl; R,3 is hydrogen or straight-chain (0χ-04)alkyl? Z is a halomethyl group of the formula: -CHFXa or -CF2Xa wherein Xa is fluorine, chlorine, bromine, or 05 iodine? X is fluorine? Y is hydrogen or fluorine? Q la·chlorine, bromine, iodine, benzenesulfonyloxy, £-toluenesulfonyloxy (tosyloxy), methylsulfonyloxy (mesyloxy), or other leaving group; B is the hexamethylenetetrammonlum group, or the phthalimido, succinimido, maleimido group, or a group of the formula -NHCO R wherein R is 2 e e CC -C4)alkyl; or other group capable of generating a primary amino group; and V is ) , j) . or .

The process depicted in SCHEME I comprises the following steps: (1) Halomethylating a malonic acid diester of Formula (1) to form the halomethyl diester of Formula (2) Qstep A J. (2) Hydrolysing the halombthyl diester under acidic conditions or catalytically hydrogenating the 3 S3457 dieater to cleave one or both of the ester groups and then treating the Intermediate soproduced with a base, whereby the Intermediate undergoes decarboxylation and elimination of a halide ion to form the acrylic acid or acrylate ester of Formula (3) £ Step B 3. (3) Reducing.the acrylic acid or acrylate ester to form the allyl alcohol of Formula (4) Q Step C J (4) Replacing the hydroxy group of the allyl alcohol of Formula (4) with a primary amino group to form the allyl primary amine of Formula (8), via formation of intermediates of Formula (5), Formula (6), or Formula (7) QSteps D - J J.

The individual process steps shown in SCHEME I, and described in general above, can be carried out in , a manner known per se in the art of chemistry.

Examples of the methods that can be employed for carrying out the particular transformations depicted in SCHEME I are described as follows: In Step A, a diester of Formula (1) is halomethylated in manner known per se by first treating the diester with a strong base to produce the corresponding carbanion and then contacting the carbanion with a suitable halomethylating agent. The strong base must be non-niibleophillc and be of sufficient strenght to remove a proton from the carbon atom adjacent to the carboxy groups of the starting diester. Suitable such bases ar.e known in the art. Examples are: (a) an alkyl lithium (e.g. n-butyl5 lithium), (b) an aryl lithium (e.g. phenyllithium), (c) a lithium dialkylamide (e.g. lithium diisopropylamide), (d) sodium or lithium amide, (e) a metal hydride (e.g. sodium or potassium hydride), (f) metal alcoholate (e.g. sodium or potassium tert-butoxlde). or (g) lithium or dilithium acetylide. The reaction between the diester and the base can be performed in an aprotic organic solvent £ such as tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethoxyethane, or dioxane, or mixtures thereof!, using ambient temperature and a reaction time ranging from about 5 minutes to about 2 hours. Preferred bases for forming the carbanion are sodium hydride in dimethoxyethane, potassium tert-butoxide/n-butv11ithlum in THF, or sodium tert-butoxlde in THF.

Suitable halomethylating agents are, for example, the polyhalomethanes of the formula: CHgFXa, CHF(Xa)2, or CF2(Xa)2 wherein Xa is chlorine, bromine, or iodine; Β 3 <1 & ΐ The selection of the particular polyhalomethane to be employed for the introduction of the halomethyl group desired in the compounds of Formula (2) will be apparent to those skilled in the art. Preferred polyhalomethanes are: CHClFj and CHBrF2 for introducing the -CHF2 group; The halomethylation of the carbanion can be carried out ln situ by adding the appropriate polyhalomethane at a temperature range of about ambient to 60·0 and allowing the reaction to proceed for about 15 minutes to 16 hours. Depending upon the reactivity of the reactants, the polyhalomethane can be introduced at a higher temperature (about 40*0, and the reaction mixture can be allowed to cool to room temperature to complete the reaction, or the polyhalomethane can be Introduced at room temperature.

A preferred procedure for carrying out Step A employs reacting the diester with sodium tert-butoxide in THF at ambient temperature for about 30 minutes to form the carbanion, treating the carbanion in situ S3457 with the halomethylating agent at 45eC for about 5 minutes, and allowing the reaction mixture to stand for about 1 hour at room temperature.

Step B can be carried out in manner known per se in two stages. In-the first stage, the halomethylmalonic acid diester of Formula (2) is cleaved by acid hydrolysis or by catalytic hydrogenation to convert either one or both of the ester groups (-COOR or b COOR ) to a free carboxylic acid group. Whether c cleavage of one or both ester groups occurs will depend upon the nature of each ester group and the conditions employed for the cleavage reaction. In order to effect cleavage of only one ester group, it is preferred that the diester be mixed, the groups defined .by R. and R being chosen so that' the ester o c group -COORb can be selectively cleaved without cleaving the ester group -COOR . The selection of c particular ester groups which can be selectively cleaved and methods for performing the selective cleavage will be apparent to those skilled in the art.

To accomplish selective cleavage of the diester, it is preferred to employ a halomethyl mixed diester of . Formula (2) wherein R is tert-butyl, benzyl, b diphenylmethyl, or triphenylmethyl and R is a c straight-chain (C -C )alkyl group (such as methyl, 4 ethyl, propyl, or n-butyl). 534S7 The ester group defined by -COOR can be b selectively hydrolyzed by treatment with an organic or inorganic acid, either with or without an added solvent, using a temperature range of about 0 to 25*C and a reaction time of about 1 to 10 hours. Ambient temperature is preferred. The choice of the acid for the hydrolysis is not critical, except that the acid should be chosen so that It can be easily removed after the hydrolysis stage. Trifluoroacetic acid is preferred since its low boiling point permits it to be easily.removed from the hydrolysis product. When Rfe is benzyl, diphenylmethyl, or triphenylmethyl and R is a c straight-chain (C -C )alkyl group, the ester group 1 4 COOR can also be selectively cleaved by subjecting b the mixed dlester of Formula (2) to catalytic hydrogenolysis using conventional procedures: for example, by treatment under a hydrogen atmosphere in the presence of a catalyst (e.g. Pd/C) at ambient temperature for 1 to 48 hours. As will be apparent to those skilled in the art, the ester groups can be chosen so that both groups can be cleaved simultaneously by acid hydrolysis or catalytic hydrogenolysis. Thus, when it is desired to cleave both ester groups simultaneously, each of Rfa and Rc should be a tert-butyl, benzyl, diphenyl, or 53437 triphenylmethyl group. In the second stage of Step B, the acid obtained by cleavage of the diester (either a diacid or a mixed acid-ester) is treated with a base whereby the acid undergoes decarboxylation and S elimination of halide ion to afford the acrylic acid or the acrylate ester of Formula (3). Whether the product is an ester QR^ is a straight-chain (C.-C.)alkyl group 3 or an acid (R is hydrogen) C depends upon whether the cleavage reaction in the first stage was performed selectively or nonselectively. The reaction can be performed using an aqueous or non-aqueous solvent. Strong bases, such as sodium hydroxide and the like, or weak bases, such as triethylamine or sodium bicarbonate, can be used.

However, with strong bases, care must be taken to avoid using an excess of base to avoid interaction with the double bond. Weak bases (which do not interact with the double bond) can be used in excess. The choice of a particular base, the reaction solvent, and reaction conditions will be apparent to those skilled in the art. A preferred procedure is to employ aqueous sodium hydroxide in THF at ambient temperature. In general, a temperature range of about 0 to 25eC and reaction time of 15 minutes to 2 hours can be used.

In Step C. the acrylic acid or acrylate ester of Formula (3) is reduced in manner known per se to yield the allyl alcohol of Formula (4). The reducing agent employed for this transformation can be any reagent which is known in the art to be capable of selectively reducing an ester function or carboxylic acid function to the corresponding carbinol in the presence of a double bond. A preferred reducing agent is diisobutylalurainum hydride (DIBAL-Hj Trade Mark) in hexane, THF, diethyl ether, or dichloromethane, or mixtures thereof. In a preferred procedure, a solution of the •acrylate methyl ester in THF is cooled to about 0 to -78*C (preferably 0 to -10°C), the DIBAL-H dissolved in hexane is added, and the temperature of the mixture is allowed to rise to ambiance. The reaction time can < be about 30 minutes to about 5 hours (preferably 1 hour). Acidic work-up of the product is desired.

The allyl alcohol of Formula (4) can be converted to the desired allyl primary amine in manner known per se to be useful for replacing an allylic hydroxyl group by an allylic primary amino group. A preferred method is shown by Step D and Step E. This involves the direct formation in manner known per se of an imido derivative of Formula (6), preferably the phthalimide and subsequent cleavage in manner known per se of the imido group to generate the primary amino group. In Step D. the imido derivative of Formula (6) can be prepared conveniently by treating the allyl alcohol of Formula (4) with the appropriate imide (i.e. phthalimide, succinimide, or maleimide) in the presence of a triarylphosphine (e.g. triphenylphosphine) or a trialkylphosphine and diethyl azodicarboxylate in an aprotic organic solvent (e.g. THF or dioxane). The reaction can be performed using a temperature range of about 0 to about 70°C and a reaction time of about 1 to 24 hours. Ambient temperature is preferred. In Step E, the imido derivative of Formula (6) can be cleaved, preferably by reaction with hydrazine in an organic solvent, such, as an alkanol (e.g. ethanol), at reflux temperature (50 to 100°C) and a reaction time of about 30 minutes to 10 hours. It is preferable to add an acid (e.g. hydrochloric aoid) after-the hydrazine treatment to convert the product to the acid addition salt. Other reagents can be used to cleave the imido function. For example, the imide can be heated with a strong mineral aoid (e.g. hydrochloric or sulfuric acid) or a mixture of hydrochloric acid and acetic acid. Acids, such as hydrobromic acid, which ard reactive towards olefins 1 usually cannot be used. The final products of Formula (8) can be conveniently purified and Isolated as the acid addition salt using conventional purification methods.

The allyl alcohol of Formula (4) can also be converted in manner known per se to the allyl primaryamine via formation (Step F) of the reactive Intermediate of Formula (5), in which the -OH group is replaced by a leaving group (Q). Suitable leaving groups are known in the art. For example, chlorine, bromine, iodine, tosyloxy, or mesyloxy can be employed. Methods for replacing the hydroxy group by the leaving group are known per se. For example, the allyl alcohol of Formula (4) can be treated with a phosphorus trihalide (e.g. PCI. or PBr ) in an organic, 3 3 solvent, such as toluene or benzene, to introduce halogen (e.g. chlorine or bromine). A preferred procedure employs phosphorus tribromide in toluene at a temperature ranging from about 0 to about 25’C (preferably 5 to 10*C) and a reaction time ranging from about 30 minutes to about 5 hours (preferably 1 to 5 hours). The allyl alcohol can also be treated with a tosyl halide or mesyl halide (e.g. tosyl chloride or mesyl chloride) In the presence of a base (e.g. pyridine) to introdutfe the tosyloxy or mesyloxy group. The reactive intermediate of Formula (5) can be converted to the allyl primary amine of Formula (8) in manner known per se by displacement of the leaving group (Q) either in Step J directly by ammonia or in Step 0 by a nucleophilic group (B) which can then be cleaved (Step H) to generate the primary amino group. Ex&mples of groups defined by B in Formula (7) which can be used to generate a primary amino group are the hexamethylenetetrammonium group, an imido group (e.g. phthalimido, succinimido, or maleimido group) or an alkylcarboxyamino group of the formula: -NHCO.R 2 e wherein R is (C-C Jalkyl. The hexamethylenee 14 tetrammonium group can be introduced by treating the reactive intermediate of Formula (5) with hexamethylenetetramine in an organic solvent t e.g. a (C-C ) alkanol or chloroform Ί using ambient l 4 temperature and a reaction time of about 30 minutes to 24 hours. The hexamethylenetetrammonium group can be cleaved to generate the primary amino group by treatment by heating with an aqueous strong acid (e.g. hydrochloric acid), preferably under reflux. Acids which are reactive to the double bond cannot be used. The imido group can be introduced by treating the reactive intermediate of Formula (5) with the appropriate alkali metal imide (e.g. sodium or potassium phthalimide, succinimide, or maleimide) in an organic solvent, such as THF, DMF, DMSO, or dioxane using a temperature range of about 40 to about 100sC (preferably about 60 to about 70*C) and a reaction time of about 2 to about 16 hours (preferably 3 hours). A preferred method employs potassium phthalimide in DMF at a temperature of about 65*C and a reaction time of about 4 hours. The imido group can be cleaved to generate the primary amino group using the methods described supra with respect to Step E of SCHEME I. The alkylcarboxyamino group -NHCOgRe can be introduced by treating the reactive intermediate of Formula (5) with an alkali metal cyanate (e.g. sodium or potassium cyanate) and a (C -C )alkanol using a 14 temperature range of about 70 to 150°C, preferably 100*C, and a reaction time of about 1 to 6 hours, preferably 2 hours. The alkylcarboxyamino group can be cleaved to generate the primary amino group by treatment with iodotrimethylsilane followed by hydrolysis. The reaction with iodotrimethylsilane is performed in an organic solvent (e.g. chloroform) using a temperature range of about 0 to about 100’C, preferably 50*C, and a reaction time of about 1 to 24 hours, preferably 1 to 2 hours.

It should be observed that, in Step B of the method depicted in SCHEME I, when Z is a dlhalomethyl group, elimination of the halide ion gives the geometric isomer in which the remaining halogen located on the double bond is oriented cis to the group represented by R C i.e. the product is a a compound of Formula (3) wherein X is fluorine, and Y le hydrogen 3.

The malonic acid diester of Formula (1) used as the starting compounds in the process depicted in SCHEME 1 are either known compounds or they can be prepared from known compounds using known methods or obvious modifications thereof. In particular, the diesters of Formula (1) can be made by acylating an appropriate carboxylic acid ester of Formula (16a) or (16b), shown below: R CHCOR a 2 2 b (16a) R CHCOR a 2 2 c (16b) In Formula (16a) or (16b), R is R- or RA- wherein R a and A have the meanings defined with respect to Formula I and II; R^ is tert-butyl, benzyl, diphenylmethyl, or tripheny.1 and R is (C^-cp20(straight-chain)alkyl, tert-butyl. benzyl, •diphenylmethyl, or triphenylmethyl. Methods of acylating the ester of Formula (16a) or (16b) are known ln the art. One method Is to treat the ester with a non-nucleophilic strong base to produce the carbanion, and then to treat the carbanion with a suitable acylating agent. Suitable strong bases are known in the art, and are discussed with respect to Step A of SCHEME I. A preferred base is lithium diisopropylamide. Any conventional acylating agent can be employed. A preferred acylating agent Is a reactive halide, of a formic acid alkyl ester, as shown in Formula (17a) or (17b): Hal-COgR^ , Hal-COgR^ (17a) (17b) wherein R& and Rq are as defined supra with respect to 15 Formula (16a) or (16b) and Hal is chlorine or bromine.

In a preferred acylation procedure, an ester of Formula (16a) or (16b) is treated with a base (e.g. lithium diisopropylamide) ln an organic solvent (e.g. THF, diethyl ether, acetonitrile, OMF, DMSO, or dioxane) at a low temperature (e.g. about -30 to about -78*C, preferably -65 to -78’C). The reaction can be allowed to proceed for a period of from 5 minutes to 2 hours, preferably about 1 hour. The acylation reaction can be performed by adding the haloformate ester to the cooled reaction mixture* containing the carbanion and allowing the mixture to warm to room temperature. The acylation is allowed to continue for a period of about 4 to 24 hours, preferably 16 hours.

The diesters of Formula (1) in SCHEME I wherein Ra S is RA-, as defined with respect to Formula II supra, can be made by an alternative method. In this method, a malonic acid diester of Formula (18): RbO£-CK»-co2.Rc: (18) wherein R. and R have the meanings given with respect b c to Formula (17a) and* (17b), supra, is alkylated using an alkylating agent of Formula (19): R-A-Q; (19) wherein RA- has the meaning given with respect to Formula II, supra, and Q is a leaving group, such as chlorine, bromine, iodine, tosyloxy, or mesyloxy. The alkylation is performed in two stages, the first being treatment with a strong base to form the carbanion and the second being treatment of the·carbanion with the alkylating agent. Methods for carrying out the malonic acid ester alkylation are discussed supra and are well known in the art.

In the compounds of Formula II and IV,· the group A is defined as a dival’ent radical which is a S34S7 bridging group inserted between the double bond and the group defined by R . It will be apparent to those skilled in the art that the divalent radical defined by A can be either symmetrical or unsymmetrlcal depending upon the particular radical employed. When A is an unsymetrical divalent radical, It will be understood that the divalent radical must be attached to the double bond by means of the terminal carbon shown on the left side of the divalent formula as written herein, and the divalent radical must be attached to the group defined by R by means of the terminal carbon shown on the right side of the divalent formula as written herein.

In process aspects, the Invention contemplates the methods of preparation as described below: (1) A method for preparing a compound of Formula XII or Formula IV which comprises reducing in manner known per se a compound of the formula: c I COR I d 0 or X- AR I I c « c I I Y COR I d 0 wherein Y, R, and A are as defined with respect to Formula II or Formula III and'R. is d hydrogen or (C -C )alkyl. 4 (2)A method as defined in (1) above wherein the reduction is carried out using diisobutylaluminum hydride.

In the following Examples, all temperatures are in degrees Centigrade Example 1 Ethyl a-earbo-tggt-butoxyQ1.4'-dimethoxy)phenylacetate A solution of lithium dilsopropylamide in THF is 5 prepared at 5*C by the addition of n-butyllithium (200 ml, 1.4 M) to dilsopropylamide (41.2 ml) in THF (SOO ml). The temperature is lowered to about -65*0 and a solution of tert-butyl 3,4-dimethoxyphenylacetate (65 g) in THF (100 ml) is added. After 1 hour at this temperature, the reaction mixture is treated with a solution of ethyl chloroformate (33.02 g) in THF (100 ml). Cooling is removed and the solution is stirred overnight at room temperature. The solvent is evaporated and the residue mixed with ether, is washed consecutatlvely with N HCl, water, and brine. The ether solution is dried and the solvent removed by evaporation. The product (91.86 g, yellowish oil) is purified by chromatography on silica gel (1 kg) using as eluant 20 % ether/80 % light petroleum to give ethyl 2-carbo-tert-butoxy(31.41-dimethoxy)pheny1acetate (61.79 g): NMR (CC14): δ 1.25, t (J 7 Hz), 3H; 1.43, s, 9H; 3.75, 3.78, two s, 6H; 4.12, q (J - 7 Hz), 2H; 4.25, s, IH; 6.72, s, 2H; 6.85, 8, IH.

Analysis for CJ7H240g: Found : C, 62.96; H, 7.26 X.

Requires : C, 62.95; H, 7.46 X. aji ii ι Example 2 Ethyl 2-carbo-tsrt-butoxy(41-methoxy)phenylacetate A solution of lithium diisopropylamide in THF (500 ml) is prepared at 5 by the addition of nbutyllithium (427 ml of 1.5 M solution) to - diisopropylamine (89.5 ml; 64.64 g) in THF (500 ml).

The temperature is lowered to about -65® and a solution of tert-butyl 4-methoxyphenylacetate (70.47 g) in THF (100 ml) is added over about 5 minutes. After 1 hour at this temperature, the reaction mixture is treated with a solution of ethyl chloroformate (34.5 g) in THF (100 ml). Cooling is removed and the solution is stirred overnight at room IS. temperature. 6 N HCI (53 ml) is added slowly so that the temperature does not rise above 20®. The THF is evaporated and the residue, dissolved in ether, is washed consecutatively with water, 1 N HCI, and water (x 4). The ether solution is dried and the solvent is removed by evaporation to give ethyl 2-carbo-tertbutoxy(4'-methoxy)phenylaoetate (93.76 g): orange oil, b.p. 124 - 125®/0.05 mm: NHR (CDClg): $-1.17, t (J - 7 Hz), 3H; 1.38, s. 9H; 3.67, s, 3H; 4.10, q (J = 7 Hz), 2H; 4.37, s, IH; centred at 6.96, A2B2(JAB = 9 Hz), 4H.

Example 3 Repeating the procedure of Example 1, but using the appropriate starting materials ln place of tertbutyl 3,4-dimethoxyphenylacetate the following compounds are obtained: . (a) Ethyl 2-carbo-tert-butoxyphenylacetate: b.p. 90·/0.06 mm: NMR (CC14): « 1.22, t (J - 7 Hz), 3H; 1.38, s, 9H; 4.07, q (J - 7 Hz), 2H; 4.32, s, IH; 7.22, s, 5H. (b) Ethyl 2-carbo-tert-butoxy(31-methoxy)phenylacetate: b.p. 132-133‘/0.04 mm: NMR (CC14): < 1.20, t (J - 7 Hz), 3H; 1.37, s, 9H; 3.70, a, 3H; 4.07, q (J « 7 Hz), 2H; 4.23, S, IH; 6.52 to 7.20, m, 4H. (c) Ethyl 2-carbo-tert-butoxyphenylpropionate: b.p. 95·/0.05 mm (oven): NMR (CDCI/: β 1.20, t (J - 7 rfz), -3H{ 1.40, 8, 9H; 3.17 and 3.55, ABg system, 3H; 4.17, q (J - 7 Hz), 2H; 7.22, S, 5H.

Example 4 Repeating the procedure of Example 2, but using the appropriate starting materials in place of tertbutyl 4-methoxyphenylacetate, the following compounds are obtained: (a) Ethyl 2-carbo-tert-butoxy(21-methoxy)phenylacetate: NMR (CCl ^): « 1.23. t (J - 7 Hz), 3H; 1.45, s, 9H; 3.77, s, 3H; 4.87, s, IH; 4.13, 6.67 q to (J - 7 Hz), 2H; 7,43, m, 4H. Analysis for C H 0 ; -^----16-22¾ Found : C, 65.04; H, 7.26 X Requires : C, 65.29; H, 7.53 % (b) Ethyl 2-carbo-tert-butoxy(4'-chloro)phenylaeetate: 10 m.p. 56-57·: NMR (CDC1 ): « 1.27, t (J - 7 Hz), 3H; 1.47, s, 9H; 4.19, q (J =* 7 Hz), 2H; 4.52, s, IH; 7.35, s, IH. Analysis for C^Ji^ClO^: 15 .Found : C, 60.32; H, 6.28 % Requires : C, 60.30; H, 6.41 X (c) Ethyl 2-carbo-tert-butoxy(31-trifluoromethyl)phenylacetate: NMR (CCl ): ί 1.23, t (J - 7 Hz), 3H; 1.43, s, 9H 20 4.13, q’(J - 7 Hz), 2H; 4.43, a, IH; 7.37 to 7.70, m; 4H.

Analysis for C F£ j Found : G, 57.97; H, 5.69 % Requires : C, 57.83; H, 5,76 % 534 57 (d) Ethyl 2-carbo-tert-butoxy(41-methoxyjphenylproplonate: NMR (CDClg): β 1.20, t (J « 7 Hz), 3H; 1.38, s, 9H; 3.12 and 3.50, ABg system, 3H; 3.75, a, 3H; 4.15, q (J - 7 Hz), 2H; centred at 6.97, AgBg system (J - 9 Hz), 4H.

Analysis for C Found : C, 66.34; H, 7.94 % Requires : C, 66.21; H, 7.84 % Example 5 Ethyl 2-dlfluoromethyl-2-carbo-tgrt-butoxy(31^'-dlmethoxyjphenylacetate A solution of ethyl 2-carbo-tert-butoxyO'.4'15 dlmethoxy)phenylacetate (9.72 g) in dimethoxyethane (DME, 80 ml) is added to sodium hydride (1.68 g as a 50-55 % dispersion in oil which was previously washed free of oil with light petroleum). When anion formation is complete the reaction mixture is heated to about 40* and a stream of chlorodifluoromethane (Freon Trade Mark) 22) is bubbled through the mixture for a few minutes. A balloon is attached to the reaction vessel and the Freon 22'is added until the balloon is full. The heating bath is then removed and the mixture ls stirred for about 16 hours. The DME is partially evaporated and the residue is mixed with water and extracted with ether. The ether solution is washed with brine and dried (MgSO^). Evaporation of the solvent gives crude ethyl 2-difluoromethyl-2-carboS tert-butoxy(3'^'-dlmethoxyjphenylacetate (9.93 g): pale-orange oil: NMR (CC14): i 1.25, t (J = 7 Hz), 3H; 1.42, s, 9H; 3.73, s, 6H; 4.20, q (J » 7 Hz), 2H; 6.25, t (J « 56 Hz), IH; 6.68, s, 2H; 6.78, s (broad), IH.

Example 6 Repeating the procedure of Example 5 but substituting the appropriate starting material in place of ethyl 2-carbo-tert-butoxy(31,4'15 dimethoxy)phenylacetate, the following compounds are obtained: (a) Ethyl 2-difluoromethyl-2-carbo-tert-butoxyphenylacetate: NMR (CC14): β 1.27, t (J - 7 Hz), 3H; 1.47, s, 9H 20 4.18, q (J » 7 Hz), 2H; 6.30, t (J = Hz), IH; 7.30, s, 5H.

Analysis for cieH3Q^2°4: Found : ¢, 61.49; H, 6.48 % Requires : C, 61.14; H, 6.41 % 3457 (b) Ethyl 2-dlfluoromethyl-2-carbo-tert-butoxv(4lmethoxy)phenylacetate: b.p. 118-119·/0.05 nun: NMR (CDCI,): 4 1.23, t (J - 7 Hz), 3H; 1.42, s, • 9H; 3.67, S, 3H; 4.20, q (J 7 Hz), 2H; 6.30, t (J · 57 Hz), IH; centred at 6.97, A2B2 (J - 9 Hz), 4H. tc) Ethyl 2-dlfluoromethyl-2-carbo-tert-butoxy(3lmethoxy)phenylacetate: b.p. 101-108°/0.05 mm: NMR (CDCI ): 4 1.16, t (J - 7 Hz), 3H; 1.37, s, 9H; 3.63, a, 3H; 4.05, q (J 7 Hz), 2H; 6.38, t (J - 54 Hz), IH; 6.63 to 7.28, m, 4H.

Analysis for C^lU.0,: Found ; C, 59.16; H, 6.41 % IS Requires : C, 59.29; H, 6.44 % (d) Ethyl 2-difluorcmcthyl-2-carbo-tert-butoxy(4*chloro)phenylacetate: NMR (CCl^): « 1.28, t (J 7 Hz), 3H; 1.48, s, 9H; 4.27, q (J - 7 Hz), 2H; 6.38, t (J 20 55 Hz), IH; 7.28, s. 4H. (e) Ethyl 2-dlfluoromothyl-2-carbo-tert-butoxyphenylproplonate: NMR (CDClg): 4 1.25, t (J 7 Hz), 3H; 1.43, s, 9H; 3.38, s, 2H; 4.20, q (J · 7 Hz), 2H; 6.03, t (J - 55 Hz), IH; 7.23, s, « 5H. 6 Analysis for cj.7H32F;°^· Found : C, 62.56; H, 6.80 % Requires : C, 62.18; H, 6.75 % Example 7 Repeating the procedure of Example 5 but substituting the appropriate starting materials in place of ethyl 2-carbo-tert-butoxy(3',4'dimethoxy)phenylacetate, and potassium-tertbutoxlde/n-butyllithium in THF in place of sodium hydride in DME, the following compounds are obtained: (a) Ethyl 2-difluoromethyl-2-carbo-tert-butoxy(21methoxylphenylacetate: NMR (CC14): β 1.25, t (J = 7 Hz), 3H; 1.47, s, 9H; 3.73, s, 3H; 4.22, q (J « 7 Hz), 2H; IS 6.53, t (J « 56 Hz), IH; 6.67 to 7.50, m, 4H.

Analysis for C^HpgFwOg: Found : C, 59.24; H, 6.45 % Requires : C, 59.29; H, 6.44 % (b) Ethyl 2-difluoromethyl-2-carbo-tert-butoxy(3'trifluoromethyl)phenylacetate: NMR (CC14): β 1.30, t (J « 7 Hz), 3H; 1.50, s, 9H; 4.35, q (J 7 Hz), 2H; 4.87, t (J « 55 Hz), IH; 7.60, m; 4H; (c) Ethyl 2-dlfluoromethyl-2-carbo-tert-butoxy(41methoxy)phenylproplonate: NMR (CDC13): s 1.25, t (J 7 Hz), 3H; 1.42, s, 9H; 3.33, a, 2H; 3.73, s, 3H; 4.18, q (J 7 Hz), 2H; 6.00, t (J - 54 Hz), IH; centre at 6.92, AgBg (JAB «9 Hz), 4H.

Analysis for C H F 0 : --18“24- 2'5 Found : C, 60.43; H, 5.71 % Requires : C, 60.32; H, 6.75 X Example 8 Ethyl (E)-2-(3',4’-dimethoxy)phenyl-3fluoroacrylate A solution of ethyl 2-dlfluoromethyl-2-carbo15 tert-butoxy(3*,4l-dlmethoxy)phenylacetate (61.70 g) in trifluoroacetic acid (152 ml) is stirred at room temperature for 1 hour whereupon the mixture is evaporated to dryness. The residue is dissolved in tetrahydrofuran (THF, 70 ml) and treated with aqueous sodium hydroxide (2M, 63 ml) at room temperature for IS minutes. The reaction mixture is diluted with water and extracted with ether. The ether solution is washed with brine, dried (MsSO ), and evaporated to yield an 4 orange oil (44.05 g). Chromatography on silica gel (200 g) using 20 X ethyl apetate in light petroleum as 3S ©luant affords an oil (39.70 g) which slowly esystallizes. Purification by recrystallization from n-sentane gives ethyl (E)-2-{3',4'-dimethoxy)phenyl3-fluoroacrylate: colorless plates, m.p. 71-72·: NMR (CC1/: β 1.27, t (J - 7 Hz), 3H; 3.75, s, 6H: 4.15, q (J - 7 Hz), 2H; 6.72, s, 3H; 7.53, d (J - 42 Hz), IH.

Analysis for °13Η1^°4; Found : C, 61.49; H, 5.94 % Requires : C, 61.41; H, 5.95 % Example 9 Repeating the procedure of Example 8 but substituting the appropriate starting materials for - 2-difluoromethyl-2-carbo-tert-butoxy(3’,4'15..dimethoxy)phenylacetate, the following compounds are obtained: (a) Ethyl (E)-2-phenyl-3-fluoroacrylate: b.p. 81e/0.4 mm: NMR (CC14): « 1.25, t (J « 7 Hz), 3H; 4.18, q (J « 7 Hz), 2H; 7.27, s, 5H; 7.80, d (J 81 Hz), IH. (b) Ethyl (E)-2-(3'-methoxy)phenyl-3-fluoroacrylate: b.p. 74-75®/0.05 mm: NMR (CDCI/: β 1.35, t (J . 7 Hz), 3H; 3.80, s, 3H; 4.25, q (J · 7 Hz), 2H; 6.77 to 7.47, m, 4H; 7.72, d (J - 82 Hz), IH.

· Analysis for ! Found : C, 63.93; H, 5.89 * Requires : C, 64.28; H, 5.84 % (c) Ethyl (E)-2-(2'-methoxy)phenyl-3-fluoroacrylate: b.p. 88·/0.05 mo: NMR (CC14): 4 1.20, t (J 7 Hz), 3H; 3.72, s, 3H; 4.13, q (J - 7 Hz), 2H; 6.67 to 7.42, m, 4H; 7.57, d (J - 82 Hz), IH.

Analysis for C^H^gFOg: Found : C, 64.45; H, 5.82 % Requires : C, 64.28; H, 5.84 % (d) Ethyl (E)-2-(3·-trifluoromethyl)phenyl-3fluoroacrylate: NMR (CDClg): 4 1.30, t (J - 7 Hz), 3H; 4.28, q (J 15 7 Hz), 2H; 7.55, ra, 4H; 7.80, d (J a 80 Hz), IH. (e) Ethyl (E)-2-(4'-chloro)phenyl-3-fluoroaerylate: NMR (CC14): 4 1.27, t (J a 7 Hz), 3H; 4.22, q (J 7 Hz), 2H; 7.27, s, 4H; 7.67, d (J a 20 81 Hz), IH. (f) Ethyl (E)-2-(4'-methoxy)benzyl-3-fluoroacrylate: b.p. 104·/0.04 mm: NMR (CDClg): 4 1.18, t (J 7 Hz), 3H; 3.53, d (J a 3 Hz), 2H; 3.70, s, 3H; 4.12, q (J a 7 Hz), 2H; centred at 6.93, AgBg (JAB - 9,Hz), 4H; 7.55, d (J ·« 83 Hz), IH.

Analysis for s Found : C, 65.50; H, 6.49 X Requires : C, 65.53; H, 6.34 X (g) Ethyl (E)-2-ben2yl-3-fluoroacrylate: b.p. 75· (oven)/0..05 nun: NMR (CDC1 ): « 1.18, t (J - 7 Hz), 3H; 3.60, d (J 11 3 - 3 Hz), 2H; 4.12, q (J - 7 Hz), 2H; 7.18, s, 5H; 7.60, d (J - 83 Hz), IH. (h) Ethyl (E)-2-(4'-methoxy)phenyl-3-fluoroacrylate: b.p. 89-90®/0.04 mm: NMR (CDC1 ): « 1.42, t (J - 7 Hz), 3H; 3.90, s, w 3H; 4.37, q (J = 7 Hz), 2H; centred at 7.17, A2B2 (Jab d (J 80 Hz), IH.

Analysis for ci:h13fQ3: Hz), 4H; 7.77, Found : C, 63.80; H, 5.83 X Requires : C, 64.28; H, 5.84 X Example 10 (£)-2-(31^'-Dlmethoxyjphenyl-S20 fluoroallyl alcohol A solution of ethyl (£)-2-(31,4'-dimethoxy)-3fluoroacrylate (35 g) in THF (650 ml) is cooled to about -78® and treated with a solution of diisobutylaluminum hydride (690 mi) in hexane (1 M solution). The cooling bath is removed and the 63457 temperature ia allowed to rise to room temperature over about 4 1/2 hours. The solution is again cooled (ca 5*) and is then cautiously treated with methanol (140 ml) followed by 10 % aqueous KOH (70 ml). The mixture is dried by the addition of MgSO^ and filtered. The solids are washed thoroughly with -methanol. Solvent is removed by evaporation to leave an almost colorless, crystalline mass (25.48 g). Usually, this product la used directly in the next reaction step without purification. If necessary, the product can be recrystallized from n-hexane which gives (E)-2-(3‘,4'-dimethoxy)phenyl-3-fluoroallyl alcohol: colorless plates, m.p. 56-57°: NMR (CDClg): « 2.60, s (broad), IH; 3.83, s, 6H; 4.25, d (J - 5 Hz), 2H; 6.78, d (J 83 Hz), IH; 6.68 to 7.20, m; 3H.

Analysis for : Found : C, 62.21; H, 6.32 % Requires : C, 62.26; H, 6.17 % Example 11 Repeating the procedure of Example 10 but substituting the appropriate starting materials for ethyl (E)-2-(3,4-dimethoxy)phenyl-3-fluoroacrylate, the following compounds are obtained: a 3 a ϊ> i (a) (E)-2-Phenyl-3-fluoroallyl alcohol: NMR (CDCl ): « 1.68, s, IH; 4.33, d (broadened, J “ 3 « 5 Hz), 2H; 6.17, 3.Ί/2 H; 7.20 to 7.63, m, 5 1/2 H.

S (fe) (E)-2-(3'-Methoxy)phenyl-3-fluoroallyl alcohol: m.p. 47-48·: NMR (CDCl ): « 2.13, 8, IH; 3.85, s, 3H; 4.37, m, w 2H; 6.92, d (broad, J - 82 Hz), IH; 7.13 to 7.53, m, 4H. (e) (E)-2-(2'-Methoxy)phenyl-3-fluoroallyl alcohol: NMR (CCIJ: δ 3.27, s, IH; 3.67, s, 3H; 4.08, d.d (J - 5Hz, 1.5 Hz), 2H; 6.60 to 7.40, m, 4H; 6.45, d (J · 82 Hz), IH. (d) (E)-2-(3*-Trifluoromethyl)phenyl-3-fluoroallyl 15 alcohol. (e) (E)-2-(4'-Chloro)phenyl-3-fluoroallyl alcohol. (f) (E)-2-(4,-Methoxy)benzyl-3-fluoroallyl alcohol: NMR (CDCl ): β 2.48, s. (broad), IH; 3.30, d (J - 2 Hz), 2H; 3.60, s, 3H; 3.70, d (J « 4 Hz), 2H; 6.52, d (J « 84 Hz), IH; centred at 6.82, A B (J «9 Hz), 2 AB 4H. (g) (E)-2-Benzyl-3-fluoroallyl alcohol: NMR (CC14): δ 3.43, m, 3H; 3.72, d (broad, J = 4 Hz), 2H; 6.53, d (J » 85 Hz), IH; 7.17, m, 5H.

B3457 (h) (E)-2-(4'-Methoxy)phenyl-3-fluoroallyl alcohol: m.p. 43-44·: NMR (CDC13): β 1.93, 8, IH; 3.80, s, 3H; 4.33, d (broad, J - 4.S Hz), 2H; 6.82, d (J 5 82 Hz), IH; centred at 7.20, AgBg (J^ - 9 Hz).

Example 12 A solution of (E)-2-(3·,4'-dimethoxy)phenyl-3fluoroallyl alcohol (25 g), triphenylphosphine (31.23 g). and phthalimide (17.52 g) in THF (450 ml) is treated with a solution of diethyl azodicarboxylate (20.74 g) in THF (100 ml). The mixture is then stirred fop about 16 hours. The THF is evaporated, and the by-products are largely removed by recrystalllzatlon from toluene, and then from ether. The solvent is evaporated and the residue is purified by chromatography on silica, gel (l kg) using 20 X ethyl acetate in light petroleum. The major fraction (20.46 g) is recrystallized from dichloromethane/nhexane to give (E)-l-fluoro-2-(3',4'-dimethoxy)j?henyl-3-phthalimidopropene (16.50 g): colorless plates, m.p. 102-103°: S3457 1 NMR (CDC1 ): * 3.80, 3.85, two overlapping 3 aingleta, 6H; 4.52, m, 2H; 6.32, s, 1/2 H, 6.68 to 7.28, m, 3H; 7.52 to 7.88, m, 4 1/2 H.

Analysis for c13HlcFM04i Found : C, 66.76; H, 4.89; N, 4.34 % Requires : 0, 66.86; H, 4.72; N, 4.10 % Example 13 Repeating the procedure of Example 12 but substituting the appropriate starting materials for (E)-.2-(3·,4'-dimethoxy)phenyl-3-fluoroallyl alcohol, the following compounds are obtained: (a) (E)-l-Fluoro-2-phenyl-3-phthalimidopropene: m.p. 98-99°: NMR (CDC1 ): « 4.55, m, 2H; 6.32, s (broad), 1/2 H; 7.13 to 7.93, m, 9 1/2 H.

Analysis for. C^H^FNO,.: Found : C, 72.63; H, 4.49; N, 4.47 % Requires : C, 72.59; H, 4.30; N, 4.98 % (b) (E)-l-Fluoro-2-(3'-methoxy)phenyl-3phthalimidopropene: m.p. 85-86°: NMR (CDClg): « 3.80, s, 3H; 4.57, m, 2H; 6.30, s •(broad), 1/2 H,; 6.63 to 7.43, m, 4H 7.50 to 7.96, m, 4 1/2 H. (c) (Ε)-l-Fluoro-2-(2'-methoxy)pheny1-3phthalimidopropene: m.p. 128-129·: NMR (CDC13): < 3.68, β, 3H; 4.50, m, 2H; 6.20, s, 1/2 H; 6.53 to 7.40, m, 4H; 7.60, m, .4 1/2 H.

Analysis for CiqHi4FW°3: Found : C, 69.43; H, 4.69; N, 4.48 X Requires : C, 69.45; H, 4.53; N, 4.50 X (d) (E)-l-Fluoro-2-(3'-trifluoromethyl)phenyl-310 phthalimidopropene: NMR (CDC1 ): « 4.57, d (J - 4 Hz, broad), 2H; 3.82, s, 1/2 H; 4.38 to 7.83, m, 8 1/2 H. (e) (E)-l-Fluoro-2-(4’-chloro)phenyl-315' phthalimidopropene: m.p. 118-119·: NMR (CDClg): « 4.50, m, 2H; 6.32, a (broad), 1/2 H; 7.07 to 7.83, m, 8 1/2 H.

. · Analysis for C^H^CIFNO:,; Found : C, 64.57; H, 3.67; N, 4.32 X Requires : C, 64.67; H, 3.51; N, 4.44 X (f) (E)-l-Fluoro-2-(4'-methoxy)benzyl-3phthalimldopropene: m.p. 138-139·: NMR (CDC1 ):’« 3.33, d (J -2.5 Hz), 2H; 3.58, s, 3H; 4.07, d (J - 3 Hz), 2H; centred at 6.83, AB (J - 9 Hz), 4H; 6.88, 2 AB d (J - 86 Hz), IH; 7.68, s (broad), 4H. (g) (E)-l-Fluoro-2-benzyl-3-phthalimidopropene: m.p. 114-115’: NMR (CDClg): β 3.45, d (J 2.5 Hz), 2H; 4.13, d.d (J > 3 Hz, 1 Hz), 2H; 6.21, s (broad), 1/2 H; 7.20 to 7.30, m, SH; 7.67, m, 5 1/2 H.

Analysis for c10Hx4FW02: Found : C, 73.22; H, 5.16; N, 4.63 % Requires : C, 73.21, H, 4.78; N, 4.74 % (h) (E)-l-Fluoro-2-(4'-methoxy)phenyl-3phthalimidopropene: m.p. 169-170’: NMR (CDClg): « 3.78, s, 3H; 4.55, d.d (J = 3.5 Hz, 1.5 Hz), 2H; 7.00, m, 1/2 H; centred at 7.50, A2B2 (Jab « 9 Hz), 4H; 7.63 to 7.90, m, 4 1/2 H.

Analysis for Cj^gH^^FNOg: Found : C, 69.42; tt, 4.51; N, 4.40 % Requires : C, 69.45; H, 4.53; N, 4.50 % .Example 14 (E)-2-(31,4'-Dimethoxy)phenyl3-fluoroallylamlne A mixture of (E)-l-fluoro-2-(3·,4'-dimethoxy)> phenyl-3-phthallmldopropene (6.82 g) and hydrazine hydrate (1.10 g) in methanol (45 ml) is refluxed for 3 hours. To the reaction mixture, ls added 18 % aqueous B34&7 hydrochloric acid (12 ml). Refluxing ie continued for another 30 minutes. The mixture is cooled and filtered. Solvent is removed by evaporation to give a residue which la triturated several times with methanol. Crystallization of the solid residue from ethanol/diethyl ether gives (E)—2—(3*,4'-dimethoxy)phenyl-3-fluoroallylamine, as the hydrochloride (2.56 g): colorless plates: m.p. 216-217·: NMR (0/): β 3.87, s, 6H overlapping 4.00, d 10 (broad, J 4 Hz), 2H; 7.10, s (broad), 3H; 7.17, d (J - 82 Hz), IH.

Analyels for .C^H^CIFNO/ Found : C, 53.38; H, 6.02; N, 5.60 % Requires : C, 53.34; H, 6.10; N, 5.65 % Example IS Repeating the procedure of Example 14, but substituting the appropriate starting materials for (E)-fluoro-2-(3',4’-dime thoxy)phenyl-3-phthalimidopropene, the following compounds are obtained: (a) (E)-2-Phenyl-3-fluoroallylamlne, as the hydrochloride: m.p. 195-196·: NMR (DgO): « 3.98, d (J 3 Hz), 2H; 7.13, d (J Hz), IH; 7.50, β, 5H.

Analysis for C H^CIFN: Found : C, 57.53; H, 5.93; N, 7.52 % Requires : C, 57.61; H, 5.91; N, 7.46 % (b) (E)-2-(3'-Methoxy)phenyl-3-fluoroallylamine, as the hydrochloride: m.p. 146-147®: NMR (DgO): 4 3.87, a, 3H; 4.00, d (J - 3.5 Hz), 2H; 7.18, d (J - SO Hz), IH; 6.91 to 7.67, m, 4H.

Analysis for C10H iaClFNO: Found : C, 55.25;' H, 5.81; N, 6.41 X Requires : C, 55.18; H, 6.02; N, 6.43 % (c) (E)-2-(2'-Methoxy.)phenyl-3-fluoroallylamlne, as hydrochloride: m.p. 224-225®: Analysis for. C^H^CIFNO: Found : C, 55.10; H, 5.89; N, 6.41 % Requires : C, 55.18; H, 6.02; N, 6.43 % (d) (E)-2-(4'-Chloro)phenyl-3-fluoroallylamine, as the 1-5 hydrochloride: m.p, 190®: NMR (CDgOD): « 3.97, d (broad, J - 4 Hz), 2H; 7.27, d (J - 81 Hz), IH; 7.53, s, 4H.

Analysis for C.H. .Cl.FN: Found : C, 48.47; H, 4.44; N, 6.26 X Requires : C, 48.67; H, 4.54; N, 6.31 X (e) (E)-2-(4'-Methoxy)benzyl-3-fluoroallylamlne, as the hydrochloride: m.p. 185-186®: Analysis for Cj^^H^p.ClFNO: Found : C, 57.09; H, 6.49; N, 6.00 X Requires : C, 57..02; H, 6.53; N, 6.05 X (f) (E)-2-Benzyl-3-fluoroallylamine, as the hydrochloride:*m.p. 179·: NMR (DgO): < 3.50, d.d (J - 3 Hz, 1 Hz), 2H; 3.63, d (J - 2.5 Hz), 2H; 7.05, d.m (J - 62 Hz), IH; 7.37, S, 5H.

Analysis for C,OH,?C1FN: Found : C, 59.30; H, 6.43; N, 6.91 X Requires : C, 59.56; H, 6.50; N, 6.95 X (g) (E)-2-(4'-Methoxy)phenyl-3-fluoroallylamine, as the hydrochloride: m.p. 87·: NMR (DgO): « 3.88, s, 3H; 3.97, d (broad, J - 3.5 Hz), 2H; 7.12, d (J 82 Hz), IH; centred at 7.30, A^B^ (J^g 9 Hz), 4H.

Analysis for θH^3C1FN0: Found : C, 54.84; H, 5.90; N, 6.24 X Requires : C, 55.18; H, 6.03; N, 6.43 X Example 16 (E)-H-Methoxycarbonyl 2-phenyl3-fluoroallylamlne A solution of phosphorus tribromide (227 mg) in toluene (2 ml) is slowly added to a solution of (E)2-pheny1-3-fluoroallyl alcohol (305 mg) in toluene at about -5· so that the temperature does not rise above 0·. The cooling bath is removed and stirring is continued for 3 hours. The reaction mixture is then poured into saturated aqueous potassium carbonate (20 ml). The mixture is extracted with ether and the ether solution is washed with water and dried (MgSO^). Evaporation of solvent gives (E)'-2-phenyl-35 fluoroallyl bromide (318 mg): colorless oil: NMR (CDClg): « 4.13, d (J - 4 Hz), 2H; 6.85, d (J « 80 Hz), IH; 7.10 to 7.50, m, 5H.

Without purification, a portion of this bromide (185 mg) is heated at 100° for 3 hours in dimethylformamide (DMF, 5 ml) containing methanol (65 mg) and potassium cyanate (60 mg). The mixture is cooled and filtered. The filtrate is then diluted with water and extracted with ether. The ether extract is washed with water, dried (MgSO ), and evaporated to 4 give'yellowish solid (135 mg). Recrystallization from diethyl ether/light petroleum gives (E)-N-methoxycarbonyl 2-phenyl-3-fluoroallylamine (123 mg): colorless needles, m.p. 73-74°: NMR (CDClg): « 3.49, s, 3H; 3.90, m, 2H; 5.23, S (broad), IH; 6.00, s (broad), 1/2 H; 7.07 to 7.50, m, 5 1/2 H.

St Example 17 2-Phenyl-3,3-dlfluoroallylamine (A) Ethyl 2-bromodifluoromethyl-2-carbo-tertbutoxyphenylacetate.

A solution of ethyl 2-carbo-tertbutoxyphenyl ace tate (15.84 g, 60 mmol) in tetrahydrofuran (THF, 200 ml) is added to sodium hydride (5.76 g, ca 120 mmol, 50-55 % dispersion in oil which was washed with dry light petroleum to remove the oil). When anion formation is complete, the bath temperature is raised to about 40s and a solution of dlbromodifluoromethane (63 g, 300 ml) in THF (100 ml) is added. The mixture is stirred at this temperature for 30 minutes, and then is allowed to cool to room temperature over 3 1/2 hours. The solvent is evaporated and the residue is treated with water. The water solution is then extracted with ether. The ether extract is washed with water, dried (MgS04), and evaporated to yield a yellow oil (21.21 g).

Chromatography on silica gel (200 g) using an eluant of 3 56 ethyl acetate in light petroleum affords a colorless oil (19.69 g) Of ethyl 2-bromodifluoromethyi-2-carbo-tert-butoxyphenylacetate: NMR (CC14): δ 1.28, t (J - 7 Hz), 3H; 1.52, s, 9H; 4.25, q (J - 7 Hz), 2H; 7.13 to 7.55, m, SH.

The product is contaminated with ethyl 2-difluoromethyl-2-carbo-tert-butoxyphenylacetate and possibly with ethyl 2-dlbromofluoromethyl-2-carbo-tert20 butoxyphenylacetate.

(B) Ethyl 2-phenyl-3,3-difluoroacrylate A solution of impure ethyl 2-bromodifluoro-2carbo-tert-butoxyphenylacetate (20.95 g) in trifluoroacetic acid (44 ml) is stirred at room temperature for 1 hour. Ti\e solvent is removed by S3 evaporation to give a pale-brown oil (17.29 g) which is then dissolved in THF (350 ml) and treated with vigorous stirring with 2 M aqueous sodium hydroxide (25.7 ml, 1 equivalent) for 15 minutes. The solution is then diluted with water and extracted with ether. The ether extract is washed with water, dried (MgSO/, and evaporated. The residual yellow oil (10.80 g) is distilled to afford ethyl 2-phenyl-3,3-difluoroacrylate: colorless oil: NMR (CC14): « 1.25, t (J 7 Hz), 3H; 4.15, q (J 7 Hz), 2H; 7.18, s (broad), 5H? The product may be contaminated with small amounts of ethyl 2-phenyl-3-fluoroacrylate and e.thyl 2-phenyl-3bromo-3-fluoroacrylate. (0) 2-Phenyl-3,3-difluoroallyl alcohol A solution of impure ethyl 2-phenyl-3,3dlfluoroacrylate (7.13 g, 33.6 mmol) ln THF (180 ml) is cooled to about -78° and treated with a solution of diisobutylaluminum hydride (136 mmol) in hexane (1 M solution). The cooling bath is removed and the temperature is allowed to rise to room temperature oVer about 45 minutes. The solution is again cooled (ca 5°) and methanol (50 ml) and then 10 % aqueous potassium hydroxide (13.5 ml) are cautiously added.

The mixture is then dried..(MgSO ) and filtered. ao‘i j ( Removal of solvent yields a yellow oil (4.60 g). Chromatography on silica gel (200 g) using 20 % ethyl acetate in light petroleum gives two major products.

The first-eluted compound is 2-phenyl-3,35 difluoroallyl alcohol (1.94 g), an almost colorless oil: NMR (CC1 ): β 2.70, s, IH; 4.13 to 4.43, m, 2H; 6.98 to 7.35, m, SH.

The oil is used without.purification in the following step. The second-eluted compound ls 2-phenyl-3fluoroallyl alcohol. (1.42 g). In addition to the above fraction, additional material (1.00 g), which is a mixture of the two compounds, is obtained.

(D) 1, l-Difluoro-2-phenyl-3-phthalimidopropene A solution of 2-phenyl-3,3-difluoroallyl alcohol (1.94 g), triphenylphosphine (2.99 g), and phthalimide (1.68 g) in THF (80 ml) is treated with a solution of diethyl azodicarboxylate (1.99’g) in THF (20 ml) at room temperature. The reaction is allowed to proceed about 16 hours. The THF is evaporated. Much of the by-product can be removed by its recrystallization from toluene and then from ether. The ether-soluble material (3.22 g) is purified by chromatography on silica gel (200 g) using 10 % ethyl acetate in light petroleum. Recrystallization of the major portion (2.12 g) from hexane affords 1,1-difluoro-2-phenyl-3phthallmldopropene: colorless needles, m.p. 102-103°: NMR (CC14): « 4.67, m, 2H; 7.28, s (broad), 5H; 7.57 to 7.88, m, 4H.

Analysis for Found : C, 68.40; H, 3.78; N, 4.68 % Requires : C, 68.22; H, 3.70; N, 4.68 % (E) 2-Phenyl-3,3-difluoroallylamlne A mixture of 1,1-difluoro-2-phenyl-310 phthalimidopropene (0.60 g) and' hydrazine hydrate (0.11 g) in ethanol (4 ml) is vigorously stirred and refluxed for 1 hour. Water (4 ml) and concentrated hydrochloric acid (4 ml) are added, and the mixture is refluxed for another hour. The filtrate is washed with ether and evaporated to dryness to leave an almost colorless residue (0.41 g). The crude amine is purified via its N-tert-butoxycarbonyl derivative: colorless needles, m.p. 44-45°: NMR (CC14): 4 1.33, s, 9H; 3.93 to 4.27, m, 2H; 4.60, s (broad), IH; 7.27, s, 5H.

Analysis for 0χ4?FgN02 : Found : C, 62.19; H, 6.28; N, 4.92 % Requires : 0, 62.44; H, 6.36; N, 5.20 X The N-tert-butoxycarbonyl derivative (0.14 g) is treated for about 16 hours at room temperature with a 3 4’5 7 saturated solution of hydrogen chloride gas in dry ether (20 ml) . After removal of solvent, the residue (0.18 g) is recrystallized from ethanol/diethyl ether to give 2-pheny1-3,3-difluoroallylamine, as the hydrochloride (0.07 g) : colorless needles, m.p. 139140*! NMR (D2O):$ 4.10, s (broad), 2H? 7.43, s, 5H. Analysis for CgHnClF^H: Found : C, 52.53? H, 5.00? N, 6.74 % Requires : C, 52.57? H, 4.90? N, 6,81 % Example 18 Ethyl 2-difluoromethyl-2-carbo-tertbutoxy (P)naphthylacetate A solution of ethyl 2-carbo-tert-butoxy(ft)15 naphthylacetate (1.54 g) in THF (10 ml, is added to a slurry of sodium tert-butoxide (0.94 g) in THF (10 ml). The mixture is stireed for 30 minutes at room S3457 temperature and the temperature is increased to 45°. A rapid stream of chlorodifluoromethane (Freon 22) is Introduced for about 5 minutes, the heating bath is removed, and the mixture is stirred, for 1 hour. Water S is added and the product is Isolated by ether extraction. Essentially pure ethyl 2-dlfluoromethyl2-carbo-tert-butoxy(ί)naphthylacetate (1.68 g) is obtained as a pale orange oil. A small portion of the oil is purified by chromatography to give crystalline material: m.p. 70-71°: NMR (CDClg): 6 1.28, t (J - 7 Hz), 3H; 1.50, s, 9H; 4.35, q (J - 7 Hz), 2H; 6.62, t (J - 56 Hz), IH; 7.38 to 7.93, m, 7H.

Analysis for C20-22-2-4s 15 Found : C, 65.81; H, 6.18 % Requires : C, 65.95; H, 6.04 % Example 19 (£)-2-(31,4*-Dimethoxy)phenyl-3fluoroallyl alcohol A solution of ethyl (E)-2-(3',4'-dimethoxy)phenyl-3-fluoroacrylate (30 g) in a mixture of dry hexane (170 ml) and dry dichloromethane (40 ml) is cooled to 0°. To this is added a 1 M solution of dilsobutylaluminum hydride (DIBAL-H) in hexane (170 ml) at such a rate that the temperature did not rise ·· above 10°. After completion of the addition (about 33457 minutes) the resulting solution is stirred at ambient temperature for 1 hour and is then cooled to about 5s. Methanol (130 ml) and 6 N hydrochloric acid (83 ml) are addled. The temperature is kept below 10° with external cooling as before. The organic layer is separated and the aqueous layer is extracted several times with ether. The combined organic solutions are washed with water and dried. Evaporation of solvent affords (E)-2-(31,41-dimethoxy)phenyl-3-fluoroallyl alcohol as a pale yellow solid mass (18.60 g).

Example 20 (S)-l-Fluoro-2-(3l^’-dlmethoxyphenyl)3-phthalimidopropene A solution of 2-(3',4'-dimethoxyphenyl)-315 fluoroallyl alcohol (13.72 g) ln dry toluene (200 ml) is cooled to about 10s and treated with a solution of phosphorous tribromide (7.59 g) in toluene (200 ml). The reaction is allowed to continue for 1 1/2 hour without cooling during which time some tar forms. The supernatant is poured into saturated aqueous potassium carbonate. Ether extraction gives (E)-l-fluoro-2(3',4’-dimethoxyphfenyl)-3-bromopropene, brown crystals (16.0 g). This Intermediate (16 g) and potassium phthalimide (11.32 g) are heated in dry DMF (130 ml) at 65’ for 4 hours, after which the mixture ls poured Into water. Extraction with ether gives (E)-l-fluoro2-(3' ^'-dlmethoxyphenyO-S-phthalimidopropene which is recrystallized from n-hexane/dichloromethane to give almost colorless needles (15.95 β)· Example 21 Repeating the procedures of Examples 2, 18, 8, and 10 in sequence, but substituting the appropriate starting materials in each procedure, the following compounds are obtained: (a) (E)-2-o-naphthyl-3-fluoroallyl alcohol: NMR (CDClg): β 2.26, s (broad), IH; 4.13, d (J = 4 Hz), 2H; 6.13, S, 1/2 H; 7.13 to 8.00, m, 7 1/2 H. (b) (E)-2-e-naphthyl-3-fluoroallyl alcohol: NMR (CDClg): « 2.73, a (broad), IH; 4.23, d (J 4.5 Hz), 2H; 6.07, s, 1/2 H; 7.27 to 8.00, m, 7 1/2 H. (e) (E)-2-(4'-methyl)phenyl-3-fluoroallyl alcohol: NMR (CDClg): 4 2.30, s, 3H; 2.57, s (broad), IH; 4.17, d (J « 5 Hz), 2H; 6.70, d (J » 82 Hz), IH; centred at 7.23, (JAB Hz), 4H.

Example 22 Repeating the procedures of Examples 12 and 14 in sequence, but substituting the appropriate starting FQ . materials in each procedure, the following compounds are obtained: (a, (E)-2-( Λ)-naphthyl-3-fluoroallylamine, as the hydrochloride: m.p. 246*: NMR (D2Q}s0 4.O7, d.d (J «= 3 Hz, 1 Hz), 2H; 6.68 s, 1/2 H; 7.53 to 8.10, m, 7 1/2 H.

Analysis for Ci^Hi^ClFN: Found : C, 65.59: H, 5.44; N, 5.90 % Requires : C, 65.69; H, 5.51, N, 5.89 % (b) (J3)-2-( )-naphthyl-3-f luoroallylamine, as the hydrochlorides m.p. 205’: nmr (CD3OD):4.05, d (J » 3.5 Hz), 2H; 6.60, s, 1/2 H? 7.37 to 8.07, m, 7 1/2 H Analysis for Cι3H1^CIFN; Found : C, 65.51; H, 5.41; N, 5.77 « Requires : C, 65.69; H, 5.51; N, 5.89 « (c) (E)-2-(4'-methyl)phenyl-3-fluoroaliylamine, as the hydrochloride: Analysis for C1 oJS 13C1FH: Found : C, 59.56; H, 6.52; N, 6.71 « Requires : C, 59.59; H, 6.45; N, 6.95 % 534 57 tert-Butyl 3,4-dimethoxyphenyl acetate A ten-liter reaction flask is charged with 3,4dimethoxyphenylacetic acid (800 g), tert-butyl acetate (8 1), and perchloric acid (24 ml). The mixture is stirred overnight at room temperature. The solution is poured slowly into a mixture of sodium bicarbonate (3.9 kg) and water (6.9 1). When the effervescence ceases, the mixture is filtered and after decantation the organic phase is dried over sodium sulfate (0.7 kg). The solvent is evaporated under reduced pressure end the residue is stirred for two hours at O’C with heptane (1.3 1). After filtration and drying, tertfeutyl 3,4-dimethoxyphenylaeetate (672 g) is obtained: m.p, 75.8®.

S Example Ethyl 2-carbo-tgr_t-butoxy(3l .A’-dlmethoxy)phenylacetate A one-hundred liter stainless reactor under nitrogen is charged with diisopropylamine (5.9 1) and tetrahydrofuran (24 1). The solution is cooled to -78° and butyllithium (15 % in hexane, 17 kg) is added during 1 hour. After stirring for 15 minutes, a solution of tert-butyl 3,4-dimethoxyphenylacetate (4.9 kg) in tetrahydrofuran (18 1) is added at -78’, and the mixture is maintained at this temperature during 1 hour. Then, a solution of ethyl chloroformate (2 1) in tetrahydrofuran-(9 1) is added at -78’ during 80 minutes. After the addition, the mixture is allowed to reach room temperature and is stirred overnight. The mixture is cooled to 10’ and HCl (5 N, 3.4 1) is added. The THF is removed under reduced pressure and the residue is taken with methylene chloride (34 1) and water (4 1). The organic phase is washed twice with a solution of sodium chloride (1.6 kg in 8 1 of water) and dried over sodium sulfate (5 kg). After filtration» the solvent is evaporated under reduced pressure and ethyl 2-carbo-tert-butoxy(3.4dlmethoxy)phenylacetate (6.345 kg) is obtained as an oil which is used without purification in the next step.

Example 25.

Ethyl 2-dlfluoromethyl-2-carbo-t-butoxy(31,4l-dimethoxyphenyl)acetate A six-liter reaction flask under nitrogen is charged with sodium tert-butoxide (250 g) and tetrahydrofuran (3 1). The mixture is stirred at room temperature and a solution of ethyl t-butyl 3,4dimethoxyphenylmalonate (750 g) in tetrahydrofuran (1 1) is added in half an hour. The temperature rises to $2* and is maintained at 30-32° for half an hour at the end of the addition. Then, a rapid stream of chlorodifluoromethane is bubbled through the solution. The temperature rises to 65°. The stirring is continued under chlorodifluoromethane for 10 minutes.

The mixture is evaporated under reduced pressure and the residue is stirred with methylene chloride (4 1) and a solution of acetic acid (0.3 1) In water (1.5 1). After decantation, the organic phase is washed with water (1.5 1) and brine (1.5 1) and dried over sodium sulfate (500 g). The solvent is evaporated 5345 under reduced pressure and the residue obtained is stirred overnight at room temperature with hexane (2 1). After filtration and drying, ethyl 2-difluoromethyl-2-carbo-t-butoxy(31,4'-dimethoxyphenyl)acetate (672 g) ls obtained as a white solid:, m.p. 55.4°. Example 26 Ethyl (£)-2-(31,4*-dimethoxy)phenyl3-fluoroacrylate A twenty-liter reaction flask is charged with ethyl 2-difluoromethyl-2-carbo-t-butoxy(3',4'dimethoxyphenyl)acetate (1.4 kg) and trifluoroacetic acid (6 1). The solution is stirred at 25° for 16 hours. The mixture is evaporated under reduced pressure. The residue is dissolved in tetrahydrofuran (-5 1) and the solution is cooled at 10-15·. Then, aqueous sodium hydroxide 2 M (2.9 1) is added and the mixture is stirred at 25° for 1 hour. Diisopropyl ether (5 1) is added and after decantation, the aqueous phase is extracted with diisopropyl ether (2 x 2 1). The organic phase is combined, washed with brine (2 1) and dried over sodium sulfate (0.5 kg). After filtration and evaporation under reduced pressure, the residue is stirred at 10° for 1 hour, with a mixture of ethyl acetate (0.2 1) and hexane (2 1). The crystals are filtered, dried, and ethyl (E)-2-(3',4'dimethoxy)phenyl-3-fluoroacrylate (0.725 kg) is . obtained: m.p. 72.6°.

Example (E)-2-(31.4'-Dlmethoxyphenyl)-3fluoroallyl alcohol A sixty-liter stainless reactor under nitrogen is 5 charged with ethyl 2—(3·,4’-dimethoxy)phenyl-3fluoroacrylate (980 g), methylene chloride (dried over • CaCL ) (1.4 1), and hexane dried over molecular sieves 2 (5.6 1). The solution is stirred and cooled to -10/ -5°. Then, a solution of DIBAL (1 M in hexane) (8.5 1) is added during X hour between -10* and -5°. At the end of the addition, the mixture is stirred two hours at room temperature. The solution Is cooled at 0° and methanol (0.7 1) is added. Then, a solution of hydrochloric acid (34 %) (2 1) in water (4 1) is added. The solvents are removed under reduced pressure. Then, methylene chloride (6 1) is added to the residue. After decantation, the aqueous phase is extracted with methylene chloride (2x21). The organic layers are combined and dried over sodium sulfate (500 g). After filtration and evaporation of the solvent under reduced pressure, the residue is dissolved in toluene (1 1) and hexane (4 1) is added with good stirring. The product crystallizes. The mixture is stirred 2 hours at room temperature and after filtration and drying, 2-(31,4'-dimethoxy)phenyl-3-fluoroallyl alcohol (776 g) is obtained: m.p. 59. 83d57 Example 28 (S)-l-Fluoro-2-(3',4'-dimethoxy)phcnyl-3phthallmido-l-propene A ten-liter reaction flask is charged with 25 (3’s4'-dimethoxy)phenyl-3-fluoroallyl alcohol (615 g) and toluene (5 1). The mixture is cooled to -5β/0· and 'a solution of phosphorus tribromide (105 ml) in toluene (0.8 1) is added at this temperature during 1 1/2 hour. The mixture is stirred at room temperature for 2 hours and a solution of potassium carbonate (300 g) in..water (1 1) is added. The mixture is stirred half an hour. After decantation the organic phase is washed with a solution of potassium carbonate (300 g) in water (1 1) and brine (1 1). After drying over sodium sulfate (500 g), the solvent is evaporated under reduced pressure. The residue is poured into a ten-liter reaction flask with DMF dried over molecular sieves (6.6 1). Then, potassium phthalimide is added and the mixture is stirred at 70° for 4 hours. The DMF is evaporated under reduced pressure and methylene chloride (8 1) and water (1.8 1) are added to the mixture. The organic phase is washed with water (2 1) and brine (2x21) and dried over sodium sulfate (500 g). After filtration, the solvent is evaporated under reduced pressure and the residue obtained is stirred at room temperature for 2 hours with methanol (2.5 1). The crystals are filtered, dried, and (E)-l-fluoro-2(3*,4'-dimethoxy)phenyl-3-phthalimido-l-propene (602 g) is obtained: m.p. 107.8*.

S Example 29 (£)-2-(3^41 -dime thoxy) phenyl3-fluoroallylamine A ten-liter reaction flask Is charged with. 1fluoro-2-(3',41-dimethoxy)pheny1-3-phthallmido-110 propene (631 g), methanol (6 1), and hydrazine hydrate (103 ,g) and the mixture ls refluxed overnight. A solution of hydrochloric acid (34 X, 0.45 1) in water (0.45 1) is added and the refluxing is-continued for 1 hour. After cooling to room temperature, the mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is stirred overnight at 0® with water (0.45 1) and acetone (5 1). After filtration and drying crude (E)-2-(3',4'-dimethoxy)phenyl-3-fluorOallylamin.e (420.2 g) is obtained. A ten-liter reaction flask is charged with the crude product (420.2 g), chloroform (4 1), water (0.4 1) and triethylamine (0.4 1). The mixture is stirred for 30 minutes. After decantation the organic phase is washed with water (0.4 1). The aqueous phases are combined and extracted with chloroform (0.8 1). The organic phase is dried over sodium sulfate (500 g), filtered, and poured into a ten-liter reaction flask. Then, a solution of hydrochloric acid (34 %, 300 ml) in water (3 1) is added with good stirring. After decantation, the aqueous phase is washed with chloroform (l 1). The aqueous phase is heated to 60’ for 1 hour with ' charcoal (5 g). After filtration, the water is evaporated under reduced pressure. When crystallization begins, acetone (4 1) is added and the mixture is stirred for 2 hours at room temperature. The white crystals are filtered, washed with chloroform (1 1) and dried at 60® under reduced pressure. (E)-2-(3',4'-dimethoxy)phenyl-3fluoroallylamine (392 g) is obtained.

Claims (16)

Claims

1. A compound of the formula: C-C or F A-R C-C Y CH 2 R 3 III XV wherein: 5 R Is 3,4-methylenedioxyphenyl: phenyl; phenyl monosubstituted, disubstituted, or trisubstituted by (C 1 -Cg)alkyl, (Cj-Cg)alkoxy, (C X -Cg)alkylcarbonyloxy, hydroxy, chlorine, bromine, iodine, fluorine, trifluoromethyl, nitro, (Ci-Cg)alkyl10 carbonyl, benzoyl, or phenyl; 1- or 2-naphthyl; 1-, 2-, or 3-indenyl; 1-, 2-, or 9-fluorenyl; 2.pyridinyl; 1-, 2-, or 3-piperidlnyl; 2- or 3pyrrolyl; 2- or 3-thienyl; 2- or 3-furanyl; 2- or 3-indolyl; 2- or 3-thianaphthenyl; or 2- or 315 benzofuranyl; Y is hydrogen or fluorine; and A Is a divalent radical of the formula: wherein Rj is hydrogen, methyl. or ethyl, and m and n, independently, are 0 or an kJ kJ tj kJ i integer from 1 to 4, provided that m + n cannot be greater than 4; -(Cf^ wherein D is oxygen or sulfur, p is an Integer from 2 to 4, and q is 0 or an integer 5 from i to 2 provided that p + q cannot be greater than 4; or -(CH 2 ) r CH»CH(CH 2 ) s -, wherein r is an integer from 1 to 3 and sbO or is an integer from 1 to 2, provided that r + s cannot be greater than 3; 10 provided that R cannot be mono-, di-, or tri-hydroxy- phenylj and R3 is hydroxy or a leaving group

2. · λ compound as claimed in Claim 1 wherein the leaving group is chlorine, bromine, tosyloxy, or mesyloxy.

3. A compound of Formula XII as claimed in any one 5 of Claims 1 and 2.

4. A compound of Formula IV as claimed in any one of Claims 1 and 2.

5. A compound as claimed in Claim 4 , wherein A is -CHg-. 10

6. · A compound as claimed in any one of Claims 1 td' 5 wherein ’ Y is hydrogen, Rj is hydroxy, and R is phenyl, (Cj-C θ) alkoxyphenyl, dl(—C )alkoxyphenyl, (Cj-Cg)alkylphenyl, chlorophenyl, trifluoromethylphenyl, 1-naphthyl, or 15 2-naphthyl.

7. A compound as claimed in Claim 6 wherein R is methoxyphenyl.

8. '. A compound as claimed in Claim 6 wherein R is ethoxyphenyl. 7 2

9. . A compound as claimed in Claim 6 wherein R is dimethoxyphenyl.

10. - A compound as claimed in Claim $ wherein R is diethoxyphenyl. 5

11. . (E)-2-(3*,4'-dimethoxy)phenyl-3-fluoroallyl alcohol.

12. . A method for preparing a compound as claimed in Claim 1 wherein Rg is hydroxy which comprises reducing in manner known per ae a compound of the 10 formula: F R F I I ι C = C or C I 1' I Y COR. y I d wherein Y, R, and A are as defined in Claim 1 and R^ is hydrogen or (C^—C )alkyl.

13. A method as claimed in Claim 12 wherein the 15 reduction is carried out using diisobutylaluminum hydride. AR 1' = C I COR I »3457

14. A method as claimed In any one of Claims 12 and 13 wherein Y is hydrogen, and R is 3,4-dimethoxyphenyl, and the product prepared is · (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallyl alcohol.

15. A method as claimed in Claim 12 and substantially as hereinbefore described.

16. A compound as claimed in any one of Claims 1 to 11 whenever prepared by a method as claimed in any one of Claims 12 to 15.