CN1078229A - Process and intermediates for the preparation of 2-substituted benzaldehydes - Google Patents

Abstract

A kind of method for preparing the 2-substituted benzoyl aldehyde compound of following formula, R in the formula ₁, R ₂With the same specification sheets of the definition of A.These compounds are used to prepare pharmaceutical active compounds.

Description

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

2-Substituted benzaldehydes are useful intermediates for the preparation of pharmaceutically active compounds. For example, some compounds which are leukotriene antagonists and are useful in the treatment of asthma can be prepared from 2-substituted benzaldehydes having the general formula (Ia) :

in

R _x is (L)a-( _CH2 ) _b- (T) _c -M;

a value is 0 or 1;

b value from 3 to 14;

c value is 0 or 1;

L and T are independently sulfur, oxygen, or _CH2 ;

M is C _1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furyl, thienyl, cyclohexyl or optionally bromo, chloro, CF ₃ , C _1-4 alkyl, C _{1- 4} alkoxy, methylthio or trifluoromethylthio monosubstituted phenyl;

R ₂ and A can be independently selected from H, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, F, Cl, Br, I, OH, NO ₂ or NH ₂ ;

Or _R1 and A are H, and _R2 is (L) _a- ( _CH2 ) _b- (T) _c -M, wherein a, b, c, L, T and M are as defined above.

Such compounds are disclosed, for example, in U.S. Patent 4,820,719, U.S. Patent 4,874,792 and European Patent EP-A 0,296,732. These documents are incorporated herein by reference. Thus, two general methods for the preparation of 2-substituted benzaldehydes have been reported in the literature: 1) Palladium-catalyzed addition of substituted 1-alkynyl compounds to 2-halobenzaldehydes, leading to coupling to directly obtain 2-(1-alkynyl)benzaldehyde; 2) convert 2-methoxybenzoic acid into 2-(2-methoxyphenyl)-4,4-dimethyl-oxazoline, and then use alkane base or aralkyl Grignard reagents to prepare the corresponding 2-(2-alkylphenyl)-4,4-dimethyl-oxazoline or 2-(2-arylalkylphenyl) -4,4-Dimethyl-oxazoline (the 2-substituted oxazoline is then treated with iodomethane, reduced with sodium borohydride, and then subjected to acid hydrolysis to produce the corresponding 2-substituted benzaldehyde). The latter method is based on the method discovered by Meyer et al., cf. J. Org. Chem., 43, 1372 (1978). A similar method for the preparation of 2-substituted benzaldehydes has also been disclosed by Perchmock et al., see J. Med. Chem., 28, 1145 (1985). Generally, these methods employ reagents that displace substituents on aromatic rings through their functional groups.

Methods are also known for nucleophilic substitution of aromatic rings to add a substituent in the ortho position of the aromatic ring. Org.Reaction26, 43-61 (1979) reported that certain functional groups containing nitrogen heteroatoms and attached to the benzene ring can stabilize the benzene ring for lithiation reactions, especially in the ortho position, and the lithiated position can then be used Treatment with an appropriate electrophile results in a substitution reaction. Functional groups that have been reported to be particularly effective for this purpose are mono- or dialkylamides, amines, N,N-dialkylhydrazones, imidazolines and oxazolines. De Silva et al. in Tetrahedron Lett., 5107 (1978) reported lithiation with sec-butyllithium and diisopropylamine in the ortho position of benzamide. Trecourt et al. in J. Org. Chem., 53, 1367 (1988) report the lithiation in the ortho position of 2-methoxypyridine with methyllithium and a catalytic amount of diisopropylamine. However, arylcarbimides have been reported to have limited synthetic applicability due to their ease of reaction at the carboimide position and α-deprotonation reactions. See Org. Reactions, 26, 57-58 (1979). Zeigler et al. reported in J.Org.Chem., 41, 1564 (1976) that arylcarboimides can also be induced to lithiate in the ortho position if adjacent ether substituents are present.

In addition, it has been reported that the methyl group can also be lithiated if it is in the ortho position of benzamides, 2-phenylimidazolines and 2-phenyloxazolines. For example, Watanabe et al reported in J.Org.Chem., 49,742 (1984) that in the synthesis of isocoumarins the side chain was extended through ortho-toluamide; Gschwend et al. in J.Org.Chem. , 40, 2008 (1975), reported that the benzyl side chain was extended by lithiation of 2-(o-tolyl)oxazoline; also Houlihan reported in U.S. Patent 4,100,165 that dilithiation The 2-(o-tolyl) imidazoline can undergo condensation reaction with esters and acyl halides.

The current methods for synthesizing 2-substituted benzaldehydes in the present invention all use expensive reagents or multi-step reaction methods, which makes them unattractive in the industrial scale preparation of 2-substituted benzaldehydes. Therefore, there is a need for alternative methods of efficiently preparing 2-substituted benzaldehydes.

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

In the formula:

_R1 is _CH2CH2- ( _L1 ) _p- ( _CH2 ) _{q- ( L2} ) _r - _CH2- (T) _s -Z;

L ₁ 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;

T is O, S, _CH2 , CH=CH, C≡C; and

Z is C _1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furyl, thienyl, cyclohexyl or optionally replaced by CF ₃ , C _1-4 alkyl, C _1-4 alkoxy , methylthio or trifluoromethylthio monosubstituted phenyl;

R ₂ and A are independently H, CF ₃ , C _1-4 alkyl, F, Cl, Br or I.

A feature of the invention is a process for the preparation of compounds of the formula:

In the formula, the definitions of A, R ₁ , R ₂ , L ₁ , L ₂ , q, p, r, s, T and Z are the same as those of the preceding formula (Ib);

The process comprises reacting a compound of formula (III) with a base and a compound of formula (IV) and then treating the reaction product with an acid;

In the formula:

The definitions of _R2 and A are the same as those of formula (Ib) above;

R ₃ is C _1-6 alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t phenyl or N(R') ₂ ;

R' is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t phenyl;

t value is 0 or 1;

In the formula:

L ₁ , L ₂ , p, q, r, s, T and Z are as defined in the above formula (Ib), and X is a substitutable group.

Another feature of the present invention is to provide novel intermediates of the following formula (II):

In the formula:

R ₁ , R ₂ and A have the same definitions as in formula (Ib);

R ₃ is C _1-6 alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t phenyl or N(R') ₂ ;

R' is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t phenyl;

The t value is 0 or 1.

Another feature of the present invention is to provide a method for the preparation of new intermediates of formula (II), which comprises the compound of formula (III)

In the formula, A, R ₂ and R ₃ are defined the same as those of formula (II), reacting with a base and the compound of formula (IV),

The definitions of L ₁ , L ₂ , p, q, r, s, T and Z in the formula are the same as in the preceding formula (Ib), and X is a substitutable group.

Another feature of the invention is to provide an improved process for the preparation of compounds of formula (II) which comprises adding to the reaction mixture a catalytic amount of an organic amine prior to the addition of the base.

Still another feature of the present invention is to provide an improved process for the preparation of compounds of formula (II) which comprises adding sodium alkoxide or potassium alkoxide to the reaction mixture.

Another feature of the present invention is to provide an improved process for the preparation of compounds of formula (II) which comprises carrying out the above reaction within a specified temperature range.

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

In the formula:

_R1 is _CH2CH2- ( _L1 ) _p- ( _CH2 ) _{q- ( L2} ) _r - _CH2- (T) _s -Z;

L ₁ and L ₂ are independently CH ₂ CH ₂ , CH=CH or C≡C;

q value from 0 to 8;

p, r and s are independently 0 or 1;

T is O, S, _CH2 , CH=CH, C≡C;

Z is C _1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furyl, thienyl, cyclohexyl or optionally replaced by CF ₃ , C _1-4 alkyl, C _1-4 alkoxy , methylthio or trifluoromethylthio monosubstituted phenyl;

R ₂ and A are independently H, CF ₃ , C _1-4 alkyl, F, Cl, Br or I;

The method comprises reacting a compound of formula (III) with a base and a compound of formula (IV) and then treating the reaction product with an acid, formula (III) being:

In the formula

The definitions of _R2 and A are the same as before;

R ₃ is C _1-6 alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t phenyl or N(R') ₂ ;

R' is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t phenyl;

t value is 0 or 1;

Formula (Ⅳ) is:

In the formula

L ₁ , L ₂ , p, q, r, s, T and Z have the same definitions as before; and

X is a displaceable group.

In addition, the present invention discloses new intermediates of the following formula (II):

In the formula

_R1 is _CH2CH2- ( _L1 ) _p- ( _CH2 ) _{q- ( L2} ) _r - _CH2- (T) _s -Z;

L ₁ and L ₂ are independently CH ₂ CH ₂ , CH=CH or C≡C;

q value from 0 to 8;

p, r and s are independently 0 or 1;

T is O, S, _CH2 , CH=CH, C≡C;

Z is C _1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furyl, thienyl, cyclohexyl or optionally replaced by CF ₃ , C _1-4 alkyl, C _1-4 alkoxy , methylthio or trifluoromethylthio monosubstituted phenyl;

R ₂ and A are independently H, CF ₃ , C _1-4 alkyl, F, Cl, Br or I;

R ₃ is C _1-6 alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t phenyl or N(R') ₂ ;

R' is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t phenyl;

The t value is 0 or 1.

Suitably Z is phenyl and _L1 and _{L2 are CH2CH2} .

Suitable _R3 is tert-butyl.

A suitable p, r and s value is 1.

Suitable values for q are 0 to 2.

Suitable T is _CH2 or C≡C.

A preferred compound is N-[2-(8-phenyloctyl)phenylmethylene]-1,1-dimethylethylamine.

Novel intermediates of formula (II) are prepared by a process which involves the following compound of formula (III):

In the formula

R ₂ and A are independently H, CF ₃ , C _1-4 alkyl, F, Cl, Br or I;

R ₃ is C _1-6 alkyl, C _3-6 cycloalkyl, (CH ₂ ) _t phenyl or N(R') ₂ ;

R' is C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂ ) _t phenyl;

t value is 0 or 1;

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

In the formula

L ₁ and L ₂ are independently CH ₂ CH ₂ , CH=CH or C≡C;

q value is 0 to 8;

p, r and s are independently 0 or 1;

T is O, S, _CH2 , CH=CH, C≡C;

Z is C _1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furyl, thienyl, cyclohexyl or optionally replaced by CF ₃ , C _1-4 alkyl, C _1-4 alkoxy , methylthio or trifluoromethylthio monosubstituted phenyl; and

X is a displaceable group.

In a preferred embodiment, the present invention discloses a method for preparing a compound of formula (Ib), which comprises reacting a compound of formula III) with a base and a compound of formula (IV), and then treating the reaction mixture with an acid . Thus, in this preferred embodiment, the entire conversion is accomplished in a single reaction vessel without isolation of intermediate products. This method uses readily available starting materials and is performed in efficient yields with a minimum number of reaction steps.

The compounds of formula (III) are hydrazones and imines, or Schiff's bases, and can generally be prepared by any of the methods commonly used in the art for the preparation of such compounds. A kind of method for preparing imine compound comprises formula (Ⅴ) compound

Reaction with an amine or hydrazine of formula _R3 - _NH2 . This reaction is usually carried out by mixing the two reactants in a non-aqueous solvent, which may be heated. A dehydrating agent can be used to complete the reaction if necessary. Common dehydrating agents are: eg molecular sieves or magnesium sulfate. In addition, a suitable solvent such as benzene or toluene can also be used to dehydrate the water produced in the reaction by azeotropic distillation. The group _R3 is _C1-6 alkyl, _C3-6 cycloalkyl, benzyl, phenyl or N(R') ₂ . Cyclohexylamine, t-butylamine, aniline and N,N-dimethylhydrazine are suitable reagents, preferably t-butylamine.

The electrophile given by the formula (IV) can be used in the usual way, such as in U.S. Patent No. 4,820,719, U.S. Patent No. 4,874,792, European Patent Application No. 0296732 and Perchanock et al. J.Med. Chem., 28, 1145 (1985), which are incorporated herein by reference. The X moiety of the electrophile represents a displaceable group which may be any group capable of being displaced by a carbon nucleophile prepared from a compound of formula (III). A number of substitutable groups are suitable, such as alkyl and aryl sulfonates, alkyl and arylalkyl acetates, benzoates and halides. Representatives of such groups are Cl, Br, I, R ₄ SO ₃ and R ₄ CO ₂ , wherein R ₄ is C _1-4 alkyl which may be substituted by 1-5 fluorine atoms, or may be substituted by one or two A halogen, C _1-4 alkyl, C _1-4 alkoxy or nitro substituted phenyl. Representative displaceable groups are tosylate, bromo-benzenesulfonate, nitrobenzenesulfonate, mesylate, triflate, acetate, chloroacetate, trifluoroacetic acid groups such as ester, benzoate, bromobenzoate, chlorobenzoate, nitrobenzoate, chlorine, bromine and iodine, preferably chlorine and bromine, particularly preferably chlorine.

In general, if the X group is not present in the precursor, the X group in the compound of formula (IV) can be prepared from the corresponding alcohol by reaction with the appropriate acid halide, acid anhydride, sulfonyl halide or suitable halogenating reagent . Typical of such reagents are toluenesulfonyl chloride, bromobenzenesulfonyl chloride, nitrobenzenesulfonyl chloride, methanesulfonyl chloride, acetyl chloride, chloroacetyl chloride, trifluoroacetic anhydride, benzoyl chloride, bromobenzoyl chloride, chlorobenzoyl chloride Acyl chloride, nitrobenzoyl chloride, oxalyl chloride or oxalyl bromide, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphorus tribromide, phosphorus trichloride, phosphorus oxychloride, and tetrabromide containing triphenylphosphine carbonized. A compound of the general formula HO-CH ₂ -(L ₁ ) _p -(CH ₂ ) _q -(L ₂ ) _r -CH ₂ -(T) _s -Z, wherein T is CH ₂ , and L ₁ or L ₂ is When CH ₂ CH ₂ , Z is C _1-4 alkyl or phenyl, they are generally commercially available. Those compounds in which T is O, S or C≡C can be obtained by combining the compound HTZ with the structure X-CH ₂ -(L ₁ ) _p -(CH ₂ ) _q -(L _{2 )} in the presence of a suitable base ) _r -CH ₂ -X compound reaction and prepared, wherein X, L ₁ , L ₂ , T, p, q and r are defined the same as before. Compounds where T is CH=CH can be prepared by partial hydrogenation of compounds where T is C≡C, for example with Lindlar catalyst or 5% palladium/BaSO ₄ catalyst and hydrogen. Hydrogenation with a palladium catalyst, such as 5% palladium on charcoal, yields compounds where T is _CH2 . When _L1 or _L2 is C≡C or CH=CH, the resulting product can be subsequently reduced to give a product _{where L1} or _L2 is CH=CH or _CH2CH2 . For example, 1-bromo-7-phenylheptane can be prepared by reacting 1,5-dibromopentane and phenylacetylene in the presence of n-butyllithium, followed by reduction with hydrogen and a palladium catalyst. In another example, 1-bromo or 1-chloro-7-phenylheptane can be prepared by coupling benzylmagnesium halide with 1,6-dibromohexane or 1-bromo-6-chlorohexane in the presence of copper be made of.

The alkylation of carboimides of formula (III) can be initiated by deprotonating the ortho-methyl group of the compound of formula (III) with a strong base. Since the metallized intermediate is reactive towards water, the activation reaction is carried out under an inert dry gas such as nitrogen or argon, although dry air can also be carried out.

The activation reaction is carried out in an aprotic solvent. Solvents suitable for this reaction are common aliphatic or aromatic hydrocarbon solvents which are not reactive to strong bases. Representative of such solvents are diethyl ether, tetrahydrofuran, dioxane, toluene, benzene, pentane, hexane, petroleum ether and mixtures thereof. Among them, diethyl ether, dioxane and tetrahydrofuran are preferred, and tetrahydrofuran is particularly preferred.

The deprotonation reaction of the ortho-methyl group requires a sufficiently strong base. Any base capable of carrying out such a deprotonation reaction without causing significant side reactions is suitable. Typical such bases are alkali metal alkyls, alkali metal amides, or alkali metal arylates. . Representative of such bases are n-butyllithium, sec-butyllithium, methyllithium, phenyllithium, lithium diisopropylamide, lithium diethylamide or lithium amide, or the corresponding sodium of such substances salt or potassium salt. Alkyllithium reagents are particularly suitable. Preference is given to n-butyllithium and lithium diisopropylamide. It is also within the scope of the invention that the alkali metal initially used may be exchanged for another metal, such as another alkali metal, copper, magnesium or zinc. It is often helpful to use a slight excess of base, such as a 1% to 25% excess, to ensure complete metallation. About one molar equivalent is usually satisfactory. It will be apparent to those skilled in the art that some of the above bases, such as alkali metal alkyls or arylates, may be incompatible with the halogen substituents in the carboimide molecule, and other A base such as lithium diisopropylamide would be more suitable.

The reaction of the compound of formula (Ⅲ) with the base is carried out by mixing the two reactants, and the reaction should be carried out at a temperature high enough that the base can cause deprotonation on the ortho-position methyl group, but cannot Too high to cause harmful side effects. The optimum temperature will therefore depend on the base and imine reactant used. If the base used is lithium dialkylamide, the reaction is typically carried out at a temperature between -20°C and 60°C; preferably the reaction is carried out at a temperature between about -10° and 40°.

It has been found that surprisingly improved yields are obtained when the reaction is carried out at a temperature between about 15° and about 35°C. Typically, when a strong base is reacted with a compound having a moiety susceptible to nucleophilic attack, such as a carboimide functionality, the reaction is carried out at a temperature of about 0°C or lower. The lower temperature is believed to prevent undesired side reactions such as nucleophilic attack of the active carboimide functional group by the base itself or by negative ions generated through the action of the base. Surprisingly, with certain bases, such as n-butyllithium plus a catalytic amount of diisopropylamine or dicyclohexylamine, by adding the base to the carboimide at about 15°C to about 35°C, the side reaction Minimize and increase yield. It is particularly suitable to conduct the reaction at a temperature between about 20°C and about 30°C. Temperatures above 55°C generally lead to increased unwanted side reactions.

Typically, the electrophile X- _CH2- ( _L1 ) _p- ( _CH2 ) _q- ( _L2 ) _r - _CH2- (T) _s -Z is added at the completion of the metallation reaction. Although it is possible to add the electrophile neat, it is more convenient to add it dissolved in the solvent used to form the metallated intermediate. The reaction is then stirred for 15 minutes to about 24 hours.

If the imine is to be isolated, the reaction solution can be diluted with an appropriate solvent, washed with water and concentrated to an oil under reduced pressure. If a purified product is desired, the product can be purified by distillation or, if appropriate, by crystallization.

The conversion of the compound of formula (II) to benzaldehyde is carried out by stirring with the imine any acid of such strength that it hydrolyzes the C=N bond. Within the scope of the present invention, inorganic acids as well as organic acids etc. are considered to be sufficiently strong acids. For example, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, benzoic acid, acetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid are suitable, preferably inorganic acids , while hydrochloric acid is particularly preferred.

In a preferred method, the reaction mixture containing product (II) can be directly hydrolyzed by adding an acid to the reaction mixture. Typically, the reaction mixture is added to a cooled solution of the acid and allowed to warm to room temperature. The reaction mixture can be monitored for the formation of the desired benzaldehyde by, for example, analytical chromatography, but typically the reaction is stirred for about 1 hour to After about 24 hours, the product is then isolated by usual techniques such as extraction.

An improved process for the preparation of compounds of formula (II) which comprises adding to the reactants a catalytic amount of an organic amine prior to the addition of the base, especially when an alkyllithium reagent is used as the base. Addition of a catalytic amount of an organic amine gives higher yields than either the absence of the amine or the addition of an equimolar amount of the amine. Suitable organic amines are secondary amines. Representative amines are diethylamine, diisopropylamine, dicyclohexylamine, piperidine, 2,6-dimethylpiperidine and 2,2,6,6-tetramethylpiperidine. Diisopropylamine, dicyclohexylamine and 2,2,6,6-tetramethylpiperidine are particularly suitable. Catalytic amounts mean about 0.01 to about 0.03 molar equivalents of organic amine per mole of carboimide, with about 0.01 to about 0.15 molar equivalents being suitable. Usually about 0.01 to 0.1 molar equivalent is used, depending on the amine used. For example, about 0.01 to about 0.05 equivalents are used for diisopropylamine and 2,2,6,6-tetramethylpiperidine.

Another feature of the present invention is to provide an improved method for the preparation of compounds of formula (II), which comprises the preparation of sodium or potassium salts of carboimides of formula (III), and combining the product with compounds of formula (IV) react. For example, 2-methylphenylcarboimide of formula (III) can be treated with a base such as n-butyllithium or lithium diisopropylamide to form a lithium salt followed by treatment with a sodium or potassium base or salt, The desired salt is formed by an exchange metal reaction. Sodium or potassium alkoxide, sodium or potassium trifluoroacetate are representative bases/salts. The reaction of this carboimide salt with a compound of formula (IV) such as 7-phenylheptyl chloride, compared with the lithium salt of the corresponding carboimide, can carry out the alkylation reaction at a lower temperature, so only Fewer side effects. Potassium salts are particularly suitable.

The following examples illustrate how to make and use the compounds, and related methods, which constitute the present invention.

The nomenclature and abbreviations used in the examples are commonly used in chemistry. Unless otherwise noted, reagents were purchased from commercial sources and used without further purification. If tetrahydrofuran was used as the reaction solvent, it was first dried over 4A molecular sieves, all other solvents were commercially available in reagent grade purity and used without further purification. All reactions in non-aqueous solutions were performed under a blanket of dry nitrogen. Melting points are determined on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Liquid chromatography was performed on a Whatman Partisil 5 ODS 3 RAC II instrument. Gas chromatographic analysis was performed with a DB-1 30m×0.53mm capillary column. IR spectra were measured with a Perkin-Elmer Model 283 infrared spectrometer. FT-IR was obtained on a Nicolet 6000 FT infrared spectrometer. Combustion analysis was performed with a Perkin-Elmer Model 240 C Elemental Analyzer. Unless otherwise noted, all HNMR (proton magnetic resonance spectra) were measured with a Bruker Instruments WM400 NMR instrument at 400 megacycles and in deuterated chloroform solution, ¹³ CNMR spectra were measured at 100 megacycles, chemical shifts from Methyl silicon is swept downfield, expressed in ppm (δ).

Annotations to HNMR are as follows: S, singlet; d, doublet; t, triplet; br, broad; m, multiplet; J, coupling constant in Hertz.

Example 1

Preparation of 1-bromo-7-phenylheptane

A solution of benzylmagnesium chloride (750 ml, 2M in tetrahydrofuran, 1.5 moles) was added to stirred 1500 ml (0.15 moles) of 0.1M _Li2CuCl4 and _1,6 at -5 to 0°C over a period of 90 minutes. - In a solution of dibromohexane (456.8 g, 1.87 mol, 1.25 equiv) in tetrahydrofuran, the reaction mixture was stirred at 0°C for 90 minutes, then carefully treated with 2.0 liters of saturated aqueous ammonium chloride. The internal temperature of the reactants was kept below 20°C during the treatment. The mixture was stirred at room temperature for 1 hour and the layers were separated. The organic layer was washed with 20% aqueous sodium chloride (4 x 500ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure at 45-50°C to an amber oil. Purification by fractional distillation under reduced pressure on a 12 inch vacuum-jacketed Vigreux column gave the desired product as a colorless oil (198.2 g, 52%). Prepare samples for analysis by redistillation: boiling point 123-124°C (1.5mmHg); FT-IR (pure liquid film) 3100-3000; 3000-2800, 2000-1700, 1604, 1496, 748, 699, 644cm ^{- 1} ; HNMR ( _CDCl3 , 400MHz) δ7.29-7.16 (m, 5H), 3.40 (t, 2H), 2.60 (t, 2H), 1.88-1.81 (m, 2H), 1.63-1.60 (m, 2H) ), 1.43-1.32 (m _, 6H); ¹³ C NMR (CDCl ₃ , 100MHz) _. Anal. Calcd. for Br: C, 61.91; H, 7.50; Br, 31.31; Found: C, 61.25; H, 7.59;

Example 2

Preparation of 7-chloro-1-phenylheptane

a) 1-Bromo-6-chlorohexane

1.6-Hexanediol (30 kilograms, 254 moles), the mixture of 48% hydrobromic acid (51 kilograms, 302 moles) and toluene is heated to reflux, azeotropic distillation removes water (34.5 kilograms), when distillation stops, the mixture Cool to 20°C and extract with a solution of concentrated hydrochloric acid (69.9 kg) and water (60 liters). After phase separation, the organic phase is dried by reheating and azeotropic distillation to remove water. The mixture was cooled to 65°C and dimethylformamide (1.11 kg) was added. Thionyl chloride (31.4 kg, 264 mol) was added over 45 minutes while maintaining the temperature between 65-68°C. The mixture was heated to 109°C over 1.25 hours and then cooled to 20°C. Then wash with 20% sodium hydroxide solution (100 liters) and water (2×150 liters, 1×100 liters) successively. Toluene (400 liters) was distilled off under reduced pressure to obtain a toluene solution of bromochlorohexane (85.5 kg, its content was determined to be 55% w/w by analysis, and the yield was 93%).

b) 7-Chloro-1-phenylheptane

At 15°C, a solution of copper tetrachloride lithium [33 liters of tetrahydrofuran, lithium chloride (0.87 kg, 19.3 moles), copper chloride (1.4 kg, 10.4 moles)] was added to a solution of benzylmagnesium chloride in tetrahydrofuran ( 160 liters, 1.86M solution, 298 moles), and the mixture was stirred for 30 minutes, and a solution of bromochlorohexane in toluene (85.5 kg solution, analyzed to determine its content as 55% W/ W, 47.1 kg, 236 mol), while maintaining the temperature between 15-20°C. Stirring was continued for 1.25 hours. A 10% ammonium chloride solution (263 liters) was added over 1 hour while maintaining the temperature below 30°C. The phases were separated and the organic phase was further washed with ammonium chloride solution (170 liters) and 20% sodium chloride solution (3 x 197 liters). The organic solution was concentrated under reduced pressure to leave an oil (56.8 kg, 77% purity by HPLC analysis, 88% corrected yield).

Example 3

Preparation of N-[(2-methylphenyl)methylene]-1,1-dimethylethylamine

A stirred solution of o-tolualdehyde (25 g, 0.21 mol) and tert-butylamine (27.75 g, 0.38 mol) in toluene (250 ml) was refluxed under standard Deam-stark conditions for 20 hours. The solution was evaporated into an oil and then distilled under reduced pressure (boiling point 70-73°C, 0.6mmHg) to obtain 33.9 grams (93%) of the product: IR (pure liquid film) 2980, 1645, 1605, 1460, 1375, 1210, 960 , 910cm ^-1 ; H NMR (400MHz, CDCl ₃ ) δ8.56 (S, 1H), 7.86-7.83 (m, 1H); 7.25-7.11 (m, 3H), 2.46 (S, 3H), 1.30 (S , 9H); ¹³ C NMR (CDCl ₃ , 100MHz) δ153.7, 137.1, 135.1, 130.5, 129.6, 127.1, 126.4, 57.5, 29.8, 19.2, GCRT7.6 points (DB-1, 30m×0.53mm, program Heating: 100°C for 5 minutes, 100-260°C. At a rate of 15°C per minute, keep at 260°C for 12 minutes).

Example 4

Preparation of 2-Methylbenzaldehyde Dimethylhydrazone

A stirred solution of o-toluene (25.0 g, 0.21 mol) and 1,1-dimethylhydrazine (25.2 g, 0.42 mol) in toluene (200 ml) was heated at reflux for 24 hours. The solution was concentrated under reduced pressure, and the residual oil was distilled under reduced pressure (51-60°C, 0.2 mmHg) to give the title product (31.98 g, 94%): IR (pure liquid film) 2950, 2850, 1580, 1550, 1455, 1025, 745cm ^-1 ; H NMR (CDCl ₃ , 400MHz) δ7.8-7.6 (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-dimethylethylamine

Under stirring, to a solution of diisopropylamine (29.14 g, 0.289 mol) in tetrahydrofuran (450 ml) cooled to -5°C was added n-butyllithium (2.5M, 114.3 ml, 0.286 mol) at a rate of The temperature of the solution should be maintained below 10°C. After the addition was complete the solution was stirred for 15 minutes with cooling. To this solution was added a solution of N-[(2-methylphenyl)-methylene]-1,1-dimethylethylamine (50.0 g, 0.286 mol) in tetrahydrofuran (65.0 ml), and the added The rate should keep the reaction temperature below 5°C. The reaction mass was stirred under cooling for 15 minutes, then a solution of 1-bromo-7-phenylheptane (72.9 g, 0.286 mol) in tetrahydrofuran (75 ml) was added rapidly, and the reaction mixture was stirred under cooling for 1 hour. It was then allowed to warm to room temperature and stirred for an additional 14 hours. Determine the content of product imine in the reaction mixture by gas chromatography analysis (RT 19.8 minutes, DB-1, 30m × 0.53mm, temperature program, 100 ° C for 5 minutes, 100-260 ° C at a speed of 15 ° C per minute, at 260 °C for 12 minutes). The reaction mixture was diluted with water and dichloromethane, the organic mixture was washed rapidly with water, and the solution was concentrated to an oil, and the product was isolated. The oil was purified by distillation.

Example 6

Preparation of N-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethylamine

A solution of 2-(8-phenyloctyl)benzaldehyde (10 g, 0.034 mol) and tert-butylamine (4.96 g, 0.068 mol) in toluene (100 ml) was stirred under standard Dean-Stark conditions. Heat to reflux for 16 hours. The solution was evaporated to an oil and vacuum distilled (boiling point 260°C, 0.15mmHg) to give the title product (11.1 g, 94%): GC RT 19.8 min (DB-1, 30m x 0.53mm, temperature programmed, 100°C 5 minutes, 100-260 ° C at a rate of 15 ° C per minute, keep at 260 ° C for 12 minutes); 'H NMR (CDCl ₃ , 400 MHz) δ8.58 (S, 1H), 7.86 (d, J = 7.5 Hz , 1H); 7.29-7.13 (m, 8H), 2.79 (t, J = 7.5Hz, 2H), 2.58 (t, J = 7.5Hz, 2H), 1.59-1.51 (m, 12H), 1.30 (S, 9H).

Example 7

Preparation of 2-(8-phenyloctyl)benzaldehyde

By hydrolysis of N-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethylamine

To a solution of N-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethylamine (0.51 g, 0.0146 mol) in tetrahydrofuran (5 ml) 10% hydrochloric acid (5 ml) was added, and the mixture was stirred at room temperature for 15 hours. Dichloromethane (10ml) and water (10ml) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (1×15 ml), the combined organic phases were dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give an oil (0.405 g, the purity was 97.4% by HPLC analysis, the corrected yield rate of 92%): IR (pure liquid film) 2920, 2880, 1695, 1600, 1455cm ^-1 ; H NMR (CDCl ₃ , 400MHz) δ10.25 (S, 1H), 7.80 (d, d, 1H, J = 1.2 and 7.7Hz); 7.45 (m, 1H), 7.33-7.13 (m, 7H), 2.98 (t, 2H, J = 7.7Hz), 2.58 (t, 2H, J = 7.7Hz), 1.58 (m , 4H), 1.30 (m, 8H).

Example 8

Preparation of 2-(8-phenyloctyl)benzaldehyde

Reaction of 1-bromo-7-phenylheptane with one molar equivalent of nitrogenous base.

Add n-butyllithium (2.5M, 114.3 ml, 0.286 mol) to a stirred solution of diisopropylamine (29.14 g, 0.289 mol) in tetrahydrofuran (450 ml) cooled to -5°C, add The speed should be such that the temperature of the solution is maintained below 10°C. After the addition was complete, the solution was stirred under cooling for 15 minutes, and to this solution was added N-[(2-methylphenyl)-methylene]-1,1-dimethylethylamine (50.0 g, 0.286 mol) A solution in tetrahydrofuran (65.0 ml) was added at such a rate as to keep the reaction temperature below 5°C. The reaction was stirred with cooling for 15 minutes, then a solution of 1-bromo-7-phenylheptane (72.9 g, 0.286 mol) in tetrahydrofuran (75 ml) was added rapidly. The reaction mixture was stirred with cooling for 1 hour, then allowed to warm to room temperature and stirred for 14 hours. The reaction mixture was treated with 10% aqueous hydrochloric acid and stirred at 0°C for 1 hour, then at room temperature for 14 hours. The reaction mixture was poured into dichloromethane (700 ml) and stirred for 5 minutes, the organic layer was separated, the aqueous layer was extracted with dichloromethane (2×700 ml), the combined organic layers were washed with 10% hydrochloric acid (2×500 ml) ), washed with saturated brine (1×350 ml), and then concentrated under reduced pressure to obtain a golden yellow oil. The crude product was distilled off by Pope still (100°C, 0.2 mmHg) to remove low boilers, the residue was treated with hexane (400 ml) and stirred for 5 minutes, the solution was allowed to settle and decanted, and the above hexane treatment was repeated Twice, the combined hexane washes were filtered through a pad of celite and concentrated to a pale yellow oil (72.5 g, 92.4% pure by HPLC, 82% corrected yield). For the purpose of analysis, a small amount of sample can be further purified by Kuger tube distillation (250 ℃, 0.1mmHg): IR (pure liquid film) 2910, 1695, 1600, 1450, 1210, 1190cm ^-1 ; H NMR (CDCl ₃ , 400MHz) δ10.25 (S, 1H), 7.80 (dd, 1H, J = 1.2 and 7.7Hz); 7.45 (m, 1H), 7.33-7.13 (m, 7H), 2.98 (t, 2H, J = 7.7Hz); 2.58 (t, 2H, J = 7.7Hz), 1.58 (m, 4H), 1.30 (m, 8H); ¹³ C NMR (CDCl ₃ , 100MHz) δ192.2, 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 points (Whatman Partisil5 ODS 3 RACⅡ, 4.6mm inner diameter × 10cm, 2ml/ 7: ₃ CH3CH: _H2O with UV detection at 211nm).

Example 9

Preparation of 2-(8-phenyloctyl)benzaldehyde

Two molar equivalents of imine and nitrogenous base and one molar equivalent of 1-chloro-7-phenylheptane were used.

A solution of lithium diisopropylamide in tetrahydrofuran (15.4 g, 0.024 mol) was added to tetrahydrofuran (30 ml) under nitrogen and cooled to -10°C. A solution of N-[(2-methylphenyl)-methylene]-1,1-dimethylethylamine (4.23 g, 0.024 mol) in tetrahydrofuran (5 ml) was added, and the mixture was placed in- Stir at 10°C for 20 minutes. A solution of phenylheptyl chloride (2.77 g, 0.012 mol) in tetrahydrofuran (5 ml) was added and the reaction mixture was heated to 58°C. Gas chromatographic analysis after 3 hours indicated that no more phenylheptyl chloride remained. The mixture was cooled to 0°C and dilute hydrochloric acid (50ml) was added at such a rate as to keep the temperature below 25°C. The solution was reheated to 58°C and maintained at this temperature for 16 hours. After cooling to 20°C, dichloromethane (100 ml) was added and the phases were separated. The aqueous phase was further extracted with dichloromethane (50 ml), the organic phases were combined, washed with water (100 ml), dried with magnesium sulfate, filtered, and the solvent was evaporated to obtain an oily product (6.96 g, its purity was determined by HPLC analysis: 28.6%, and the corrected yield was 57%).

Using the above reaction conditions, but stirring the reaction mixture at room temperature for 20 hours instead of reflux for 3 hours as in the original procedure, the corrected yield was 59%.

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

Example 10

Preparation of 2-(8-phenyloctyl)benzaldehyde

Potassium was exchanged for lithium as a basic counterion/with a different imine.

a) Add N-[(2-methylphenyl)-methylene]-1,1-dimethylethylamine (5.00 g, 29 mmol) to lithium diisopropylamide at -10°C [28.5 mmol; prepared from diisopropylamine (4.0 mL, 2.89 g, 29 mmol) and n-butyllithium (2.5M, 11.43 mL, 28.5 mmol)] in THF (50 mL) . After stirring at this temperature for 75 minutes, a solution of potassium tert-butoxide (1.49M, 19.2 mL, 28.5 mmol) in THF was added. After stirring for a further 15 minutes, 1-chloro-7-phenylheptane (3.77 g, 17.9 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 hours. Hydrochloric acid (6M, 5ml) was added and the mixture was heated at reflux for 90 minutes. The aqueous layer was separated and extracted with hexane (2 x 200ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed by evaporation under reduced pressure to give an oil (7.44g). Its analysis showed it to contain 65% w/w phenyloctylbenzaldehyde (4.84 g, 16.5 mmol, 92%).

b) Using the procedure of a) above, but using N-[(2-methylphenyl)-methylene]-isopropylamine and N-[(2-methylphenyl)methylene]-n-butyl amines, the following results are obtained:

R ₃ Ratio

Imine Substituent Imine:PHC Yield (%)

(ⅰ) tert-butyl 1.6:1 92

(ii) Isopropyl 2.0:1 31

(ⅰ) n-butyl 2.0:1 ～10

Example 11

Preparation of 2-(8-phenyloctyl)benzaldehyde

Using catalytic amounts of nitrogenous bases / comparing different electrophiles.

a) Phenylheptyl Bromide/Phenylheptyl Iodide

i) At 0°C, to N-[(2-methylphenyl)-methylene]-1,1-dimethylethylamine (5.0 g, 0.03 mol) and N,N,N',N' - To a solution of tetramethylethylenediamine (3.31 g, 0.03 mol) in tetrahydrofuran (40 ml) was slowly added n-butyllithium (2.5M, 11.4 ml, 0.03 mol). The solution was stirred for an additional 30 minutes, followed by the rapid addition of a solution 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 hours. The reaction mixture was treated with 10% aqueous hydrochloric acid and stirred for 30 minutes. The layers were separated, dichloromethane (50 ml) was added to the organic layer, and the organic phase was washed with saturated saline solution (50 ml). The organic phase was then dried (magnesium sulfate) and concentrated to an oil, yielding 2-(8-phenyloctyl)benzaldehyde (3.8 g, 45%): IR (clean liquid film) 2920, 2880, 1695, 1600, 1455cm ^-1 ; H NMR (CDCl ₃ , 400MHz) δ10.25 (S, 1H), 7.80 (dd, 1H, J = 1.2 and 7.7Hz); 7.45 (m, 1H), 7.33-7.13 (m, 7H), 2.98 (t, 2H, J = 7.7Hz); 2.58 (t, 2H, J = 7.7Hz), 1.58 (m, 4H), 1.30 (m, 8H).

ii) Using the procedure of (a)(i), but substituting 1-iodo-7-phenylheptane for 1-bromo-7-phenylheptane, 2-(8 -phenyloctyl)benzaldehyde.

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

i) N-[(2-methylphenyl)methylene]-1,1-dimethylethylamine (2.8 g, 0.016 mol) and 2,2,6,6-tetramethylpiperidine ( 0.23 g, 0.0016 mol) in tetrahydrofuran (10 ml) was cooled to -5°C. To this solution was added n-butyllithium (1.6M, 10ml, 0.016mol) over 40 minutes maintaining the temperature at -5°C. A solution of 1-bromo-7-phenylheptane (3.4 g, 0.0133 mol) in tetrahydrofuran (5 ml) was added rapidly at -5°C, at which time the temperature of the reaction rose rapidly to 40°C and cooled to room temperature After the reaction mixture was stirred for 1 hour, the reaction mixture was treated with dilute hydrochloric acid and stirred at room temperature for 16 hours. The product was isolated by the usual method (5.0 g, 75% purity, 96% corrected yield).

ii) Using the procedure of (b)(i), but substituting 1-chloro-7-phenylheptane for 1-bromo-7-phenylheptane, prepared in 87% corrected yield Phenyloctylbenzaldehyde.

Example 12

Preparation of 2-(8-phenyloctyl)benzaldehyde

Effect of varying temperature on the formation of anions by different nitrogenous bases

a) N-[(2-methylphenyl)methylene]-1,1-dimethylethylamine (11.2 g, 0.064 mol) and 2,2,6,6-tetramethyl A solution of piperidine (0.9 g, 0.0064 mol) in tetrahydrofuran (40 ml) was cooled to -5°C. To this solution was added n-butyllithium (1.6M, 40ml, 0.064mol) via a syringe pump over 60 minutes at such a rate as to maintain the temperature below 0°C. The reaction mixture was stirred for 30 minutes, then a solution of 1-chloro-7-phenylheptane (11.23 g, 0.053 mol) in tetrahydrofuran (20 ml) was added rapidly and the reaction mixture was heated at 50-55°C for two hours. The reaction mixture was cooled to 40°C and quenched by the slow addition of dilute hydrochloric acid (100 ml of hydrochloric acid diluted with 300 ml of water). The mixture was heated at 50-60°C for 2.5 hours to complete the hydrolysis reaction. The mixture was cooled to room temperature, the organic phase was separated and the aqueous phase was extracted with hexane (100ml). The combined organic extracts were washed with water (100 mL). The extract was dried over magnesium sulfate, filtered and the filter cake was washed with hexane. Concentration of the organic solution under reduced pressure afforded 2-(8-phenyloctyl)benzaldehyde as an oil (14.5 g, 69.3% purity by HPLC, 87% after correction). %).

b) To a stirred solution of N-[(2-methylphenyl)methylene]-1,1-dimethylethylamine (21.0 g, 0.12 mol) in tetrahydrofuran (75 ml) over 1 hour Add n-butyllithium (1.54M, 78ml, 0.12mol) to the mixture at such a rate as to maintain the temperature between 20-30°C under cooling. The mixture was stirred for 30 minutes and a solution of 1-chloro-7-phenylheptane (21.05 g, 0.1 mol) in tetrahydrofuran (40 ml) was added rapidly. The reaction mixture was heated at 50°C for 3 hours and quenched by the slow addition of dilute hydrochloric acid. The reaction mixture was heated at 50-60°C for 2.5 hours to complete the hydrolysis reaction. The mixture was cooled to room temperature and the organic phase was separated. The aqueous phase was extracted with hexane, the organic extracts were combined, washed with water, dried with magnesium sulfate, filtered and washed with hexane, and the organic solution was concentrated under reduced pressure to obtain 2-(8-phenyloctyl)benzaldehyde, It was an oil (34.56 g, 65.3% pure by HPLC analysis, 77% corrected yield).

c) Using the same procedure as (a) or (b), but varying the temperature of the nitrogenous base and anion formation, the following results are obtained:

Amines Anion formation Solution yield Impurity distribution

Temperature (°C) (%) (%PHE ^* ) (%PHC ^** )

i) (isopropyl) ₂ NH -5 55 7.2 17.3

ii) (isopropyl) 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

ⅵ) TMP ⁺⁺ 25 89 0.7 0.7

ⅶ)-- 0 45 ND ND

ⅷ)-- 25 77 ND ND

Original note:

＝苯基庚烯DCA ⁺ = Cyclohexylamine PHE

= Phenylheptene

＝苯基庚基氯化物TMP ⁺⁺ = Tetramethylpiperidine PHC

= Phenylheptyl chloride

ND = not determined

d) Using the procedure (a) or (b), but using 1-bromo-7-phenylheptane, the following results were obtained:

Amines Anion formation Solution yield Impurity distribution

Temperature (℃) (%) (%PHE ^· ) (%)PHB ^***

i) (isopropyl) ₂ NH 0 89 ND ND

ⅱ) TMP 25 96 ND ND

Original note:

PHB ^… = phenylheptyl bromide

Many variations of these examples will be apparent to a person skilled in the art, and the invention is not limited to these examples, but includes all variations contained in the following claims.

Claims (22)

1, a kind of method for preparing following formula: compound:

In the formula:

R ₁Be CH ₂CH ₂-(L ₁) _p-(CH ₂) _q-(L ₂) _r-CH ₂-(T) _s-Z;

L ₁And L ₂Be CH independently of one another ₂CH ₂, CH=CH or C ≡ C;

The q value is 0 to 8;

P, r and s value are 0 or 1 independently of one another;

T is O, S, CH ₂, CH=CH, C ≡ C;

Z is C _1-4Alkyl, ethynyl, trifluoromethyl, pseudoallyl, furyl, thienyl, cyclohexyl or at random by CF ₃, C _1-4Alkyl, C _1-4The mono-substituted phenyl of alkoxyl group, methylthio group or trifluoromethylthio;

R ₂With A be H independently of one another, CF ₃, C _1-4Alkyl, F, Cl, Br or I;

This method comprises formula III compound and a kind of alkali and the reaction of formula IV compound, uses the acid treatment reaction product then:

In the formula

R ₂With the definition of A with preceding identical;

R ₃Be C _1-6Alkyl, C _3-6Cycloalkyl, (CH ₂) _tPhenyl or N (R ') ₂Base;

R ' is C _1-6Alkyl, C _3-6Cycloalkyl or (CH ₂) _tPhenyl; And the t value is 0 or 1;

X-CH ₂-(L ₁) _p-(CH ₂) _q-(L ₂) _r-CH ₂-(T) _s-Z (Ⅳ)

In the formula

L ₁, L ₂, p, q, r, s, the definition of T and Z is with preceding identical, and X is a replaceable group.

2, by the process of claim 1 wherein that alkali is in about 15 ℃ to about 35 ℃ compounds that are added to formula III, and used alkali is lithium alkylide or lithium diisopropyl amido.

3, by the process of claim 1 wherein R ₂With A be H, R ₃Be the tertiary butyl, X is bromine or chlorine.

4, by the process of claim 1 wherein that used acid is mineral acid.

5, by the method for claim 4, acid wherein is hydrochloric acid.

6, a kind of method is wherein with the N-[(2-aminomethyl phenyl) methylene radical]-1, the salt acid treatment is then used in the organic amine of 1-dimethyl amine and n-Butyl Lithium and catalytic amount and the reaction of 1-chloro-7-phenyl heptane.

7, a kind of method is wherein with the N-[(2-aminomethyl phenyl) methylene radical]-1, the salt acid treatment is then used in 1-dimethyl amine and lithium diisopropyl amido and potassium tert.-butoxide and the reaction of 1-chloro-7-phenyl heptane.

8, a kind of method for preparing the formula II compound:

In the formula

R ₁Be CH ₂CH ₂-(L ₁) _p-(CH ₂) _q-(L ₂) _r-CH ₂-(T) _s-Z;

L ₁And L ₂Be CH independently ₂CH ₂, CH=CH or C ≡ C;

The q value is 0 to 8;

P, r and s value are 0 or 1 independently;

T is O, S, CH ₂, CH=CH, C ≡ C;

Z is C _1-4Alkyl, ethynyl, trifluoromethyl, pseudoallyl, furyl, thienyl, cyclohexyl is perhaps at random by CF ₃, C _1-4Alkyl, C _1-4The mono-substituted phenyl of alkoxyl group, methylthio group or trifluoromethylthio;

R ₂With A be H independently, CF ₃, C _1-4Alkyl, F, Cl, Br or I;

R ₃Be C _1-6Alkyl, C _3-6Cycloalkyl, (CH ₂) _tPhenyl or N(R ') ₂;

R ' is C _1-6Alkyl, C _3-6Cycloalkyl or (CH ₂) _tPhenyl;

The t value is 0 or 1;

This method comprises following formula III compound

A in the formula, R ₂And R ₃Definition with preceding identical;

Compound reaction with a kind of alkali and following formula IV:

In the formula

L ₁, L ₂, T, Z, p, q, the definition of r and s is with preceding identical;

X is a replaceable group.

9, by the method for claim 8, alkali wherein is alkali metal alkyl compound, basic metal arylide or basic metal amination thing.

10, by the method for claim 9, alkali wherein is lithium alkylide.

11, by the method for claim 9, alkali wherein is lithium diisopropyl amido or butyllithium.

12,, wherein there is the organic amine of catalytic amount by the method for claim 10.

13, by the method for claim 12, organic amine wherein is a Diisopropylamine, 2,2,6, and 6-tetramethyl piperidine or dicyclohexylamine; And with respect to every mole of formula III compound, the consumption of organic amine is about 0.01 to 0.15 molar equivalent.

14, by the method for claim 10, wherein alkali and formula III compound react to about 35 ℃ temperature condition at about 15 ℃.

15, by the method for claim 11, wherein before adding the formula IV compound, alkoxide sodium or alkoxide potassium are added in the reaction mixture.

16, press the method for claim 8, wherein R ₃It is the tertiary butyl.

17, by the method for claim 16, wherein X is bromine or chlorine.

18, by the method for claim 17, wherein Z is a phenyl, L ₁And L ₂Be CH independently ₂CH ₂

19, the compound of following formula:

In the formula

R ₁Be CH ₂CH ₂-(L ₁) _p-(CH ₂) _q-(L ₂) _r-CH ₂-(T) _s-Z;

L ₁And L ₂Be CH independently ₂CH ₂, CH=CH or C ≡ C;

The q value is 0 to 8;

P, r and s value are 0 or 1 independently;

T is O, S, CH ₂, CH=CH, C ≡ C;

Z is C _1-4Alkyl, ethynyl, trifluoromethyl, pseudoallyl, furyl, thienyl, cyclohexyl is perhaps at random by CF ₃, C _1-4Alkyl, C _1-4The mono-substituted phenyl of alkoxyl group, methylthio group or trifluoromethylthio;

R ₂With A be H independently, CF ₃, C _1-4Alkyl, F, Cl, Br or I;

R ₃Be C _1-6Alkyl, C _3-6Cycloalkyl, (CH ₂) _tPhenyl or N(R ') ₂Base;

R ' is C _1-6Alkyl, C _3-6Cycloalkyl or (CH ₂) _tPhenyl; With

The t value is 0 or 1.

20, press the compound of claim 19, wherein R ₃It is the tertiary butyl.

21, press the compound of claim 19, wherein L ₁And L ₂Be CH ₂CH ₂, and Z is a phenyl.

22, by the compound of claim 21, it is a N-[(2-(8-phenyl octyl group)-phenyl) methylene radical]-1, the 1-dimethyl amine.