MXPA01000917A - Crystal modification of lipoic acid - Google Patents
Crystal modification of lipoic acidInfo
- Publication number
- MXPA01000917A MXPA01000917A MXPA/A/2001/000917A MXPA01000917A MXPA01000917A MX PA01000917 A MXPA01000917 A MX PA01000917A MX PA01000917 A MXPA01000917 A MX PA01000917A MX PA01000917 A MXPA01000917 A MX PA01000917A
- Authority
- MX
- Mexico
- Prior art keywords
- lipoic acid
- mixture
- solvent
- toluene
- solvents
- Prior art date
Links
- 235000019136 lipoic acid Nutrition 0.000 title claims description 24
- 229960002663 thioctic acid Drugs 0.000 title claims description 21
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 title claims description 16
- 230000004048 modification Effects 0.000 title description 3
- 238000006011 modification reaction Methods 0.000 title description 3
- AGBQKNBQESQNJD-SSDOTTSWSA-N Lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 claims abstract description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 10
- 239000011877 solvent mixture Substances 0.000 claims description 9
- 239000008079 hexane Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 7
- 239000002778 food additive Substances 0.000 claims description 3
- 235000013373 food additive Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 235000015872 dietary supplement Nutrition 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drugs Drugs 0.000 claims 1
- AGBQKNBQESQNJD-ZETCQYMHSA-N (S)-lipoic acid Chemical compound OC(=O)CCCC[C@H]1CCSS1 AGBQKNBQESQNJD-ZETCQYMHSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- YYLLIJHXUHJATK-UHFFFAOYSA-N Cyclohexyl acetate Chemical compound CC(=O)OC1CCCCC1 YYLLIJHXUHJATK-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000005712 crystallization Effects 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- CPBZARXQRZTYGI-UHFFFAOYSA-N 3-cyclopentylpropylcyclohexane Chemical compound C1CCCCC1CCCC1CCCC1 CPBZARXQRZTYGI-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000003165 Abomasum Anatomy 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- RWGFKTVRMDUZSP-UHFFFAOYSA-N Cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- HASGOCLZFTZSTN-UHFFFAOYSA-N cyclohexane;hexane Chemical compound CCCCCC.C1CCCCC1 HASGOCLZFTZSTN-UHFFFAOYSA-N 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- URLKBWYHVLBVBO-UHFFFAOYSA-N p-xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
The invention relates to enantiomer-free crystalline (R) or (S) lipoic acid, where the reflection line at 2&THgr;=23°is the most intensive one in the 13°to 30°range in the 2&THgr;diffractogram.
Description
"MODIFICATION OF THE GLASS OF THE LIPOIC ACID
The present invention relates to a process for preparing crystalline α-lipoic acid in high yields, a new modification of the α-lipoic acid crystal and its use. Α-lipoic acid is used in the food industry and in pharmaceutical formulations. When speaking of lipoic acid below, this always refers to the enatiomerically pure (R) - or (S) -lipoic acid) compounds. Processes for preparing enantiomerically pure lipoic acid are described, for example, in Bulman-Page et al., J. Chem. Soc., Chem. Commun. 1986, 1409. In addition, the racemate can be prepared very effectively by the process described in Patent Number EP 0 586 987. Resolution of the enantiomers can be carried out using chiral amines (e.g., Patent Number 0 543 088). The (R) -lipoic acid can also be isolated from natural sources (Reed et al., JACS 1953 Volume 75, 1267). The (R) -lipoic acid can also be prepared in an enantiomerically pure form by the process described in Patent Number EP 487 986. The crude product is subsequently recrystallized from pentane, hexane or cyclohexane.
Alternatively, the crude product can be recrystallized from a 2: 1 mixture of cyclohexane / ethyl acetate (Patent Number EP 0 595 896). When the precise conditions and recrystallization yields are disclosed, a yield of 40 percent, based on the crude product, is obtained from cyclohexane at a temperature of 5 ° C to 10 ° C, and a yield of 31 percent, based on in the crude product, it is obtained at a temperature of about -15 ° C of the cyclohexane / ethyl acetate mixture. The above processes for preparing pure crystalline (R) - or (S) -a-lipoic acid provided yields that are unsatisfactory for the industrial preparation of α-lipoic acid. Increasing the yield by re-using the mother liquor for crystallization is technically complicated and usually leads to an increase in impurities that are highly undesirable in pharmaceutical processing in the food industry. An object of the present invention is to develop a process for preparing lipoic acid of pure pharmaceutical grade, in a favorable form for pharmaceutical processing. The crystalline forms produced up to now have X-ray diffractograms [registered diffractometer patterns of transmission - -
using Cu Ka? »(2-theta) radiation] published by Reed and others for the cyclohexane (+) -alpha-lipoic acid and in Patent Number EP 0 593 896 (cyclohexane / ethyl acetate). We have found that this object is achieved by dissolving the α-lipoic acid in an organic solvent having a dielectric constant e of 1.95 to 2.4. The organic solution of a-lipoic acid is then cooled to a temperature of 0 ° C to -20 ° C, providing a crystalline form that is new to enantiomerically pure a-lipoic acid, has a new type of distribution of line intensity in The X-ray diffractogram is suitable for pharmaceutical processing. In addition, the product according to the present invention is obtained in high purity (with <0.1 percent impurities) in yields of 75 percent or more. The invention can be applied both in the pharmaceutical industry and in the food industry where lipoic acid is used as a food additive and also in dietary supplements. The most intense line within the range of 15 ° to 30 ° in the 2 T diffractogram of the crystalline product, according to the present invention, is a line of 23 °. The crystalline products according to the present - -
invention have an intensity ratio of 2 T = 23 ° to 2 T = 18.2 ° of at least 1. In addition, the use of -Xo solvents according to the present invention having a dielectric constant of 1.95 to 2.4, has the additional advantage in relation to those described in the literature that, in crystallization, they provide a very pure crystalline product in high yields. As solvents or components of the solvent mixtures, it is possible to use, for example: straight or branched chain, saturated or monounsaturated or polyunsaturated hydrocarbons having a chain length of C5 to Cß, cycloaliphatic hydrocarbons such as cyclopentane, cyclohexane or methylcyclohexane or monohalogenated or polyhalogenated hydrocarbons, preferably chlorinated, having a chain length of 1 to 4 carbon atoms. It is possible to use either solvent mixtures such as hexane or heptane of technical grade, wherein the hexane or heptane is the main component or also the pure solvents. Preference is given to solvent mixtures of aliphatic and aromatic hydrocarbons. In addition, substituted or unsubstituted monocyclic and polycyclic aromatic products are also possible as solvents or solvent components. Examples that can be mentioned are toluene, o-, -
m- and p-xylene, ethylbenzene, propylbenzene and isopropylbenzene and mesitylene. In addition, the solvents or solvent mixtures used in accordance with the present invention have to have a melting temperature of less than 0 ° C, preferably of less than -20 ° C, particularly preferably of less than -40 ° C. Preference is also given to solvents that have a low toxicity, since the resulting lipoic acid should be used as a drug or food additive. The preferred upper limit for the dielectric constant is 2.2; specific preference is given on a scale of 2.0 to 2.1. The preferred upper limit for the temperature scale of the crystallization is -5 ° C, particularly preferably -10 ° C. The process can also be carried out at lower temperatures, provided that the solvent or mixture of solvents does not become solid. A preferred lower temperature limit is -20 ° C. Preferred solvent mixtures are those of toluene or xylene with C5-C7 aliphatics in a volume ratio of 1: 1 to 1: 4; specific preference is given to a technical-grade mixture of toluene and hexane or toluene of technical quality and heptane.
-
The lipoic acid is recrystallized from a solvent or solvent mixture using a weight ratio of lipoic acid to solvent preferably from 1: 5 to 1:15, particularly preferably from 1: 8 to 1:12. In the case of a mixture of solvents, the lipoic acid is preferably first dissolved in a polar mixture or in the polar solvent component and the remaining non-polar solvent component for recrystallization is then added before cooling to a temperature of 0 ° C. -20 ° C. In aqueous solution (1 gram of lipoic acid in 20 milliliters of 1N NaOH), the product obtained according to the present invention has an absorbency of < 0.300 (430 nm, path length = 1 centimeter).
Example 1
grams of the (R) -a-lipoic acid was introduced in 67 milliliters of a 1: 1 solvent mixture of technical grade toluene / hexane and at 50 ° C. This provided a solution that was filtered. The filtered material [sic] was washed with 33 milliliters of hexane (technical grade). The combined solutions were maintained at a temperature of 0 ° C to 5 ° C for 1 hour in ice water and subsequently stirred for another hour at about -15 ° C while being cooled with a mixture of ice / sodium chloride. The crystals were subsequently filtered off with suction and dried at room temperature under reduced pressure: 8.1 grams of the (R) - (+) -a-lipoic acid.
Example 2
grams of the crude (R) -a-lipoic acid was dissolved in 35 milliliters of toluene at 50 ° C. 35 milliliters of technical grade heptane was added, the solution was filtered at 50 ° C through 4 grams of silica gel F 60 and an additional 35 milliliters of technical grade heptane were added to the filtrate. The solution was cooled to 0 ° C to 5 ° C, stripped and, after 1 hour, cooled to -15 ° C at a cooling rate of 5 ° C per hour. The desired product was isolated by filtration by suction in a frit, the crystalline product was washed twice with 15 milliliters of technical grade heptane and dried in a stream of nitrogen: 8.0 grams of the (R) -a-lipoic acid, temperature of fusion of 47.9 ° -48.9 ° C; [a] 24β = 113.7 ° C, c = 1 in benzene, purity in accordance with GC = 99.95 percent analysis; all trace components < 0.05 percent per area.
The lipoic acids prepared according to the present invention were subjected to X-ray diffraction analysis using Cu-K-alpha radiation. Figure 1 shows a pulvi-diffractogram of a prior art (R) -lipoic acid of cyclohexane. Figure 2 shows a pulvidifractogram of a prior art (R) -lipoic acid of cyclohexane / ethyl acetate. Figure 3 shows a pulvidifractogram of a (R) -lipoic acid of the present invention.
Claims (8)
1. The enantiomerically pure R- or S-lipoic acid for which the line of reflection at 2 T = 23 ° C is the most intense within the range of 15 ° to 30 ° in the diffractogram 2 T.
2. A process for preparing crystalline lipoic acid, which comprises crystallizing the lipoic acid at a temperature of 0 ° C to -20 ° C from a solvent or mixture of solvents having a dielectric constant e of 1.95 to 2.4.
3. A process according to claim 2, wherein a solvent mixture of the aliphatic and aromatic hydrocarbons is used.
4. A process according to claim 3, wherein the solvent mixture used is a mixture of toluene and hexane or a mixture of toluene and heptane.
5. The R-lipoic acid obtainable according to claim 3 or 4.
The lipoic acid obtainable according to any of claims 2 to 4.
7. The use of lipoic acid according to claim 1, 5 or 6 to prepare drugs.
8. The use of lipoic acid according to claim 1, 5 or 6 as a food additive or as a component of dietary supplements.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19834608.5 | 1998-07-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01000917A true MXPA01000917A (en) | 2001-11-21 |
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