CN1733690A - Processes for preparing 2-(omega-alkoxycarbonylalkanoyl)-4- butanolides omega-hydroxy-(omega-3)-keto fatty esters, and derivatives thereof - Google Patents
Processes for preparing 2-(omega-alkoxycarbonylalkanoyl)-4- butanolides omega-hydroxy-(omega-3)-keto fatty esters, and derivatives thereof Download PDFInfo
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Abstract
In industrial production of omega -hydroxyaliphatic acid being an important intermediate for large cyclic lactone-based perfumes, using dicarboxylate ester which is inexpensive and readily obtainable, a method, with high yield and improved selectively, for making a 2-( omega -alkoxycarbonylalkanoyl)-4-butanolide and an alkaline metal salt thereof, an ester of omega -hydroxy-( omega -3)-ketoaliphatic acid as a novel compound and a derivative thereof, and a method for making the same are provided.
Description
The application is that application number is 98800882.3 Chinese the dividing an application of applying for of PCT.
Technical field
The present invention relates to can be used as that various synthesis materials and even intermediate use, particularly the important intermediate as macrolides spice in the perfume industry field is 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone and the manufacturing process of derivative and the manufacturing process of novel ω-hydroxyl-(ω-3)-keto fatty esters and derivative thereof that the intermediate in ω-hydroxy fatty acid manufacturing processed obtains.
In addition, the important intermediate that the present invention also relates to above-mentioned macrolides spice is 2-(ω-carbalkoxy alkane the acyl)-an alkali metal salt of 4-butyrolactone and separation and purification method of derivative and unreacted dicarboxylic ester thereof in the manufacturing of ω-hydroxy fatty acid.
And then, the important intermediate that the invention still further relates to above-mentioned macrolides spice is ω-hydroxyl-(ω-3)-ketofatty acid and salt, dicarboxylic acid and salt thereof and α in the manufacturing of ω-hydroxy fatty acid, alpha, omega-dihydroxy-δ, the separation and recovery method of (ω-3)-alkane diketone.
Background technology
An alkali metal salt of the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid
(in the formula, n represents 7～13 integer, and M represents basic metal), and the ω-hydroxyl shown in the general formula (10)-(ω-3)-ketofatty acid
(in the formula, n is 7～13 integer) can be used as various synthesis materials and even intermediate and uses, particularly the important intermediate of macrolides spice in the perfume industry field.
2-(ω-carbalkoxy alkane acyl)-4-butyrolactone can be used as various synthesis materials and even intermediate uses, particularly as the important intermediate of macrolides spices such as cyclopentadecane acid lactone in the perfume industry field or ring hexadecanoic acid lactone, the intermediate in promptly above-mentioned ω-hydroxy fatty acid manufacturing effectively uses.
Formerly have technical, as the synthesis method of ω-hydroxy fatty acid, known have propose in the Japanese kokai publication hei 5-86013 communique, be the method for initial substance with ω-cyano group undecane acid esters and gamma-butyrolactone.
Yet, this method is a raw material owing in general having any problem and compare expensive 11-cyano group undecanoic acid methyl esters with the raw material availability, use ω-when position cyano group changes into carboxyl to generate ammonia at last and make to handle and become miscellaneous, meanwhile also can produce reasons such as detrimentally affect to the fragrance of desired substance, can't be very satisfactory as industrial manufacturing process.
In addition, synthesis method as ω-hydroxy fatty acid, having mentioned in the flat 5-86013 communique of Japanese kokai publication hei 3-11036 communique and Te Kai with α-(ω-cyano group alkane acyl)-gamma-butyrolactone is that one of the method for initial substance, advantage of this method are to issue unboiled water in the existence of alkali metal hydroxide by α-(ω-cyano group alkane acyl)-gamma-butyrolactone to separate the intermediate ω-hydroxyketone nitrile that obtains with decarboxylic reaction be oil-soluble, thereby the separation of a large amount of water that use or the alkaline carbonate that generates as byproduct of reaction is easy in the reaction.
Yet, because the starting raw material of this α-(ω-cyano group alkane acyl)-gamma-butyrolactone is a raw material with availability difficulty and relatively more expensive ω-cyano group undecane acid esters generally, make ω-when position cyano group changes into carboxyl generate ammonia at last and make to handle and become numerous and diverse, meanwhile also can produce reasons such as detrimentally affect to the fragrance of object, also can't be very satisfactory as industrial manufacturing process.
In addition, mentioned in the open WO 97-06156 communique of international patent application with availability extremely easy and cheap, general formula (1) ROOC (CH
2) dicarboxylic ester and the gamma-butyrolactone shown in the nCOOR (in the formula, the integer of n=7～13, R are alkyl) be the method for starting raw material.This method is that dicarboxylic ester excessive for gamma-butyrolactone removes the methyl alcohol limit reaction that is generated on mixed at room temperature, normal pressure heated and stirred, limit and obtains 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone in the presence of the condensing agent of being made up of alkali, and this method also is excellent method.
Yet selectivity and yield all can't be very satisfactory, and must add a large amount of excessive alkali base aqueous solution when intermediate 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone hydrolysis and decarboxylic reaction.Thereby, have when the Wolff-Kishner of next step reduction and must distill the such problem of big water gaging of removing.
And then, in this method, in order to improve with dicarboxylic ester shown in the above-mentioned general formula (1) is the purpose of the selectivity of benchmark, for the addition of gamma-butyrolactone, make the dicarboxylic ester of 2 times of above excess quantities of mole, and, also to from reaction mixture, reclaim unreacted dicarboxylic ester in order in next step reaction, to utilize this raw material again.
In this reaction, in order to separate unreacted dicarboxylic ester and 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone, can adopt and make the condensation reaction solution acidifying earlier, extract after scouring and reclaim solvent with the ethyl acetate equal solvent, make resulting reaction mixture simple distillation then, be separated into unreacted dicarboxylic ester and the method for distilling condenses 2-(ω-carbalkoxy alkane the acyl)-4-butyrolactone in the remnants of defeated troops in the portion of distillating.
Yet, this method must adopt numerous and diverse technology of the numerous like this steps of extracting operation or simple distillation, in addition, also have 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone to decompose the sorrow of such problem during distillation, and when next step carries out alkaline hydrolysis, decarboxylic reaction, Wolff-Kishner reduction, also must have in 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone that acidifying obtains and add the so numerous and diverse technology of alkali once more.
In addition, Japanese kokai publication hei 4-134047 communique has been put down in writing ω-hydroxy fatty acid or its ester, α, the method for separating and recovering of tertiary mixtures such as omega-diol and dicarboxylic acid or its ester, but have the such compound of carbonyl a bit not relate to for intramolecularly.
Summary of the invention
People such as present inventor, with regard to the method for the open WO 97-06156 communique of international patent application to use strong basicity alkali in a large number, with the separation difficulty of reaction water, need the terms of settlement of the such problem of many heats and processing step to study with keen determination, discovery is as the intermediate of ω-hydroxy fatty acid manufacturing usefulness, just can address the above problem, thereby finish the present invention via novel cpd ω-hydroxyl-(ω-3)-keto fatty esters.
Purpose of the present invention, thus be will provide a kind of and improved above-mentioned prior art, use and to obtain easily and the manufacturing process of derivatives such as good industrial favourable 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone of cheap raw material dicarboxylic ester, high yield and selectivity and an alkali metal salt thereof.
In addition, people such as present inventor also find, in the presence of alkali, from condensation reaction solution with gamma-butyrolactone and the preparation of excessive dicarboxylic ester, when being separated with the unreacted dicarboxylic ester, resultant of reaction carries out solid-liquid separation with inert solvent and water or alkali aqueous solution extraction or with inert solvent, separation and purification condensation reaction thing 2-(ω-carbalkoxy alkane the acyl)-an alkali metal salt of 4-butyrolactone and method of derivative and unreacted ester thereof expeditiously just, thus reach the present invention.
Further purpose of the present invention is can advantageously be used as novel cpd ω-hydroxyl-(ω-the 3)-keto fatty esters of intermediate in the industry manufacturing of the important intermediate ω-hydroxy fatty acid that will be provided at macrolides spice, and then the method for making this ω-hydroxyl-(ω-3)-keto fatty esters and derivative thereof with high yield is provided.
Of the present invention more further purpose be to reclaim ω-hydroxyl-(ω-3)-ketofatty acid and salt, by product dicarboxylic acid and salt and α with good selective separation respectively during the industry of the important intermediate ω-hydroxy fatty acid that will be provided at macrolides spice is made, alpha, omega-dihydroxy-δ, the method for (ω-3)-alkane diketone.
The manufacturing process of the 2-of the present invention that the present invention is used for achieving the above object (ω-carbalkoxy alkane acyl)-4-butyrolactone and an alkali metal salt thereof is a kind of like this manufacturing process, it is characterized in that when the dicarboxylic ester shown in gamma-butyrolactone and the general formula (1)
ROOC(CH
2)nCOOR (1)
Condensation reaction takes place and makes the 2-shown in the general formula (2) (ω-carbalkoxy alkane acyl)-4-butyrolactone in (in the formula, n is 7～13 integer, and R is an alkyl)
(in the formula, n is 7～13 integer, and R is an alkyl), or an alkali metal salt of the 2-shown in the general formula (3) (ω-carbalkoxy alkane acyl)-4-butyrolactone
When (in the formula, n is 7～13, and R is an alkyl, and M is a basic metal),, and carry out condensation reaction to wherein adding gamma-butyrolactone and alkali metal alcoholates by the dicarboxylic ester shown in the above-mentioned general formula of heated and stirred (1).
Here, as better example, the R that comprises above-mentioned general formula (1) is the alkyl person of carbon number 1～6, and above-mentioned condensation reaction under reduced pressure limit steams pure limit and advances passerby, and above-mentioned condensation reaction is advanced passerby in the mode that the decompression degree changes more than two sections.
Secondly, the an alkali metal salt and the unreacted dicarboxylic ester separation and purification of 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone shown in the general formula (3) that above-mentioned steps is made, but in the present invention, one of such separation and purification method is the following is the separation and purification method of feature: when separating an alkali metal salt of 2-shown in the above-mentioned general formula (3) (ω-carbalkoxy alkane acyl)-4-butyrolactone and unreacted dicarboxylic ester from the condensation reaction solution of gamma-butyrolactone and dicarboxylic ester shown in the above-mentioned general formula (1), carry out solid-liquid separation with inert solvent in an alkali metal salt of its 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone.
In addition, the another kind of separation and purification method of the present invention is the following is the separation and purification method of feature: from the condensation reaction solution of gamma-butyrolactone and dicarboxylic ester shown in the above-mentioned general formula (1), separate an alkali metal salt of 2-shown in the above-mentioned general formula (3) (ω-carbalkoxy alkane acyl)-4-butyrolactone, and an alkali metal salt of ω-hydroxyl shown in the derivative general formula (4)-(ω-2)-carboxyl-(ω-3)-ketofatty acid
(in the formula, n is 7～13, and M is a basic metal), and an alkali metal salt of ω-hydroxyl-(ω-the 3)-ketofatty acid shown in the general formula (5)
(in the formula, n is 7～13, and M is a basic metal), and an alkali metal salt of the ω-hydroxyl shown in the general formula (6)-(ω-2)-carboxyl-(ω-3)-keto fatty esters
When (in the formula, n is 7～13, and R is an alkyl, and M is a basic metal) and unreacted dicarboxylic ester, water or alkali aqueous solution extraction.Here, can and the compound shown in above-mentioned general formula (3), (4), (5) and (6) be extracted with inert solvent and water or alkali aqueous solution.
In addition, according to the present invention, can make the ω-hydroxyl shown in the general formula (7)-(ω-3)-keto fatty esters
(in the formula, the integer of n=7～13, R are alkyl).
The manufacturing process of ω-hydroxyl of the present invention-(ω-3)-keto fatty esters is that selective hydrolysis partly takes place the gamma-butyrolactone with an alkali metal salt of 2-shown in the general formula (3) (ω-carbalkoxy alkane acyl)-4-butyrolactone, decarboxylic reaction is the method for feature
(in the formula, the integer of n=7～13, R are alkyl, and M is a basic metal).And, in the present invention, by making an alkali metal salt of the 2-shown in the general formula (3) (ω-carbalkoxy alkane acyl)-4-butyrolactone
(in the formula, the integer of n=7～13, R are alkyl, and M is a basic metal) heating hydrolysis, decarboxylic reaction in the presence of faintly acid also can obtain ω-hydroxyl-(ω-3)-keto fatty esters.
ω-hydroxyl-(ω-3)-keto fatty esters shown in the general formula (7) that obtains according to the present invention
(in the formula, n is 10 or 11, and R is an alkyl) is novel cpd.Here, the R of above-mentioned general formula (7) is preferably the alkyl of carbon number 1～6.
According to the present invention, to the mixture that contains from condensation reaction solution isolating general formula (3), (4), (5) and (6), add necessary amount alkali, carry out after moisture, decarboxylation handles, from containing an alkali metal salt of the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid
(in the formula, n represents 7～13 integer, and M represents basic metal), and the long chain dicarboxylic acid an alkali metal salt shown in the general formula (8)
(in the formula, n represents 7～13 integer, and M represents basic metal), and the α shown in the general formula (9) of the by product that generates when coming from condensation reaction, alpha, omega-dihydroxy-δ, (ω-3)-alkane diketone
(in the formula, n=7～13) in the tertiary mixture, with the α shown in the above-mentioned general formula of organic solvent extraction (9), alpha, omega-dihydroxy-δ, (ω-3)-alkane diketone, or from this mixture the α shown in the above-mentioned general formula of selectivity partial crystallization (9), alpha, omega-dihydroxy-δ, (ω-3)-alkane diketone, the α shown in just can the above-mentioned general formula of Separation and Recovery (9), alpha, omega-dihydroxy-δ, (ω-3)-alkane diketone.
According to the present invention, from containing the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid an alkali metal salt
(in the formula, n represents 7～13 integer, and M represents basic metal), and the long chain dicarboxylic acid an alkali metal salt shown in the general formula (8)
(in the formula, n represents 7～13 integer, M represents basic metal) mixture in ω-hydroxyl-(ω-the 3)-ketofatty acid an alkali metal salt shown in the above-mentioned general formula of selectivity partial crystallization (5), thereby make it solid-liquid separation and be separated into filter cake and filtrate, shown in ω-hydroxyl-(ω-3)-ketofatty acid an alkali metal salt shown in just can the above-mentioned general formula of Separation and Recovery (5) and the above-mentioned general formula (8) and the long chain dicarboxylic acid an alkali metal salt.
The mixture that contains the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid an alkali metal salt is adjusted to pH=5～7 with mineral acid, ω-hydroxyl-(ω-the 3)-ketofatty acid shown in just can Separation and Recovery general formula (10)
(in the formula, the integer of n=7～13), and the long chain dicarboxylic acid an alkali metal salt shown in the general formula (8).
The filtrate of containing the long chain dicarboxylic acid an alkali metal salt shown in the general formula (8) is further adjusted to pH=3～5 with mineral acid, the long chain dicarboxylic acid shown in just can Separation and Recovery general formula (11)
(in the formula, the integer of n=7～13).
In addition, even pass through the combination of these means, also can reach target of the present invention.
Embodiment
In the present invention, at first, use the dicarboxylic ester shown in gamma-butyrolactone and the general formula (1)
ROOC(CH
2)nCOOR (1)
Condensation reaction takes place in (in the formula, the integer of n=7～13, R are alkyl), prepares the 2-shown in the general formula (2) (ω-carbalkoxy alkane acyl)-4-butyrolactone
(in the formula, the integer of n=7～13, R are alkyl), or an alkali metal salt of the 2-shown in the general formula (3) (ω-carbalkoxy alkane acyl)-4-butyrolactone
(in the formula, the integer of n=7～13, R are alkyl, and M is a basic metal).
The condensation reaction of dicarboxylic ester and gamma-butyrolactone is complicated in the presence of alkaline condensing agent, can infer, because of the difference of the reaction methods such as removal of its raw materials used adding method or the methyl alcohol that generates, selectivity, yield can be subjected to very big influence.Therefore, people such as present inventor are conceived to the result that studies with keen determination with the reaction mechanism of the generation associated of above-mentioned alcohol, find all to obtain 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone and an alkali metal salt thereof well as the following stated that works selectivity and yield.
That is, at first, in the fs, making the alcohol that generated fully under the condition of evaporation, drip gamma-butyrolactone and alkali metal alcoholates in the dicarboxylic ester in the heated and stirred while reduce pressure, the limit is reacted alcohol outside steaming reaction system; Then, as subordinate phase, by further raising decompression degree and heated and stirred, the limit makes remaining alcohol shift out reaction system outside to react.Find, by carrying out like this, can selectivity and yield all obtain 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone and an alkali metal salt thereof well.
Therefore, one of feature of the present invention is to add gamma-butyrolactone and alkali metal alcoholates in the dicarboxylic ester in heated and stirred, and in this case, gamma-butyrolactone and alkali metal alcoholates both can mix interpolation (dropping) also can be added respectively.
This reaction is preferably under reduced pressure the limit and alcohol is steamed the system outside reacts.In addition, according to the present invention, as the subordinate phase after above-mentioned, be preferably further raising decompression degree and heated and stirred, the limit makes remaining alcohol shift out the continuation reaction of system outside, thereby improves selectivity and yield.
The general formula that uses among the present invention (1) ROOC (CH
2) R of the dicarboxylic ester shown in the nCOOR (in the formula, the integer of n=7～13, R are alkyl), from viewpoint easy to use, the good especially alkyl that is to use carbon number 1～6.As the concrete example of this R, can enumerate methyl, ethyl, propyl group, butyl, isobutyl-, amyl group, hexyl etc.Especially good is methyl.
As the dicarboxylic ester preferably shown in the general formula (1), can enumerate 1 particularly, 12-dodecanedioic acid dimethyl ester or 1,13-undecane dicarboxylic acid dimethyl ester (brassylic acid dimethyl ester) etc.
In addition, according to the present invention, condensation reaction is to carry out in the presence of alkali metal alcoholates, but as alkali metal alcoholates, is preferably the alkali metal alcoholates shown in general formula R ' OM (R ' is the alkyl of carbon number 1～4 in the formula, and M is a basic metal).
As the concrete example of said alkali metal alcoholates here, can enumerate sodium methylate, sodium ethylate, sodium propylate, sodium butylate, potassium methylate, potassium ethylate, potassium propylate and butanols potassium etc.
The usage quantity of these alkali metal alcoholates is not particularly limited among the present invention, but for gamma-butyrolactone, is preferably and uses 0.1～5 equivalent, is more preferably and uses 0.5～3 equivalent.If the usage quantity of alkali metal alcoholates is few, then yield is low, if usage quantity reach a certain amount of more than then yield reach capacity and cause selectivity on the contrary and descend.
In addition, in the present invention, for gamma-butyrolactone, the usage quantity of dicarboxylic ester shown in the general formula (1) is preferably molar excess, good especially is 2 times more than the mole.If dicarboxylic ester is 2 times more than the mole, selectivity is improved.
In enforcement of the present invention, having under the remaining situation of unreacted dicarboxylic ester, be preferably and from reaction mixture, reclaim unreacted dicarboxylic ester, and cyclically utilizing is in condensation reaction, to improve reaction efficiency.In the present invention, extraction of the recovery water of unreacted dicarboxylic ester or alkali aqueous solution or solid-liquid separation just can easily be carried out in the reaction mixture, thereby combine with the excessive use and the cyclically utilizing of dicarboxylic ester, just can realize more high efficiency reaction.
In the condensation reaction of the present invention,, be preferably and under reduced pressure carry out condensation reaction in order to remove alcohol expeditiously.As reduced pressure, be preferably 50～760mmHg, good especially is the scope of 100～600mmHg.And decompression can divide more than 2 sections and carries out.For example, as the fs, react about 500～700mmHg that the alcohol that generated of can reducing pressure to can fully evaporate, and, the decompression degree is brought up to about 50～300mmHg reacted as subordinate phase.
Here, the Heating temperature condition of condensation reaction is not particularly limited, but to be set in and reduce pressure concern the aspect than appropriate condition, 30～200 ℃ more fortunately, good especially be scope at 50～150 ℃.
Among the present invention, solvent is not necessary to use especially, but so long as do not reduce the active solvent of alkali metal alcoholates, can add the solvent that uses in the general ester condensation yet and react.
Reaction formation of the present invention can be with any carrying out in intermittent type, continous way, the multi-stage type.
An alkali metal salt of 2-(ω-carbalkoxy alkane the acyl)-4-butyrolactone that obtains according to the present invention, as described later, can be easily and the important intermediate of this macrolides spice of ω-hydroxy fatty acid of deriving with high yield.
The resultant of reaction of the condensation reaction of dicarboxylic ester and gamma-butyrolactone is a 'beta '-ketoester type compound shown in the general formula of the present invention (1), in this reaction solution usually with general formula (3)
The state of an alkali metal salt that (in the formula, the integer of n=7～13, R are alkyl, and M is a basic metal) is such exists.Can judge that an alkali metal salt shown in this general formula (3) is that solubleness is extremely low to organic solvents such as normal hexanes.And, can judge this salt if drop into then dissolving easily in the alkali aqueous solution, promptly make gamma-butyrolactone part and terminal ester partial hydrolysis, generate general formula (4)
(in the formula, the integer of n=7～13, M are basic metal) such dicarboxylic acid an alkali metal salt, and different because of the addition of alkali metal hydroxide, and decarboxylic reaction takes place and becomes general formula (5) in a part
(in the formula, n=7～13, M represents basic metal) such an alkali metal salt.
On the other hand, dicarboxylic ester remains in the reaction solution with its original unreacted form shown in the excessive general formula (1) that uses in the condensation reaction of the present invention.This compound is very soluble for organic solvents such as normal hexanes.
Therefore, people such as present inventor are conceived to the 2-result that (ω-carbalkoxy alkane acyl)-4-butyrolactone an alkali metal salt is studied with keen determination to the solvability of organic solvent or water, found easily thereby also to separate respectively with high yield obtaining 2-(ω-carbalkoxy alkane the acyl)-an alkali metal salt of 4-butyrolactone and process for purification of derivative and unreacted dicarboxylic ester thereof, thereby finished the present invention.
According to the present invention, the method (to call solid-liquid isolation method in the following text) that an alkali metal salt shown in the general formula (3) and the unreacted dicarboxylic ester shown in the general formula (1) is separated by solid-liquid separation such as filtrations is arranged.
That is, interpolation unreacted dicarboxylic ester can dissolve but to alkali or 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone an alkali metal salt organic solvent inert, the unreacted dicarboxylic ester fully be dissolved in condensation reaction solution, forms the suspension with salt.This suspension is separated into solution part and solid part by means of filtering or centrifugation some itself known method like this.Solid part carries out thorough washing with solvent, removes the unreacted dicarboxylic ester.Solution part mixes with washings concentrated after, the former state cyclically utilizing is in next condensation reaction.
On the other hand, solid part both can be used as it is, and also can acidifying becomes 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone and re-used.In addition, can also drop in the alkali aqueous solution and be used for hydrolysis, decarboxylic reaction.
According to the present invention, the salt extraction that makes 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone in addition respectively is in water layer and make the unreacted dicarboxylic ester be extracted into separation method (to call the alkali extraction process in the following text) in the organic layer.
Promptly, add water or alkali aqueous solution in condensation reaction solution, make an alkali metal salt dissolving of 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone, this mixed solution separates with the separatory method, the unreacted dicarboxylic ester reclaims with the organic layer form, and washing back cyclically utilizing is in next condensation reaction.
On the other hand, can extract the compound of an alkali metal salt, the general formula (6) of general formula (3), general formula (5) an alkali metal salt that generates because of the different general formula of the addition of alkali metal hydroxide (4) an alkali metal salt and then because of the different part decarboxylic reaction of the addition of alkali metal hydroxide in the water layer.This point, the crystallisate that extraction obtains after the water layer acidifying that obtains by aforesaid operations carries out compositional analysis just can be clear.This crystallisate can be told and contain the 2-shown in general formula (2) compound, long chain dicarboxylic acid, the general formula (12) (ω-carboxyl alkane acyl)-4-butyrolactone
ω-hydroxyl shown in (in the formula, n=7～13) and the general formula (10)-(ω-3)-ketofatty acid
(in the formula, n=7～13) is as principal constituent.
Among the present invention, consider as follows about 2-(ω-carboxyl alkane acyl)-4-butyrolactone this point of 2-(ω-carbalkoxy alkane the acyl)-4-butyrolactone that contains general formula (2) in the crystallisate and general formula (12).That is, can infer that an alkali metal salt shown in the general formula (3) is if be dissolved in the alkali aqueous solution, then its gamma-butyrolactone part hydrolysis and generate the compound shown in the general formula (6) rapidly.
This compound is if acidifying will generate the such compound of general formula (13)
(n=7～13, R is an alkyl), but this thing dewaters easily and the formation lactonic ring, thereby can obtain the compound of general formula (2).In addition, can infer that different because of the addition of alkali, the terminal ester of general formula (6) part also can hydrolysis and generate an alkali metal salt of the dicarboxylic acid of general formula (4).
And the compound of this general formula (4) is if acidifying just generates the dicarboxylic acid shown in the general formula (14)
Dewatering easily and form lactonic ring in (n=7～13), this compound, thereby can obtain 2-(ω-carboxyl alkane the acyl)-4-butyrolactone of general formula (12).
In addition, the generation of above-mentioned ω-hydroxyl-(ω-3)-ketofatty acid is owing to using the above alkali metal hydroxide of hydrolysis necessary amounts to cause due to the beta-keto acid decarboxylic reaction.
The water layer that obtains like this can former state be used for the hydrolysis and the decarboxylic reaction of next step.
Operable solvent among the present invention, the salt that needs only alkali or 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone is inert, just is not particularly limited.As concrete example, can enumerate organic solvents such as pentane, hexane, heptane, octane, hexanaphthene, benzene,toluene,xylene, diethyl ether, isopropyl ether.
In addition, even in the alkali extraction process, also can implement without solvent, but better with the person.The usage quantity of solvent for condensation reaction solution, is preferably 0～10 times of weight, is more preferably 0.5～5 times of weight.Temperature in solvent during the extraction of the temperature in when dissolving and alkali, so long as organic layer solidified temperature just is not particularly limited, but usually in 0 ℃～100 ℃ scope, 20～50 ℃ scope more fortunately.
In the present invention, as the operable strong basicity alkali of alkaline extraction method, just be not particularly limited so long as can extract 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone, its an alkali metal salt and derivative person, but can use alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline carbonate such as yellow soda ash and salt of wormwood, alkaline-earth metal hydroxide such as hydrated barta etc.
Concentration about alkaline solution is not particularly limited, but is preferably the scope 0.5～50%, is more preferably the scope 1～15%.And, also unqualified about usage quantity, but for condensation reaction solution, be preferably 0.1～10 times of weight, be more preferably 0.5～2 times.In addition, refining form of the present invention can be with any carrying out in intermittent type, the continous way.
And then people such as present inventor find, add weak acid, heating such as phosphoric acid in an alkali metal salt of the above-mentioned 2-that obtains (ω-carbalkoxy alkane acyl)-4-butyrolactone, can obtain the ω-hydroxyl shown in the general formula (7)-(ω-3)-keto fatty esters well by yield
(in the formula, the integer of n=7～13, R are alkyl).And find that the compound shown in this general formula (7) is oil-soluble, thereby can easily separate with reaction soln with the separatory method, thereby the present invention finished.This ω-hydroxyketone fatty acid ester in the manufacturing of the important intermediate ω of macrolides spice-hydroxy fatty acid, can be used as intermediate and uses in the perfume industry field.
In the ω-hydroxyl shown in the above-mentioned general formula (7)-(ω-3)-keto fatty esters, n is that ω-hydroxyl-(ω-3)-keto fatty esters of 10 or 11 is a novel cpd.
That is,, make the gamma-butyrolactone of the above-mentioned 2-that obtains (ω-carbalkoxy alkane acyl)-4-butyrolactone an alkali metal salt that selective hydrolysis, decarboxylic reaction partly take place, can obtain the ω-hydroxyl shown in the general formula (7)-(ω-3)-keto fatty esters according to the present invention
(in the formula, the integer of n=7～13, R are alkyl).And, according to the present invention, heat in the presence of faintly acid by an alkali metal salt that makes the 2-shown in the above-mentioned general formula (3) (ω-carbalkoxy alkane acyl)-4-butyrolactone, make it to take place hydrolysis, decarboxylic reaction, just can prepare the ω-hydroxyl shown in the general formula (7)-(ω-3)-keto fatty esters.
Operable faintly acid kind is not particularly limited in hydrolysis of the present invention, the decarboxylic reaction, but as concrete example, can enumerate phosphoric acid, tetra-sodium and carbonic acid etc., can also use SODIUM PHOSPHATE, MONOBASIC etc.And the faintly acid usage quantity is not particularly limited, and for 1 mole of an alkali metal salt of 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone, can use 0.5～3 equivalent, better 0.5～1 equivalent.
In addition, the operable water yield is not particularly limited in the reaction of the present invention, but for an alkali metal salt of 2-(ω-carbalkoxy alkane acyl)-4-butyrolactone, is preferably with 2～20 times ratio and uses.
Also can use water-miscible organic solvent in hydrolysis of the present invention, the decarboxylic reaction, concrete example as water-miscible organic solvent, can enumerate methyl alcohol, ethanol, glycol ether, triglycol, diox, tetrahydrofuran (THF), 1,2-glycol dimethyl ether etc., the usage quantity of these water-miscible organic solvents, for water 1 weight part, be preferably in the scope of 0.05～3 weight part.
This type of reaction of the present invention is a reacting by heating.According to the present invention, can in the presence of faintly acid such as phosphoric acid, heat, but the temperature of this reaction is preferably in 80～110 ℃ scope.In addition, the reaction times can suitably be selected according to temperature of reaction and the raw material that is added etc., but generally is about 1～20 hour.Reaction can be with any carrying out in intermittent type and the continous way.The separation of resultant of reaction and refining can be carried out with the known unit operation of separatory, extraction, washing, recrystallization etc. itself.
ω-hydroxyl shown in the general formula that obtain according to the present invention, above-mentioned (7)-(ω-3)-keto fatty esters can be easily, good, the industrial important intermediate ω-hydroxy fatty acid that advantageously is derivatized to macrolides spice of yield.
Promptly, ω-hydroxyl-(ω-3)-keto fatty esters can be by heating in the aqueous solution of alkali metal hydroxide or in water-miscible organic solvent/water mixed solvent, make it-hydrolysis of COOR base, and become an alkali metal salt of ω-hydroxyl-(ω-the 3)-ketofatty acid of general formula (5).Then, by means of well-established law Wolff-Kishner reduction make-CO-base keto-acid is reduced into-CH
2-Ji, thus be derivatized to ω-hydroxy fatty acid.Like this, ω-hydroxyketone fatty acid ester itself also can be used as synthesis material and intermediate, especially can be used as the intermediate in the manufacturing of the important intermediate ω-hydroxy fatty acid of macrolides spice such as thibetolide or dihydroambrettolide in the perfume industry field.
According to the present invention, and then, the condensation reaction thing of above-mentioned dicarboxylic ester and gamma-butyrolactone with aforesaid method under alkaline condition, extract, hydrolysis, decarboxylic reaction, the further hydrolysis of condensation reaction by product, the decarboxylation that exist in the reaction mixture, compound shown in the general formula of generation (9)
(in the formula, the integer of n=7～13) separates or Crystallization Separation with organic solvent extraction.In addition, residuary water solution is handled at preset temperature, make an alkali metal salt selective crystallization of ω-hydroxyl-(ω-3)-ketofatty acid, be separated into filter cake and filtrate with solid-liquid isolation method, thus dicarboxylic acid an alkali metal salt shown in ω-hydroxyl shown in the Separation and Recovery general formula (5)-(ω-3)-ketofatty acid an alkali metal salt and the general formula (8).Perhaps, resulting filter cake and filtrate are used mineral acid treatment respectively, respectively ω-hydroxyl-(ω-3)-ketofatty acid shown in the Separation and Recovery general formula (10)
(in the formula, n=7～13), and dicarboxylic acid shown in the general formula (11)
(in the formula, n=7～13).
Perhaps, the mixture that contains long chain dicarboxylic acid an alkali metal salt shown in ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid an alkali metal salt and the general formula (8) is adjusted to pH=5～7 with mineral acid, make that general formula (10) is separated out, solid-liquid separation, thus long chain dicarboxylic acid an alkali metal salt shown in ω-hydroxyl shown in the Separation and Recovery general formula (10)-(ω-3)-ketofatty acid and the general formula (8).And, in case of necessity, further its filtrate is adjusted to pH 3～5 with mineral acid, make that the compound shown in the general formula (11) is separated out, solid-liquid separation, thus the long chain dicarboxylic acid shown in the Separation and Recovery general formula (11).
For example, from containing ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid an alkali metal salt, α shown in long chain dicarboxylic acid an alkali metal salt shown in the general formula (8) and the general formula (9), alpha, omega-dihydroxy-δ, in the mixture of (ω-3)-alkane diketone, compound shown in the general formula (9) is removed in extraction, perhaps handle mixed solution and the selectivity partial crystallization goes out general formula (9) at preset temperature, solid-liquid separation, the aqueous solution of removing behind the filter cake is further handled at preset temperature, the selectivity partial crystallization goes out general formula (5) compound, after solid-liquid isolation method is separated into liquid cake and filtrate, under the situation that contains a small amount of general formula (5) compound, filtrate is adjusted to pH=5～7 with mineral acid, partial crystallization, solid-liquid separation goes out the compound of general formula (10), thus the long chain dicarboxylic acid an alkali metal salt shown in the ω-hydroxyl shown in the Separation and Recovery general formula (10)-(ω-3)-ketofatty acid and the general formula (8).In addition, can also enumerate filtrate and further adjust to pH3～5, partial crystallization, solid-liquid separation go out general formula (11), thus the method for the long chain dicarboxylic acid an alkali metal salt shown in the Separation and Recovery general formula (8) etc.
Among the present invention, the α of extracting and separating general formula (9) from reaction mixture, alpha, omega-dihydroxy-δ, operable organic solvent during (ω-3)-alkane diketone so long as be inertia and water insoluble person under alkaline condition, just is not particularly limited.As concrete example, can enumerate benzene,toluene,xylene, 1,2,3,4-tetralin, naphthane, pentane, hexane, heptane, octane, hexanaphthene, isopropyl ether and dibutyl ether etc.Wherein, the especially good toluene that is to use.
Among the present invention, the usage quantity of organic solvent is not particularly limited, but from operation, viewpoints such as subsidiary material expense for reaction mixture, are preferably 0.5～20 times of weight, and especially good is 1～10 times of weight.
Among the present invention, the extraction temperature of general formula (9) is not particularly limited, but from the good more reverse side of the high more extraction efficiency of temperature, promptly extract the boiling point problem of used organic solvent and water, be preferably 50～110 ℃, especially good be in 60～90 ℃ scope.Be noted that the compound that also contains general formula (5) in the organic layer, but just can reclaim major part with the warm water back extraction.
Among the present invention, the partial crystallization temperature of general formula (9) compound is subjected to the composition of reaction mixture easily, especially water ratio influences, but so long as can make general formula (9) compound crystal and can make the salt dissolved temperature of general formula (5) and (8), just is not particularly limited.But,, be preferably-20～80 ℃ from operational problem, good especially is 0～40 ℃.
During the compound partial crystallization of general formula (9), the water ratio of reaction mixture is subjected to the composition and the temperature effect of reaction mixture easily, but so long as can make the compound crystal of general formula (9) and can make the salt dissolved water ratio of general formula (5) and (8), just is not particularly limited.But, from operational problem, be preferably 50～99% (weight), especially good is 70～90% (weight).
The general formula that generates among the present invention (9) crystalline solid-liquid separating method can use usual methods such as centrifugal settling, centrifuge dehydration and filtration.Be noted that the salt of also having sneaked into general formula (5) and general formula (8) in the resulting filter cake, but can further improve the purity of filter cake formula of (9) compound, and can reclaim the salt of general formula (5) and general formula (8) with aqueous solution form by washings such as waters.
In addition, among the present invention, the form of extraction step can be that intermittent type, multistage slot type and continous way etc. are any.
The partial crystallization condition of the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid an alkali metal salt below is described.
Among the present invention, the partial crystallization temperature of general formula (5) compound is subjected to the composition of reaction mixture easily, especially water ratio influence, but so long as can generate the crystallization of general formula (5) compound and the temperature that can dissolve general formula (2) compound, just be not particularly limited.But,, be preferably-20～80 ℃ from operational problem, especially good is 0～40 ℃.
Among the present invention, the water ratio of reaction mixture is subjected to the composition and the temperature effect of reaction mixture easily, but so long as can generate the crystallization of general formula (5) compound and can make the water ratio of general formula (8) compound dissolution, just is not particularly limited.But, from operational problem, be preferably 50～99% (weight), especially good be 70～90% (weight).
The crystalline solid-liquid separating method that generates among the present invention can use usual methods such as centrifugal settling, centrifuge dehydration and filtration.Be noted that the compound of also having sneaked into general formula (8) in the resulting filter cake, but can further improve the purity of filter cake formula of (5) compound, and can reclaim general formula (8) compound with aqueous solution form by washings such as waters.
The filter cake that obtains in the manufacturing of macrolide both can former state also can carry out acidifying earlier and be used further to subsequently reduction reaction.Reduction reaction can be carried out with the known method of Wolff-Kishner reduction or Clemmensen reduction etc. itself.
Employed mineral acid is not particularly limited during an alkali metal salt acidifying of general formula (5) and general formula (8), but better use lipid acid after sulfuric acid or hydrochloric acid, the acidifying obtain because of its shape different, but can use solid-liquid separation such as centrifugal settling, centrifuge dehydration and filtration, or with organic solvent extraction means such as benzene,toluene,xylene, pentane, hexane, heptane, octane, hexanaphthene, diethyl ether, isopropyl ether, ethyl acetate, methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.
Among the present invention, the pH when obtaining general formula (10) with mineral acid from the mixture of general formula (5) and general formula (8) is preferably 5～7, and especially good is 5.5～6.5.And then the pH when making general formula (8) acidifying obtain general formula (11) is preferably 3～5, and especially good is 3.5～4.5.Make pH drop to the following person of this value, the rate of recovery, the purity of general formula (11) are all no problem, but the increase of mineral acid usage quantity, auxiliary material takes increase thereupon, thereby bad.
Embodiment
Below describe the present invention in detail with embodiment.But, following embodiment is illustrative, is not determinate explanation going up in all senses.
(embodiment 1)
1, the 12-dodecanedioic acid dimethyl ester (105.00g 406.4mmol) packs in the reaction unit, under the decompression state of 600mmHg in 105 ℃ of heated and stirred.(8.75g, 101.6mmol) (19.60g 101.6mmol) in mixed at room temperature, is added drop-wise to 1 of heating with 30 fens clock times to gamma-butyrolactone, in the 12-dodecanedioic acid dimethyl ester, steams methyl alcohol while dripping with 28% (weight) sodium methylate-methanol solution.After former state was carried out reaction in 30 minutes, the 200mmHg that reduces pressure further reacted 120 minutes.
Then, after making it to get back to normal pressure, in cooling, the impouring dilute hydrochloric acid, use ethyl acetate extraction.Organic layer washing, with behind the anhydrous magnesium sulfate drying, steam solvent.(oil bath temperature 170～180 ℃/0.5～0.2mmHg) is to steam 1 of surplus, 12-dodecanedioic acid dimethyl ester in residual oily matter underpressure distillation.Obtain overhead product 81.9g and distillation residue 25.1g.
Distillation residue are partly used the result of gc analysis, show compound shown in the general formula (2) that contains 88.6% (weight) (n=10, R=Me).Yield is 80.2%, and selectivity is 83.2%.
(embodiment 2)
1, the 12-dodecanedioic acid dimethyl ester (105.00g 406.4mmol) adds in the reaction unit, under the decompression state of 600mmHg in 105 ℃ of heated and stirred.(8.75g, 101.6mmol) (19.60g 101.6mmol) in mixed at room temperature, is added drop-wise to 1 of heating with 30 fens clock times to gamma-butyrolactone, in the 12-dodecanedioic acid dimethyl ester, steams methyl alcohol while dripping with 28% (weight) sodium methylate-methanol solution.After former state was carried out reaction in 30 minutes, the 200mmHg that reduces pressure further reacted 240 minutes.
Then, after making it to get back to normal pressure, in cooling, the impouring dilute hydrochloric acid, use ethyl acetate extraction.Organic layer washing, with behind the anhydrous magnesium sulfate drying, steam solvent.(oil bath temperature 170～180 ℃/0.5～0.2mmHg) is to steam 1 of surplus, 12-dodecanedioic acid dimethyl ester in residual oily matter underpressure distillation.Obtain overhead product 82.2g and distillation residue 26.5g.The result of chemical examination lingering section show contain 88.1% general formula (2) compound (n=10, R=Me).Yield is 81.4%, and selectivity is 87.9%.
(embodiment 3)
1, the 12-dodecanedioic acid dimethyl ester (105.00g 406.4mmol) adds in the reaction unit, under the decompression state of 500mmHg in 105 ℃ of heated and stirred.(8.75g, 101.6mmol) (19.60g 101.6mmol) in mixed at room temperature, is added drop-wise to 1 of heating with 30 fens clock times to gamma-butyrolactone, in the 12-dodecanedioic acid dimethyl ester, steams methyl alcohol while dripping with 28% (weight) sodium methylate-methanol solution.After former state was carried out reaction in 30 minutes, the 100mmHg that reduces pressure further reacted 120 minutes.
After making it to get back to normal pressure, in cooling, the impouring dilute hydrochloric acid, use ethyl acetate extraction.Organic layer washing, with steaming solvent behind the anhydrous magnesium sulfate drying.(oil bath temperature 170～180 ℃/0.5～0.2mmHg) steams 1 of surplus, the 12-dodecanedioic acid dimethyl ester in residual oily matter underpressure distillation.Obtain overhead product 81.4g and distillation residue 27.2g.The result of chemical examination residue part show contain 88.3% general formula (2) compound (n=10, R=Me).Yield is 81.6%, and selectivity is 86.0%.
(comparative example 1)
1, the 12-dodecanedioic acid dimethyl ester (105.00g, 406.4mmol), gamma-butyrolactone (8.75g, 101.6mmol) and 28% (weight) sodium methylate-methanol solution (19.60g, 101.6mmol) 50 ℃ of mixing, the limit steams the methyl alcohol limit and is warmed up to 110 ℃ with 45 fens clock times.After former state was carried out reaction in 30 minutes, the 630mmHg that reduces pressure carried out reaction in 30 minutes.
Make it to get back to normal pressure, further react 30 minutes after, cooling, in the impouring dilute hydrochloric acid, use ethyl acetate extraction.Organic layer washing, with behind the anhydrous magnesium sulfate drying, steam solvent.(oil bath temperature 170～180 ℃/0.5～0.2mmHg) steams 1 of surplus, the 12-dodecanedioic acid dimethyl ester in residual oily matter underpressure distillation.Obtain overhead product 81.5g and distillation residue 25.6g.The result of chemical examination residue part show contain 85.1% general formula 1 compound (n=10, R=Me).Yield is 79.0%, and selectivity is 79.0%.
(embodiment 4) (solid-liquid isolation method)
From 1,12-dodecanedioic acid dimethyl ester (105.00g, 406.4mmol) and gamma-butyrolactone (8.75g, 101.6mmol) and 28% (weight) sodium methylate-methanol solution (19.60g, 101.6mmol) the condensation reaction solution 116.2g (partial acidification, quantitative results, confirm contain condenses 25.71g, unreacted ester 80.70g) of preparation is 50 ℃ of heated and stirred.To wherein adding normal hexane 565g, the limit is cooled to 20 ℃ of limits and stirs, and becomes by the suspension that shows that lurid throw out and transparent supernatant liquor are formed.Make this suspension be separated into throw out and supernatant liquor with pressure filter.Filter cake normal hexane thorough washing.
Filtrate is mixed with washings, steams normal hexane, obtains enriched material 80.94g.The enriched material quantitative analysis by gas chromatography, show contain 99.2% general formula (1) compound (n=10, R=Me).Its rate of recovery is 99.5%.
After the 1.00g acidifying among the filter cake 35.35g that further obtains, use ethyl acetate extraction.Organic layer washing back with anhydrous magnesium sulfate drying, steam solvent, obtain the 0.92g crystallization.When quantitative analysis by gas chromatography is used in this crystallization, show and contain general formula (2) compound (n=10, R=Me) 0.73g, general formula (1) compound (n=10, R=Me) 0.01g.The rate of recovery of general formula (2) compound is 100% (weight), and the survival rate of general formula (1) dicarboxylic ester is 0.4% (weight).
(embodiment 5)
From 1,12-dodecanedioic acid dimethyl ester (64.73g, 207.2mmol), gamma-butyrolactone (4.46g, 51.8mmol) and 28% (weight) sodium methylate-methanol solution (9.99g, 51.8mmol) condensation reaction solution (a part of acidifying, quantitative results, confirm contain condenses 12.25g, unreacted ester 42.61g) of preparation is 50 ℃ of heated and stirred.To wherein adding normal hexane 50.0g, stirred 2 minutes.To wherein adding water 50.0g, former state stirred 30 minutes.Organic layer washing, concentrated, the concentration that obtains with 94.1% contains general formula (1) compound (n=10, crystallisate 44.31g R=Me).The rate of recovery is 97.9%.
And then, after acidifying in the direct impouring dilute sulphuric acid of water layer, with ethyl acetate extraction, washing.Behind anhydrous magnesium sulfate drying, steam solvent, obtain crystallization.When quantitative analysis by gas chromatography was used in this crystallization, the concentration that obtains with 71% contained general formula (2) compound (n=10, crystallisate 13.11g R=Me).The rate of recovery is 78.2%.
(embodiment 6) (alkali extraction process)
From 1,12-dodecanedioic acid dimethyl ester (105.00g, 406.4mmol), gamma-butyrolactone (8.75g, 101.6mmol) and 28% (weight) sodium methylate-methanol solution (19.6g, 101.6mmol) condensation reaction solution (a part of acidifying, quantitative results, confirm contain condenses 25.49g, unreacted ester 80.82g) of preparation is 50 ℃ of heated and stirred.To wherein adding normal hexane 104.4g, stirred 2 minutes.To wherein adding 5%KOH aqueous solution 107.5g, former state stirred 120 minutes.After leaving standstill 5 minutes, separatory is divided into organic layer and water layer.Organic layer washing, concentrated, the concentration (quantitative values) that obtains with 98.8% contains general formula (1) compound (n=10, crystallisate 80.9g R=Me).The rate of recovery is 98.9%.
And then, water layer is directly dropped in the dilute sulphuric acid after the acidifying, with ethyl acetate extraction, washing.Behind anhydrous sodium sulfate drying, steam solvent, obtain crystallization.When quantitative analysis by gas chromatography is used in this crystallization, judge and contain 23.1% general formula (10) compound (n=10).In addition, the 1.00g crystallization separates the colourless crystallization 0.61g that obtains with silica gel chromatography, with infrared spectroscopy (IR), when nuclear magnetic resonance method (NMR) is resolved, shows it is general formula (12) compound (n=10).
(embodiment 7) (alkali extraction process)
From 1,12-dodecanedioic acid dimethyl ester (105.00g, 406.4mmol), gamma-butyrolactone (8.75g, 101.6mmol) and 28% (weight) sodium methylate-methanol solution (19.60g, 101.6mmol) condensation reaction solution (a part of acidifying, quantitative results, confirm contain condenses 25.58g, unreacted ester 80.56g) of preparation is 50 ℃ of heated and stirred.To wherein adding hexanaphthene 139.7g, stirred 2 minutes.To wherein adding 5%KOH aqueous solution 143.9g, former state stirred 10 minutes.After leaving standstill 5 minutes, separatory is divided into organic layer and water layer.Organic layer washing, when concentrating, the concentration (quantitative values) that obtains with 98.9% contains general formula (1) compound (n=10, crystallisate 81.62g R=Me).The rate of recovery is 100.0%.
(reference example 1)
After in the water layer that embodiment 3 obtains, adding 49%KOH aqueous solution 23.3g, refluxed 2 hours.Then, after the dilute sulphuric acid acidifying, use ethyl acetate extraction.Organic layer washing, with anhydrous sodium sulfate drying, steam solvent, obtain coarse crystallization 27.50g.This thing shows general formula (10) compound (n=10) that contains 80.2% (weight) with the result of quantitative analysis by gas chromatography.(n=10, yield R=Me) is 99.0% to condensation reaction solution formula of (2) compound.
(comparative example 2)
From 1,12-dodecanedioic acid dimethyl ester (105.00g, 406.4mmol), gamma-butyrolactone (8.75g, 101.6mmol) and 28% (weight) sodium methylate-methanol solution (19.60g, 101.6mmol) preparation condensation reaction solution (a part of acidifying, quantitative results, confirm to contain condenses 25.68g, unreacted ester 80.67g) in the impouring dilute hydrochloric acid, use ethyl acetate extraction.Organic layer washing, with behind the anhydrous magnesium sulfate drying, (oil bath temperature 170～180 ℃/0.5～0.2mmHg) is superfluous 1 to steam, the 12-dodecanedioic acid dimethyl ester to steam the oily residue underpressure distillation that obtains behind the solvent.Obtain overhead product 802g and distillation residue 31.55g.When overhead product is used quantitative analysis by gas chromatography, show contain 98.3% general formula (1) compound (n=10, R=Me).The rate of recovery is 98%.
In addition, after the distillation residue 2.00g acidifying, use ethyl acetate extraction.Organic layer washing back, with anhydrous sodium sulfate drying, steam solvent, obtain the 1.88g crystallization.When quantitative analysis by gas chromatography is used in this crystallization, show concentration with 84.0% (weight) contain general formula (5) compound (n=10, R=Me).Refining yield is 97.00%.
Secondly, with distillation residue 2.00g, sodium hydroxide (1.75g, 13,7mmol), water 40g and methyl alcohol 20g mix reflux 4 hours.After cooling, the acidifying, use ethyl acetate extraction.Behind organic layer water Xian, with anhydrous sodium sulfate drying, steam solvent, obtain coarse crystallization 1.57g.This thing shows general formula (10) compound (n=10) that contains 86.6% (weight) with the result of quantitative analysis by gas chromatography.Yield is 95% (mol) (mutual-through type (a 2) compound).
(embodiment 8)
From 1,12-dodecanedioic acid dimethyl ester (105.00g, 406.4mmol), gamma-butyrolactone (8.75g, 101.6mmol) and 28% (weight) sodium methylate-methanol solution (19.60g, 101.6mmol) the condensation reaction solution 113.2g (a part of acidifying, quantitative results, confirm contain condenses 25.65g, unreacted ester 80.84g) of preparation is 50 ℃ of heated and stirred.To wherein adding normal hexane 550g, the limit is cooled to 20 ℃ of limits and stirs, and makes suspension.Make it to be separated into throw out and supernatant liquor with pressure filter.Filtration residue normal hexane thorough washing.
The filtration residue 35.55g that obtains drops in 10% phosphate aqueous solution (50.8mmol).Further append water (350g) and 1,4-diox (250g) 100 ℃ of reactions 5 hours, is separated into 2 layers with reaction solution.The organic layer separatory, water layer extracts with toluene.Its organic layer and toluene extract steam solvent after merging, washing, and obtain the 26.60g crystallisate.This crystallisate separates, result refining, that analyze is as follows, through confirming, is the 15-hydroxyl-12-ketone pentadecylic acid methyl esters that is equivalent to general formula (7) compound.
1H-NMR(600MHz、TMS、CDCl
3)
1.28(12H，m，CH
2-4～9)，1.57(2H，tt，J＝7.3，7.2，CH
2-10)，1.61(2H，tt，J＝7.3，
7.0，CH
2-3)，1.84(2H，tt，J＝6.7，6.3，CH
2-14)，2.30(2H，t，J＝7.5，CH
2-2)，
2.43(2H，t，J＝7.5，CH
2-11)，2.56(2H，t，J＝6.9，CH
2-13)，3.65(2H，t，J＝6.1，
CH
2-15)，3.67(3H，s，CH
3)
13C-NMR(150MHz、CDCl
3)
23.86(CH
2-10)，24.92(CH
2-3)，26.50(CH
2-14)，29.09～29.36(CH
2-4～9)，
34.08(CH
2-2)，39.48(CH
2-13)，42.92(CH
2-11)，51，40(CH
3)，62.33(CH
2-OH)
174.30(C(＝O)0)，211.76(C＝O)
In addition, the result of gc analysis, show contain 79.3% general formula (7) compound (n=10, R=Me).Yield is 72.6% (for gamma-butyrolactone).
(embodiment 9)
From 1,12-dodecanedioic acid dimethyl ester (105.00g, 406.4mmol), gamma-butyrolactone (8.75g, 101.6mmol) and 28% (weight) sodium methylate-methanol solution (19.60g, 101.6mmol) the condensation reaction solution 113.2g (a part of acidifying, quantitative results, confirm contain condenses 25.65g, unreacted ester 80.84g) of preparation is 50 ℃ of heated and stirred.To wherein adding normal hexane 550g, the limit is cooled to 20 ℃ of limits and stirs, and makes suspension.With pressure filter it is separated into throw out and supernatant liquor.Filtration residue normal hexane thorough washing.The filtration residue 35.55g that obtains drops among the 10% phosphate aqueous solution 49.8g (50.8mmol).Further in reaction unit, add disodium hydrogen phosphate,anhydrous (13.63g, 96.0mmol) and water (350g) and 1,4-diox (250g), after 5 hours, reaction solution is separated into 2 layers 100 ℃ of reactions.The organic layer separatory, water layer extracts with toluene.Its organic layer and toluene extract steam solvent after merging, washing, and obtain the 26.56g crystallisate.
This thing is with the result of gc analysis, show contain 80.2% general formula (7) compound (n=10, R=Me).Yield is 73.3% (for gamma-butyrolactone).
(reference example 2)
General formula (7) compound (n=10, R=Me) (10.1g, 35mmol) with sodium hydroxide (2.80g, 0.070mol) and water (25.2g) mixing, reflux 4 hours.To wherein adding glycol ether 60ml, steam with being about to it.After 1 hour, add 85% water and add hydrazine 10.3ml, stirred 40 minutes at 110 ℃.Heat up then, make to reach 195～200 ℃ in the system, heated and stirred is 16 hours then.During this period, the part that can steam all moves on to outside the system.Cooling then after the dilute sulphuric acid acidifying, is used chloroform extraction.Chloroform layer washing, with steaming solvent behind the anhydrous magnesium sulfate drying, obtain 8.92g crystalline reaction mixture.
The result of reaction mixture trimethyl silylization, gc analysis shows and contains 97.2% general formula (5) compound (n=10).(n=10, R=Me) yield of Ji Suaning is 96% from general formula (1) compound.
(reference example 3)
The reaction mixture preparation
From 1, (105.00g, 406.4mmol) (8.75g, 101.6mmol) (19.60g, 101.6mmol) Pei Zhi condensation reaction solution is 50 ℃ of heated and stirred with 28% (weight) sodium methylate-methanol solution with gamma-butyrolactone for the 12-dodecanedioic acid dimethyl ester.To wherein adding normal hexane 104.4g, stirred 2 minutes.To wherein further adding 5.5%NaOH aqueous solution 73.87g, former state stirred 120 minutes.Leave standstill separatory after 5 minutes, be divided into organic layer and water layer.Add 41%NaOH aqueous solution 19.00g in the water layer, the 2 hours postcooling to 80 ℃ of refluxing obtain reaction mixture 126.52g.
(embodiment 10)
1,18-dihydroxyl-4, the extraction of 15-octadecane diketone is reclaimed
A part of limit insulation of the reaction mixture that above-mentioned reference example obtains extracted 20 minutes at the toluene of 80 ℃ of weight such as Bian Yong.This operation repeats 5 times, and organic layer that obtains and water layer are used ethyl acetate extraction after using the dilute sulphuric acid acidifying respectively.Organic layer steams solvent after with the saturated common salt water washing, obtains crystallisate.Use the HPLC quantitative analysis respectively, the results are shown in Table 1.
(table 1)
1,18-dihydroxyl-4, the extraction results of 15-octadecane diketone
| Weight in the mixture | Organic layer | Water layer | |||
| Weight | The rate of recovery | Weight | The rate of recovery | ||
| 15-hydroxyl-12-ketone pentadecylic acid | 16.85 | 0.63 | 3.74 | 16.22 | 96.26 |
| Dodecanedioic acid | 2.63 | 0.04 | 1.52 | 2.59 | 98.48 |
| 1,18-dihydroxyl-4,15-octadecane diketone | 1.74 | 1.73 | 99.43 | 0.01 | 0.57 |
(embodiment 11)
Making with extra care of 15-hydroxyl-12-ketone pentadecylic acid
After the water ratio of the reaction mixture that above-mentioned reference example 3 obtains adjusts to 84%, carry out 2 hours partial crystallizations with 40 ℃ of thermostatic baths and handle.The crystallisate of separating out is separated into filter cake part and filtrate with centrifugal filter.Behind the water furnishing soup compound that the filter cake interpolation is 40 ℃, be separated into filter cake part and filtrate with centrifugal filter, filtrate and above-mentioned filtrate merge.After using the dilute sulphuric acid acidifying respectively, use ethyl acetate extraction.Organic layer steams solvent after using the saturated common salt water washing, obtains crystallisate.The results are shown in the table 2 with the HPLC quantitative analysis respectively.
(table 2)
1,18-dihydroxyl-4, the extraction results of 15-pentadecane diketone
| Weight in the mixture | Filter cake | Filtrate | |||
| Weight | The rate of recovery | Weight | The rate of recovery | ||
| 15-hydroxyl-12-ketone pentadecylic acid | 16.85 | 0 | 0.00 | 16.85 | 100.00 |
| Dodecanedioic acid | 2.63 | 0 | 0.00 | 2.63 | 100.00 |
| 1,18-dihydroxyl-4,15-octadecane diketone | 1.74 | 1.72 | 98.85 | 0.02 | 1.15 |
(embodiment 12)
Making with extra care of 15-hydroxyl-12-ketone pentadecylic acid
The reaction mixture limit insulation that above-mentioned reference example 3 obtains extracted 20 minutes at the toluene of 80 ℃ of weight such as Bian Yong.This operation repeats 5 times, and the water layer that obtains carries out 2 hours partial crystallizations with 20 ℃ of thermostatic baths to be handled.The crystallisate of separating out is separated into filter cake part and filtrate with centrifugal filter.After using the dilute sulphuric acid acidifying respectively, use ethyl acetate extraction.Organic layer steams solvent after using the saturated common salt water washing, obtains crystallisate.Respectively with the table 3 that the results are shown in of HPLC quantitative analysis.
(table 3)
The refining result of 15-hydroxyl-12-ketone pentadecylic acid
| Weight in the mixture | Filter cake | Filtrate | ||||
| Weight | The rate of recovery (%) | Crystallization moderate purity (%) | Weight | The rate of recovery (%) | ||
| 15-hydroxyl-12-ketone pentadecylic acid | 6.84 | 6.72 | 98.24 | 98.48 | 0.12 | 1.76 |
| Dodecanedioic acid | 1.09 | 0.04 | 3.42 | 0.55 | 1.053 | 96.58 |
Be noted that and contain the sodium salt 7.28g corresponding in the isolating crystallisate of partial crystallization before the vitriolization from the result of table 3 as can be seen, contain the sodium salt 1.25g corresponding in the filtrate with dodecanedioic acid with 15-hydroxyl-12-ketone pentadecylic acid.
(embodiment 13)
PH adjusts the 15-hydroxyl-12-ketone pentadecylic acid of method and makes with extra care
The reaction mixture limit insulation that above-mentioned reference example 3 obtains like that extracted 20 minutes at the toluene of 80 ℃ of weight such as Bian Yong.This operation repeats 5 times, and the water layer that obtains carries out partial crystallization processing in 2 hours with 20 ℃ thermostatic bath.The crystallisate of separating out is separated into filter cake part and filtrate with centrifugal filter.The filtrate that obtains transfers to pH=6.5 with sulfuric acid, and the crystallisate of separating out is separated into filter cake part and filtrate with centrifugal filter.Filtrate further transfers to pH=3.0 with sulfuric acid, and the crystallisate of separating out obtains filter cake with centrifugal filter.Use the HPLC quantitative analysis respectively, the results are shown in table 4.
(table 4)
PH adjusts the refining result of 15-hydroxyl-12-ketone pentadecylic acid of method
| Weight in the mixture | The pH=6.5 filter cake | The pH=3.0 filter cake | ||||
| Weight | The rate of recovery (%) | Crystallization moderate purity (%) | Weight | The rate of recovery (%) | ||
| 15-hydroxyl-12-ketone pentadecylic acid | 0.24 | 0.23 | 95.35 | 99.5 | 0.011 | 4.65 |
| Dodecanedioic acid | 2.11 | 0 | 0.00 | 0 | 2.11 | 100.00 |
The possibility of utilizing on the industry
According to the present invention, 2-(ω-alkoxy carbonyl group alkane acyl)-4-butyrolactone and alkali metal salt thereof can be with holding facile cheap raw material dicarboxylic ester, with high yield and selectively good, industrial also favourable manufacture method obtain.
According to the present invention, from the condensation reaction liquid that obtains by the reaction of dicarboxylic ester and gamma-butyrolacton, can be industrial advantageously, easy and with high yield separation and purification become alkali metal salt and derivative and the unreacted ester of 2-(ω-alkoxy carbonyl group alkane acyl)-4-butyrolactone.
And then, according to the present invention, can also high yield, industrial novel compound ω-hydroxyl-(ω-the 3)-ketofatty acid ester that advantageously obtains. Therefore, by this ω-hydroxyl-(ω-3)-ketofatty acid ester being used for the manufacturing of the important intermediate ω-hydroxy fatty acid of macrolides spice, since needn't as the prior art method, use a large amount of strong basicity alkali and also easily and reaction water from, thereby make significant reduction of processing step number become possibility, help advance industrialized manufacture method thereby can provide.
In addition, according to the present invention, particularly in the perfume industry field in the manufacturing of the important intermediate ω-hydroxyl of operable macrolides spice-(ω-3)-ketofatty acid, can be selectively good, separate and recover inconvenient α on the prior art expeditiously, alpha, omega-dihydroxy-δ, (ω-3)-alkane diketone, ω-hydroxyl-(ω-3)-ketofatty acid and salt thereof, dicarboxylic acids and salt thereof.
Claims (15)
1. ω-the hydroxyl shown in the general formula (7)-(ω-3)-keto fatty esters
In the formula, n is 10 or 11, and R is an alkyl.
2. ω-hydroxyl-(ω-the 3)-keto fatty esters of claim 1 record, the R that it is characterized in that described general formula (7) is the alkyl of carbon number 1～6.
3. the separation and recovery method of an alkali metal salt of an alkali metal salt of the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid and the long chain dicarboxylic acid shown in the general formula (8)
In the formula, n is 7～13 integer, and M represents basic metal
In the formula, n is 7～13 integer, M represents basic metal, it is characterized in that from the mixture of an alkali metal salt of an alkali metal salt that contains the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid and the long chain dicarboxylic acid shown in the general formula (8) selectivity partial crystallization goes out an alkali metal salt of the ω-hydroxyl shown in the described general formula (5)-(ω-3)-ketofatty acid, and by making its solid-liquid separation be separated into filter cake and filtrate.
4. the α shown in the general formula (9), alpha, omega-dihydroxy-δ, the separation and recovery method of (ω-3)-alkane diketone
In the formula, n=7～13, it is characterized in that from an alkali metal salt of the long chain dicarboxylic acid shown in an alkali metal salt general formula (8) that contains the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid and the α shown in the general formula (9), alpha, omega-dihydroxy-δ, take out the α shown in the described general formula (9) with organic solvent extracting in this mixture of three kinds of (ω-3)-alkane diketone, alpha, omega-dihydroxy-δ, (ω-3)-alkane diketone, or the selectivity partial crystallization goes out the α shown in the general formula (9) from this mixture, alpha, omega-dihydroxy-δ, (ω-3)-alkane diketone
In the formula, n represents 7～13 integer, M represent basic metal,
In the formula, n represents 7～13 integer, and M represents basic metal.
5. the separation and recovery method of an alkali metal salt of the long chain dicarboxylic acid shown in the ω-hydroxyl shown in the general formula (10)-(ω-3)-ketofatty acid and the general formula (8)
In the formula, n represents 7～13 integer
In the formula, n represents 7～13 integer, M represents basic metal, and the mixture that it is characterized in that containing an alkali metal salt of an alkali metal salt of the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid and the long chain dicarboxylic acid shown in the general formula (8) is adjusted to pH=5～7 with mineral acid
In the formula, n represents 7～13 integer, and M represents basic metal.
6. the separation and recovery method of the long chain dicarboxylic acid shown in the ω-hydroxyl shown in the general formula (10)-(ω-3)-ketofatty acid and the general formula (11)
N is the integer of 7-13 in the formula,
In the formula, n is 7～13 integer, it is characterized in that filter cake and filtrate that claim 3 obtains uses mineral acid treatment respectively.
7. the separation and recovery method of the long chain dicarboxylic acid shown in the general formula (11)
In the formula, n is 7～13 integer, and the filtrate that it is characterized in that containing in the claim 5 an alkali metal salt of the long chain dicarboxylic acid shown in the general formula (8) is adjusted to pH=3～5 with mineral acid.
8. the separation and recovery method of an alkali metal salt of an alkali metal salt of the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid and the long chain dicarboxylic acid shown in the general formula (8), it is characterized in that selectivity partial crystallization in the mixture of an alkali metal salt of an alkali metal salt of ω-hydroxyl-(ω-the 3)-ketofatty acid shown in the general formula (5) that Accessory Right requirement 4 obtains and the long chain dicarboxylic acid shown in the general formula (8) goes out an alkali metal salt compound of the ω-hydroxyl shown in the general formula (5)-(ω-3)-ketofatty acid, and make it to be separated into filter cake and filtrate by solid-liquid separation.
9. the separation and recovery method of the long chain dicarboxylic acid shown in the ω-hydroxyl shown in the general formula (10)-(ω-3)-ketofatty acid and the general formula (11)
In the formula, n is 7～13 integer
In the formula, n is 7～13 integer, it is characterized in that isolated filter cake of claim 8 and filtrate uses mineral acid treatment respectively.
10. the separation and recovery method of an alkali metal salt of the long chain dicarboxylic acid shown in the ω-hydroxyl shown in the general formula (10)-(ω-3)-ketofatty acid and the general formula (8)
In the formula, the integer of n=7～13 is characterized in that the mixture of an alkali metal salt of an alkali metal salt of the ω-hydroxyl shown in the isolated general formula of claim 4 (5)-(ω-3)-ketofatty acid and the long chain dicarboxylic acid shown in the general formula (8) is adjusted to pH=5～7 with mineral acid.
11. the separation and recovery method of the long chain dicarboxylic acid shown in the general formula (11)
In the formula, the integer of n=7～13, the filtrate that it is characterized in that containing in the claim 10 an alkali metal salt of the long chain dicarboxylic acid shown in the general formula (8) is adjusted to pH=3～5 with mineral acid.
12. the separation and recovery method of an alkali metal salt of the long chain dicarboxylic acid shown in the ω-hydroxyl shown in the general formula (10)-(ω-3)-ketofatty acid and the general formula (8)
In the formula, the integer of n=7～13 is characterized in that the isolated filtrate of containing an alkali metal salt of the ω-hydroxyl shown in a small amount of general formula (5)-(ω-3)-ketofatty acid is adjusted to pH=5～7 with mineral acid in the claim 3.
13. the separation and recovery method of the long chain dicarboxylic acid shown in the general formula (11)
In the formula, the integer of n=7～13 is characterized in that isolated in the claim 12, as to contain an alkali metal salt of the long chain dicarboxylic acid shown in the general formula (8) filtrate further adjusts to pH=3～5 with mineral acid.
14. the separation and recovery method of an alkali metal salt of the long chain dicarboxylic acid shown in the ω-hydroxyl shown in the general formula (10)-(ω-3)-ketofatty acid and the general formula (8)
In the formula, the integer of n=7～13 is characterized in that isolated in the claim 8, as to contain an alkali metal salt of the ω-hydroxyl shown in a small amount of general formula (5)-(ω-3)-ketofatty acid filtrate adjusts to pH=5～7 with mineral acid.
15. the separation and recovery method of the long chain dicarboxylic acid shown in the general formula (11)
In the formula, the integer of n=7～13 is characterized in that the isolated filtrate of containing an alkali metal salt of the long chain dicarboxylic acid shown in the general formula (8) is adjusted to pH=3～5 with mineral acid in the claim 14.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18902197A JP4706887B2 (en) | 1997-06-30 | 1997-06-30 | Process for producing 2- (ω-alkoxycarbonylalkanoyl) -4-butanolide |
| JP189022/97 | 1997-06-30 | ||
| JP189021/97 | 1997-06-30 | ||
| JP215752/97 | 1997-07-25 | ||
| JP55827/98 | 1998-02-20 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988008823A Division CN100341865C (en) | 1997-06-30 | 1998-06-30 | Processes for preparing 2-('omega'-alkoxycarbonylalkanoyl)-4-butanolides, 'omega'-hydroxy-('omega'-3)-keto fatty esters, and derivatives thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1733690A true CN1733690A (en) | 2006-02-15 |
| CN100436401C CN100436401C (en) | 2008-11-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2005100916714A Expired - Fee Related CN100436401C (en) | 1997-06-30 | 1998-06-30 | Processes for preparing 2-(omega-alkoxycarbonylalkanoyl)-4- butanolides omega-hydroxy-(omega-3)-keto fatty esters, and derivatives thereof |
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|---|---|
| JP (1) | JP4706887B2 (en) |
| CN (1) | CN100436401C (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5808106A (en) * | 1995-08-04 | 1998-09-15 | Katou; Tetsuya | Method for producing 2-(ω-alkoxycarbonyl alkanoyl)-4-butanolide and a long-chain ω-hydroxycarboxylic acid |
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1997
- 1997-06-30 JP JP18902197A patent/JP4706887B2/en not_active Expired - Lifetime
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| CN100436401C (en) | 2008-11-26 |
| JP4706887B2 (en) | 2011-06-22 |
| JPH1121283A (en) | 1999-01-26 |
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