CN1078229A - The method and the intermediate that prepare the 2-substituted benzaldehyde - Google Patents
The method and the intermediate that prepare the 2-substituted benzaldehyde Download PDFInfo
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- CN1078229A CN1078229A CN93102980A CN93102980A CN1078229A CN 1078229 A CN1078229 A CN 1078229A CN 93102980 A CN93102980 A CN 93102980A CN 93102980 A CN93102980 A CN 93102980A CN 1078229 A CN1078229 A CN 1078229A
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- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/516—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of nitrogen-containing compounds to >C = O groups
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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 the new intermediate and the method for preparation useful intermediates in the synthetic drugs active agent.
The phenyl aldehyde that 2-replaces is the useful as intermediates of preparation pharmaceutical active compounds, for example, some as the leukotrienes antagonist and can be used to treat asthma compound can by have following general formula (I 2-substituted benzaldehyde a) makes:
Wherein
R
xBe (L) a-(CH
2)
b-(T)
c-M;
The a value is 0 or 1;
The b value is 3 to 14;
The c value is 0 or 1;
L and T are sulphur independently, oxygen, or CH
2;
M is C
1-4Alkyl, ethynyl, trifluoromethyl, pseudoallyl, furyl, thienyl, cyclohexyl or at random by bromine, chlorine, CF
3, C
1-4Alkyl, C
1-4The mono-substituted phenyl of alkoxyl group, methylthio group or trifluoromethylthio;
R
2Can be independently selected from H, CF with A
3, C
1-4Alkyl, C
1-4Alkoxyl group, F, Cl, Br, I, OH, NO
2Or NH
2;
Perhaps R
1With A be H, R
2Be (L)
a-(CH
2)
b-(T)
c-M, a wherein, b, c, L, the definition of T and M is with preceding identical.
This compounds is at for example United States Patent (USP) 4,820,719, and United States Patent (USP) 4,874 is disclosed in 792 and European patent EP-A0,296,732.These documents are incorporated this paper as a reference into.Therefore, reported two kinds of general methods that prepare the 2-substituted benzaldehyde in the document: 1) under the palladium katalysis with the 1-alkynyl compounds that replaces to the addition of 2-halogeno-benzene formaldehyde, cause coupling and directly obtain the 2-(1-alkynyl) phenyl aldehyde; 2) O-Anisic Acid is converted into the 2-(2-p-methoxy-phenyl)-4,4-dimethyl-oxazoline, handle with alkyl or aralkyl Grignard reagent then, to prepare corresponding 2-(2-alkyl phenyl)-4,4-dimethyl-oxazoline or 2-(2-arylalkyl phenyl)-4,4-dimethyl-oxazoline (handle the oxazoline that 2-replaces with methyl iodide then, use sodium borohydride reduction, carry out acid hydrolysis again and promptly produce corresponding 2-substituted benzaldehyde).A kind of method in back is based on the method that people such as Meyer finds, can be referring to J.Org.Chem., and 43,1372(1978).The method that similarly prepares the 2-substituted benzaldehyde was also once disclosed by people such as Perchmock, can be referring to J.Med.Chem., and 28,1145(1985).Generally, these methods are to adopt by substituent reagent on its functional group's displacement aromatic ring.
Thereby it also is known making aromatic ring generation nucleophilic substitution add a substituent method at the ortho position of aromatic ring.Org.Reaction26,43-61(1979) report some and contain nitrogen heteroatom and the functional group that is connected on the phenyl ring can make phenyl ring that lithiation is become stable, particularly at the ortho position, the available then suitable electrophilic reagent in the position of lithiumation is handled and the generation substitution reaction.Reported for reach this purpose especially effectively functional group be one or the dialkyl amide class, amine, N, N-dialkyl group hydrazone class, imidazolines and oxazoline class.People such as De Silva are at Tetrahedron Lett., and 5107(1978) middle report carries out lithiation with s-butyl lithium and diisopropylamine at the ortho position of benzamide.People such as Trecourt are at J.Org.Chem., 53,1367(1988) in report carry out lithiation with the Diisopropylamine of lithium methide and catalytic amount at the ortho position of 2-methoxypyridine.But according to reports aryl carbon imines class then react in carbon imines position easily and α owing to them-deprotonation reaction has only limited synthetic suitability.Referring to Org.Reactions, 26,57-58(1979).Zeigler etc. are at J.Org.Chem., and 41,1564(1976) report on the magazine, if there is contiguous ether substituting group to exist, then aryl carbon imines class also can be induced and the adjacent lithiation taken place.
In addition, existing report, if methyl is to be in benzamides, the ortho position of 2-benzylimidazoline class and 2-oxazolyl phenyl quinoline class, then methyl also can be by lithiumation.For example, people such as Watanabe are at J.Org.Chem., 49,742(1984) in report, in Isocoumarin 〉97 class synthetic through ortho position toluamide expansion side chain; People such as Gschwend are at J.Org.Chem., 40,2008(1975) in report, via 2-(neighbour-tolyl) lithiumation of oxazoline extends the benzyl side chain; Also have Houlihan at United States Patent (USP) 4,100, report in 165, the 2-(neighbour of two lithiumations-tolyl) tetrahydroglyoxaline can with ester and carboxylic acid halides class generation condensation reaction.
The method of the 2-substituted benzaldehyde among existing synthetic the present invention is all used expensive reagent or polystep reaction method, and this makes them prepare in the 2-substituted benzaldehyde in technical scale does not have magnetism.Therefore, need the method for the other effective 2-of preparation substituted benzoyl aldehydes.
An object of the present invention is to provide a kind of new and effectively preparation have the method for following formula (I b) 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;
Q is 0 to 8;
P, r and s are 0 or 1 independently;
T is O, S, CH
2, CH=CH, C ≡ C; With
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, CF
3, C
1-4Alkyl, F, Cl, Br or I.
A feature of the present invention is the method for preparing following formula: compound:
A in the formula, R
1, R
2, L
1, L
2, q, p, r, s, the definition of T and Z is identical with front formula (I b);
This method comprises formula III compound and a kind of alkali and the reaction of formula IV compound, the product that reacts with acid treatment then;
In the formula:
R
2Identical with the definition of A and top formula (I b);
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;
In the formula:
L
1, L
2, p, q, r, s, the definition of T and Z is identical with top formula (I b), and X is a replaceable group.
Another feature of the present invention provides down the new intermediate of formula II:
In the formula:
R
1, R
2Identical with in the definition of A and the formula (I b);
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.
Another feature of the present invention provides a kind of method for preparing the new intermediate of formula II, and it comprises the compound formula III
A in the formula, R
2And R
3Definition and formula II identical, react with a kind of alkali and formula IV compound,
L in the formula
1, L
2, p, q, r, s, T and Z definition and front formula (I b) in identical, X is a replaceable group.
Another feature of the present invention provides a kind of improved method for preparing the formula II compound, and it is included in a kind of organic amine that adds before the alkali adding catalytic amount in the reaction mixture.
The present invention also has another feature to provide a kind of improved method for preparing the formula II compound, and it comprises and adds alkoxide sodium or alkoxide potassium in the reaction mixture.
Another feature of the present invention provides a kind of improved method for preparing the formula II compound, and it is included in carries out above-mentioned reaction in the specific temperature range.
The invention discloses the method for useful as intermediates and a kind of preparation formula (I b) 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 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 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, CF
3, C
1-4Alkyl, F, Cl, Br or I;
This method comprises that with formula III compound and a kind of alkali and the reaction of formula IV compound use the acid treatment reaction product then, formula III is:
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 ')
2;
R ' is C
1-6Alkyl, C
3-6Cycloalkyl or (CH
2)
tPhenyl;
The t value is 0 or 1;
Formula IV is:
In the formula
L
1, L
2, p, q, r, s, T and Z definition with preceding identical; With
X is a replaceable group.
In addition, the invention discloses down the new intermediate of formula II:
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 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 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, 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.
Suitable Z is a phenyl, L
1And L
2Be CH
2CH
2
Suitable R
3It is the tertiary butyl.
Suitable p, r and s value are 1.
Suitable q value is 0 to 2.
Suitable T is CH
2Or C ≡ C.
A kind of preferred compound is a N-[2-(8-phenyl octyl group) phenylmethylene]-1, the 1-dimethyl amine.
The new intermediate of formula II prepares with a kind of like this method, comprises following formula III compound:
In the formula
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;
React with a kind of alkali and a kind of formula IV compound:
In the formula
L
1And L
2Be CH independently
2CH
2, CH=CH or C ≡ C;
The q value is 0 to 8;
P, r and s 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 or at random by CF
3, C
1-4Alkyl, C
1-4The mono-substituted phenyl of alkoxyl group, methylthio group or trifluoromethylthio; With
X is a replaceable group.
In a preferred embodiment, the invention discloses the method for a kind of preparation formula (I b) compound, it comprises the wushu III) compound and a kind of alkali and a kind of formula IV compound react, use the acid treatment reaction mixture then.So in the preferred embodiment, whole conversion is finished in a single reaction container, need not isolation of intermediate products.This method is used the raw material that obtains easily and with effective productive rate, is carried out with minimum reactions steps.
The formula III compound is hydrazone class and imines class, or western Buddhist alkali, and any one method for preparing this compounds commonly used prepares in common available the specialty.A kind of method for preparing imine compound comprises wushu (V) compound
With a kind of formula R
3-NH
2Amine or hydrazine react.This reaction normally mixes two kinds of reactants in a kind of non-aqueous solvent, and can heat and carry out.Available in case of necessity dewatering agent impels reaction to carry out fully.Common dewatering agent is: for example, and molecular sieve or sal epsom.In addition, also can be with a kind of appropriate solvent such as benzene or toluene, the method for the water that produces in the reaction by azeotropic distillation reached the dehydration purpose.Radicals R
3Be C
1-6Alkyl, C
3-6Cycloalkyl, benzyl, phenyl or N(R ')
2Cyclo-hexylamine, TERTIARY BUTYL AMINE, aniline and N, N-dimethylhydrazine are suitable reagent, preferably use TERTIARY BUTYL AMINE.
The electrophilic reagent that provides by formula IV, available usual method is such as at United States Patent (USP) 4,820, No. 719, United States Patent (USP) 4,874, No. 792, people J.Med.Chem. such as No. 0296732, european patent application and Perchanock, 28,1145(1985) middle disclosed method prepares, and they incorporate this paper as a reference into.The X of electrophilic reagent partly represents a replaceable group, and it can be can be by any group of carbon nucleophile institute metathetical by the formula III compound.It is suitable that many replaceable groups are arranged, such as alkyl and aromatic yl sulphonate, and alkyl and arylalkyl acetic ester, benzoic ether and halogen.The representative of this class group has Cl, Br, I, R
4SO
3And R
4CO
2, R wherein
4Be can be by the C of 1-5 fluorine atom replacement
1-4Alkyl, or can be by one or two halogen, C
1-4Alkyl, C
1-4The phenyl that alkoxyl group or nitro replace.Representational displaceable group has tosylate, bromo-benzene sulfonate, nitrobenzene-sulfonic acid ester, methanesulfonates, triflate, acetic ester, monochloroacetic acid ester, triflutate, benzoic ether, bromo-benzoate, chloro-benzoic acid ester, nitrobenzoyl acid esters, chlorine, group such as bromine and iodine, preferred chlorine and bromine, preferred especially chlorine.
Generally, if in precursor, there is not the X group, then the X group in the formula IV compound can by corresponding alcohol by with suitable carboxylic acid halides, acid anhydrides, sulfonic acid halide or suitable halide reagent react and make.Typical this class reagent has toluene sulfonyl chloride, bromobenzene sulfonyl chloride, nitrobenzene sulfonyl chloride, methylsulfonyl chloride, Acetyl Chloride 98Min., chloro-acetyl chloride, trifluoroacetic anhydride, Benzoyl chloride, bromo-benzoyl chloride, chloro-benzoyl chloride, nitrobenzoyl chloride, oxalyl chloride or oxalyl bromine, spirit of salt, Hydrogen bromide, hydroiodic acid HI, phosphorus tribromide, phosphorus trichloride, phosphorus oxychloride and the carbon tetrabromide that contains triphenylphosphine.General formula HO-CH
2-(L
1)
p-(CH
2)
q-(L
2)
r-CH
2-(T)
sThe compound of-Z, T wherein is CH
2, L
1Or L
2Be CH
2CH
2, Z is C
1-4During alkyl or phenyl, generally all can buy from the market.And T wherein is O, those compounds of S or C ≡ C can be in the presence of a kind of suitable alkali by being compound H-T-Z and structure X-CH
2-(L
1)
p-(CH
2)
q-(L
2)
r-CH
2The compound of-X reaction and making, X wherein, L
1, L
2, T, p, the definition of q and r is with preceding identical.T is that the compound of CH=CH can be that the compound of C ≡ C carries out partial hydrogenation and makes with T, for example uses Lindlar catalyzer or 5% palladium/BaSO
4Catalyzer and hydrogen carry out hydrogenation.Use palladium catalyst, when for example 5% Pd/carbon catalyst carried out hydrogenation, producing T was CH
2Compound.Work as L
1Or L
2When being C ≡ C or CH=CH, the product that obtains can reduce subsequently and produce L
1Or L
2Be CH=CH or CH
2CH
2Product.For example, 1-bromo-7 phenyl heptane can be reacted in the presence of n-Butyl Lithium by pentamethylene bromide and phenylacetylene, then with the reduction of hydrogen and palladium catalyst and make.In another example, 1-bromine or 1-chloro-7-phenyl heptane can be by benzyl magnesium halide and 1, the coupling and making under copper participates in of 6-dibromo-hexane or 1-bromo-6-chlorohexane.
The alkylated reaction of the carbon imines of formula III can come initiation reaction with the highly basic deprotonation by the ortho position methyl the formula III compound.Because metallized intermediate is active to water, so priming reaction will be at a kind of inert dry gas, such as carrying out in nitrogen or the argon gas, though also can carry out in the exsiccant air.
Priming reaction carries out in aprotic solvent, and the solvent that is suitable for this reaction is common fat or the aromatic hydrocarbon solvent that highly basic is not had reactive behavior.The representative of this kind solvent has ether, tetrahydrofuran (THF), dioxan, toluene, benzene, pentane, hexane, sherwood oil and their mixture.Wherein preferred ether, dioxan and tetrahydrofuran (THF), preferred especially tetrahydrofuran (THF).
The enough strong alkali of deprotonation reaction needed of ortho position methyl.Anyly can carry out such deprotonation reaction, can not cause that again the alkali of obvious side reaction all is suitable simultaneously, typically this class alkali has alkali metal alkyl compound, basic metal amination thing, or basic metal arylide.The representative of this class alkali has n-Butyl Lithium, s-butyl lithium, lithium methide, phenyl lithium, di-isopropyl amination lithium, diethyl amination lithium or Lithamide, or the corresponding sodium salts of this class material or sylvite.Alkyl lithium reagents is specially suitable.Preferred n-Butyl Lithium and diisopropyl amination lithium.Other metal of the commutative one-tenth of basic metal of initial usefulness, other basic metal for example, copper, magnesium or zinc, this is also within the scope of the invention.With excessive slightly alkali, such as excessive 1% to 25%, react completely to guarantee metallization, usually be helpful.An about molar equivalent normally is satisfied with.For these professional those skilled in the art, obviously knowing in the above-mentioned alkali has, for example alkali metal alkyl compound or arylide, may be inconsistent with the halogenic substituent in the carbon imines molecule, at this moment using other alkali, such as diisopropyl amination lithium, will be more suitably.
The formula III compound mixes two kinds of reactants with the reaction of alkali and carries out, and reaction should be carried out under sufficiently high temperature, and this temperature can make alkali cause deprotonation on the methyl of ortho position, but can not be too high and cause deleterious side reaction.Therefore best temperature will depend on used alkali and imine reaction thing.If used alkali is dioxane amination lithium, reaction is carried out between-20 ℃ to 60 ℃ typically; Reaction is preferably carried out between approximately-10 ° to 40 °.
Have been found that when being reflected at when carrying out between about 15 ° to about 35 ℃, can obtain the surprising productive rate that has improved.Typically, when highly basic when having to the reaction of the compound of nucleophilic attack sensitive portions (for example carbon imines functional group), reaction is to carry out under about 0 ℃ or lower temperature.Lower temperature is believed can prevent that undesirable side reaction from taking place, and for example the negative ion of alkali itself or the effect generation by alkali is to the nucleophilic attack of active carbon imine.Be unexpectedly, use some alkali, add the Diisopropylamine or the dicyclohexylamine of catalytic amount,, can make side reaction reduce to minimum and make gain in yield by alkali being added in the carbon imines at about 15 ℃ to about 35 ℃ such as n-Butyl Lithium.It is specially suitable being reflected between about 20 ℃ to about 30 ℃.The temperature that is higher than 55 ℃ generally can cause increasing of undesirable side reaction.
Typical practice is to add electrophilic reagent X-CH when metallization reaction is finished
2-(L
1)
p-(CH
2)
q-(L
2)
r-CH
2-(T)
s-Z.Though can add purified electrophilic reagent, be it to be dissolved in the solvent that is used for forming the metallization intermediate add again more easily.Then reactant was stirred 15 minutes to about 24 hours.
If separating imine, available appropriate solvent diluting reaction solution washes with water and concentrating under reduced pressure becomes oily matter.As want the product of purifying, can be with product by distillation, if or suitable, purify by crystallization.
Available any its intensity of reaction that the formula II compound is converted into phenyl aldehyde can make the acid of C=N key hydrolysis stir with imines and finish.Within the scope of the invention, mineral acid and organic acid etc. all are considered to enough strong acid.For example, methylsulfonic acid, toluenesulphonic acids, trifluoracetic acid, phenylformic acid, acetic acid, hydrofluoric acid, spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid and phosphoric acid all are suitable, the most handy mineral acid, and hydrochloric acid is particularly preferred.
In a preferred method, the reaction mixture that contains product (II) can pass through acid is added direct hydrolysis in the reaction mixture.Generally be that reaction mixture is added in the cooling solution of acid, allow it be warming to room temperature again, reaction mixture can be by monitoring the generation of the phenyl aldehyde of wanting such as analyzing chromatogram, but typical practice is that reactant was stirred about 1 hour to about 24 hours, comes separated product with common technology such as extracting operation then.
A kind of through the improved method for preparing the formula II compound, it is included in and adds before the alkali earlier a kind of organic amine that adds catalytic amount in the reactant, particularly when usefulness alkyl lithium reagents during as alkali.The organic amine that adds catalytic amount can obtain productive rate all high when not having this amine or adding this amine of equimolar amount.Suitable organic amine is a secondary amine.Representational amine has diethylamine, Diisopropylamine, dicyclohexylamine, piperidines, lupetidine and 2,2,6,6-tetramethyl piperidine.Diisopropylamine, dicyclohexylamine and 2,2,6, the 6-tetramethyl piperidine is specially suitable.Catalytic amount is meant with respect to every mole of carbon imines with about 0.01 organic amine to about 0.03 molar equivalent, about 0.01 to about 0.15 molar equivalent be suitable.Usually with about 0.01 to 0.1 molar equivalent, it depends on used amine.For example for diisopropylamine and 2,2,6, the 6-tetramethyl piperidine approximately uses 0.01 to about 0.05 equivalent.
Another feature that the present invention also has provides a kind of improved method for preparing the formula II compound, and it comprises the sodium or the sylvite of the carbon imines for preparing formula III, and this product and formula IV compound are reacted.For example, the 2-aminomethyl phenyl carbon imines of formula III can be handled with a kind of alkali such as n-Butyl Lithium or di-isopropyl amination lithium and make the formation lithium salts, and then with sodium or potash or salt processing, forms desired salt by metal exchange reaction.Alkoxide sodium or potassium, sodium trifluoroacetate or sylvite are representational alkali/salt.This carbon inferior amine salt and formula IV compound, can carry out alkylated reaction, thereby have only less side reaction compared with the lithium salts with corresponding carbon imines such as the muriatic reaction of 7-phenyl heptyl under lower temperature.With sylvite is specially suitable.
How the following example explanation is made and is used these compounds and relevant method, and they have constituted the present invention.
Name and abbreviation used among the embodiment are general in the specialty chemical.Unless dated especially, reagent be buy from market and promptly be used without further purifying.Tetrahydrofuran (THF) is if as reaction solvent, can use the 4A molecular sieve drying earlier, and all other solvents are to buy from market and promptly be used without further purifying with SILVER REAGENT purity.Reaction in all non-aqueous solution all is to finish under the protection of drying nitrogen.Fusing point is measured on Thomas-Hoover capillary melting point determination instrument, and not calibrated.Liquid chromatography is finished on Whatman Partisil 5 ODS 3 RAC II type instruments.Gas chromatographic analysis is to finish with the capillary column of DB-1 30m * 0.53mm.IR spectrum is with Perkin-Elmer Model283 type determination of infrared spectroscopy.FT-IR obtains on Nicolet 6000 FT infrared spectrometers.Combustion analysis is made of Perkin-Elmer 240 C type elemental analysers.Unless dated especially, all HNMR(proton resonance spectrum) in 400 megacycles and chloroformic solution of deuteration, measure with Bruker Instruments WM400 nuclear magnetic resonance analyser,
13The CNMR spectrum is measured at 100 megacycles, and chemical shift is swept to low from tetramethylsilane, uses ppm(δ) expression.
Note to HNMR is as follows: S, singlet; D, doublet; T, triplet; Br, broad peak; M, multiplet; J, coupling constant is in hertz.
Embodiment 1
The preparation of 1-bromo-7-phenyl heptane
At-5 to 0 ℃, in the clock time solution of benzylmagnesium chloride (750 milliliters, 2M tetrahydrofuran solution, 1.5 moles) was added to 1500 milliliters of (0.15 mole) 0.1M Li that stirring in 90 minutes
2CuCl
4With 1, in the formed solution, reaction mixture stirred 90 minutes at 0 ℃ 6-dibromo-hexane (456.8 grams, 1.87 moles, 1.25 equivalents), handled carefully with 2.0 liter saturated aqueous ammonium chlorides then in tetrahydrofuran (THF).The reactant internal temperature remains on below 20 ℃ in treating processes.Mixture is in stirring at room 1 hour and layering, and organic layer washs with 20% sodium chloride aqueous solution (4 * 500 milliliters), and dry (sal epsom) filters, and becomes an amber oily thing at 45-50 ℃ of concentrating under reduced pressure.Vigreux post with one 12 inches band vacuum jackets carries out the vacuum fractionation purification, obtains desired product, is a colorless oil (198.2 grams, 52%).Analyze the sample of usefulness by the vapor enrichment preparation: boiling point 123-124 ℃ (1.5mmHg); The pure liquid film of FT-IR() 3100-3000; 3000-2800,2000-1700,1604,1496,748,699,644cm
-1; HNMR(CDCl
3, 400MHz) δ 7.29-7.16(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);
13C NMR(CDCl
3, 100MHz). and δ 142.7,128.4,128.2,125.6,35.9,34.0,32.8,31.4,29.1,28.6, and 28.1. presses C
13H
19Br analytical calculation value: C, 61.91; H, 7.50; Br, 31.31; Experimental value: C, 61.25; H, 7.59; Br, 31.47.
Embodiment 2
The preparation of 7-chloro-1-phenyl heptane
A) 1-bromo-6-chlorohexane
(30 kilograms of 1.6-hexylene glycols, 254 moles), (51 kilograms of 48% Hydrogen bromides, 302 moles) and the mixture heating up of toluene to refluxing, azeotropic distillation removes and anhydrates (34.5 kilograms), when distillation stops mixture being cooled to 20 ℃ of solution that also form with concentrated hydrochloric acid (69.9 kilograms) and water (60 liter) and extracting.After the phase-splitting organic phase is carried out drying by reheating to dewater with azeotropic distillation.Mixture is cooled to 65 ℃, adds dimethyl formamide (1.11 kilograms).In 45 minutes, add thionyl chloride (31.4 kilograms, 264 moles) while holding temperature between 65-68 ℃.Mixture at 1.25 hours internal heating to 109 ℃, is cooled to 20 ℃ then.Use 20% sodium hydroxide solution (100 liter) and water (2 * 150 liters, 1 * 100 liter) washing more successively.Pressure reducing and steaming toluene (400 liter) promptly obtains the toluene solution (85.5 kilograms, its content of assay determination is 55%W/W, yield 93%) of bromine chlorohexane.
B) 7-chloro-1-phenyl heptane
At 15 ℃, tetrachloro copper lithium [tetrahydrofuran (THF) 33 liters, (0.87 kilogram of lithium chloride, 19.3 mole), (1.4 kilograms of cupric chlorides, 10.4 solution mole)] is added to solution (160 liters of benzylmagnesium chloride in tetrahydrofuran (THF), 1.86M solution, 298 moles) in, and mixture stirred 30 minutes, in 3 hours toward wherein adding bromine chlorohexane solution (85.5 kilograms of solution in toluene, its content of assay determination is 55%W/W, 47.1 kilogram, 236 moles), holding temperature is between 15-20 ℃ simultaneously.Continue to stir 1.25 hours.Added 10% ammonium chloride solution (263 liter) in 1 hour, holding temperature is below 30 ℃ simultaneously.Ammonium chloride solution (170 liter) and 20% sodium chloride solution (3 * 197 liter) washing are further used in phase-splitting, organic phase.This organic solution of concentrating under reduced pressure, and a residual oily matter (56.8 kilograms, HPLC analyzes and records its purity is 77%, the yield after the correction is 88%).
Embodiment 3
The N-[(2-aminomethyl phenyl) methylene radical]-1, the preparation of 1-dimethyl amine
Stir down, will formed solution refluxes 20 hours under the Deam-stark of standard condition in toluene (250 milliliters) by neighbour-tolyl aldehyde (25 grams, 0.21 mole) and TERTIARY BUTYL AMINE (27.75 restrain 0.38 mole).Solution evaporation carries out underpressure distillation (boiling point 70-73 ℃ 0.6mmHg), promptly obtains the pure liquid film of 33.9 gram (93%) product: IR() 2980,1645,1605,1460,1375,1210,960,910cm after becoming an oily matter
-1; H NMR(400MHz, CDCl
3) δ 8.56(S, 1H), 7.86-7.83(m, 1H); 7.25-7.11(m, 3H), 2.46(S, 3H), 1.30(S, 9H);
13C NMR(CDCl
3, 100MHz) δ 153.7,137.1,135.1,130.5,129.6,127.1,126.4,57.5,29.8,19.2, the GCRT7.6 branch (DB-1,30m * 0.53mm, temperature programming: 100 ℃ 5 minutes, 100-260 ℃.Press the speed of 15 ° of per minute intensifications, kept 12 minutes) at 260 ℃.
Embodiment 4
The preparation of 2-tolyl aldehyde dimethyl hydrazone
Stir down, will be by neighbour-tolyl aldehyde (25.0 grams, 0.21 mole) and 1, the solution that 1-dimethylhydrazine (25.2 restrain 0.42 mole) is formed reflux 24 hours in toluene (200 milliliters).Solution decompression concentrates, remaining oily matter be depressurized distillation (51-60 ℃ 0.2mmHg), obtains title product (31.98 restrain 94%): the pure liquid film of IR() 2950,2850,1580,1550,1455,1025,745cm
-1; H NMR(CDCl
3, 400MHz) 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).
Embodiment 5
N-[(2-(8-phenyl octyl group) methylene radical phenyl)]-1, the preparation of 1-dimethyl amine
Stir down, in the solution that the Diisopropylamine (29.14 grams, 0.289 mole) that is cooled to-5 ℃ forms, add n-Butyl Lithium (2.5M, 114.3 milliliters in tetrahydrofuran (THF) (450 milliliters), 0.286 the speed of adding should be kept the temperature of solution below 10 ℃ mole).Adding back solution stirred 15 minutes under cooling.In this solution, add the N-[(2-aminomethyl phenyl)-methylene radical]-1, the solution of 1-dimethyl amine (50.0 grams, 0.286 mole) in tetrahydrofuran (THF) (65.0 milliliters), the speed of adding should keep temperature of reaction to be lower than 5 ℃.Reactant stirred 15 minutes under cooling, add 1-bromo-7-phenyl heptane (72.9 grams then soon, 0.286 solution in tetrahydrofuran (THF) (75 milliliters) mole), reaction mixture stirred 1 hour under cooling, allowed it be warmed to room temperature and restir 14 hours then.Content by product imine in the gas chromatographic analysis assaying reaction mixture (RT 19.8 minutes, DB-1,30m * 0.53mm, temperature programming, 100 ℃ 5 minutes, the 100-260 ℃ of speed with 15 ℃ of per minutes heats up, and keeps 12 minutes at 260 ℃).Water and methylene dichloride dilute reaction mixture, and water washs organic mixture apace, and solution concentration is become an oily matter, separated product.Oily matter is purified by distillation.
Embodiment 6
N-[(2-(8-phenyl octyl group) methylene radical phenyl)]-1, the preparation of 1-dimethyl amine
Stir down, will be by 2-(8-phenyl octyl group) solution of phenyl aldehyde (10 grams, 0.034 mole) and TERTIARY BUTYL AMINE (4.96 grams, 0.068 mole) formation in toluene (100 milliliters) reflux 16 hours under the Dean-Stark of standard condition.Solution is evaporated into an oily matter, and carry out vacuum distilling (260 ℃ of boiling points, 0.15mmHg) (11.1 restrain promptly to obtain title product, 94%): 19.8 fens (DB-1 of GC RT, 30m * 0.53mm, temperature programming, 100 ℃ 5 minutes, the 100-260 ℃ of speed with 15 ℃ of per minutes heats up, and keeps 12 minutes at 260 ℃); ' H NMR(CDCl
3, 400MHz) δ 8.58(S, 1H), 7.86(d, J=7.5Hz, 1H); 7.29-7.13(m, 8H), 2.79(t, J=7.5Hz, 2H), and 2.58(t, J=7.5Hz, 2H), 1.59-1.51(m, 12H), 1.30(S, 9H).
Embodiment 7
2-(8-phenyl octyl group) preparation of phenyl aldehyde
By N-[(2-(8-phenyl octyl group) phenyl) methylene radical]-1, the hydrolysis of 1-dimethyl amine
Toward N-[(2-(8-phenyl octyl group) phenyl) methylene radical]-1, adding 10% hydrochloric acid (5 milliliters) in the solution that 1-dimethyl amine (0.51 gram, 0.0146 mole) forms in tetrahydrofuran (THF) (5 milliliters), and mixture stirring at room 15 hours.Add methylene dichloride (10 milliliters) and water (10 milliliters), and layering.Water layer extracts with methylene dichloride (1 * 15 milliliter), the organic phase of merging, and dry (sal epsom) filters, concentrating under reduced pressure gets oily matter (0.405 restrains, and its purity of HPLC assay determination is 97.4%, and the yield after the correction is 92%): the pure liquid film of IR() 2920,2880,1695,1600,1455cm
-1; H NMR(CDCl
3, 400MHz) δ 10.25(S, 1H), 7.80(d, d, 1H, J=1.2 and 7.7Hz); 7.45(m, 1H), 7.33-7.13(m, 7H), and 2.98(t, 2H, J=7.7Hz), and 2.58(t, 2H, J=7.7Hz), 1.58(m, 4H), 1.30(m, 8H).
Embodiment 8
2-(8-phenyl octyl group) preparation of phenyl aldehyde
Nitrogenous base and the reaction of 1-bromo-7-phenyl heptane with a molar equivalent.
Toward what stirring, be cooled to add n-Butyl Lithium (2.5M, 114.3 milliliters in-5 ℃ the solution of Diisopropylamine (29.14 gram, 0.289 mole) formation in tetrahydrofuran (THF) (450 milliliters), 0.286 the speed of adding should make the temperature maintenance of solution below 10 ℃ mole).After adding, solution stirred 15 minutes under cooling, added the N-[(2-aminomethyl phenyl in this solution)-methylene radical]-1,1-dimethyl amine (50.0 grams, 0.286 the solution that forms in tetrahydrofuran (THF) (65.0 milliliters) mole), the speed of adding should make temperature of reaction remain on below 5 ℃.Reactant stirred 15 minutes under cooling, promptly added the solution of 1-bromo-7-phenyl heptane (72.9 grams, 0.286 mole) in tetrahydrofuran (THF) (75 milliliters) then.Reaction mixture stirred 1 hour under cooling, allowed it be warmed to room temperature then and stirred 14 hours.Reaction mixture is handled with 10% aqueous hydrochloric acid, stirs 1 hour at 0 ℃, then stirring at room 14 hours.In the reaction mixture impouring methylene dichloride (700 milliliters) and stirred 5 minutes, tell organic layer, water layer extracts with methylene dichloride (2 * 700 milliliters), merge organic layer, wash with 10% hydrochloric acid (2 * 500 milliliters), use saturated common salt water washing (1 * 350 milliliter) again, concentrating under reduced pressure gets a golden yellow oily matter then.This crude product is by (100 ℃ of Pope distillers, 0.2mmHg) steam low-boiling-point substance, resistates was handled and is stirred 5 minutes with hexane (400 milliliters), allow the solution sedimentation, and decantation, heavily be covered with again and state hexane and handle twice, the hexane washing lotion that merges is filtered through Celite pad, and be condensed into a light yellow oil (72.5 grams, be 92.4% through its purity of HPLC assay determination, the yield after the correction is 82%).The purpose of be analyzing, can with a small amount of sample further through the distillation of Coorg pipe purify (250 ℃, 0.1mmHg): the pure liquid film of IR() 2910,1695,1600,1450,1210,1190cm
-1; H NMR(CDCl
3, 400MHz) δ 10.25(S, 1H), 7.80(dd, 1H, J=1.2 and 7.7Hz); 7.45(m, 1H), 7.33-7.13(m, 7H), and 2.98(t, 2H, J=7.7Hz); 2.58(t, 2H, J=7.7Hz), 1.58(m, 4H), 1.30(m, 8H);
13C NMR(CDCl
3, 100MHz) δ 192.2,145.7, and 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 minutes (Whatman Partisil5 ODS 3 RAC II, 4.6mm internal diameter * 10cm, 7: 3 CH of 2 ml/min
3CH: H
2O detects with UV at 211nm).
Embodiment 9
2-(8-phenyl octyl group) preparation of phenyl aldehyde
With the imines of two molar equivalents and the 1-chloro-7-phenyl heptane of a nitrogenous base and a molar equivalent.
The solution that forms in tetrahydrofuran (THF) at following di-isopropyl amination lithium of nitrogen protection (15.4 grams, 0.024 mole) is added in the tetrahydrofuran (THF) (30 milliliters) and is cooled to-10 ℃.Add the N-[(2-aminomethyl phenyl)-methylene radical]-1, the solution that 1-dimethyl amine (4.23 grams, 0.024 mole) forms in tetrahydrofuran (THF) (5 milliliters), and mixture-10 ℃ of stirrings 20 minutes.Add phenyl heptyl muriate (2.77 grams, 0.012 mole) in tetrahydrofuran (THF) (5 milliliters) solution and reaction mixture is heated to 58 ℃.Gas chromatographic analysis shows that no longer including phenyl heptyl muriate retains after 3 hours.Mixture is cooled to 0 ℃, adds dilute hydrochloric acid (50 milliliters), the speed of adding should make temperature remain on below 25 ℃.Solution is heated to 58 ℃ and kept 16 hours in this temperature again.After being cooled to 20 ℃, add methylene dichloride (100 milliliters), and phase-splitting.Water further uses methylene dichloride (50 milliliters) to extract, and merges organic phase, water (100 milliliters) washing, after dried over mgso, filter evaporating solvent, promptly get an oily product (6.96 restrain, and its purity of HPLC assay determination is 28.6%, and the productive rate after the correction is 57%).
Use above-mentioned reaction conditions, but reaction mixture stirring at room 20 hours, the backflow in the replacement origin operation 3 hours, the yield after calibrated is 59%.
Use above-mentioned reaction conditions, but carbon imines and amine alkali being molar equivalents with respect to the muriatic consumption of phenyl heptyl, is 42% after the yield that then obtains is calibrated.
Embodiment 10
2-(8-phenyl octyl group) preparation of phenyl aldehyde
With the potassium exchange lithium as alkalescence to ion/with different imines.
A) at-10 ℃ the N-[(2-aminomethyl phenyl)-methylene radical]-1,1-dimethyl amine (5.00 gram, 29 mmoles) is added to di-isopropyl amination lithium [28.5 mmoles; By Diisopropylamine (4.0 milliliters, 2.89 the gram, 29 mmoles) and n-Butyl Lithium (2.5M, 11.43 milliliters, 28.5 mmoles) obtained] at the THF(50 milliliter) and in formation solution in.After this temperature stirs 75 minutes, add the solution of potassium tert.-butoxide (1.49M, 19.2 milliliters, 28.5 mmoles) in THF.Behind the restir 15 minutes, add 1-chloro-7-phenyl heptane (3.77 grams, 17.9 mmoles).Reactant allows to be warmed to room temperature and stirred 16 hours.Add hydrochloric acid (6M, 5 milliliters), and mixture reflux 90 minutes.Divide water-yielding stratum, extract with hexane (2 * 200 milliliters), merge organic phase, use dried over sodium sulfate, filter, solvent removed by evaporation at reduced pressure promptly gets an oily matter (7.44 gram).It is carried out analysis revealed, and it contains the phenyl octyl group phenyl aldehyde (4.84 grams, 16.5 mmoles, 92%) of 65%W/W.
B) use above-mentioned schedule of operation a), but use the N-[(2-aminomethyl phenyl)-methylene radical]-Isopropylamine and N-[(2-aminomethyl phenyl) methylene radical]-n-Butyl Amine 99, obtain following result:
R
3Ratio
Imines substituting group imines: PHC productive rate (%)
(ⅰ) tertiary butyl 1.6:1 92
(ⅱ) sec.-propyl 2.0:1 31
(ⅰ) normal-butyl 2.0:1～10
Embodiment 11
2-(8-phenyl octyl group) preparation of phenyl aldehyde
Nitrogenous base/more different electrophilic reagent with catalytic amount.
A) phenyl heptyl bromide/phenyl heptyl iodide
ⅰ) at 0 ℃, toward the N-[(2-aminomethyl phenyl)-methylene radical]-1,1-dimethyl amine (5.0 grams, 0.03 mole) and N, N, N ', N '-Tetramethyl Ethylene Diamine (3.31 grams, 0.03 mole) slowly add n-Butyl Lithium (2.5M, 11.4 milliliters, 0.03 mole) in the solution that in tetrahydrofuran (THF) (40 milliliters), forms.Other 30 minutes of solution stirring then adds the solution of 1-bromo-7-phenyl heptane (7.28 grams, 0.03 mole) in tetrahydrofuran (THF) (10 milliliters) apace.Allowing reaction mixture be warmed to room temperature and to continue stirred 15 hours.With 10% aqueous hydrochloric acid reaction mixture, and stirred 30 minutes.Layering adds methylene dichloride (50 milliliters) in organic layer, organic phase is washed with the saturated common salt aqueous solution (50 milliliters).Then organic phase drying (sal epsom), and be condensed into an oily matter, promptly produce 2-(8-phenyl octyl group) phenyl aldehyde (3.8 grams, 45%): the pure liquid film of IR() 2920,2880,1695,1600,1455cm
-1; H NMR(CDCl
3, 400MHz) δ 10.25(S, 1H), 7.80(dd, 1H, J=1.2 and 7.7Hz); 7.45(m, 1H), 7.33-7.13(m, 7H), and 2.98(t, 2H, J=7.7Hz); 2.58(t, 2H, J=7.7Hz), 1.58(m, 4H), 1.30(m, 8H).
ⅱ) with (a) schedule of operation (ⅰ), but replace 1-bromo-7-phenyl heptane with 1-iodo-7-phenyl heptane, the result has prepared 2-(8-phenyl octyl group with 34% productive rate) phenyl aldehyde.
B) 1-bromo-7-octyl group heptane/1-chloro-7-phenyl heptane
ⅰ) the N-[(2-aminomethyl phenyl) methylene radical]-1,1-dimethyl amine (2.8 grams, 0.016 mole) and 2,2,6, the solution that 6-tetramethyl piperidine (0.23 gram, 0.0016 mole) forms in tetrahydrofuran (THF) (10 milliliters) is cooled to-5 ℃.In 40 minutes, add n-Butyl Lithium (1.6M, 10 milliliters, 0.016 mole) and holding temperature in this solution at-5 ℃.Add 1-bromo-7-phenyl heptane (3.4 grams apace at-5 ℃, 0.0133 the solution in tetrahydrofuran (THF) (5 milliliters) mole), at this moment temperature of charge rises to 40 ℃ soon, after being cooled to room temperature reaction mixture was stirred 1 hour, add the dilute hydrochloric acid reaction mixture, and stirring at room 16 hours.With usual method separated product (5.0 grams, purity 75%, the yield 96% after calibrated).
ⅱ) with (b) schedule of operation (ⅰ), but with 1-chloro-7-phenyl heptane replacement 1-bromo-7-phenyl heptane, the result with 87% calibrated after yield prepared phenyl octyl group phenyl aldehyde.
Embodiment 12
2-(8-phenyl octyl group) preparation of phenyl aldehyde
Temperature Influence when changing different nitrogenous bases and forming negatively charged ion
A) stir down, the N-[(2-aminomethyl phenyl) methylene radical]-1,1-dimethyl amine (11.2 grams, 0.064 mole) and 2,2,6, the solution that 6-tetramethyl piperidine (0.9 gram, 0.0064 mole) forms in tetrahydrofuran (THF) (40 milliliters) is cooled to-5 ℃.Added n-Butyl Lithium (1.6M, 40 milliliters, 0.064 mole) by a syringe pump in this solution in 60 minutes, the speed of adding should make temperature maintenance below 0 ℃.Reaction mixture was stirred 30 minutes, promptly add the solution of 1-chloro-7-phenyl heptane (11.23 grams, 0.053 mole) in tetrahydrofuran (THF) (20 milliliters) then, reaction mixture was 50-55 ℃ of heating two hours.Reaction mixture is cooled to 40 ℃ and make reaction terminating by slowly adding dilute hydrochloric acid (100 milliliters of hydrochloric acid dilute with 300 ml waters).Mixture was finished hydrolysis reaction in 2.5 hours 50-60 ℃ of heating.The mixture cool to room temperature is told organic phase, and water extracts with hexane (100 milliliters).Merge organic extracting solution, water (100 milliliters) washing.Extracting solution is dry on sal epsom, filters back hexane wash filter cake.Under reduced pressure organic solution is concentrated, promptly obtains 2-(8-phenyl octyl group) phenyl aldehyde is an oily matter (14.5 grams, HPLC analyzes and records its purity is 69.3%, the productive rate after calibrated is 87%).
B) the methylene radical past N-[(2-aminomethyl phenyl that is stirring in 1 hour)]-1,1-dimethyl amine (21.0 grams, 0.12 mole) in the solution of tetrahydrofuran (THF) (75 milliliters), add n-Butyl Lithium (1.54M, 78 milliliters, 0.12 the mole), the speed of adding should the cooling under holding temperature between 20-30 ℃.The mixture stirring was also promptly added the solution of 1-chloro-7-phenyl heptane (21.05 grams, 0.1 mole) in tetrahydrofuran (THF) (40 milliliters) in 30 minutes.Reaction mixture heated 3 hours at 50 ℃, and made reaction terminating by slowly adding dilute hydrochloric acid.Reaction mixture 50-60 ℃ of heating 2.5 hours, is finished hydrolysis reaction.Mixture is cooled to room temperature and tells organic phase.The water hexane extraction, merge organic extracting solution, wash with water, use dried over mgso, filter back hexane wash filter cake, concentrating under reduced pressure organic solution, promptly get 2-(8-phenyl octyl group) phenyl aldehyde, be an oily matter (34.56 grams, HPLC analyzes and to record its purity is 65.3%, the productive rate after calibrated is 77%).
C) use and (a) or (b) identical operations program, but change nitrogenous base and form anionic temperature, obtain following result:
The amine negatively charged ion forms solution productive rate profile of impurities
Temperature (℃) (%) (%PHE
*) (%PHC
*)
ⅰ) (sec.-propyl)
2NH-5 55 7.2 17.3
ⅱ) (sec.-propyl)
2NH 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 annotation:
DCA
+=cyclo-hexylamine PHE
=phenyl heptene
TMP
++=tetramethyl piperidine PHC
=phenyl heptyl muriate
The ND=undetermined
D), but with 1-bromo-7-phenyl heptane, obtain following result with (a) or schedule of operation (b):
The amine negatively charged ion forms solution productive rate profile of impurities
Temperature (℃) (%) (%PHE
) (%) PHB
* *
ⅰ) (sec.-propyl)
2NH 0 89 ND ND
ⅱ)TMP 25 96 ND ND
Original annotation:
PHB
=phenyl heptyl bromide
The variation pattern of many these examples obviously can also be arranged for these professional those skilled in the art, the invention is not restricted to these examples, it comprises all changes mode that is comprised in the following claim.
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85838492A | 1992-03-25 | 1992-03-25 | |
| US858,384 | 1992-03-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1078229A true CN1078229A (en) | 1993-11-10 |
Family
ID=25328179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93102980A Pending CN1078229A (en) | 1992-03-25 | 1993-03-25 | The method and the intermediate that prepare the 2-substituted benzaldehyde |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0643682A4 (en) |
| JP (1) | JPH07507060A (en) |
| KR (1) | KR950701310A (en) |
| CN (1) | CN1078229A (en) |
| AU (1) | AU3967993A (en) |
| CA (1) | CA2132639A1 (en) |
| FI (1) | FI944413A (en) |
| HU (1) | HUT70046A (en) |
| IL (1) | IL105128A0 (en) |
| MA (1) | MA22843A1 (en) |
| MX (1) | MX9301626A (en) |
| NO (1) | NO943548L (en) |
| SI (1) | SI9300146A (en) |
| TW (1) | TW267157B (en) |
| WO (1) | WO1993019033A1 (en) |
| ZA (1) | ZA932049B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108689861A (en) * | 2018-05-28 | 2018-10-23 | 吉林大学 | A kind of preparation method of N- ethyls -3- phenylpropylamines |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWM317981U (en) | 2007-02-16 | 2007-09-01 | Int Bicycle Products Corp | Handlebar of transportation vehicle |
| CN113620761B (en) * | 2021-08-26 | 2022-06-17 | 西北工业大学 | Preparation method for synthesizing aryl aldehyde compound by reducing aryl secondary amide or aryl secondary amide derivative with phenylsilane |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3637851A (en) * | 1967-10-18 | 1972-01-25 | Tenneco Chem | N - cycloalkyl-chlorobenzylidenimines and herbicidal compositions containing same |
| US3466164A (en) * | 1968-03-29 | 1969-09-09 | Tenneco Chem | Process for the control of plant growth with n-(substituted benzylidene) alkyl amines |
| US3910944A (en) * | 1974-11-20 | 1975-10-07 | Upjohn Co | Spiro(cyclopropane-1,4{40 -(4H)-s-triazolo-(4,3-a)(1,4)benzodiazepines) |
| US4198349A (en) * | 1977-10-06 | 1980-04-15 | William H. Rorer, Inc. | Benzylideneaniline derivatives |
| US4231962A (en) * | 1978-06-08 | 1980-11-04 | Ciba-Geigy Corporation | 3-Phenoxybenzylideneamines and 3-benzylbenzylideneamines |
| US4874792A (en) * | 1985-04-19 | 1989-10-17 | Smithkline Beckman Corporation | Thiophenyl Alkanoic acids useful as leukotriene antagonists |
| DE3535451A1 (en) * | 1985-10-04 | 1987-04-09 | Bayer Ag | METHOD FOR PRODUCING N-ALKYL-SUBSTITUTED HYDROXYLAMMONIUM CHLORIDES AND NEW N-ALKYL-SUBSTITUTED HYDROXYLAMMONIUM CHLORIDES |
-
1993
- 1993-03-22 IL IL105128D patent/IL105128A0/en unknown
- 1993-03-23 ZA ZA932049A patent/ZA932049B/en unknown
- 1993-03-23 MA MA23138A patent/MA22843A1/en unknown
- 1993-03-23 MX MX9301626A patent/MX9301626A/en unknown
- 1993-03-25 HU HU9402743A patent/HUT70046A/en unknown
- 1993-03-25 CN CN93102980A patent/CN1078229A/en active Pending
- 1993-03-25 CA CA002132639A patent/CA2132639A1/en not_active Abandoned
- 1993-03-25 WO PCT/US1993/002803 patent/WO1993019033A1/en not_active Application Discontinuation
- 1993-03-25 JP JP5516838A patent/JPH07507060A/en active Pending
- 1993-03-25 EP EP93909170A patent/EP0643682A4/en not_active Withdrawn
- 1993-03-25 SI SI9300146A patent/SI9300146A/en unknown
- 1993-03-25 AU AU39679/93A patent/AU3967993A/en not_active Abandoned
- 1993-06-15 TW TW082104786A patent/TW267157B/zh active
-
1994
- 1994-09-23 NO NO943548A patent/NO943548L/en unknown
- 1994-09-23 FI FI944413A patent/FI944413A/en not_active Application Discontinuation
- 1994-09-26 KR KR1019940703384A patent/KR950701310A/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108689861A (en) * | 2018-05-28 | 2018-10-23 | 吉林大学 | A kind of preparation method of N- ethyls -3- phenylpropylamines |
| CN108689861B (en) * | 2018-05-28 | 2021-02-26 | 吉林大学 | Preparation method of N-ethyl-3-phenylpropylamine |
Also Published As
| Publication number | Publication date |
|---|---|
| KR950701310A (en) | 1995-03-23 |
| ZA932049B (en) | 1994-09-21 |
| SI9300146A (en) | 1993-12-31 |
| JPH07507060A (en) | 1995-08-03 |
| WO1993019033A1 (en) | 1993-09-30 |
| CA2132639A1 (en) | 1993-09-30 |
| IL105128A0 (en) | 1994-01-25 |
| NO943548D0 (en) | 1994-09-23 |
| NO943548L (en) | 1994-11-23 |
| EP0643682A4 (en) | 1995-06-07 |
| MA22843A1 (en) | 1993-10-01 |
| HU9402743D0 (en) | 1994-12-28 |
| MX9301626A (en) | 1994-07-29 |
| FI944413A0 (en) | 1994-09-23 |
| TW267157B (en) | 1996-01-01 |
| FI944413A (en) | 1994-11-23 |
| HUT70046A (en) | 1995-09-28 |
| AU3967993A (en) | 1993-10-21 |
| EP0643682A1 (en) | 1995-03-22 |
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