CN109400556A - A kind of synthetic method of D- (-)-pantoic acid lactone - Google Patents
A kind of synthetic method of D- (-)-pantoic acid lactone Download PDFInfo
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- CN109400556A CN109400556A CN201811637904.XA CN201811637904A CN109400556A CN 109400556 A CN109400556 A CN 109400556A CN 201811637904 A CN201811637904 A CN 201811637904A CN 109400556 A CN109400556 A CN 109400556A
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- pantoic acid
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- phenylethylamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of synthetic methods of vitamin B5 synthesis key intermediate D- (-)-pantoic acid lactone, it is reacted as chiral selectors with racemic pantoic acid alkali metal salt using (R)-(+)-α-phenylethylamine hydrochloride or sulfate, it is filtered to remove inorganic salts, mother liquor concentrations obtain pantoic acid-(R)-phenyl ethylamine diastereomer double salt, diastereomer double salt is purified using the method for recrystallization or mashing, filter (D)-pantoic acid-(R)-phenyl ethylamine double salt, and (L)-pantoic acid-(R)-phenyl ethylamine double salt dissolution is in a solvent, (D)-pantoic acid-(R)-phenyl ethylamine double salt is using decomposition, acidification cyclization obtains D- (-)-pantoic acid lactone.
Description
Technical field
The present invention relates to a kind of vitamin Bs5Synthesize the synthetic method of key intermediate D- (-)-pantoic acid lactone.
Background technique
Calcium pantothenate, entitled N- (2,4- dihydroxy -3,3- dimethylbutanoyl)-Beta-alanine calcium of chemistry are commonly called as dimension life
Plain B5, distribute widely in nature, be that human body and animal maintain the indispensable micro substance of normal physiological.Pantothenic acid is coenzyme
The coenzyme component part of A participates in protein, fat, the metabolism of sugar in vivo in the synthesis of antibody and safeguards hair, skin
And blood health aspect is also played an important role.Other than medicinal, calcium pantothenate also can be used as nutritional supplement and add as food
Agent and feed addictive, the domestic annual requirement to calcium pantothenate reaches 2000t or more, and global annual requirement reaches 10000t or more.
Calcium pantothenate has a chiral centre, and natural calcium pantothenate is D-form, and the calcium pantothenate of L- configuration does not have bioactivity.Such as Fig. 3 institute
Show, the synthetic route of the general solution calcium of DL- is mainly using isopropanol as starting material, and carrying out aldol condensation with formaldehyde, (Aldol condensation is anti-
Answer) hydroxyl spy valeral is obtained, then carry out strecker with hydrogen cyanide and react, strecker reaction product is closed through cyan-hydrolysis, acidification
Ring obtains DL- pantoic acid lactone, then obtains calcium pantothenate with beta- glycine reactant.There are mainly two types of sides for the synthesis of natural calcium pantothenate
Method: 1) calcium pantothenate is condensed to yield by racemic pantoic acid lactone and beta- alanine, then obtains D-form isomery through chemical resolution
Body；2) D- (-)-pantoic acid lactone is first prepared, then is condensed to yield D-VB5 calcium with beta- alanine.It is split out by pantothenic acid
D-VB5 can undoubtedly waste the raw material of half, therefore the method for splitting for developing D- (-)-pantoic acid lactone has certain economics
Meaning.
D- (-)-pantoic acid lactone (English name D- (-)-Pantolactone), chemical name D (-)-a- hydroxyl one β, β
One dimethyl-gamma-butyrolacton, synthetic method have asymmetric syntheses, chemical resolution and Enzymatic Resolution, main in industrial production at present
To use chemical resolution and two kinds of Enzymatic Resolution.Most earlier than 1940 reports such as Stiller are chiral selectors using quinine,
(J.Am.Chem.Soc.1940, (62), 1785-1795.) are split to pantoic acid lactone.United States Patent (USP) in 1945
US2460239 report splits pantoic acid lactone with ephedrine, and British patent GB605444 is reported using strychnia within 1948
Racemic pantoic acid lactone is split for resolving agent.Quinine, ephedrine strychnia are organic-biological alkali, not only price
Valuableness, and be difficult to obtain, a large amount of industrial applications higher costs.United States Patent (USP) US3480645 reports L-Leu within 1969
It splits, patent RM56538 report uses the left-handed amino substance of by-product of chloramphenicol base, i.e. L- p-nitrophenyl -2 within 1974
The method that amino-1,3-propanediol splits pantoic acid lactone as chiral selectors, it is left-handed compared to for preceding concentration resolving agent
Amino substance is relatively good to the fractionation effect of pantoic acid lactone, but reagent cost or relatively high, after stopping production with chloramphenicol, the party
Method loses superiority, is gradually eliminated.α-phenylethylamine is that cost is relatively low, is usually used in the fractionation of chiral acid, United States Patent (USP)
US3185710 report (R)-(+)-α-phenylethylamine and racemic pantoic acid lactone carry out ammonolysis reaction, are formed among amides
Body carries out crystallization purifying using the dissolubility difference of the two and separates D-form isomers for a pair of of non-corresponding isomers compound,
The amide intermediate is hydrolyzed again, hydrolyzate extraction and recovery (R)-(+)-α-phenylethylamine under alkalinity, then is acidified cyclization and obtains D-
Pantoic acid lactone.The main problem of this method is that amide intermediate is easy to happen racemization during hydrolysis, so as to cause
The chiral purity of obtained pantoic acid lactone is not high, needs repeatedly to refine the synthesis that just can be used for calcium pantothenate after purification.
Summary of the invention
The object of the present invention is to provide a kind of synthetic methods of D- (-)-pantoic acid lactone.
In order to achieve the above object, the present invention provides a kind of synthetic method of D- (-)-pantoic acid lactone, feature exists
In, comprising: using (R)-(+)-α-phenylethylamine hydrochloride or (R)-(+)-α-phenylethylamine sulfate as chiral selectors, with
Racemic pantoic acid alkali metal salt reacts in a solvent forms D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt, using knot
Brilliant or mashing method carries out fractionation purification to the double salt, obtains in D- (-)-pantoic acid using decomposing with acidification cyclization
Ester.
Preferably, the solvent is dehydrated alcohol, anhydrous methanol, ethyl acetate or their mixture.
Preferably, the solvent used when the crystallization is ethyl alcohol, ethyl acetate, methylene chloride or their mixture.
Preferably, diastereomer double salt and the ratio of the solvent used are 1: 1~1:100 when the crystallization.
Preferably, the temperature precipitated crystal when the crystallization is 0 DEG C~25 DEG C.
Preferably, the alkali that the decomposition uses is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide or sodium isopropylate
Aqueous solution or alcoholic solution.
Preferably, the preparation method of (R)-(+)-α-phenylethylamine hydrochloride or (R)-(+)-α-phenylethylamine sulfate
It include: that hydrochloric acid is added in (R)-(+)-α-phenylethylamine or sulfuric acid is added at salt, alternatively, (R)-(+)-α-phenylethylamine is dissolved in
In methanol, ethyl alcohol or water, it is passed through hydrogen chloride or hydrochloric acid is added or sulfuric acid is added into salt；Remove solvent again, dry (R)-(+)-
α-phenylethylamine hydrochloride or (R)-(+)-α-phenylethylamine sulfate.
Preferably, the pantoic acid alkali metal salt is pantoic acid sodium or pantoic acid potassium.
It is highly preferred that the preparation method of the pantoic acid sodium or pantoic acid potassium includes: by racemic pantoic acid lactone
It is dissolved in methanol, ethyl alcohol or water, the sodium hydroxide or potassium hydroxide solid or methanol solution or ethanol solution of equivalent is added
Or aqueous solution carries out ring-opening reaction, removes solvent, dry pantoic acid sodium or pantoic acid potassium；
Preferably, the use (R)-(+)-α-phenylethylamine hydrochloride or (R)-(+)-α-phenylethylamine sulfate are as hand
Property resolution reagent, reacts to form D/L- pantoic acid-(R)-(+)-α-benzene second with racemic pantoic acid alkali metal salt in a solvent
The specific steps of amine double salt include: pantoic acid sodium salt or sylvite to be dissolved in methanol, ethyl alcohol or ethyl acetate, then (R)-is added dropwise
The methanol of (+)-α-phenylethylamine hydrochloride or its sulfate, ethyl alcohol or ethyl acetate solution, are stirred at room temperature 2-24h, are filtered to remove
The solid being precipitated is reacted, mother liquor is spin-dried for, dry D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt；Or by pantoic acid sodium salt
Or sylvite is dissolved in methanol or ethyl alcohol, and (R)-(+)-α-phenylethylamine hydrochloride or its sulfate is added portionwise, 2- is stirred at room temperature
For 24 hours, it is filtered to remove the solid that reaction is precipitated, mother liquor is spin-dried for, dry D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt.
Preferably, the step of method using crystallization carries out fractionation purification to the double salt includes: that DL- is general
Solve acid-(R)-(+)-α phenyl ethylamine double salt methylene chloride, chloroform, dichloroethanes, acetate-methanol or ethyl acetate-ethanol
Mixed solvent recrystallization, filtration drying obtain Pantothenic acid-(R)-(+)-α phenyl ethylamine double salt.
It is highly preferred that the method using crystallization carries out the step of splitting purification to the double salt further include: will
The mother liquor concentrations recycling design of recrystallization, residue are redissolved in isopropanol, and in batches or sodium hydroxide, hydrogen-oxygen is added in dropwise addition
Change potassium, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide solid or alcoholic solution, it is stirred at room temperature 2~for 24 hours, filter consolidating for precipitation
Body, the solid contain L- pantoic acid sodium or sylvite, and mother liquor, which is removed under reduced pressure solvent and recycles, obtains R- (+)-α phenyl ethylamine.
It is highly preferred that the method using crystallization carries out the step of splitting purification to the double salt further include: will
The mother liquor concentrations recycling design of recrystallization, residue are redissolved in isopropanol, in batches or be added dropwise be added equivalent hydrogen-oxygen
Change sodium, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide solid or alcoholic solution, it is stirred at room temperature 2~for 24 hours, mistake
The solid being precipitated is filtered, the solid contains L- pantoic acid sodium or sylvite, and mother liquor, which is removed under reduced pressure solvent and recycles, obtains R- (+)-α benzene
Ethamine.
It is highly preferred that the method using crystallization carries out the step of splitting purification to the double salt further include: will
The solid containing L- pantoic acid sodium or sylvite is dissolved in methanol or ethyl alcohol, and sodium methoxide is added or sodium ethoxide, temperature rising reflux disappear
Rotation, evaporating solvent under reduced pressure, residue is outstanding to be dissolved in isopropanol, and room temperature mashing is filtered, dry, obtains DL- pantoic acid lactone.
It is highly preferred that the method using crystallization carries out the step of splitting purification to the double salt further include: will
The solid containing L- pantoic acid sodium or sylvite is dissolved in methanol or ethyl alcohol, and 1 equivalents of methanol sodium or sodium ethoxide is added, heats up back
Flowing racemization for 24 hours, evaporating solvent under reduced pressure, residue is outstanding to be dissolved in isopropanol, and room temperature is beaten 1h, filters, and it is dry, obtain DL- pantoic acid
Lactone.
It is highly preferred that the ratio of double salt and the solvent used is 1: 1~1:100, the dissolution of double salt when the described recrystallization
Temperature is room temperature to solvent reflux temperature, and the temperature for crystallizing crystallization is between 0 DEG C~25 DEG C.
Preferably, the specific steps of the decomposition include: to be dissolved in Pantothenic acid-(R)-(+)-α phenyl ethylamine double salt
In isopropanol or methanol, in batches or sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or the tert-butyl alcohol is added in dropwise addition
Potassium solid or alcoholic solution, are stirred at room temperature 2-24h, filter the solid of precipitation, and as Pantothenic acid sodium or sylvite, mother liquor is removed under reduced pressure
Solvent recycles and obtains R- (+)-α phenyl ethylamine.
It is highly preferred that the specific steps of the decomposition include: to dissolve Pantothenic acid-(R)-(+)-α phenyl ethylamine double salt
In isopropanol or methanol, in batches or be added dropwise be added equivalent sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, the tert-butyl alcohol
Sodium or potassium tert-butoxide solid or alcoholic solution, are stirred at room temperature 2-24h, filter the solid of precipitation, as Pantothenic acid sodium or sylvite, female
Liquid, which is removed under reduced pressure solvent and recycles, obtains R- (+)-α phenyl ethylamine.
Preferably, the specific steps of the acidification cyclization include: the Pantothenic acid sodium for obtaining hydrolysis or sylvite dissolution
Yu Shuizhong, it is dry with acetic acid esters or alkyl halide dissolution extraction with hydrochloric acid or sulphur acid for adjusting pH≤2, it is distilled to recover solvent, obtains D-
(-)-pantoic acid lactone.
The present invention use (R)-(+)-α-phenylethylamine hydrochloride or sulfate as chiral selectors with it is racemic
D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt is made (for diastereomer double salt, hydroxyl in the reaction of pantoic acid alkali metal salt
Hydrochlorate), purified with the method for recrystallization or mashing to diastereomer double salt, filters (D)-pantoic acid-(R)-phenyl ethylamine
Double salt alkali neutralization is recycled resolving agent, then is acidified to obtain D- (-)-pantoic acid lactone method by double salt.
Compared with prior art, the beneficial effects of the present invention are:
The present invention has synthesized vitamin B5 synthesis key intermediate D- (-)-pantoic acid lactone, and preparation step is simple, yield
Height, the present invention also provides the recoverying and utilizing methods of resolving agent, this not only improves saving and splits cost, the recycling of resource.
Detailed description of the invention
Fig. 1: the resolution process route of D-pantoyl lactone；
The racemization of Fig. 2: L- pantoic acid and the recycling of R- (+)-α phenyl ethylamine；
Fig. 3 is the synthetic route of calcium pantothenate.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
The preparation of embodiment one (R)-(+)-α-phenylethylamine hydrochloride
A: 48.4 grams of (R)-(+)-α-phenylethylamine, (3-5 DEG C) side under ice-water bath are added in 1000 milliliters of round-bottomed flasks
It stirs side and 35 milliliters of concentrated hydrochloric acids is added dropwise, be added dropwise in 30 minutes, stirring at normal temperature, which was spin-dried for removing solvent after 2 hours, obtains (R)-
(+)-α-phenylethylamine hydrochloride, it is 2 hours dry at 60 DEG C, 61.8 grams of yield, yield 98.1%.
Or B: 48.5 grams of (R)-(+)-α-phenylethylamine are dissolved in ethyl alcohol (can also be methanol), (3-5 under ice-water bath
DEG C) it is passed through hydrogen chloride gas 30 minutes, stirring at normal temperature 2 hours, evaporating solvent under reduced pressure obtained (R)-(+)-α-phenylethylamine hydrochloride,
It is 2 hours dry at 60 DEG C, 62.3 grams of yield, yield 98.9%.
The preparation of two pantoic acid sodium salt of embodiment
104.1 grams of racemic pantoic acid lactones are dissolved in 40 milliliters of water in 1000 milliliters of round-bottomed flasks, then will
32.4 grams of sodium hydroxides are dissolved in 80 milliliters of water, and sodium hydrate aqueous solution is added dropwise while stirring under 60 DEG C of heating, drips in 1 hour
Add it is complete, at 60 DEG C continue 3 hours progress ring-opening reactions of heating stirring after, remove solvent and obtain pantoic acid sodium salt, at 60 DEG C
It is 2 hours dry, 131.1 grams of yield, yield 96.3%.
The preparation of three pantoic acid sylvite of embodiment
105.2 grams of racemic pantoic acid lactones are dissolved in 40 milliliters of water in 1000 milliliters of round-bottomed flasks, then will
45.3 grams of potassium hydroxide are dissolved in 80 milliliters of water, and potassium hydroxide aqueous solution is added dropwise while stirring under 60 DEG C of heating, drips in 1 hour
Add it is complete, at 60 DEG C continue 3 hours progress ring-opening reactions of heating stirring after, remove solvent and obtain pantoic acid sylvite, at 60 DEG C
It is 2 hours dry, 149.3 grams of yield, yield 99.2%.
The preparation of example IV DL- pantoic acid-(R)-(+)-α-phenylethylamine double salt
Using resulting (R)-(+)-α-phenylethylamine hydrochloride of A in embodiment one as chiral selectors, with embodiment
Two resulting racemic pantoic acid sodium salts or the resulting pantoic acid sylvite of embodiment three react form the general solution of D/L- in a solvent
Acid-(R)-(+'s)-α-phenylethylamine double salt, specific steps are as follows:
8.6 grams of racemic pantoic acid sodium salts: being dissolved in 40 milliliters of anhydrous methanols by A in 100 milliliters of round-bottomed flasks, then
7.9 grams of (R)-(+)-α-phenylethylamine hydrochlorides are dissolved in and are slowly dropped in 25 milliliters of dehydrated alcohols in the round-bottomed flask,
It finishes, is stirred to react at room temperature 3 hours, be placed in cooling crystallization at 0 DEG C, after standing 24 hours, be filtered to remove what reaction was precipitated
Solid, it is dry after 2.7 grams of white crystals, mother liquor is spin-dried for removing solvent, dry DL- pantoic acid-(R)-(+)-α-phenylethylamine
13.7 grams of double salt, yield 102.1%.
8.6 grams of racemic pantoic acid sodium salts: being dissolved in 40 milliliters of dehydrated alcohols by or B in 100 milliliters of round-bottomed flasks,
7.9 grams of (R)-(+)-α-phenylethylamine hydrochlorides are dissolved in again and are slowly dropped to the round-bottomed flask in 25 milliliters of dehydrated alcohols
In, it finishes, is stirred to react at room temperature 3 hours, be placed in cooling crystallization at 0 DEG C, after standing 24 hours, be filtered to remove reaction and be precipitated
Solid, it is dry after 2.6 grams of white crystals, mother liquor is spin-dried for removing solvent, dry DL- pantoic acid-(R)-(+)-α-benzene second
13.6 grams of amine double salt, yield 101.3%.
8.6 grams of racemic pantoic acid sylvite: being dissolved in 40 milliliters of ethyl acetate by or C in 100 milliliters of round-bottomed flasks,
7.9 grams of (R)-(+)-α-phenylethylamine hydrochlorides are dissolved in again and are slowly dropped to the round-bottomed flask in 25 milliliters of ethyl acetate
In, it finishes, is stirred to react at room temperature 3 hours, be placed in cooling crystallization at 0 DEG C, after standing 24 hours, be filtered to remove reaction and be precipitated
Solid, it is dry after 2.8 grams of white crystals, mother liquor is spin-dried for removing solvent, dry DL- pantoic acid-(R)-(+)-α-benzene second
13.2 grams of amine double salt, yield 98.4%.
The preparation of five Pantothenic acid-R- (+) of embodiment-α-phenylethylamine double salt
Fractionation purification, specific steps are carried out to the double salt that example IV A is obtained using the method for crystallization are as follows:
A: DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) is hanged and is dissolved in methylene chloride in (1000mL), is added
Heat, which is back to, to be completely dissolved, cooled to room temperature (25 DEG C) stirring and crystallizing for 24 hours, filter, it is dry, obtain Pantothenic acid-R-
(+)-α-phenylethylamine double salt, 4.7 grams of yield, yield 47%, predominantly L- pantoic acid-R- (+)-α-phenylethylamine double salt in mother liquor.
Or B: DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) is hanged and is dissolved in chloroform in (300mL), is heated back
Flow to and be completely dissolved, cooled to room temperature (25 DEG C) stirring and crystallizing for 24 hours, filter, it is dry, obtain Pantothenic acid-R- (+)-α-
Phenyl ethylamine double salt, 4.2 grams of yield, yield 42%, predominantly L- pantoic acid-R- (+)-α-phenylethylamine double salt in mother liquor.
Or C: DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) is hanged and is dissolved in dichloroethanes in (200mL), is added
Heat, which is back to, to be completely dissolved, cooled to room temperature (25 DEG C) stirring and crystallizing for 24 hours, filter, it is dry, obtain Pantothenic acid-R-
(+)-α-phenylethylamine double salt, 4.5 grams of yield, yield 45%, predominantly L- pantoic acid-R- (+)-α-phenylethylamine double salt in mother liquor.
Or D: by DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) it is outstanding be dissolved in methylene chloride-methanol (100mL,
100:1, v/v) in, be heated to reflux to being completely dissolved, cooled to room temperature (25 DEG C) stirring and crystallizing for 24 hours, filter, it is dry,
Pantothenic acid-R- (+)-α-phenylethylamine double salt, 44 grams of yield, yield 44%, predominantly L- pantoic acid-R- (+)-α-in mother liquor
Phenyl ethylamine double salt.
Or E: DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) is hanged and is dissolved in acetate-methanol mixed solvent
In (50mL, 10:1, v/v), ethyl acetate being slowly added dropwise into the reaction solution, finishes, (25 DEG C) of room temperature stirrings for 24 hours, are filtered, Gu
Body object is washed with ethyl acetate, dry, obtains Pantothenic acid-R- (+)-α-phenylethylamine double salt, and 4.3 grams of yield, yield 43%, mother liquor
In predominantly L- pantoic acid-R- (+)-α-phenylethylamine double salt.
Or F: by DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) it is outstanding be dissolved in ethyl acetate-ethanol (30mL, 8:2,
V/v) in the mixed solvent, heating and refluxing to dissolve, cooled to room temperature (25 DEG C) stirring and crystallizing for 24 hours, filter, solids acetic acid
Ethyl ester washing, it is dry, obtain Pantothenic acid-R- (+)-α-phenylethylamine double salt, 4.5 grams of yield, yield 45%, predominantly L- in mother liquor
Pantoic acid-R- (+)-α-phenylethylamine double salt.
Or G: by DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) it is outstanding be dissolved in acetate-methanol (20mL, 6:4,
V/v) mixed solvent is heated to 40-60 DEG C of mashing for 24 hours, is cooled to room temperature (25 DEG C), filters, and solids is washed with ethyl acetate,
It is dry, obtain Pantothenic acid-R- (+)-α-phenylethylamine double salt, 4.3 grams of yield, yield 43%, predominantly L- pantoic acid-R- in mother liquor
(+)-α-phenylethylamine double salt.
Or H: by DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) it is outstanding be dissolved in ethyl acetate-ethanol (15mL, 5:5,
V/v) mixed solvent is heated to 30-40 DEG C of mashing for 24 hours, is cooled to room temperature (25 DEG C), filters, and solids is washed with ethyl acetate,
It is dry, obtain Pantothenic acid-R- (+)-α-phenylethylamine double salt, 4.6 grams of yield, yield 46%, predominantly L- pantoic acid-R- in mother liquor
(+)-α-phenylethylamine double salt.
Or I: by DL- pantoic acid-R- (+)-α-phenylethylamine double salt (10g) it is outstanding be dissolved in ethyl acetate-ethanol (10mL, 4:6,
V/v) mixed solvent is beaten under room temperature (25 DEG C) for 24 hours, and filtering, solids is washed with ethyl acetate, dry, obtains Pantothenic acid-R-
(+)-α-phenylethylamine double salt, 4.5 grams of yield, yield 45%, predominantly L- pantoic acid-R- (+)-α-phenylethylamine double salt in mother liquor.
The preparation of six Pantothenic acid sodium salt of embodiment and the recycling of R- (+)-α-phenylethylamine
Resulting Pantothenic acid-the R- (+) of five A of embodiment-α-phenylethylamine double salt is decomposed, specific steps are as follows:
A: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, hydroxide is added portionwise
It 0.8 gram of sodium, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium 3.01
Gram, yield 97.4%；It is to recycle to obtain 2.43 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield 100%.
Or B: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, methanol is added portionwise
It 1.1 grams of sodium, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium 3.4
Gram, yield 98.4%；It is to recycle to obtain R- (+) -2.42 grams of α-phenylethylamine R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent,
Yield 99.5%.
Or C: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, ethyl alcohol is added portionwise
It 1.4 grams of sodium, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium 2.99
Gram, yield 96.7%；It is to recycle to obtain 2.40 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield 98.8%.
Or D: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, isopropyl is added portionwise
It 1.7 grams of sodium alkoxide, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium
2.98 grams, yield 96.4%；It is to recycle to obtain 2.41 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield
99.2%.
Or E: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, tertiary fourth is added portionwise
It 2.0 grams of sodium alkoxide, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium
3.01 grams, yield 97.1%；It is to recycle to obtain 2.42 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield
99.6%.
The preparation of seven Pantothenic acid sylvite of embodiment and the recycling of R- (+)-α-phenylethylamine
Resulting Pantothenic acid-the R- (+) of five A of embodiment-α-phenylethylamine double salt is decomposed, specific steps are as follows:
A: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, hydroxide is added portionwise
It 1.2 grams of potassium, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium salt
3.6 grams, yield 96.1%；It is to recycle to obtain 2.4 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield 99.2%.
Or B: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, methanol is added portionwise
It 1.4 grams of potassium, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium salt
3.5 grams, yield 93.5%；It is to recycle to obtain 2.5 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield 103.3%.
Or C: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, ethyl alcohol is added portionwise
It 1.7 grams of potassium, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium salt
3.5 grams, yield 93.5%；It is to recycle to obtain 2.5 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield 103.3%.
Or D: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, isopropyl is added portionwise
It 2.0 grams of potassium alcoholate, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sodium
3.3 grams, yield 88.1%；It is to recycle to obtain 2.4 grams of R- (+)-α-phenylethylamine that mother liquor, which is concentrated under reduced pressure and removes solvent, yield 99.2%.
Or E: Pantothenic acid-R- (+) -5.4 grams of α-phenylethylamine double salt is dissolved in 20mL isopropanol, tertiary fourth is added portionwise
It 2.3 grams of potassium alcoholate, is stirred at room temperature for 24 hours, there is solid precipitation, filter the solid of precipitation, solids is dry to get Pantothenic acid sylvite
3.2 grams, yield 85.4%；Mother liquor, which is concentrated under reduced pressure, to be removed solvent and recycles to obtain 2.5 grams of R- (+)-α-phenylethylamine, and 103.3%.
The preparation of eight D-pantoyl lactone of embodiment
As shown in Figure 1, the resulting Pantothenic acid sodium of six A of embodiment or the resulting Pantothenic acid potassium of seven A of embodiment are carried out
It is acidified cyclization, specific steps are as follows:
A: 7.5 grams of Pantothenic acid sodium salt are dissolved in 10 milliliters of water, and enriching hydrochloric acid adjusts PH to 1-2 (including 2), room temperature
Stirring 30 minutes, makes to be extracted with ethyl acetate, and organic layer is dried, filtered with anhydrous magnesium sulfate, after vacuum distillation recovered solvent
To 5.4 grams of D- (-)-pantoic acid lactone, yield 94.7%, enantiomeric excess 98.3%.
Or B: 15 grams of Pantothenic acid sodium salt are dissolved in 15 milliliters of water, and enriching sulfuric acid adjusts PH to 1-2 (including 2), often
Temperature stirring 30 minutes, makes to be extracted with ethyl acetate, and organic layer is dry with anhydrous magnesium sulfate, obtains D- (-)-after being distilled to recover solvent
11.0 grams of pantoic acid lactone, yield 96.0%, enantiomeric excess 97.6%.
Or C: 7.5 grams of Pantothenic acid sylvite are dissolved in 10 milliliters of water, and enriching sulfuric acid adjusts PH to 1-2 (including 2), often
Temperature stirring 30 minutes, makes to be extracted with ethyl acetate, and organic layer is dry with anhydrous magnesium sulfate, obtains D- (-)-after being distilled to recover solvent
5.3 grams of pantoic acid lactone, yield 92.5%, enantiomeric excess 99.0%.
Or D: 15 grams of Pantothenic acid sylvite are dissolved in 20 milliliters of water, and enriching hydrochloric acid adjusts PH to 1-2 (including 2), often
Temperature stirring 30 minutes, makes to be extracted with ethyl acetate, and organic layer is dry with anhydrous magnesium sulfate, obtains D- (-)-after being distilled to recover solvent
11.1 grams of pantoic acid lactone, yield 96.9%, enantiomeric excess 97.2%.
Nine L- pantoic acid sodium of embodiment and the recycling of R- (+)-α-phenylethylamine
L- pantoic acid-R- (+)-α-phenylethylamine double salt mother liquor concentrations recycling design will be contained obtained in five A of embodiment,
10.8 grams of residue are dissolved in 20 milliliters of isopropanols, and sodium hydroxide 1.61g is added portionwise, is stirred at room temperature for 24 hours, there is solid analysis
Out, the solid of precipitation is filtered, the solid contains L- pantoic acid sodium, and solids is dry to get 6.1g grams of sodium of L- pantoic acid, it receives
Rate 98.7%；Mother liquor is removed under reduced pressure solvent and obtains 4.9 grams of R- (+)-α-phenylethylamine, and 100.4%.
The racemization of ten L- pantoic acid sodium of embodiment and the recycling of R- (+)-α-phenylethylamine
As shown in Fig. 2, by the resulting solid containing L- pantoic acid sodium of embodiment nine 10 grams be dissolved in 20 milliliters of anhydrous second
In alcohol, 4.0 grams of sodium ethoxide of 1 equivalent being added, are heated to reflux racemization for 24 hours, solution optically-active is monitored less than 1 °, and basic racemization is complete,
Vacuum distillation recycling ethyl alcohol, residue is outstanding to be dissolved in 30mL isopropanol, and room temperature is beaten 1h, filters, dry, obtains DL- pantoic acid sodium
9.5 grams, yield 95%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, the substantial technological content model being not intended to limit the invention
It encloses, substantial technological content of the invention is broadly defined in the scope of the claims of application, any technology that other people complete
Entity or method also or a kind of equivalent change, will if identical with defined in the scope of the claims of application
It is considered as being covered by among the scope of the claims.
Claims (10)
1. a kind of synthetic method of D- (-)-pantoic acid lactone characterized by comprising use (R)-(+)-α-phenylethylamine hydrochloric acid
Salt or (R)-(+)-α-phenylethylamine sulfate are anti-in a solvent with racemic pantoic acid alkali metal salt as chiral selectors
D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt should be formed, the double salt is torn open using the method for crystallization or mashing
Divide purification, obtains D- (-)-pantoic acid lactone with acidification cyclization using decomposing.
2. the synthetic method of D- (-)-pantoic acid lactone as described in claim 1, which is characterized in that used when the described crystallization
Solvent be ethyl alcohol, ethyl acetate, methylene chloride or their mixture；When the described crystallization diastereomer double salt with use
The ratio of solvent is 1: 1~1:100；The temperature precipitated crystal when the described crystallization is 0 DEG C~25 DEG C；What the decomposition used
Alkali is the aqueous solution or alcoholic solution of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide or sodium isopropylate.
3. the synthetic method of D- (-)-pantoic acid lactone as described in claim 1, which is characterized in that (R)-(+)-α-
The preparation method of phenethylamine hydrochloride or (R)-(+)-α-phenylethylamine sulfate includes: that salt is added in (R)-(+)-α-phenylethylamine
Sulfuric acid is added into salt in acid, alternatively, (R)-(+)-α-phenylethylamine is dissolved in methanol, ethyl alcohol or water, hydrogen chloride is passed through or is added
Enter hydrochloric acid or sulfuric acid is added into salt；Remove solvent again, dry (R)-(+)-α-phenylethylamine hydrochloride or (R)-(+)-α-benzene
Ethamine sulfate.
4. the synthetic method of D- (-)-pantoic acid lactone as described in claim 1, which is characterized in that the pantoic acid alkali gold
Belonging to salt is pantoic acid sodium or pantoic acid potassium；The preparation method of the pantoic acid sodium or pantoic acid potassium includes: will be racemic general
Solution acid lactone is dissolved in methanol, ethyl alcohol or water, be added equivalent sodium hydroxide or potassium hydroxide solid or methanol solution or
Ethanol solution or aqueous solution carry out ring-opening reaction, remove solvent, dry pantoic acid sodium or pantoic acid potassium.
5. the synthetic method of D- (-)-pantoic acid lactone as described in claim 1, which is characterized in that the use (R)-
(+)-α-phenylethylamine hydrochloride or (R)-(+)-α-phenylethylamine sulfate are as chiral selectors, with racemic pantoic acid alkali
Metal salt reacts that form the specific steps of D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt include: by pantoic acid in a solvent
Sodium salt or sylvite are dissolved in methanol, ethyl alcohol or ethyl acetate, then (R)-(+)-α-phenylethylamine hydrochloride or its sulfate is added dropwise
Methanol, ethyl alcohol or ethyl acetate solution, 2-24h is stirred at room temperature, is filtered to remove the solid that reaction is precipitated, mother liquor is spin-dried for, dry
Obtain D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt；Or pantoic acid sodium salt or sylvite are dissolved in methanol or ethyl alcohol, in batches
(R)-(+)-α-phenylethylamine hydrochloride or its sulfate is added, 2-24h is stirred at room temperature, is filtered to remove the solid that reaction is precipitated, it is female
Liquid is spin-dried for, dry D/L- pantoic acid-(R)-(+)-α-phenylethylamine double salt.
6. the synthetic method of D- (-)-pantoic acid lactone as described in claim 1, which is characterized in that the use crystallization
The step of method carries out fractionation purification to the double salt includes: by DL- pantoic acid-(R)-(+)-α phenyl ethylamine double salt dichloro
Methane, chloroform, dichloroethanes, acetate-methanol or ethyl acetate-ethanol mixed solvent recrystallization, filtration drying obtain D-
Pantoic acid-(R)-(+)-α phenyl ethylamine double salt.
7. the synthetic method of D- (-)-pantoic acid lactone as claimed in claim 6, which is characterized in that the use crystallization
Method carries out the step of splitting purification to the double salt further include: by the mother liquor concentrations recycling design of recrystallization, residue weight
It is newly dissolved in isopropanol, in batches or sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or tertiary fourth is added in dropwise addition
Potassium alcoholate solid or alcoholic solution, it is stirred at room temperature 2~for 24 hours, and the solid of precipitation is filtered, the solid contains L- pantoic acid sodium or sylvite,
Mother liquor, which is removed under reduced pressure solvent and recycles, obtains R- (+)-α phenyl ethylamine.
8. the synthetic method of D- (-)-pantoic acid lactone as claimed in claim 7, which is characterized in that the use crystallization
Method carries out the step of splitting purification to the double salt further include: is dissolved in the solid containing L- pantoic acid sodium or sylvite
In methanol or ethyl alcohol, sodium methoxide or sodium ethoxide is added, temperature rising reflux racemization, evaporating solvent under reduced pressure, residue is outstanding to be dissolved in isopropanol
In, room temperature mashing is filtered, and it is dry, obtain DL- pantoic acid lactone.
9. the synthetic method of D- (-)-pantoic acid lactone as described in claim 1, which is characterized in that the decomposition it is specific
Step includes: that Pantothenic acid-(R)-(+)-α phenyl ethylamine double salt is dissolved in isopropanol or methanol, and in batches or hydrogen is added in dropwise addition
Sodium oxide molybdena, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide solid or alcoholic solution, are stirred at room temperature 2-24h, mistake
Filter the solid being precipitated, as Pantothenic acid sodium or sylvite, mother liquor, which is removed under reduced pressure solvent and recycles, obtains R- (+)-α phenyl ethylamine.
10. the synthetic method of D- (-)-pantoic acid lactone as described in claim 1, which is characterized in that the acidification cyclization
Specific steps include: that the obtained Pantothenic acid sodium of hydrolysis or sylvite are dissolved in the water, with hydrochloric acid or sulphur acid for adjusting pH≤2,
It is dry with acetic acid esters or alkyl halide dissolution extraction, it is distilled to recover solvent, obtains D- (-)-pantoic acid lactone.
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| CN112457181A (en) * | 2020-12-11 | 2021-03-09 | 黄冈美丰化工科技有限公司 | Synthesis method of D-calcium pantothenate |
| CN112939911A (en) * | 2019-12-11 | 2021-06-11 | 常州工程职业技术学院 | Chiral resolution process for preparing key intermediate of levo-Corey lactone |
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