TW426685B - Diastereomeric esters of etodolac-an antiarthritic drug and method for the optical resolution of etodolac - Google Patents

Abstract

The present invention pertains to a method for the optical resolution of (±)-etodolac-an antiarthritic drug, comprising the following steps: (1) the formation of diastereoisomeric esters between (±)-etodolac and (1R, 2R, 3R, 5S)-(-)-isopinocamphenol, comprising the direct cyclization of 7-ethyltryptophol with a 3-ketopentanoic ester or its enol ether derivative to form said diastereoisomeric esters, wherein the 3-ketopentanoic ester was prepared by the esterification of 3-ketopentanoic acid with (1R, 2R, 3R, 5S)-(-)-isopinocamphenol; (2) the fractional crystallization and isolation of the resultant diastereoisomeric esters in an appropriate solvent; and (3) the recovery of etodolac with high optical purity and (1R, 2R, 3R, 5S)-isopinocamphenol. The present invention also pertains to the diastereomeric esters of etodolac.

Description

Instruction of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 42β68 5. Α7 ----- Β7_ V. Description of the invention (1) Background of the invention Itodoxamine is a non-steroidal anti-inflammatory developed by Wyeth-Ayerst Laboratories in the United States Agent, whose trade name is Lodine, is used clinically to treat arthritis. Due to the increasing trend of the elderly population in various countries around the world, its use may also increase accordingly. The chemical structure of ITO; S has an asymmetric center containing several acid substituents, and is therefore suitable for the separation of individual optical isomers by optical analysis. About (±) _Itodore, (+) _ Comparison of anti-inflammatory activity between Itodol and Itodore 'has been published by Demerson, C. A, et al. The results of pharmacological tests show that the inhibitory activities of the above compounds on arachidonic acid are as follows: (soil) _Itodolite: IC50 = 24〇μ1νΙ, (+ > Itodolite: IC50 = 12O μΜ '㈠- Itodore: ic50 > 4OO μΜ (see

Demerson, C. A., Humbers L. G ,, Abraham, N. A., Schilling, G. 5 Martel, R. R., Pace-Asciak, C. J. Med. Chem., 1983 26 > ,, 1778). Judging from this, itodore has substantially better anti-inflammatory activity than (±) _Itodore and (-)-Itodore, and its effect on the human body may also be better. May be lower. The above judgment has been partially confirmed. An international patent (patent publication number WO 95/27713) of the British CHIROSCIENCE company discloses a salt formed by L-reduced glucosamine or its alkylated derivative and isodore, which can be applied to the human body. Because, L-reducing glucosamine is an amine sugar derivative acceptable to the human body. The results of a human test published by it show that the salt formed by (+ Itodolite and ^ reduced glucosamine derivatives has better anti-inflammatory and analgesic effects. Among them, (+)-Itodolite is based on L- Reduced glucosamine is an optical analysis reagent, with (±) _Ito ------...--------_- 4 -_ This paper size applies to the Chinese National Standard (CNS) Λ4 Specifications (210X297 public holidays) (Please read the precautions on the back before filling in this page)

* 1T 426685. Α7 Β7 V. Description of the invention (2)… prepared by the optical analysis of Dore. The previous techniques of itotore's optical analysis are also revealed only by the above two articles. Among them, Demerson et al. Used (±) -Itodoleide and camphor alcohol (L-(-)-borneol) to make an esterification reaction to prepare diastereomers, and then used the palmar tube The column (chiraicolumn) was subjected to a large number of separations (50 g scale), and finally subjected to hydrolysis to obtain the individual itodore single optical isomers. Because chromatography requires a large number of expensive solid phases and a large number of solvents', although it can prepare a sufficient amount of a single optical isomer for pharmacological testing, it is not industrially effective in terms of economic benefits. Available price. Using L-reduced glucosamine and its alkylated derivatives as optical analytical reagents, it is possible to successfully isolate a single optical isomer of itodole '. However, whether it is reduced glucosamine or its alkylated derivatives Both are highly water-soluble. Although it can achieve the purpose of optical analysis of Itodore, it cannot be recycled, so its use is limited to the application of Itodore-L-reducing glucosamine salt derivative itself. Brief description of the invention The invention is a method for analyzing the micro-analysis of Guantodore, which includes 1) the formation of (soil) · Itodole and (1R, 2R, 3R, 5SH-) isoanthopic acid diastereomers Isomers '. 2) The diastereoisomers of esters formed by the crystals and the separations' and 3) Recovering itodolite and (1R, 2R, 3R, 5SH _) _ with high optical purity Isoprenol. According to the method of the present invention, the recovery rate of (1R, 2R, 3R, 5S) • ㈠_isoospolenol can reach more than 97% β. Another aspect of the present invention relates to the novelity of the above-mentioned itodorol and isosporol. Ester diastereomers. Detailed description of the invention. &Quot; The present invention is an optical analysis method of Guan Yi Todorei, which includes the following steps ____ -5- This paper size is applicable to the Chinese national standard (CNS > A4 present grid (210 × 2 mm) (Please read the precautions on the back before filling out this page) Order printed by the Consumers Cooperative of the Central Economic and Technical Bureau of the Ministry of Economic Affairs 426685, A7 B7 V. Invention Description (3): 1) Formation (±)-Itodore and ( 1R, 2R, 3R, 55) _ (_) 1 Esterisomeric isomers, including (±) _Itodol and (1R, 2R, 3R, 5SH-) Isoprenol is directly reacted to form diastereoisomers, or 7-ethyl tryptanol is reacted with a kind of 3 bis-] valerate or its ether derivative through cyclization reaction to produce The acetic diastereoisomer, wherein the 3-ketovalerate is esterified with 3-ketovaleric acid and (1R, 2R, 3R, 5S) _ (-) _ isosinol Those obtained by the reaction; 2) Partial crystallization and single ionization of the ester diastereomers formed in an appropriate solvent; and recovery of Itodol and (1R, 2R, 3R, 5S) -fluorene-isosperbutanol. The reaction process involved in the method of the present invention is as follows: a) 洱 (Please read the precautions on the back before filling this page)

D. C, C. (or E. D. C,) cha (1R; 2R, 3R, 5S)-(.). Isoporoxol Order CH Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs,

1) Partial crystallization

c2H5 or 2) '0H7CH, 0H, Up 3) H30 +

\ / 〇2h

0.H This paper size applies the Chinese national standard (CNS> Λ4 specification (210 x 297 public holidays) ^ 2668 5. A7 V. Description of the invention (4) b)

Ο Ο 00 HO +, OH

Ο ο

〇Η

Or Lewis acid (please read the notes on the back before filling this page) CA 7-ethyl tryptanol

-a Printed by the Shell Sample Consumer Cooperative of the Central Bureau of Procurement, Ministry of Economic Affairs

t- 1) partly crystalline 2) -OH / O ^ OR H ^ O 3) I ^ O +

This paper size applies to the Chinese National Standard (CNS) Λ4 specification (2 丨 0 公 297 mm) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 42668 5, a7 A7 __ B7 V. Description of the invention (5) " According to the invention In the first step of the method, as shown in the above reaction scheme, the diastereomers of Igandoretide can be prepared in two different ways: 1) (±) -Itodole and (1R, 2R, 3R , 5SH _) _ Isosinol in a suitable solvent, directly in the presence of a dehydrating agent such as DCC or EDC to form ^ degree crystalline ester diastereomers, of which (1R, 2R, 3R, 58) _bu > Isospinol is commercially available, or it can be prepared from the inexpensive pinene through hydrogenation, methylation and oxidation in three consecutive steps. For the preparation method, refer to Organic Syntheses, Coll. Vol. VI. . 719. 2) 7-ethylchromeol is cyclized with a 3-ketovalerate or its ene ether derivative to generate the above-mentioned ester diastereomers, wherein the 3-ketovalerate is composed of 3-ketovaleric acid is prepared by esterification with (1R, 2R, 3R, 5S) -b) -isopinepine. 7-ethyltryptanol is known in the art, for example, U.S. Patent No. 3,843,681 (1974). The cyclization reaction involved in the second pathway of the present invention needs to be catalyzed by an acid, and a series of acid test results show that a Lewis acid is preferred, such as BF ^ OEh or BF3. In addition, in the cyclization reaction, the activity of the allyl ether derivative of 3-ketovalerate is better than that of 3-ketovalerate. When the cyclization reactant has high activity, not only the amount of Lewis acid can be reduced, but also the yield of the cyclization reaction can be improved. The above-mentioned 3-ketovalerate derived from (-)-isospercatenol is prepared as follows: 1) 3-ketovaleric acid and (1R, 2R, 3R, 5S)-(-)-iso pine Alcohol generates ester diastereomers in the presence of a dehydrating agent (such as DCC or EDC); 2) the obtained vinegar bamboo organism and trimethyloiftho-formate in the presence of an acid catalyst In the following, fluorenyl ether derivatives are formed, of which -8- This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (2IOXN7 male 牦) ----------) ------, 1τ- ----- ^ 「(Please read the notes on the back before filling out this page) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives / 12R68 5. A7 ______B7 V. Description of the invention (6) The acid catalyst can be p-toluene Sulfuric acid or DOWEX-50W acid resin. We have carried out in-depth research and testing on the conditions of the optical analysis method of the present invention, and the test results have found that: 1) the preferred solvent used in the method of the present invention is ornithanol, among which absolute ethanol Preferably, the preferred concentration of the esters produced by 2) (soil) -Itodole and (1R, 2R, 3R, 5 S) isosinate in absolute ethanol is 0'135 / Halo rose to 0145 g / ml, of which 0140 g / ml is better, that is, at this concentration range, better recovery rate and optical purity can be obtained. 3) The addition of seed crystals can accelerate the formation of crystals. And can improve the optical purity of the product 'wherein the seed system is separated from the optically separated individual-optical isomers (+) _ Itodore or (-)-Itodore and (1R, 2R, 3R, 5S)-(-)-Isoporoxol is prepared by generating separate ester compounds in the presence of dehydrating agent DC'C or EDC. 4) The operating temperature of partial crystallization can be at or below room temperature. Under the condition of below room temperature, the crystallization period can be shortened and the optical purity of the product can be improved by the addition of seed crystals. The method of the present invention will be further illustrated by the following examples, but it is not intended to limit the present invention. Example 1 The test of (±) -Itodole and (1R, 2R, 3R, 5S)-(-)-isospinolinol was used as a formature to prepare ester diastereomers. ( ±) _Itodol (20 g, 0.07 mole) '4- (dimethylamine) pyridine (10 g) and (1R, 2R, 3R, 5S)-(-)-isosperbutanol ( 12.9 g, 〇_〇84 Mol) was sequentially added to 600 ml of anhydrous acetic acid, and the solution was ice-cooled to 0 ° C, followed by d.c.c (18'2 g, 0.088 mole), and then stirred at room temperature for 12 hours. The resulting solution was After filtration, the obtained filtrate was concentrated, and the obtained residue was passed through a short section of ________-9 -________ This paper size is applicable to the Chinese national standard (CNS) Λ4 specification (210 × 24 ^ ¥) '". (Please read the precautions on the back first Fill out this page again) Order 42668 printed by the Employees' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 5. A7 ___B7____ V. Description of the invention (7) Silica gel column chromatography, and n-hexane-ethyl acetate (10: 1 volume ratio ) As the eluent to obtain the desired diastereomer (30.2 g, 97.6%). 115-117 ° C 0 NMR (CDC13, 500 MHz) 9.17 (brs, 1H), 7.35 (d, J = 7.0 Hz, 1H), 7.05 (m, 1H), 7.00 (d, J-6.70 Hz, 1H), 5.10 (m, 1H), 4.03 (m, 1H), 3.95 (m, 1H), 2.80-3.00 (m, 4H), 1.50-2.80 (m,, 5H), 1.37 (t, J = 7.0 Hz, 3H), 1.22 (s, 3H), 1.12 (d, J = 7.50 Hz, 1H), 1.05 (d, J = 7.5 Hz, 1H), 0.98 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H) »MS (EI): m / z (relative intensity) 423 (M +, 35), 394 (28), 25 8 (42), 228 (100). If E.D.C is used instead of D.C.C to repeat the same condensation reaction as described above, the desired diastereomers can be obtained by simply washing and concentrating the water. Example 2 Preparation of 3-ketovalerate The procedure described in Example 1 was repeated, except that (±) -itodole was replaced with 3-ketovaleric acid (8.12 g, 0.07 mole) to obtain the desired compound ( 15.88 g, 90%). The obtained compound was a yellow oil, WNMR ^ CDCh, 200 MHz) 5.11 (m, 1H), 3.45 (s, 2H), 3.18 (m, 1H), 2.59 (m, 1H), 2.58 (q, J = 7.2 Hz, 2H), 0.90-2.50 (m, 17H) »Example 3 Preparation of an allyl ether derivative of 3-ketovalerate Dissolve 3-ketovalerate (6.16 g, 24.44 mmol) in In 200 ml of trimethyl orthoformate, 10 g of DOWEX- ^ OW acid resin was added, and after heating under reflux for 10 hours, the resulting solution was filtered and concentrated under reduced pressure and vacuum distillation to remove excess trimethyl orthoformate. To obtain the 3-ether ketovalerate ether ______- 1Q -______ This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (mm) {Please read the precautions on the back before filling this page}

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives / 12 6 6 8 5, A7 B7 V. Description of the invention (8) Derivatives (5.7 g, 87.66%). It is a white solid with a melting point of 48. -49 ° C > * H NMR (CDC13, 500 MHz), 5.11 (m, 1H), 4.99 (s, 1H), 3.65 (s, 3H), 2.79 (m, 2H), 2.60 (m, 1H) , 2.40 (m, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.85 (m, 1H), 1.73 (m, 2H), 1.24 (s, 3H), 1.11 (m, 6H), 0.97 (s, 3H) 〇 If p-toluene.sulfonic acid (1 g) is used instead of DOWEX-50W for the same reaction, the excess trimethyl orthoformate is removed by vacuum distillation, and the concentrated solution is diluted with digas methane. After regeneration, the solution was washed with a 10% NaCO3 solution and then with water. The organic solution was dried over anhydrous magnesium sulfate, and concentrated to obtain a 3-ketovalerate allyl-ether derivative (5.16 g, 80%). Example 4 Cyclization of 7-ethylchromeol and .3-ketovalerate to prepare ester non-enantiomeric isomers 7-ethylchromeol (22.5 g, 0.119 moles) and The obtained 3-ketovalerate (30 g, 0.119 mole) was dissolved in dry digas methane (500 ml) and added; 8? 3 (^ 12 (10 ml, 0.0796 mole) ), And then stirred at room temperature for 12 hours. The resulting solution was diluted with ice water, and then washed with 10% sodium carbonate aqueous solution, and then washed with water. The organic solution was dried over anhydrous magnesium sulfate and concentrated. The residue was concentrated with benzene. Recrystallize with a mixed solvent of petroleum ether to obtain the desired diastereoisomer (31 g, 60%). The analysis data is the same as that of the compound prepared in Example 1. Column), the ratio of the di-isomers is about 1: 1. Example 5 Cyclization of 7-ethylchromeol and an ene ether derivative of 3-ketovalerate to make the paper scale applicable to the Chinese National Standard (CNS ) A4 size (210 X 297 mm) -------- 「—! ^ ------ Order ------ r「 f Please read the precautions on the back of Jing before filling this page 4 2668 5. Economy Printed on A7 B7 by the Consumers 'Cooperative of the Central Bureau of Quasi-Economy. 5. Description of the invention (9) Preparation of ester diastereomers: 7-ethyl tryptanol (29.2 g' 0.154 mol) and the one obtained in Example 3 3_ Ketovalerate's ether derivatives (4.1 g, 0,154 moles) were dissolved in dry digas methane (2500 ml) and a catalytic amount of BF3OEt2 (0.6 ml, 4.77 mmol) was added and then at room temperature After stirring for 2 hours, the resulting solution was diluted with ice water, and then washed with a 1Q% sodium bicarbonate aqueous solution, and then washed with water. The organic solution was concentrated after drying over anhydrous magnesium sulfate, and the residue was mixed with benzene and petroleum ether. The solvent was recrystallized to obtain the desired diastereomer (58 g '89%). The analytical data was the same as that of the compound prepared in Example 1' by HPLC analysis (palm tube. Column). The ratio of the isomers is about 1: 1. Example 6 Partial Crystallization of Ester Diastereomers The ester diastereomers (10 g, 0.0236 mole) was added to 70 ml of absolute ethanol, and after stirring for 15-15 minutes, the solution appeared clear Then, when the solution was cooled to room temperature, 50 mg of an ester compound formed by esterification of (+)-Itodol and (1R, 2R, 3R, 5SH-)-isosinol was added. As a seed crystal, the needle crystals (5.99 g, 60%) were collected by β filtration after standing at 0 ° C for 4 hours, and the melting point was 115-117 ° C, [a] D = -72. (C = l'0, ethanol). Example 7 (Ten Itorodore and (1R, 2R, 3R, 5SV1 Epinenol) Take the needle-shaped crystals that were early separated from Example 6, grams, Moore) and hydrogen Potassium oxide (3.5 g, 0.06 25 mol) was added to methanol (100 ml) and water (26 ml) and then heated under reflux for 2 hours, and the resulting solution was distilled off under reduced pressure. This paper is in accordance with Chinese national standards (CNS ) Λ4 gauge pile (210X ^ 7 male rear) " --------- V ------ Order -------, "(Please read the precautions on the back before filling in this Page} A7 V. Description of the invention (10) Methanol, after diluting the residual liquid with water, #extract with methane, the extract was recovered by drying and concentration (1R, 2R, 3R, 5S) _Isopyron algae (2 38g, 98 / 〇), all of its analysis data are with the commercial standard The same product. The aqueous layer was acidified with concentrated hydrochloric acid to ρΗ = ι, and then extracted with methane gas. The extract was dried and concentrated to obtain (+) Itodore (40 g, 98〇 / 〇). (c = zlO, ethanol), optical purity 99.0%. --------. 1 ------ Order ------- * 4ri (Please read the notes on the back first and fill out this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Standard home country and middle school use moderate rule paper S Ν grid 4

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Claims (1)

For the month 614 (% Zhili ,; s — Chinese applied for the name of the public (September 6th, application for a patent 囷 1 · An optical analysis method for the anti-arthritis drug etodolac), which includes: υ Form (earth) -esterol diastereomers of itodore and (ir, 2R, 3R, 5S) _isopinocamphenol; 2) Partial crystallization in a suitable solvent Function to separate the ester diastereomers obtained, wherein the appropriate solvent is selected from the group consisting of c5_c1 () alkanes, Cl-Ce aliphatic alcohols, tCi_C6 compounds substituted with 1-3 halogen atoms, and associations, C2_C: 0 ethers, benzene, toluene, or dimethylbenzyl, or a mixture of two or more of these solvents; and 3) performing hydrolysis to recover a single itodore optical isomer. 2 · The method according to item 1 of the scope of patent application, wherein the method of step 丨) forming ester diastereomers includes a) (±) _Itodole and (1R, 2R, 3R, 5S)- (-) _ Isospinol reacts directly to generate the ester diastereomer, or b) 7-ethylchromeol and a 3-ketovalerate or its ether derivative in Louis In the presence of an acid, this ester is a non-enantiomeric isomer through a cyclization reaction, in which 3-ketovalerate is composed of 3-ketovaleric acid and (1R, 2R, 3R, 5S) -iso pine It is prepared by esterification of alginate. 3. The method according to item 2 of the scope of patent application, wherein the Lewis acid is selected from the group consisting of dentified boron, autophosphorus, zinc digas, tin tetragas, or aluminum. 4. The method according to item 1 of the scope of patent application, wherein the solvent used for part of the crystallization is Ci-Ce aliphatic alcohol. 5_ According to the method in item 4 of the patent scope, the solvent used for some of the crystallization is anhydrous ethanol. 6_ The method according to item 1 of the scope of patent application, wherein the crystallization of step 2) is made by the standard ^ -¾— (please read the notes on the back before filling in this X) II Shellfish Consumption of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a cooperative CHO 426685, storage C8 D8 々, patent application scope It can increase the crystallization rate by adding seed crystals. 7. The method according to item 3 of the scope of patent application, wherein the Lewis acid is selected from BF3 OEt! Or BF3. 8, —An ester with the following chemical structure: (Please read the notes on the back before filling out this page) Printed by the Male Workers Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) For the month 614 (% Zhili ,; s — Chinese applied for the name of the public (September 6th, application for a patent 囷 1 · An optical analysis method for the anti-arthritis drug etodolac), which includes: υ Form (earth) -esterol diastereomers of itodore and (ir, 2R, 3R, 5S) _isopinocamphenol; 2) Partial crystallization in a suitable solvent Function to separate the ester diastereomers obtained, wherein the appropriate solvent is selected from the group consisting of c5_c1 () alkanes, Cl-Ce aliphatic alcohols, tCi_C6 compounds substituted with 1-3 halogen atoms, and associations, C2_C: 0 ethers, benzene, toluene, or dimethylbenzyl, or a mixture of two or more of these solvents; and 3) performing hydrolysis to recover a single itodore optical isomer. 2 · The method according to item 1 of the scope of patent application, wherein the method of step 丨) forming ester diastereomers includes a) (±) _Itodole and (1R, 2R, 3R, 5S)- (-) _ Isospinol reacts directly to generate the ester diastereomer, or b) 7-ethylchromeol and a 3-ketovalerate or its ether derivative in Louis In the presence of an acid, this ester is a non-enantiomeric isomer through a cyclization reaction, in which 3-ketovalerate is composed of 3-ketovaleric acid and (1R, 2R, 3R, 5S) -iso pine It is prepared by esterification of alginate. 3. The method according to item 2 of the scope of patent application, wherein the Lewis acid is selected from the group consisting of dentified boron, autophosphorus, zinc digas, tin tetragas, or aluminum. 4. The method according to item 1 of the scope of patent application, wherein the solvent used for part of the crystallization is Ci-Ce aliphatic alcohol. 5_ According to the method in item 4 of the patent scope, the solvent used for some of the crystallization is anhydrous ethanol. 6_ The method according to item 1 of the scope of patent application, wherein the crystallization of step 2) is made by the standard ^ -¾— (please read the notes on the back before filling in this X) II Shellfish Consumption of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a cooperative