SI9300146A - Processes and intermediates for the preparation of 2-substituted benzaldehydes - Google Patents

Abstract

Processes for preparing 2-substituted benzaldehydes of general formula (I), wherein: R1 is CH2CH2-(L1)p-(CH2)q-(L2)r-CH2-(T)s-Z; L1 and L2 are independently CH2CH2, CH=CH or C=C; q is 0 to 8; p, r and s are independently 0 or 1; T is O, S, CH2, CH=CH, C=C; and Z is C1-4alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with CF3, C1-4alkyl, C1-4alkoxy, methylthio, or trifluoromethylthio; and R2 and A are independently H, CF3, C1-4alkyl, F, Cl, Br or I; are useful for preparing pharmaceutically active compounds.

Description

SMITHKLINE BEECHAM CORPORATION

Methods and intermediates for the preparation of 2-substituted benzaldehydes

FIELD OF THE INVENTION

The present invention relates to novel intermediates and processes for the preparation of useful intermediates in the synthesis of pharmaceutically active agents.

Background

2-Substituted benzaldehydes are useful intermediates for the preparation of pharmaceutically active compounds. E.g. various compounds that are leukotriene antagonists and useful in the treatment of asthma can be prepared from 2-substituted benzaldehydes of the general formula (Ia):

R.

(Ia)

A

4r where:

R _x (LV ^ -iTVM;

a is O or 1;

b 3 or 14;

c O to 1;

L and T are independently sulfur, oxygen or CH ₂ ; and MC-alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with Br, Cl, CF _3, C _M-alkyl, C _M alkoxy, methylthio or trifluoromethylthio;

R 2 and A are independently selected from H, CF ₃ , C ₁₄ -alkyl, C ₁₄ -alkoxy, F, Cl, Br, J, OH, NO ₂ or NH _? ;

or R is _; and AH, and R _{2 is} (L) _a - (CH 2) _b - (T) _c- M, where a, b, c, L, T and M are as defined above.

Such compounds are described e.g. in the U.S. U.S. Patent No. 4,820,719; U.S. Patent Nos. 4,874,792 and EP-A 0 296 732, the descriptions of which are incorporated herein by reference. Thus, these patents describe two general processes for the preparation of 2-substituted benzaldehydes:

1) palladium catalyzed addition of a substituted 1-alkynyl compound to 2-halobenzladehyde causes coupling to provide 2- (1-alkynyl) benzaldehyde directly and

2) 2-Methoxy-benzoic acid can be converted to 2- (2-methoxy-phenyl) -4,4-dimethyloxosoline and treated with an alkyl or aralkyl Grignard reagent to prepare the corresponding 2- (2-alkyl phenyl) -4,4 -dimethyl-oxazoline or 2- (2-aralkyl phenyl) -4,4dimethyl-oxazoline (post-treatment of 2-substituted oxazoline with methyl iodide, reduced with sodium borohydride and subsequent acid hydrolysis to produce the corresponding 2-substituted benzaldehyde). The latter procedure is based on the procedures described by Meyers et al., J. Org. Chem., 43, 1372 (1978). Similar procedures for the preparation of 2-substituted benzaldehydes have been described by Perchonock et al., J. Med. Chem. 28, 1145 (1985). In general, these methods employ reagents that functionally replace the aryl ring substituents.

Methods for adding an ortho substituent to an aryl ring by making the aryl ring nucleophilic are also known. Org. Reactions, 26, 43-61 (1979) describes that certain functional groups containing nitrogen heteroatoms bound to phenyl rings can stabilize the phenyl ring, depending on the lithiation, preferably in the ortho position. The lithium site can then be treated with a suitable electrophilic reagent to effect substitution. The functional groups mentioned herein as particularly effective for this purpose are mono- or di-alkylamides, amines, Ν, dial-dialkylhydrazones, imidazolines and oxazolines. De Silva et al., Tetrahedron Lett., 5107 (1978) describes the ortholyticization of benzamide using sec-butyllithium a and diisopropylamine, and Trecourt et al., J. Org. Chem. 53, 1367 (1988) describes the ortho lithiation of 2-methoxy-pyridine with methyllithium and a catalytic amount of diisopropylamine. Arylcarbimines, however, have been described as having limited synthetic use due to their tendency to undergo reaction on azomethane bonds and α-deprotonation. See Org. Reactions, 26, 57-58 (1979). Zeigler et al., J. Org. Chem., 41, 1564 (1976) describes that arylcarbimines can induce ortholithiation to occur if a neighboring ether substituent is present.

In addition to the stack, it is described that methyl groups can be lithified when placed in the ortho position of benzamides, 2-phenyl imidazolines and 2-phenyl oxosolines. Thus, Watanabe et al., J. Org. Chem., 49, 742 (1984) describes chain extension via ortho-toluamide in isocoumarin synthesis; Gschwend, et al., J. Org. Chem. 40, 2008 (1975) describes the extension of the benzyl chain via the lithiation of 2- (o-tolyl) oxazolines; and Houlihan, U.S.A. patent 4,100,165 describes the condensation of diluted 2- (o-tolyl) imidazoline with esters and acyl halides.

Current processes for the synthesis of 2-substituted benzaldehydes of the present invention employ expensive reagents or multi-step processes, which makes these processes uninteresting in the commercial preparation of 2-substituted benzaldehydes. Therefore, there is a need for an effective alternative process for the preparation of 2-substituted benzaldehydes.

Summary of the Invention

It is an object of the present invention to provide a novel and effective process for the preparation of compounds of formula (Ib):

R.

(Ib) where:

L and L _{2 are} independently CH ₂ CH ₂ , CH = CH or C = C;

q is 0 to 8;

p, r and s are independently 0 or 1;

is TO, S, CH ₂ , CH = CH, C = C; and CC ₁₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl, ¹ is optionally mono-substituted with a CF _3, C _M-alkyl, C ^ alkoxy, methylthio, or three fluoro methylthio; and R ₂ and A are independently H, CF _3, C _M-alkyl, F, Cl, Br or I.

One feature of the present invention is a process for the preparation of a compound of the formula:

Oh

R, (Ib) wherein A, Rj, R ₂ , L _r L ₂ , q, p, r, s, T and Z are as defined above for formula (Ib), which involves the metabolism of a compound of formula:

NR ₃ (III) where:

R ₂ and A are as defined above in formula (Ib); R _{3 is} C ₁₆ -alkyl, C _{3 6} -cycloalkyl; (CH ₂ ) _t -phenyl or N (R ') ₂ ; R 1 is C ₁₆ -alkyl, C _3-6 cycloalkyl or (CH ₂ ) ₍ -phenyl; and t is 0 or 1;

with a base and a compound of the formula:

X-CH ₂ - (Lj) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ - (T) _s -Z (IV) where:

L _p L ₂ , p, q, r, s, T and Z as defined above for formula (Ib) and X is a substituted group;

and treating its product with acid.

Another feature of the present invention is a novel intermediate of formula (II):

where:

R p is R ₂ and A as defined for formula (Ib);

R _{3 is} C 1-6 alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t -phenyl or N (R ') ₂ ;

R 'is _6- alkyl, C _3-6 -cycloalkyl or (CH ₂ ) _t -phenyl; and t is 0 or 1.

Another feature of the present invention is a process for the preparation of a novel intermediate of formula (II), which involves the metabolism of a compound of formula (III):

wherein A, R ₂ and R _{3 are} as defined for formula (II); with a base and a compound of formula (IV):

^^ - (^) ^ (^ - (^) ^^ - (^ - 7 (IV) where:

Lp is L ₂ , p, q, r, s, T and Z as defined above for formula (Ib) and X is a substituted group.

Another feature of the present invention is an improved process for the preparation of a compound of formula (II), which involves the addition of a catalytic amount of an organic amine to the reaction mixture before addition of the base.

Another feature of the present invention is an improved process for the preparation of a compound of formula (II) which involves the addition of sodium or potassium alkoxide to the reaction mixture.

Another feature of the present invention is an improved process for the preparation of a compound of formula (II) which involves conducting a reaction within a specified temperature range.

Detailed description of the invention

The present invention relates to useful intermediates and process for the preparation of compounds of formula (Ib):

where:

R _x is L _x and L ₂ independently CH ₂ CH ₂ , CH = CH or CsC; q is 0 to 8;

p, r and s are independently 0 or 1;

is TO, S, CH ₂ , CH = CH, C ^ C; and ZC is _M- alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono-substituted with CF ₃ , C 1-6 alkyl, C 1-4 alkoxy, methylthio or trifluoromethylthio; and R ₂ and A are independently H, CF ₃ , C _{x 4} -alkyl, F, Cl, Br or J, which involves the metabolism of a compound of the formula:

N-R,

CH ₃ (III) where:

R ₂ and A are as defined above;

R ₃ C _x _ ₆ alkyl, C _{3 6} cycloalkyl, (CH _{2) t} -phenyl or N (R ') _2; R 1 is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t -phenyl; and t is 0 or 1;

with a base and a compound of the formula:

^ - (LJp - ^ - ^ - C ^ - ^ - Z (IV) where:

L _p L ₂ , p, q, r, s, T and Z are as defined above; and X is a substituted group;

and treating its product with acid.

Thus, the present invention relates to novel intermediates of formula (II):

NR ₃

R.

(II) where:

L and L _{2 are} independently CH ₂ CH ₂ , CH = CH or C = C;

q is 0 to 8;

p, r and s are independently 0 or 1;

is TO, S, CH ₂ , CH = CH, C = C; and ZC-alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with CF _3, C ₁₄ -alkyl, C _M alkoxy, methylthio or trifluoromethylthio;

R ₂ and A are independently H, CF ₃ , C _{3 4} -alkyl, F, Cl, Br or J;

is R ₃ C ₁ . _6- alkyl, C ₃ . ₆ -cycloalkyl, (CH ₂ ), - phenyl or N (R ') ₂ ;

R 1 is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t -phenyl; and t is O or 1.

Z is phenyl and L and L are ₂ CH ₂ CH ₂ .

R _{3 is} t-butyl.

P, r and s 1 are appropriate.

Q 0-2 is appropriate.

T CH ₂ or C = C is appropriate.

The preferred compound is N- [2- (8-phenyloctyl) phenyl) -methylene] -1,1-dimethylethanamine.

New intermediates of formula (II) are prepared by a process involving the metabolism of a compound of formula (III):

where:

R ₂ and A are independently H, CF _3, C _M-alkyl, F, Cl, Br or I; is R ₃ Cj. ₆ -alkyl, C ₃₆ -cycloalkyl, (CH _{2) f} phenyl or N (R ') _2; R 1 is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t -phenyl; and t is 0 or 1;

with a base and a compound of formula (IV):

X-CH ₂ - (Lj) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ - (T) _s -Z (IV) where:

L and L _{2 are} independently CH ₂ CH ₂ , CH = CH or CsC;

q is 0 to 8;

p, r and s are independently 0 or 1;

T is O, S, CH ₂ , CH = CH or C ^ C; and Z is a C ₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituian CF _3, C _M-alkyl, C ^ alkoxy, methylthio or trifluoromethylthio; and X is a replaceable group.

In a preferred embodiment, the present invention relates to a process for the preparation of a compound of formula (Ib), which involves reacting a compound of formula (III) with a base and a compound of formula (IV), and treating the reaction mixture with an acid. Thus, in a preferred embodiment, the whole conversion is achieved in a single reaction vessel without isolation of the intermediate. This process uses readily available materials and expires in effective winnings in a minimum number of process steps.

The compounds of formula (III) are hydrazones and imines or Schiff bases and are generally prepared by any means conventional in the art for the preparation of such compounds. One procedure for the preparation of imines involves the metabolism of a compound of formula (V):

with an amine or hydrazine of the formula R ₃ -NH ₂ . Such reactions are usually conducted by mixing the reactants in a non-aqueous solvent and, optionally, by heating the two reactants. If necessary, dehydration agents can be used to guide the reaction against the product. Conventional dehydrating agents are e.g. molecular sieves or magnesium sulfate. Alternatively, dehydration can be carried out by azeotroping the water formed by the reaction from a suitable solvent such as benzene or toluene. The R ₃ group is C 1-6 alkyl, C _3-6 cycloalkyl, benzyl, phenyl or N (R ') ₂ . Suitable reagents are cyclohexylamine, t-butyl amine, aniline and N, N-dimethyl hydrazine. t-butyl amine is preferred.

The electrophile given by formula (IV) is prepared by conventional methods such as those described in U.S. Pat. U.S. Patent No. 4,820,719; U.S. Patent 4,874,792, EPA 0 296 732, and Perchonock et al., J. Med. Chem., 28, 1145 (1985), which are incorporated herein by reference. The X portion of the electrophile represents an interchangeable group that any group may be capable of replacing with a carbon nucleophile prepared from a compound of formula (III). A large number of substitutable groups such as alkyl and aryl sulfonates, alkyl and aralkyl acetates, benzoates and halogens are suitable. Representatives of this class are CI,

Br, I, R ₄ SO ₃ and R ₄ CO _2, where R ₄ C _M alkyl, optionally substituted with 1-5 fluorine atoms, or phenyl optionally substituted with one or two halogens, C _M - alkyl, C ₁₄ -alkoxy or nitro groups. Representatives of the substituent groups are toluenesulfonate, bromobenzenesulfonate, nitrobenzenesulfonate, methanesulfonate, trifluoromethanesulfonate, acetate, chloroacetate, trifluoroacetate, benzoate, bromobenzoate, chlorobenzoate, nitrobenzoate, chloro, bromo and iodo. Chloro and bromo are preferred. Chloro is especially preferred.

General group X, compounds of formula (IV), if not present in the precursor, is prepared from the corresponding alcohol by digestion with a suitable acyl halide, anhydride, sulfonyl halide or a suitable halogenating agent. Typical such reagents are toluenesulfonyl chloride, bromobenzenesulfonyl chloride, nitrobenzenesulfonyl chloride, methanesulfonyl chloride, acetyl chloride, chloroacetyl chloride, trifluoroacetyl anhydride, benzoyl chloride, bromobenzoyl chloride, chlorobenzoyl chloride, nitrobenzoyl chloride, oxalyl chloride or bromide, hydrochloric acid, hydrobromic acid, hydroiodic acid , phosphorus tribromide, phosphorus trichloride, phosphorus oxychloride, and carbon tetrabromide with triphenyl phosphine. Compounds of Formula HO-CH ₂ - (L ₁ ) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ - (T) _s -Z, where T is CH ₂ , L _x or L ₂ are CH ₂ CH ₂ and ZC is _M- alkyl or phenyl are commercially available. Compounds where TO, S or C = C can be prepared by metabolizing a HTZ compound with a compound of the structure X-CH ₂ - (L ₁ ) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ -X, wherein X, L _in L ₂ , T, p, q and r are as defined above in the presence of a suitable base. Compounds where T CH = CH can be prepared by the scheme of hydrogenation of compounds in which TC = C, such as with a Lindlar catalyst or 5% palladium on barium sulfate and hydrogen. Hydrogenation with a palladium catalyst, such as 5% palladium on charcoal, yields a compound containing T CH ₂ . When L ₁ or C = C or CH = CH, the resulting product can be reduced later to give a product in which 1 ^ or Lj is CH = CH or CT ^ CH ^ Eg. 1-Bromo-7-phenylheptane is prepared from 1,5-dibromopentane and phenylacetylene in the presence of n-butyllithium, followed by reduction with hydrogen through a palladium catalyst. Alternatively, 1-bromo or 1-chloro-7-phenylheptane can be prepared via copper-mediated coupling of benzylmagnesium halide with 1,6-dibromohexane or 1-bromo-6-chlorohexane.

The alkylation of the cabimine of formula (III) is initiated by digesting the compound of formula (III) with a strong base to deprotonate the ortho methyl group. Since the metallized intermediate is reactive with water, the activation reaction is suitably carried out in an internal, dry atmosphere, such as nitrogen or argon, and dry air is sufficient.

The activation reaction is carried out in an aprotic solvent. Suitable solvents for this reaction are conventional aliphatic or aromatic hydrocarbon solvents which are non-reactive with strong bases. Representatives of such solvents are diethyl ether, tetrahydrofuran, dioxane, toluene, benzene, pentane, hexane and petroleum ethers and mixtures thereof. Diethyl ether, dioxane and tetrahydrofuran are preferred. Particularly preferred is tetrahydrofuran.

A base of sufficient strength is required to deprotonate the orthomethyl group. Any base capable of carrying out such deprotonation without causing significant side reactions is suitable. Typical such bases are alkyl alkali metal, alkali metal amine, or aryl alkali metal. Typical bases are n-butyl lithium, sec-butyl lithium, methyl lithium, phenyl lithium, lithium diisopropylamide, lithium diethylamide or lithium amide, or a suitable sodium or potassium salt of any of these types. Particularly suitable are alkyl lithium reagents. Preferred are n-butyl lithium and lithium diisopropylamide. It is also within the scope of the present invention that the metal of the base initially used can be substituted for another metal, e.g. other alkali metal, copper, magnesium or zinc. It is often helpful to use a slight molar excess of base such as 1% to 25% to provide complete metallization. About one molar equivalent is normally satisfactory. It will be apparent to one skilled in the art that some of these bases, such as alkyl or aryl alkali metals, may be incompatible with the halogen substituent in carbimine and other bases such as lithium diisopropylamide may be more suitable.

The reaction of the compound of formula (III) with the base is carried out by mixing the two reactants. The reaction should be carried out at a temperature sufficient to cause the base to deprotonate the orthomethyl group, but not so high as to cause adverse side reactions. So the optimum temperature will depend on the base used and the imine reactant. If the base is lithium dialkylamide, the reaction is typically carried out between about -20 ° C and 60 ° C; the reaction is suitably carried out between about -10 ° C and 40 ° C.

It has been found that surprisingly improved yields are obtained when the reaction proceeds between about 15 ° C and about 35 ° C. Typically, when strong bases are reacted with compounds that have a part that is susceptible to nucleophilic attack, such as carbimine function, the reactions are conducted at temperatures of about 0 ° C and below. These lower temperatures are assumed to prevent adverse side reactions, such as a nucleophilic attack on labile carbimine functionality with the base alone or with the anion generated by the action of the base. Unexpectedly, with some bases, such as n-butyllithium, optionally a catalytic amount of diisopropylamine or dicyclohexylamine, the side reactions are minimized and yields are increased by adding the base to carbimine at about 15 ° C to about 35 ° C. Keeping the reaction between about 20 ° C and about 30 ° C is particularly advantageous.

Temperatures above 55 ° C generally result in an increase in adverse reactions.

The electrophile X-CH ₂ - (L ₁ ) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ - (T) _J -Z, is typically added after completion of the metallization reaction. Although the electrophile can be added undiluted, it is usually added in a solvent such as the one used to form the metallized intermediate. The reaction mixture was then allowed to stir for about 15 minutes to about 24 hours.

To isolate the imine, the reaction solution is diluted with a suitable solvent, washed with water and concentrated in vacuo to an oil. If a purified product is desired, the product is purified by distillation or, if appropriate, by crystallization.

The conversion of the compound of formula (II) to benzaldehyde is achieved by mixing the imine with any acid of sufficient strength to cause hydrolysis of the C = N bond. The present invention is considered to be mineral acids, organic acids, and the like. sufficiently strong acids. E.g. methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, benzoic acid, acetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid. Mineral acids are preferred. Hydrochloric acid is particularly preferred.

In a preferred process, the reaction mixture containing product (II) is hydrolyzed directly by the addition of acid to the reaction mixture. The general reaction mixture was added to the cooled acid solution and then allowed to warm to room temperature. The formation of the desired benzaldehyde can be observed in the reaction mixture, e.g. by analytical chromatography, and typically the reaction mixture is stirred from about 1 hour to about 24 hours. The product is then isolated by conventional techniques such as extraction finishing.

An improved process for the preparation of a compound of formula (II) involves the addition of a catalytic amount of an organic amine to the reaction mixture before addition of the base, especially when alkyl lithium reagent is used as the base. When a catalytic amount of an organic amine is used, higher yields are obtained than when the amine is absent or when the whole molar equivalent of the amine is used. A suitable organic amine is a secondary amine. Typical amines are diethylamine, diisopropylamine, dicyclohexylamine, piperidine, 2,6-dimethylpiperidine and 2,2,6,6-tetramethylpiperidine. Particularly suitable are diisopropylamine, dicyclohexylamine and 2,2,6,6-tetramethylpiperidine. The catalytic amount may be from about 0.01 to about 0.3 molar equivalent of an organic amine relative to carbimine. About 0.01 to about 0.15 molar equivalent is appropriate. Typically, it is about 0.01 to 0.1 molar equivalent, depending on the amine used. E.g. about 0.01 to about 0.05 equivalents is useful for diisopropylamine and 2,2,6,6-tetramethylpiperidine.

Another feature of the present invention is an improved process for the preparation of a compound of formula (II), which includes the preparation of the carbimine sodium or potassium salt of formula (III) and the metabolism of the product with a compound of formula (IV). E.g. 2-Methyl-phenylcarbimine of formula (III) can be treated with a base such as n-butyllithium or lithium diisopropylamide to form the lithium salt and further treated with a sodium or potassium base or salt to form the desired metal exchange metal salt. Sodium or potassium alkoxide or sodium or potassium trifluoroacetate are typical bases / salts. Reaction of the carbimine salt with a compound of formula (IV), such as 7-phenylheptyl chloride, results in alkylation at lower temperatures and with fewer side reactions than is obtained with a comparable lithium salt of carbimine. The use of potassium salt is particularly suitable.

The following examples illustrate how to make and use the compounds and methods that substantiate this invention.

Examples

In the cases, nomenclature and abbreviations common to the chemical industry are used. Unless otherwise stated, reagents were obtained from commercial suppliers and used without further purification. Tetrahydrofuran, when used as a reaction solvent, was dried over 4.1O ^'10 m molecular sieves. All other solvents were obtained from commercial suppliers as reagent pure and used without further purification. All non-aqueous reactions were carried out under a dry nitrogen atmosphere. Melting points were recorded on Thomas-Hoover capillary melting point apparatus and are uncorrected. Liquid chromatography was performed on Whatman Partisil® 5 ODS 3 RAC II. Gas chromatographic analyzes were performed on a DB-1 30 m X 0.53 mm capillary column. The IR spectrum was recorded on a Perkin-Elmer model 283 infrared spectrophotometer. FT-IR spectra were obtained on a Nicolet 6000 FT infrared spectrometer. Combustion analyzes were performed on a Perkin-Elmer 240 C elemental analyzer. Unless otherwise stated, all the above ^ -NMR (proton magnetic resonance) spectra were obtained at 400 MHz using a Bruker Instruments WM 400 spectrometer in deuterochloroform solution. ¹³ C-NMR spectra were obtained at 100 MHz. The chemical shifts are recorded in ppm (δ) lower box than tetramethylsilane. The k ^ H-NMR interpretations are as follows: s singlet; d doublet; t triplet; br wide; m multiplet; J coupling constant in Hertzs.

Example 1

Preparation of l-bromo-7-phenylheptane

To a mixed solution of 1500 ml (0.15 mol) of 0.1 M Li ₂ CuCl ₄ and 1,6-dibromohexane (456.8 g, 1.87 mol, 1.25 eq) in tetrahydrofuran, at -5 to 0 A solution of benzyl magnesium chloride (750 ml, 2 M in tetrahydrofuran, 1.5 mol) was added over 90 min. The reaction mixture was stirred at 0 ° C for 90 min, then carefully quenched with 2.01 saturated aqueous ammonium chloride. Keep the internal reaction temperature below 20 ° C during quenching. The mixture was stirred for 1 h at room temperature and the layers separated. The organic layer was washed with 20% aqueous sodium chloride (4 x 500 ml). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo at 45 to 50 ° C to an amber oil. Purification by fractional vacuum distillation over a 30.48 cm vacuum-coated Vigreux column gave the desired product as a colorless oil (198.2 g, 52%). The analytical sample is prepared by pre-distillation:

Boiling point: 123-124 ° C (199,983 Pa); FT-IR (pure film) 3100-3000, 3000-2800, 2000-1700,

1604,1496,748,699,644 cm '¹; ^X H NMR (CDQ ₃ , 400 MHz) δ 7.29-7.16 (m, 5 H), 3.40 (t, 2 H), 2.60 (t, 2 H), 1.88-1 , 81 (m, 2 H), 1.63-1.60 (m, 2 H), 1.43-1.32 (m, 6 H); ¹³ C NMR (CDCl3, 100 MHz) δ 142,7,128,4,128,2,125,6,35,9,34,0,32,8,31,4,29,1,28,6,

28.1.

Calculated for C ₁₃ H ₁₉ No: C 61.19; H 7.50; Br 31.31

Found: C, 61.25; H, 7.59; No. 31.47.

Example 2

Preparation of 7-chloro-1-phenylheptane

a) 1-Bromo-6-chlorohexane

A mixture of 1,6-hexanediol (30 kg, 254 mol), 48% hydrobromic acid (51.0 kg, 302 mol) and toluene was heated to reflux. The water (34.5 kg) was removed under azeotropic conditions. When the distillation is complete, the mixture is cooled to 20 ° C and extracted with a solution of concentrated hydrochloric acid (69.9 kg) and water (60 L). The phases are separated and the organic phase is dried by reheating and removing the water by azeotropic distillation. The mixture was cooled to 65 ° C and dimethylformamide (1.11 kg) was added. Thionyl chloride (31.41 kg, 264 mol) was added for 45 min while maintaining the temperature between 65-68 ° C. The mixture was heated to 109 ° C for 1.25 h and cooled to 20 ° C. It is then sequentially washed with 20% sodium hydroxide solution (100 ml) and water (2 x 1501,1 x 1001). Toluene (4001) was removed in vacuo to give bromochlorohexane as a toluene solution (85.5 kg, 55% w / w by analysis, 93% yield).

b) 7-chloro-1-phenylheptane

A solution of lithium tetrachloroacuprate [THF 33 1, lithium chloride (0.87 kg, 19.3 mol), copper (II) chloride (1.4 kg, 10.4 mol)] was added to a solution of benzylmagnesium chloride (160 1, 1. 86 M, 298 mol) in tetrahydrofuran at 15 ° C and the mixture was stirred for 30 min. Bromochlorohexane in toluene (85.5 kg solution, 55% w / w by analysis, 47.1 kg, 236 mol) was added for 3 h while maintaining the temperature between 15-20 ° C. Stirring was continued for a further 1.25 h. Add 10% ammonium chloride solution (263 l) for 1 h and keep the temperature below 30 ° C. The phases were separated and the organic phase was further washed with ammonium chloride solution (1701) and 20% sodium chloride solution (3 x 197 l). The organic solution was concentrated in vacuo to give an oil (56.8 kg, 77% pure by HPLC analysis, 88% corrected yield).

Example 3

Preparation of N-F (2-methylphenyl) methylene-1,1-dimethylethanamine

A stirred solution of o-tolualdehyde (25 g, 0.21 mol) and t-butylamine (27.75 g, 0.38 mol) in toluene (250 ml) was refluxed under standard Dean-Stark conditions for 20 h. The solution was evaporated to an oil which was vacuum distilled: (hot: 70-73 ° C, 79.98 Pa) to give 33.9 g (93%) of the product: IR (pure) 2980,1645,1605,1460, 1375,1210, 960,910 cm ^-1 ; Ή NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.86-7.83 (m, 1H), 7.25-7.11 (m, 3H), 2.46 (s, 3 H), 1.30 (s, 9 H); ¹³ C NMR (CDCl 3, 100 MHz) δ 153.7, 137.1, 135.1,

130.5, 129.6, 127.1, 126.4, 57.5, 29.8, 19.2; GC RT 7.6 min (DB-1, 30 m x 0.53 mm, program: 100 ° C 5 min, 100-260 ° C at 15 ° C / min, kept at 260 ° C for 12 min).

Example 4

Preparation of 2-methylbenzaldehyde dimethyl hydrazone

A stirred solution of o-tolualdehyde (25.0 g, 0.21 mol) and 1,1-dimethyl hydrazine (25.2 g, 0.42 mol) was refluxed in toluene (200 ml) for 24 h. The solution was concentrated in vacuo and the remaining oil was vacuum distilled (51-60 ° C, 26.66 Pa) to give the title product (31.98 g, 94%): IR (pure) 2950, 2850,1580,1550,1455, 1025, 745 cm ^-1 ; Ή NMR (CDCl3, 400 MHz) δ 7.8-7.6 (m, 1H), 7.4-7.3 (m, 1H), 7.1-6.9 (m, 3H), 2, 9 (s, 6H), 2.4 (s, 3H).

Example 5

Preparation of N - [(2- (8-Phenyloctyl) phenyl) methylene] -1.1-dimethylethanamide

To the stirred solution of diisopropylamine (29.14 g, 0.289 mol) in tetrahydrofuran (450 ml) cooled to -5 ° C was added n-butyllithium (2.5 M, 114.3 ml, 0.286 mol) at the rate at which keep the temperature of the solution below 10 ° C. After the addition is complete, the solution is stirred for 15 min with cooling. To this solution was added N - [(2-methylphenyl) methylene] -1,1-dimethylethanamine (50.0 g, 0.286 mol) in tetrahydrofuran (65.0 ml) at such a rate as to maintain the reaction temperature below 5 ° C. The reaction mixture was stirred for 15 min by cooling, then 1-bromo-7-phenylheptane (72.9 g, 0.286 mol) in tetrahydrofuran (75 ml) was added rapidly. The reaction mixture was stirred for 1 h with cooling, then allowed to warm to room temperature and stirred for an additional 14 h. The reaction mixture was analyzed by gas chromatography for the imine product (RT 19.8 min, DB-1, 30 m X 0.53 mm, program, 100 ° C for 5 min, 100-260 ° C at 15 ° C / min, kept at 260 ° C (12 min). The product is isolated by diluting the reaction mixture with water and methylene chloride, rapidly washing the organic mixture with water and concentrating the solution to oil. The oil is purified by distillation.

Example 6

Preparation of N - [(2- (8-Phenyloctyl) phenyl) -methylene-1,1-dimethylethanamine

A mixed solution of 2- (8-phenyloctyl) benzaldehyde (10 g, 0.034 mol) and t-butylamine (4.96 g, 0.068 mol) in toluene (100 ml) was refluxed under standard Dean-Stark conditions 16

h. Evaporate the solution to vacuum distillation oil (260 ° C, 19.20 Pa) to give the title product (11.1 g, 94%): GC RT 19.8 min (DB-1, 30 m X 0.53 mm, program, 100 ° C for 5 min, 100-260 ° C at 15 ° C / min, kept at 260 ° C for 12 min); NMR (CDCl ₃ , 400 MHz) δ 8.58 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.29-7.13 (m, 8H), 2.79 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 1.59-1.51 (m, 12H), 1.30 (s, 9H) .

Example 7

Preparation of 2- (8-phenyloctyl) benzaldehyde

Via hydrolysis of N - [(2- (8-phenyloctyl) phenyl) methylene] -1,1-dimethylethanamine

To a solution of N - [(2- (8-phenyloctyl) phenyl) methylene] -1,1-dimethylethanamine (0.51 g, 0.0146 mol) in tetrahydrofuran (5 ml) was added 10% aqueous hydrochloric acid (5 ml) and the mixture was stirred at room temperature for 15 h. Methylene chloride (10 ml) and water (10 ml) were added and the layers separated. The aqueous layer was extracted with methylene chloride (1 x 15 ml), the combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo to an oil (0.405 g, 97.4% pure by HPLC analysis, 92% corrected yield: IR ( pure) 2920,2880,1695,1600,1455 cm ^-1 ; ^X H NMR (CDCl ₃ , 400 MHz) δ 10.25 (s, 1 H), 7.80 (dd, 1 H, J = 1.2) and 7.7 Hz), 7.45 (m, 1 H), 7.33-7.13 (m, 7 H), 2.98 (t, 2 H, J = 7.7 Hz), 2, 58 (t, 2 H, J = 7.7 Hz), 1.58 (m, 4 H), 1.30 (m, 8 H).

Example 8

Preparation of 2- (8-phenyloctyl) benzaldehyde

Use of one mole equivalent of nitrogen and l-bromo-7-phenylheptane base.

To the stirred solution of diisopropylamine (29.14 g, 0.289 mol) in tetrahydrofuran (450 ml) cooled to -5 ° C was added n-butyllithium (2.5 M, 114.3 ml, 0.286 mol) at such a rate as to maintain the temperature solutions below 10 ° C. After the addition is complete, the solution is stirred for 15 min with cooling. To this solution was added N - [(2-methylphenyl) -methylene] 1,1-dimethylethanamine (50.0 g, 0.286 mol) in tetrahydrofuran (65.0 ml) at such a rate as to maintain the reaction temperature below 5 ° C. The reaction mixture was stirred for 15 min with cooling, then rapidly added 1-bromo-7-phenylheptane (72.9 g, 0.286 mol) in tetrahydrofuran (75 ml). The reaction mixture was stirred for 1 h with cooling, then allowed to warm to room temperature and stirred for an additional 14 h. The reaction mixture was quenched with 10% aqueous hydrochloric acid and stirred for 1 h at 0 ° C and then at ambient temperature for 14 h. The reaction mixture was poured into methylene chloride (700 ml) and stirred for 5 min. The organic layer was removed and the aqueous layer was extracted with methylene chloride (2 X 700 ml). The combined organic layers were washed with 10% hydrochloric acid (2 X 500 ml) and saturated brine (1 X 350 ml), then concentrated in vacuo to a golden oil. The crude product was run through Pope Stili (100 ° C, 26.66 Pa) and the residue was treated with hexane (400 ml) with stirring for 5 min. Allow the solution to settle and decant. The hexane treatment was repeated twice more and the combined hexane washes were then filtered through a Celite® stopper and concentrated to a pale yellow oil (72.5 g, 92.4% pure by HPLC analysis, 82% yield corrected). For analytical purposes, further purify a small sample with Kugelrohr distillation (250 ° C, 13.33 Pa): IR (pure) 2910, 1695, 1600, 1450, 1210,1190 cm ^-1 ; ^X H NMR (CDCl 3, 400 MHz) δ 10.25 (s, 1 H), 7.80 (dd, 1 H, J = 1.2 and 7.7 Hz), 7.45 (m, 1 H) , 7.33-7.13 (m, 7 H), 2.98 (t, 2 H, J = 7.7 Hz), 2.58 (t, 2 H, J = 7.7 Hz), 1 , 58 (m, 4 H), 1.30 (m, 8 H); ¹³ C NMR (CDCl 3, 100 MHz) δ 192.2, 145.7, 142.8, 133.7,

133.6, 131.3, 130.9, 128.3, 128.2, 126.3, 125.5, 35.9, 32.4, 32.4, 31.4, 29.5, 29, 4, 29.3, 29.2; HPLC RT 5.8 min (Whatman Partisil® 5 ODS 3 RAC II, 4.6 mm LD. X 10 cm, 2 ml / min, 7: 3 CH 2 N 4 O, UV detection at 211 nm).

Example 9

Preparation of 2- (8-phenyloctyl) benzaldehyde

Use of two mole equivalents of imma and a nitrogen base and one mole equivalent of l-chloro-7-phenylheptane.

A solution of lithium diisopropylamide in THF (15.4 g, 0.024 mol) was added to THF (30 ml) and cooled to -10 ° C under a nitrogen atmosphere. A solution of N - [(2methylphenyl) -methylene] -1,1-dimethylethanamine (4.23 g, 0.024 mol) in THF (5 ml) was added and the mixture was stirred at -10 ° C for 20 min. Phenylheptyl chloride (2.77 g, 0.012 mol) in THF (5 ml) was added and the mixture warmed to 58 ° C. Gas chromatographic analysis indicated that no phenylheptyl chloride remained after 3 h. The mixture was cooled to 0 ° C and diluted HCl (50 ml) was added while keeping the temperature below 25 ° C. The solution was again warmed to 58 ° C, which was then maintained for 16 h. After cooling to 20 ° C, methylene chloride (100 ml) was added and the phases separated. The aqueous phase was further extracted with methylene chloride (50 ml) and the combined organic phases were washed with water (100 ml). After drying over magnesium sulfate, filtration and evaporation of the solvent, the product was obtained as an oil (6.96 g, 28.6% pure by HPLC analysis, 57% yield corrected).

Using the above conditions, but by stirring the reaction mixture at room temperature for 20 h instead of refluxing for 3 h, a corrected yield of 59% was obtained.

Using the above conditions, but using one molar equivalent of carbimine and an amine base relative to phenylheptyl chloride, a corrected yield of 42% was obtained.

Example 10

Preparation of 2- (8-phenyloctyl) benzaldehyde

Substitution of potassium for lithium as a basic counter ion / use of different imines.

a) N - [(2-methylphenyl) methylene] -1,1-dimethylethanamine (5.00 g, 29 mmol) was added to a solution of lithium diisopropylamide [28.5 mmol; prepared from diisopropylamine (4.0 ml, 2.89 g, 29 mmol) and n-butyl lithium (2.5 M, 11.43 ml, 28.5 mmol)] in THF (50 ml) at -10 ° C . After stirring at this temperature for 75 min, a solution of potassium t-butoxide (1.49 M, 19.2 ml, 28.5 mmol) in THF was added. After a further 15 min, 1-chloro-7-phenylheptane (3.77 g, 17.9 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Hydrochloric acid (6 M, 5 ml) was added and the mixture was refluxed for 90 min. The aqueous layer was separated and extracted with hexane (2 X 200 ml). The combined organic fractions were dried over sodium sulfate, filtered and the solvents removed by evaporation under reduced pressure to give an oil (7.44 g). Analysis of this material shows that it contains 65% w / w phenyloctylbenzaldehyde (4.84 g, 16.5 mmol, 92%).

b) Use of process (a), except for the substitution of N - [(2-methylphenyl) methylene] -isopropylamine and N - [(2-methylphenyl) methylene] -n-butylamine, for the following results:

R ₃ ratio

imine substituent imin: PHC profit (%) i) t-Bu 1.6: 1 92 E) i-Pr 2.0: 1 31 iii) n-Bu 2.0: 1 ~ 10

Example 11

Preparation of 2- (8-phenyloctyl) benzaldehyde

Use of catalytic amount of nitrogen base / priming of various electrophiles.

a) Phenylheptyl bromide / phenylheptyl iodide

i.) To a solution of N - [(2-methylphenyl) methylene] -1,1-dimethylethanamine (5.0 g, 0.03 mol) and Ν, Ν, Ν ', Ν'-tetramethylethylene diamine (3.31 g , 0.03 mol) in tetrahydrofuran (40 ml) was slowly added n-butyl lithium (2.5 M, 11.4 ml, 0.03 mol) at 0 ° C. The solution was stirred for an additional 30 min, followed by the rapid addition of 1-bromo-7-phenylheptane (7.28 g, 0.03 mol) in tetrahydrofuran (10 ml). The reaction mixture was allowed to warm to room temperature and stirring was continued for 15 h. The reaction mixture was quenched with 10% aqueous hydrochloric acid (50 ml) and stirred for 30 min. The layers were separated, methylene chloride (50 ml) was added to the organic layer, and the organics were washed with saturated brine (50 ml). The organics were then dried (magnesium sulfate) and concentrated to an oil to give 2- (8-phenyloctyl) benzaldehyde (3.8 g, 45%): IR (pure film) 2920, 2880,

1695, 1600.1455 cm ⁴ ; Ή NMR (CDCl 3, 400 MHz) δ 10.25 (s, 1 H), 7.80 (dd, 1 H, J = 1.2 and 7.7 Hz), 7.45 (m, 1 H) , 7.33-7.13 (m, 7 H), 2.98 (t, 2 H, J = 7.7 Hz), 2.58 (t, 2 H, J = 7.7 Hz), 1 , 58 (m, 4 H), 1.30 (m, 8 H).

ii) Using procedure (a) (i), other than using 1-iodo-7-phenylheptane instead of 1-bromo-7-phenylheptane, 2- (8-phenyloctyl) benzaldehyde is prepared in 34% yield.

b) 1-bromo-7-phenylheptane / 1-chloro-7-phenylheptane

i) A solution of N - [(2-methylphenyl) methylene] -1,1-dimethylethanamine (2.8 g, 0.016 mol) and 2,2,6,6-tetramethylpiperidine (0.23 g, 0.0016 mol) in The tetrahydrofuran (10 ml) was cooled to -5 ° C. To this 40 min, n-BuLi (1.6 M, 10 ml, 0.016 mol) was added and the temperature was maintained at -5 ° C. A solution of 1-bromo-7-phenylheptane (3.4 g, 0.0133 mol) in tetrahydrofuran (5 ml) at -5 ° C was added rapidly. The temperature rises rapidly to 40 ° C and, after cooling to ambient temperature, the mixture is stirred for 1 h. The mixture was quenched by the addition of dilute hydrochloric acid and stirred at ambient temperature for 16 h. The product was isolated in the usual way (5.0 g, 75% pure, 96% yield corrected).

ii) Using solution (b) (i) other than using 1-chloro-7-phenylheptane instead of 1-bromo-7-phenylheptane, phenyloctyl benzaldehyde was prepared in 87% corrected yield.

Example 12

Preparation of 2- (8-phenyloctyl) benzaldehyde

The effect of changing the temperature at which an anion is formed for different nitrogen bases

a) A mixed solution of N - [(2-methylphenyl) methylene] -1,1-dimethylethanamine (11.2 g, 0.064 mol) and 2,2,6,6-tetramethylpiperidine (0.9 g, 0.0064 mol) in tetrahydrofuran (40 ml) was cooled to -5 ° C. Within 60 min, n-BuLi (1.6 M, 40 ml, 0.064 mol) from the injection pump was added, keeping the temperature below 0 ° C. The mixture was stirred for 30 min and 1-chloro-7-phenylheptane (11.23 g, 0.053 mol) in tetrahydrofuran (20 ml) was added rapidly. The reaction mixture was heated to 50-55 ° C for 2 h. The reaction mixture was cooled to 40 ° C and quenched by the slow addition of dilute hydrochloric acid (100 ml of acid diluted with 300 ml of water). The hydrolysis is completed by heating the mixture to 50-60 ° C for 2.5 h. The mixture was cooled to ambient temperature and the organic phases separated. The aqueous phase was extracted with hexane (100 ml) and the combined organic extracts washed with water (100 ml). The extracts were dried over magnesium sulfate and, after filtering and washing the filter cake with hexane, the organic solution was concentrated in vacuo to give 2- (8-phenyloctyl) benzaldehyde as an oil (14.5 g, 69.3% pure by HPLC analysis, 87% corrected profit).

b) To a mixed solution of N - [(2-methylphenyl) methylene] -1,1-dimethylethanamine (21.0 g, 0.12 mol) in tetrahydrofuran (75 ml), n-BuLi was added for 1 h (1.54 M) (78 ml, 0.12 mol) so that the temperature is maintained between 20-30 ° C by cooling. The mixture was stirred for 30 min and 1-chloro-7-phenylheptane (21.05 g, 0.1 mol) in tetrahydrofuran (40 ml) was added rapidly. The mixture was heated to 50 ° C for 3 h and quenched by the slow addition of dilute hydrochloric acid. The hydrolysis is completed by heating the mixture to 50-60 ° C for 2.5 h. The mixture was cooled to ambient temperature and the organic phases separated. The aqueous phase was extracted with hexane and the combined organic extracts were washed with water. The extracts were dried over magnesium sulfate and, after filtering and washing the filter cake with hexane, the organic solution was concentrated in vacuo to give 2- (8phenyloctyl) benzaldehyde as an oil (34.56 g, 65.3% pure by HPLC analysis, 77% corrected profit).

c) Using the same procedure as in (a) or (b), except for changing the nitrogen base and the temperature at which the anion is formed, the following results are obtained:

amine anion tem.PCj solution yield (% j impurity f% PHE * j profile (% PHC ** j i) (i-Pr) ₂ NH -5 55 7.2 17.3 ϋ) (i-Pr) ₂ NH 25 94 1.8 0 iii) DCA ⁺ -5 48 8.6 14.9 iv) DCA ⁺ 25 83 1.7 0.1 v) TMP ⁺⁺ -5 87 0.6 0.4 you) TMP ⁺⁺ 25 89 0.7 0.7 vii) - 0 45 ND ND viii) __ 25 77 ND ND

DCA ⁺ = dicyclohexylamine TMP ⁺⁺ = tetramethylpiperidine

PHE * = Phenylheptene PHC ** = Phenylheptyl chloride

d) Using the procedure (a) or (b), with the exception of the substitution of l-bromo-7-phenylheptane, the following results are obtained:

amine anion tem.PC) solution yield (% j impurity (% PHE *) profile (% PHB ***) (i-Pr) ₂ NH 0 89 ND ND TMP 25 96 ND ND

PHB *** = Phenylheptyl bromide

One skilled in the art will see many variations of these examples, and the present invention is not limited to these examples, but includes all variations covered by the claims that follow.

For

SMITHKLINE BEECHAM CORPORATION:

PATENT PISANNA

LJUBLJANA "

Claims (22)

PATENT APPLICATIONS A process for the preparation of a compound of the formula: Oh A (Ib) where: L and L ₂ are independently CH ₂ CH ₂ , CH = CH or C = C; q 0 to 8; p, r and s are independently 0 or 1; TO, S, CH ₂ , CH = CH, C = C; and ZC _M alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with CF _3, C _M-alkyl, C _M alkoxy, methylthio or trifluoromethylthio; and R ₂ and A are independently H, CF ₃ , C 1-6 alkyl, F, Cl, Br or J; characterized in that it involves the metabolism of a compound of the formula: NR ₃ R. (III) where: R ₂ and A are as defined above; R _{3 is} C _3-6 alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t -phenyl or N (R ') ₂ ; R 1 is C 1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t -phenyl; and t is 0 or 1; with a base and a compound of the formula: X-CH ₂ - (L ₁ ) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ - (T) _$ -Z (IV) where: Lp are L ₂ , p, q, r, s, T and Z as defined above and X is a substituted group; and treating its product with acid. A process according to claim 1, characterized in that the base is added to the compound of formula (III) at about 15 ° C to about 35 ° C and the base is lithium alkyl or lithium diisopropyl amide. Process according to claim 1, characterized in that R ₂ and AH, R _{3 are} t-butyl and X is bromo or chloro. Process according to claim 1, characterized in that the acid is a mineral acid. 5. The process according to claim 4, wherein the acid is hydrochloric acid. 6. A process characterized in that N - [(2-methylphenyl) methylene] -1,1-dimethyl-ethanamine is reacted with n-butyllithium and a catalytic amount of organic amine and l-chloro-7-phenylheptane and subsequently treated with hydrochloric acid. 7. A process characterized in that N - [(2-methylphenyl) methylene] 1,1-dimethylethanamine is reacted with lithium diisopropylamide, potassium butoxide and 1-chloro-7-phenylheptane and subsequently treated with hydrochloric acid. 8. A process for the preparation of a compound of the formula: (ii) where: ΐς CH ₂ CH ₂ - (L ₁ ) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ - (T) _s -Z; L »! and L ₂ is independently CH ₂ CH ₂ , CH = CH or C ^ C; q Odo8; p, r and s are independently 0 or 1; TO, S, CH ₂ , CH = CH, C = C; and ZC ₁₄ -alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl, optionally mono-substituted with CF ₃ , C ₁₄ -alkyl, C 1-4 alkoxy, methylthio or trifluoromethylthio; and R ₂ and A are independently H, CF ₃ , C ₁₄ -alkyl, F, Cl, Br or J; R _{3 is} C ₁₆ -alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t -phenyl or N (R ') ₂ ; R ₁ is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t -phenyl; and t is 0 or 1; characterized in that it involves the metabolism of a compound of formula (III): wherein A, R ₂ and R _{3 are} as defined above; with a base and a compound of formula (IV): X-CH ₂ - (L ₁ ) _p - (CH ₂ ) _q - (L ₂ ) _r -CH ₂ - (T) _s -Z (IV) where: L _p L ₂ , T, Z, p, q, r, and s are as defined above; and X is a replaceable group. A process according to claim 8, characterized in that the base is alkyl alkali metal, aryl alkali metal or an alkali metal amine. 10. The process of claim 9, wherein the base is lithium alkyl. A process according to claim 9, characterized in that the base is lithium diisopropylamide or butyl lithium. Process according to claim 10, characterized in that a catalytic amount of an organic amine is present. Process according to claim 12, characterized in that the organic amine is diisopropylamine, 2,2,6,6-tetramethylpiperidine or dicyclohexylamine and the organic amine is present in an amount of about 0.01 to 0.15 molar equivalent of the compound of formula (III) . Process according to claim 10, characterized in that the base and the compound of formula (III) are reacted at a temperature of about 15 ° C to about 35 ° C. Process according to claim 11, characterized in that sodium or potassium alkoxide is added to the reaction mixture before the addition of the compound of formula (IV). 16. The process of claim 8 wherein R _{3 is} t-butyl. Process according to claim 16, characterized in that X is bromo or chloro. Process according to claim 17, characterized in that Z is phenyl and Lj and L _{2 are} independently ch ₂ ch ₂ . 19. A compound of the formula: N- ^R 3 R. (II) where: Lj and L ₂ are independently CH ₂ CH ₂ , CH = CH or ChC; q 0 to 8; p, r and s are independently 0 or 1; Τ 0.8.0 ^ 01 = 01, C = C; and The Cj ^ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with _CF3, C ^ -alkyl, C ^ alkoxy, methylthio or trifluoromethylthio; R ₂ and A are independently H, CF _y C _M-alkyl, F, O, Br or I; R _{3 is} C ₁₆ -alkyl, C 1-4 cycloalkyl, (CH 4 -phenyl or N (R ') ₂ ; R ₁ is C 1-6 alkyl, C _3-4 cycloalkyl or (CH ₂ ) ₍ -phenyl; and t is O or 1. A compound according to claim 19 wherein R _{3 is} t-butyl. 21. A compound according to claim 19, wherein L1 and O4 are O and Z is phenyl. A compound according to claim 21, characterized in that N - [(2- (8-phenyloctyl) phenyl) methylene] -1,1-dimethylethanamine.