CN108314621A - A method of manufacture long chain diacid monoesters - Google Patents
A method of manufacture long chain diacid monoesters Download PDFInfo
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- CN108314621A CN108314621A CN201810350214.XA CN201810350214A CN108314621A CN 108314621 A CN108314621 A CN 108314621A CN 201810350214 A CN201810350214 A CN 201810350214A CN 108314621 A CN108314621 A CN 108314621A
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- diacid
- monoesters
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- toluene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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Abstract
The present invention provides a kind of method of manufacture long chain diacid monoesters.The method includes there are acidic catalyst and in toluene, diacid is reacted with benzyl alcohol or the tert-butyl alcohol；Cooled reaction solution is precipitated until remaining diacid；Filter out two acid deposits；Further cooled reaction solution is precipitated until monoesters；And filter out the sediment of the monoesters of Formulas I.The method of the present invention can harvest the monoesters of high yield and the by-product that would not want to is reduced to zero.
Description
Technical field
The present invention relates to the synthesis of the mono-esterification long chain diacid of the mono-esterification method more particularly to formula (I) of long chain diacid.
Background technology
Monoesters can be obtained by different methods：1) mono-esterification of diacid；2) transesterification of cyclic anhydride；With 3) diester
Selective ester cracking.
Recent decades, to realize that the mono-esterification of long chain diacid is always the target pursued in high yield.Babler and Moy is proposed
Continuously extracted from reaction mixture mono-ester product (synthesising communication (Synthetic Communications) (1979), 9
(7),pp.669-75)。
Ogawa et al. is proposed using aluminium powder and is shown that the mono-esterification for the diacid that up to 12 carbon atoms may be implemented (is changed
Association's journal, chemical communication (Journal of the Chemical Society, Chemical Communications)
1986,17)。
However, Santacroce et al. shows that using aluminium oxide as catalyst be unsuccessful for long chain diacid.
Carbon atom number is higher, and yield declines (Green Chemistry (Green Chemistry) (2016), 18 (21), pp.5764-5768).
Other research groups have delivered carries out mono-esterification (biotechnology bulletin (Biotechnology with enzymatic reaction
Letters) (1995), 17 (9), pp.939-42) or (Chemical Society's journal, Perkin can report mono-esterification on resin：It is organic and
Bioorganic Chemistry (Perkin Transactions 1:Organic and Bio-Organic Chemistry)(1999),
(20),pp.3023-3027)。
All above methods have following common ground, and how they are not shown by mono-ester product and raw material and diester
Separation.
Babler et al. set forth " separation diacid, list in they are about the article of traumatic acid (traumatic acid)
The mixture of ester and diester is difficult " (synthesising communication (1979), 9 (7), pp.669-75).
Nearest publication such as EP 3199546A1 (2015) show the yield of the mono-esterification of long chain diacid down to 33%.
WO2017/095201 shows that the yield of the synthesis of octadecane diacid -1- (phenyl methyl) ester is 49%.
Therefore, there is still a need for a kind of improvement technique detaching raw material with reaction product.
P can be any blocking group of acid, especially aromatics carbochain or aliphatic straight chain and branch carbochain.
Invention content
The inventors found that a kind of by crystallizing easily by monoesters (I) and unreacted diacid (II) and two
The method of ester (III) separation.This is that recycling unreacted product has opened possibility in another esterification cycle.
In one aspect of the invention, a kind of side of the long chain diacid monoesters of the diacid manufacture formula (I) by formula (II) is provided
Method,
Wherein n=9~15, P=benzyl or tertiary butyl, the described method comprises the following steps：
There are acidic catalyst and in toluene, diacid and the benzyl alcohol or the tert-butyl alcohol of formula (II) carry out instead
It answers；
Cooled reaction solution is precipitated until remaining diacid；
Filter out two acid deposits；
Further cooled reaction solution is precipitated until monoesters；And
Filter out the sediment of the monoesters of Formulas I.
In further preferred embodiment, diacid (II) and corresponding diester respectively in further saponification step and
It is recovered in further esterif iotacation step.
In further preferred embodiment, diacid (II) is synthesized by the hydrogenation of unsaturated diacid.
The above embodiment of the present invention illustrates how to detach the side of diacid, monoesters and diester in the reactive mixture
Method.In addition, the method that it shows each undesirable by-product in recycling synthesis.Therefore, the single of high yield has been harvested to protect
It protects product and the by-product that would not want to is reduced to zero.Therefore, environment is protected by low waste technique.
Description of the drawings
Fig. 1 is the flow chart of method according to the embodiment of the present invention；
Fig. 2 is the flow chart of the method for another embodiment according to the present invention；
Fig. 3 is the flow chart of the method for a further embodiment according to the present invention.
Specific implementation mode
Definition
Long chain diacid (also referred to as diacid) be have on the positions α and the positions ω in formula (II) there are two acid functional group carboxylic
Acid.For the present invention, there is 14 (n=9) to 20 (n=15) a carbon atom on the chain of used diacid.
Diester is described as when diacid with alcohol with 1:2 ratio is reacted and two acid functional groups are converted into corresponding ester when institute
The ester of formation.
Monoesters is described as only one in two carboxylic acid functionals of diacid and is esterified generated molecule.
When being esterified long chain diacid, if raw material is used with equimolar ratio, obtained between diacid and alcohol a pair of
One reaction can be ideal.At least if turning to target with monoesters.
However, example in the prior art shows only to realize that mono-esterification is not easy to.Completed using different technologies
The task.
Since diacid and diester are difficult to detach from desirable mono-ester product sometimes, this is more important.
The present inventor had now been found that solve the problems, such as this and by differential responses product be separated from each other and with original
The method of material matter separation.
In one embodiment of the invention, the esterification of diacid is carried out in toluene.Toluene has following effect：Anti-
After answering, unreacted diacid is crystallized out and can be filtered off at reduced temperatures for new esterification cycle.
In further step, when further decreasing temperature, monoesters is obtained with the solid form that can be filtered off.
Inventor has been realized in the straightforward procedure for detaching reaction product with remaining raw material.The raw material and
Solvent can be reused in process.Therefore, waste is not generated.Referring to scheme shown in Fig. 1.
In a preferred embodiment of the invention, diacid (II) there are acidic catalyst and there are in the case of toluene with
Alcohol is esterified to form monoesters (I), referring specifically to following scheme.
P can be any linear or branched alkyl group or aryl, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl,
Isobutyl group, tertiary butyl, amyl, isopentyl, tertiary pentyl, phenyl, benzyl, p-methylphenyl or similar group.The acidic catalyst
Agent is preferably p-methyl benzenesulfonic acid.Relative to the total weight of reactant, the dosage of toluene is preferably 8-12ml/g, more preferably
10ml/g。
The possible structure of P includes result shown in following chemical formula.
Under the cited reaction conditions, monoesters (I) also part is reacted with diester (III).
According to the present invention, then the mixture of diacid (II), monoesters (I) and diester (III) is there are toluene
It is cooling to occur until crystallizing.Which results in the precipitations of diacid (II).Diacid (II) is detached by being separated by solid-liquid separation, it then can be
Recycling diacid (II) in second esterification cycle.Scheme shown in Figure 1.Cooling temperature ranges preferably from 0-40 DEG C, example
Such as, it can be preferably 0 DEG C, 10 DEG C, 20 DEG C, 25 DEG C and 30 DEG C.Specific temperature or its range depend on used long-chain two
The length and used alcohol type of acid.
Mother liquor from diacid separation can be further used for the separation of monoesters (I) and diester (III).It can be cold by its
But, it optionally concentrates, starts second of crystallization with low polar solvent completion.Which results in the precipitations of monoesters (I).By solid
Liquid detaches to detach monoesters (I).The recrystallization of the monoesters (I) can further improve chemical purity.
The mother liquor of separation from monoesters (I) is rich in diester (III).The mother liquor can be handled in saponification so as to
Form diacid (I).The diacid can be further used in composition sequence.
As saponification step, any reaction can all be considered leading to ester linkage breaking and generate free acid.If blocking group P
Derived from the entity such as benzyl alcohol for being easy to hydrogenolysis cracking, then the saponification step can be such as alkalinity or acid saponification or hydrogenation
Step.
In another preferred embodiment of the present invention, the unsaturated precursor shown in such as WO 2008/15506 closes
At diacid, and alcohol used can hydrogenolysis cracking, for example, benzyl alcohol.In this case, by adding two ester solutions to system
Hydrogenolysis step when standby unsaturated diacid, can also recycle diester.Scheme shown in Figure 2.
Therefore, in another embodiment, by making the commercial ω-alkene-obtained of formula (IV) with metathesis reaction
α-carboxylic acid reaction is to form the unsaturated diacid of formula (V) (according to Mwangi, Martin T.；Runge,M.Brett；Bowden,
Ned B., American Chemical Society's proceedings (Journal of the American Chemical Society), 2006,
Vol.128, #45p.14434-14435), then the unsaturated diacid hydration is at diacid (II).Referring to following reaction formula.
Subsequent diacid is esterified with benzyl alcohol into single benzyl ester.Referring to following reaction formula.
In another embodiment of the present invention, it is in hydrogenolytic conditions to be esterified diacid (II) by methods known in the art
Under not cleavable ester.It is returned in a similar manner from reaction mixture and from the diester of the cracking found in side line liquid stream
It is possible to receive diacid (II).The technique that product is formed and recycled by the specific embodiment is as shown in Figure 3.
By the invention it is possible to realize manufacture mono-esterification diacid and hardly loss material and not will produce the work of waste material
Industry method, this is because most of materials are recyclable without expensive purification step.
Total recovery after 10 cycles is higher than 80%, and the total recovery after 6 cycles is more than or equal to 76%.
Embodiment
Embodiment 1：20 carbon -10- enedioic acids
The Shiyixisuan Undecylenic Acid and 195g toluene of 65g are packed into inerted reactor.At 40 DEG C, in slight nitrogen
Under conditions of persistently removing headspace air under purging, by the AS2053 nitros-Grela-I2SIPr of 100mg, (purchase is certainly
Apeiron companies) solution in 65g toluene is added in 5 hours in the first solution.Aging 2 hours will be reacted, will then be heated
Until forming clear solution (about 80 DEG C).Solution is finally cooled to room temperature (about 20 DEG C), the product being separated and dried after precipitation.
Obtain 53.0g title compounds.The GC-MS analyses of sample (use BSTFA (bis- (trimethyl silyl) trifluoroacetyls of N, O-
Amine) derivatization treatment) show product contain 97.5% the title product in the form of E and Z isomer mixtures, 1.0% ten
Nine carbene diacid, 0.3% Shiyixisuan Undecylenic Acid and a small amount of other impurities homologue of product (mainly).
Embodiment 2：20 carbon -10- enedioic acids
The Shiyixisuan Undecylenic Acid and 60g toluene of 20g are packed into inerted reactor.At 40 DEG C, blown in slight nitrogen
Under conditions of sweeping lower persistently removing headspace air, by the M73SIPr (buying from Umicore companies) of 40mg in 20g toluene
In solution be added in 5 hours in the first solution.Aging 2 hours will be reacted, then heating is until form clear solution (about 80
℃).Solution is finally cooled to room temperature (about 20 DEG C), the product being separated and dried after precipitation.Obtain 14g title compounds.
Sample GC-MS analysis shown (with BSTFA derivatization treatments) product contain 97% in the form of E and Z isomer mixtures
Title product, 1.3% nonadecene diacid, 0.2% Shiyixisuan Undecylenic Acid and a small amount of other impurities (mainly product
Homologue).
Embodiment 3：20 carbon -10- enedioic acids
The Shiyixisuan Undecylenic Acid and 60g toluene of 20g are packed into inerted reactor.At 40 DEG C, blown in slight nitrogen
Under conditions of sweeping lower persistently removing headspace air, by the AS2086 (buying from Apeiron companies) of 40mg in 20g toluene
Solution be added in 5 hours in the first solution.Aging 2 hours will be reacted, then heating is until form clear solution (about 80
℃).Solution is finally cooled to room temperature (about 20 DEG C), the product being separated and dried after precipitation.Obtain 15g title compounds.
Sample GC-MS analysis shown (with BSTFA derivatization treatments) product contain 98% in the form of E and Z isomer mixtures
Title product, 0.8% nonadecene diacid, 0.1% Shiyixisuan Undecylenic Acid and a small amount of other impurities (mainly product
Homologue).
Embodiment 4：Eicosane diacid
20 carbon -10- enedioic acids of 53g (coming from embodiment 1), 480g THF (tetrahydrofuran) are packed into stirred autoclave
With 0.7g palladium on carbon (5%Pd, hydrophilic catalyst).Headspace becomes nitrogen and then becomes hydrogen first.Under 80 DEG C/10 bars
Carry out hydrogenation 3 hours.Then the batch reactant is cooled to 50 DEG C and filters out catalyst.For security reasons, it is washed with water
Wash filter cake.Filter cake (palladium on carbon of recycling) can be reused in next hydrogenation without being further processed.True
The lower concentrated mother liquor (THF of recycling can be used for next group without being further processed) of sky, supplement 320g toluene are simultaneously further dense
It is reduced to about 170mL.The batch reactant is cooled to 20 DEG C, the solid being separated and dried after precipitation.Obtain 50g title compounds
Object.
Product samples GC-MS analysis shown (with BSTFA derivatization treatments) product contain 99% title compound,
0.1% 20 carbon -10- enedioic acids and a small amount of other impurities (the mainly homologue of product).
Embodiment 5：20- (benzyloxy) -20- oxo arachic acids
In the reactor for being equipped with Dean-Stark separator (Dean Stark trap), it is packed into 50g eicosanes two
Acid, 1.2g p-methyl benzenesulfonic acid (pTSA), 500g toluene and 9.5g benzyl alcohols.Mixture is flowed back until Dean-Stark separator
In be no longer collected into water.The reaction is cooled to 40 DEG C and filter.By filter cake (unreacted raw material) and 0.6g p-methyl benzenesulfonic acid,
250g toluene and 6.3g benzyl alcohols merge, and put back in the reactor for being equipped with Dean-Stark separator.The reaction is cooled to
It 45 DEG C and filters.It by filter cake (the unreacted raw materials of 10g) drying and puts aside, and can be used for next batch.It will be separated by solid-liquid separation
Mother liquor be cooled to 12 DEG C, be isolated by filtration precipitation after product.Filter cake is recrystallized from the 2- propyl alcohol of 200g.Obtain 27g
Title compound.
Product samples GC-MS analysis shown (with BSTFA derivatization treatments) product contain 99.5% title compound,
0.2% eicosane diacid and a small amount of other impurities (the mainly homologue of product).
By the mother liquor concentrations of 12 DEG C of toluene crystallizations to about 100mL, 0.5g palladium on carbon is supplemented, and carried out under 80 DEG C/10 bars
Hydrogenation 3 hours.By batch reactant filtering (80 DEG C) and it is cooled to 20 DEG C.The substance of precipitation is separated and dried.Obtain 10g
Eicosane diacid can be used for next reaction.
Embodiment 6：14- (benzyloxy) -14- oxo tetradecanoic acids
In the reactor for being equipped with Dean-Stark separator (Dean Stark trap), it is packed into the 40g tetradecanes two
Acid, 1.3g p-methyl benzenesulfonic acid, 380g toluene and 10.1g benzyl alcohols.By mixture reflux until in Dean-Stark separator not
Regather water.The reaction is cooled to 26 DEG C and filter.By filter cake (unreacted raw material) and 0.6g p-methyl benzenesulfonic acid, 180g first
Benzene and 6.7g benzyl alcohols merge, and put back in the reactor for being equipped with Dean-Stark separator.Mixture is flowed back until enlightening
It is no longer collected into water in peace Rodney Stark separator.Reactant is cooled to 26 DEG C and is filtered.By filter cake (the unreacted raw materials of 8g)
It dries and puts aside, and can be used for next batch.The mother liquor of separation of solid and liquid is merged, toluene is removed by vacuum distillation, it should
Batch is completed with 400g heptane, is crystallized at 50 DEG C, is cooled to 30 DEG C, and the product after precipitation is isolated by filtration.From 190g's
Filter cake is recrystallized in 2- propyl alcohol.Obtain 24g title compounds.
Product samples GC-MS analysis shown (with BSTFA derivatization treatments) product contain 99.9% title compound,
0.1% tetracosandioic acid and a small amount of other impurities (the mainly homologue of product).
The mother liquor concentrations that heptane is crystallized supplement 100mL toluene and 0.5g palladium on carbon, and carry out hydrogen under 80 DEG C/10 bars
Change 3 hours.By batch reactant filtering (80 DEG C) and it is cooled to 20 DEG C.Material after precipitation is separated and dried.Obtain 8g
Tetracosandioic acid can be used for next reaction.
Reuse of the eicosane diacid that embodiment 7 to 16 recycles in 6 continuous cycles
The result recycled the following table shows 6.When the diacid of recycling is used for subsequent cycle, the total recovery of 6 cycles is
About 76%, separately add about 10% remaining eicosane diacid.Respectively embodiment 7 to 16 is carried out with embodiment 4 and 5 similar modes.
Embodiment 17：18- tert-butoxy -18- oxo octadecanoid acids
By 20g octadecane diacids, the p- N of 1.5g, N- dimethyl aminopyridines (DMAP), 180g toluene and the 20g tert-butyl alcohols
Mixture flows back.Solution of the 14.6g di-tert-butyl dicarbonates in 8g toluene and the 0.8g tert-butyl alcohols are added dropwise to mixture
In, and maintain the reflux for overnight, then removing partial solvent (about 50%), be cooled with an ice bath reaction mixture under reflux.Point
From simultaneously dried solidss, 5g octadecanoid acids are harvested, subsequent batches are used for.
Mother liquor is filtered by silica pad, solvent switch is heptane.In the cooling condition, knot is passed through by the mixture
Crystalline substance can isolate 9g title products.
The GC-MS analyses of Product samples (use MTBSTFA [N- t-butyldimethylsilyi-N- methyl trifluoros acetamide]
Derivatization treatment) show product contain 99% title compound, 0.1% octadecane diacid di tert butyl carbonate and<0.1% octadecane
Diacid.
The mother liquor concentrations that heptane is crystallized supplement 100mL toluene and 0.5g p-methyl benzenesulfonic acid.The batch reactant is flowed back
It stays overnight and is cooled to 20 DEG C.Substance after precipitation is separated and dried.6g octadecane diacids are obtained, can be used for next anti-
It answers.
Claims (3)
1. a kind of method of the long chain diacid monoesters of diacid manufacture formula (I) by formula (II),
Wherein n=9~15, P=benzyl or tertiary butyl, the described method comprises the following steps：
There are acidic catalyst and in toluene, the diacid of formula (II) is reacted with benzyl alcohol or the tert-butyl alcohol；
Cooled reaction solution is precipitated until remaining diacid；
Filter out two acid deposits；
Further cooled reaction solution is precipitated until monoesters；And
Filter out the sediment of the monoesters of Formulas I.
2. according to the method described in claim 1, wherein, diacid (II) and corresponding diester are respectively in further saponification step
It is recovered in further esterif iotacation step.
3. according to the method described in claim 1, wherein, diacid (II) is synthesized by the hydrogenation of unsaturated diacid.
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| CN112771020A (en) * | 2018-09-27 | 2021-05-07 | 富士胶片株式会社 | Method for producing dicarboxylic acid monoester |
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| KR20170065016A (en) * | 2015-12-02 | 2017-06-12 | 한미약품 주식회사 | A protein conjugate comprising a fatty acid derivative as a linker and a method for preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20170065016A (en) * | 2015-12-02 | 2017-06-12 | 한미약품 주식회사 | A protein conjugate comprising a fatty acid derivative as a linker and a method for preparation thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112771020A (en) * | 2018-09-27 | 2021-05-07 | 富士胶片株式会社 | Method for producing dicarboxylic acid monoester |
| CN112771020B (en) * | 2018-09-27 | 2023-11-07 | 富士胶片株式会社 | Process for producing dicarboxylic acid monoester |
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