JPS5925356A - (d)-2-(6-methoxy-2-naphthyl)propionic acid, medicinally acceptable salts and manufacture of novel intermediates - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides (d)-2-(6-medoxy-2-naphthyl)
The present invention relates to a method for producing propionic acid and its pharmaceutically acceptable salts. In the following, these will be referred to as naproxen and naproxen salt, respectively.

Naproxen is a well-known anti-inflammatory, analgesic and antipyretic agent.

Naproxen and naproxen salts are optically active substances and can generally be prepared from a mixture of the (d) enantiomer and the C1,) enantiomer.

European Patent Application No. 79102502.6 and European Patent Application No. 80103828.2 contain N-R as a resolving agent.
-D-glucamine (wherein R is alkyl having 1 to 36 carbon atoms or cycloalkyl having 3 to 8 carbon atoms) or a salt thereof is described to produce naproxen and naproxen salts. has been done. The resolution method described in these two European patent applications involves forming a salt of a mixture of the two enantiomers with N-R-D-glucamine, and then subjecting this salt to fractional crystallization in a relatively Separation of the less soluble naproxen salt from the other relatively more soluble enantiomer salt by crystallization is included. British Patent Specification No. 1,274,271 has d.

The preparation of no-2-(5-hero-6-medoxy-2-naphthyl)propionic acids and that these acids can be resolved with alkaloids such as cinchonidine is described.

In the present invention, N-R-D-glucamine (wherein R is alkyl having 1 to 18 carbon atoms, preferably 2 to 18 carbon atoms or cycloalkyl having 3 to 8 carbon atoms) ) or salts thereof, preferably N-R-D-glucamine in which R is alkyl or cycloalkyl having 5 to 8 carbon atoms, prepare certain naproxen precursors that can be easily converted to naproxen. It has been found that it can be used as a resolving agent for Therefore, the present invention includes N-R-D-glucamine or a salt thereof as a resolving agent for producing a naproxen precursor.

These resolving agents form diastereomeric (d) naproxen precursor salts from which the naproxen precursor salts can be isolated. Preferred separation methods include fractional crystallization of the diastereomeric salts. .

Accordingly, the present invention encompasses the use of these resolving agents in conjunction with a naproxen precursor that has the same propionic acid functionality as naproxen while at the same time displacing the moiety remote from the chiral center of the naproxen molecule. characterized by the presence of substituents located at . These substituents can be easily converted to naproxen substituents. In a preferred embodiment, the distance between the point of attachment of these substituents to the naphthalene ring and the chiral center, ie, the carbon atom to which the methyl group is attached, is about 5.8
~6.6X. Particularly preferred substituents in the present invention are a halogen substituent at the 5-position of the naphthyl ring and a hydroxyl group at the 6-position of the molecule. Both groups can be easily converted into substituents of naproxen (ie, a bulky atom for the 5-position and a methoxy group for the 6-position) while maintaining the configuration of the molecule.

More specifically, the naproxen precursor has the general formula:
X is selected from the group of chlorine and bromine, p
and when n is 1, R' is hydrogen or methyl, or when n is O, R1 is hydrogen.] These naproxen precursors also include salts of the compound represented by general formula (1).

The compound of general formula (1) in the form of a racemic mixture is a known compound. For example, compound (d,t)-2-(5
-bromo-6-medoxy-2-naphthyl)propionic acid is described in German Patent No. 1.934,460 [
This is a compound in which R' is methyl, X is bromine, and n is 1 in the general formula (I). Belgian Patent No. 752,627 discloses compounds of general formula (I) in which R' is methyl, X is chlorine, and n is 1
) has been described in the form of its racemic mixture.

West German patent application No. 1793825 and Italian patent application No. 25778-A/76 disclose compounds of general formula (1) (wherein R1 is hydrogen, X is halogen, Q, and n is 0 or i). ) have been described in the form of their racemic mixtures.

However, salts of compounds of general formula (I) and individual enantiomers of compounds of general formula (I) have not been previously disclosed.

In summary, the process of the present invention comprises N-R-D-glucamine, where R is alkyl having 1 to 18 carbon atoms, preferably 2 to 18 carbon atoms or 6 to 18 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms) or salts thereof to resolve a mixture of (d) enantiomer and CI) enantiomer of general formula (1) or a mixture of their soluble salts. , substantially the N-R of the naproxen precursor
- forming a product consisting of a D-glucamine salt, which product is cleaved into a free naproxen precursor, which precursor is then sequentially converted into nazoloxene or a pharmaceutically acceptable naproxen salt; can be converted.

Racemic mixtures of compounds of general formula (I) are preferred starting materials for the process of the invention, although racemic mixtures result after carrying out known chemical syntheses.

As used herein, the term "6alkyl" refers to straight-chain and branched-chain hydrocarbon groups having from 1 to 18 carbon atoms. Typical alkyl groups include methyl, ethyl, n -propyl, I-propyl+n-butyl, i-butyl, n-hexyl.

n-octyl 8 n-dodecyl, n-octadecyl, etc. are included.

The term "cycloalkyl" as used herein is 3-
Refers to an alicyclic hydrocarbon group having 8 carbon atoms.

Typical cycloalkyl groups include cyclopropyl, cyclobutyl, Schiftepentyl, cyclohexyl, methylcyclohexyl, cycloheptyl and cyclooctyl. Among the cycloalkyl groups, cyclohexyl and cycloheptyl are currently preferred.

Preferred resolving agents include N-alkylglucamine (with the exception of R
is alkyl having 2 to 18 carbon atoms), and a more preferred resolving agent is N-alkylglucamine, where R is alkyl having 6 to 18 carbon atoms.

Particularly preferred resolving agents at present within the scope of the invention are:
N-ethyl-D-glucan, N-n-propyl-D-
1' lucamine + N-n-7" thi-D-glucamine, N-n-octyl-D-glucamine, N-decyl-D-" lucamine and n-hexadecyl-D-glucamine.

In general formula (I), a naproxen precursor in which R1 is hydrogen, X is a halogen selected from the group of chlorine and bromine, and n is 1, or R1 is hydrogen and n
The presently preferred resolving agent in connection with the naproxen precursor where is O is N-methyl-D-glucamine.

The resolving step of the present invention involves a step in which there is no significant difference between the solubility of the salt of the naproxen precursor of general formula (I) and the resolving agent, and the solubility of the salt of the other enantiomer and the resolving agent. It is carried out in an active organic solvent, usually at a temperature between room or ambient temperature and elevated temperatures up to the reflux temperature of the commonly used solvent. Naproxen precursors and resolving agents (e.g., N-methyl-D-glucamine, N-n-10vir-D-1''lucamine.

The salt with N-butyl-D-glucamine or N-octyl-D-glucamine is significantly less soluble in the selected solvent than the salt with the other enantiomer and the resolving agent. .

Therefore, when a heated solution of these salts is cooled to usually near ambient or room temperature, such salts consisting of naproxen precursor and resolving agent will preferentially crystallize out of the solution. Suitable solvents include water, such as methanol.

ethanol, n-pro/(nol, impropatol,
Butanol, pentanol, hexanol.

Cyclohexanol, 2-ethylhexanol.

C of benzyl alcohol, furfuryl alcohol, etc. ~
C1o monohydric alcohols (particularly Cl-CIO alkano-/'), e.g. evapoethylene glycol, 1.2-propylene glycol, 1. 02-C6 dihydric alcohols such as 3-zo-pyrene glycol, C3-C4 trihydric alcohols such as e.g. evaglycerol, e.g. acetone, acetylacetone, ethyl methyl ketone.

Included are Cl to Cl ketones such as diethyl ketone, di-n-propyl ketone, diisopropyl ketone, and diisobutyl ketone. Other solvents include mono- and di(lower) alkyl ethers of ethylene glycol and diethylene glycol, dimethyl sulfoxide, sulfolane,
These include formamide, dimethylformamide, N-methylpyrrolidone, pyridine, dioxane, dimethylacetami F, and the like.

C1-C3 alcohols, such as methanol and impropatol, especially methanol, are currently preferred solvents. Sufficient water can be added to the solvent if all of the material added to the solvent must be dissolved. A mixture of a polar solvent and an aromatic hydrocarbon such as toluene or benzene, for example a mixture of methanol and toluene (metal being the main component), can be used as the solvent medium.

The starting material (i.e., a mixture of the naproxen precursor and another enantiomer or a mixture of soluble salts thereof) is heated in the presence of a resolving agent to an elevated temperature, typically ranging from about 6 oc to about 100 C or the reflux temperature of the solvent. Heat is applied to dissolve all of the starting material added to the solvent.

If desired, the solvent can be maintained at an elevated temperature until all of the starting materials are dissolved. After maintaining the solution at elevated temperature for the desired period of time, it is preferred to allow the solution to reach ambient temperature. The resulting crystalline precipitate is rich in salts of naproxen precursor and resolving agent. The final temperature to which the solution is heated is selected based on practical considerations, but is usually selected such that the temperature difference provides a sufficiently high yield of crystals. The crystallization mixture may be maintained at a relatively low temperature until crystallization is complete or nearly complete, usually on the order of about 30 minutes to about several hours. The resulting crystalline precipitate is filtered off and washed.

The crystalline material (i.e. the salt-rich material of naproxen precursor and resolving agent) obtained at this stage of the process of the invention after separation by filtration and washing is placed in water and heated if necessary. and redissolve the crystalline material. For N-R-D-glucamine that is soluble in water, the resulting solution is acidified, for example using a mineral acid such as sulfuric acid or hydrochloric acid, or an organic acid such as acetic acid, and the solution obtained in this way is The crystalline precipitate is separated by one filtration, washed and dried. A crystalline product is obtained consisting essentially of naproxen precursor. For glucamines that are not soluble in water, a salt-rich substance consisting of the naproxen precursor and such a resolving agent is added to e.g. potassium hydroxide or other strong base with a pKa value greater than 10 to cleave the salt. treated with a strong base such as
It is then filtered to remove the resolving agent and treated with 1 solution' (il
- After acidification, filtration, washing and drying, it is possible to obtain a crystalline product consisting essentially of naproxen precursor.

In order to obtain an optically pure naproxen precursor, prior to the cleavage of the salt-rich material of the naproxen precursor and the resolving agent, the naproxen precursor and the resolving agent are further recrystallized one or more times in a solvent. The salt-rich substance is redissolved, the solvent is heated to the desired temperature (usually elevated temperature), the crystallization of the resulting solution is promoted by the salt of the naproxen precursor and the resolving agent, and the resulting solution is Cooling is preferred. Each such recrystallization further increases the proportion of naproxen precursor and resolving agent salts in the recrystallized material. By performing a single recrystallization step prior to redissolving and subsequent acidification of the resulting crystalline product, a purity product containing approximately 97-99% of pure naproxen precursor is obtained. K, N-#-ru D-f Kamin because it can be done,
N-ethyl-D-glucamine, N-propyl-D-
Glucamine, N-n-butyl-D-glucamine, N-n
-hexyl-D-glucamine and N-n-octyl-D
- Glucamine is a particularly suitable resolving agent within the scope of the invention.

However, the salt of the resolving agent and naproxen precursor can be easily recovered by filtration and has an acceptable high optical purity without the need for one or more recrystallizations prior to the cleavage step. N-methyl-
D-glucamine, N-ethyl-D-glucamine and N-
n-octyl-D-glucamine is the currently preferred resolving agent. Additionally, the cleavage can be carried out under alkaline or acidic conditions.

N-n-octyl-D-glucamine is virtually insoluble in water, thus making it possible to recover it from aqueous systems in high yields. This also applies to other resolving agents of the invention in which R is an alkyl having at least 6 carbon atoms, such as in which R is an alkyl having 6 to 18 carbon atoms. .

To recover the other enantiomer, a substance enriched in the other enantiomer of the general formula <Il or their N-R-D-glucamine salts, where R is the same as defined above, is used. can be processed. This substance can then be racemized according to known methods.

See for example 1) yson US Pat. No. 3,686,183.

The amount of resolving agent used in accordance with the present invention (of the general formula (11) to be resolved (on a molar basis relative to 1,1 acid) ranges from about 50 to 100 parts. B16 of the remainder of the resolving agent, if desired, since only about 50% (on a molar basis relative to the d,l acid being resolved) of the resolving agent is required to form a relatively insoluble salt consisting of the resolving agent. minutes (usually on the order of up to about 40-50 moles) can be replaced by relatively inexpensive bases.

These bases include inorganic bases such as alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, or organic tertiary amines such as triethylamine, triethanolamine, tributylamine, etc. with a pKa value of at least 8. Organic bases having the following are included.

The term "mixture of di enantiomer and (1) enantiomer" represented by general formula 1 includes salts of these enantiomers that are dissolved in the solvent used in the resolution method of the present invention. Such salts include, for example, the corresponding sodium salts, potassium salts, lithium salts, etc. Such salts are represented by the general formula (I) (dllbutyric acid fJ
It may be prepared by adding an alkali metal hydroxide, for example a base such as sodium hydroxide or potassium hydroxide, to a solution of a mixture of I-form acids. A mixture of d-2-(6-medoxy-2-naphthyl)propionate and no-2-(6-medoxy-2-naphthyl)zolopionate is prepared according to the invention by d-2,-(6-medoxy-2-naphthyl). can be resolved by using a salt of a resolving agent that reacts to form the NRD-glucamine salt of naphthyl)propionic acid. Suitable glucamine salts include inorganic or organic acid salts, such as hydrochloride and acetate. Others include propionate, butyrate, isobutyrate, sulfate, nitrate, maleate, etc. Therefore, the term “'N-
R-D-glucamine'' (where R is the same as defined above) is a combination of d-2-(6-medoxy-2-naphthyl)propionic acid and!!-2-(6-medoxy-2-naphthyl) When used with a suitable salt of a mixture of zolopionic acids, N can result in the resolution of the present invention.
- is meant to include salts of glucamine.

The acid represented by general formula (i) is produced by the known method as explained above. West German Patent No. 1,934,46
0, Belgian Patent No. 752,627, West German Patent Application No. 1.668,654, West German Patent Application No. 1,793,
No. 825 and Italian Patent Application No. 25778-A/76
I would like to see the publication published.

After obtaining the naproxen precursor of general formula (I) in optically pure or crude form, this precursor can be converted into naproxen or a pharmaceutically acceptable salt thereof. For compounds of general formula (I) where R1 is ice water or methyl, SX is halogen and n is 1, conversion to naproxen requires dehalogenation of the compound of general formula (I). do. This method thus requires exchange of the halogen with ice water.

When R1 is ice water, X is halogen, and υ and n are 1, it is preferable to first methylate the compound and then remove the 5-position halogen, as explained below.

The naproxen precursor 2-(5-halo-6-medoxy-2-naphthyl)propionic acid can be subjected to a dehalogenation reaction. This reaction does not affect the structure of the rest of the molecule during the formation of naproxen. Suitable methods include magnesium alcoholades, e.g., alkaline earth metal alcoholades such as magnesium methylate, and tri(lower) alkyl amines, e.g. triethylamine, in an inert solvent such as an alcohol or alkanol to produce the alcoholade or alkaloid. The reaction of a tertiary amine such as a tertiary amine with a resolved 5-eno compound of general formula (I) is included. The reaction is carried out between 30°C and the reflux temperature of the solvent. For example, a mixture of magnesium powder, methanol and a molar excess of triethylamine is mixed and the mixture f is maintained under an inert atmosphere, such as a nitrogen atmosphere. The resolved 2-(5-halo 6-medoxy-2-naphthyl)zolopionic acid is added to the anhydrous methanol solution. After the reaction is complete, ie after 1 hour at reflux temperature, hydrochloric acid is added to the reaction mixture in order to dissolve all the remaining magnesium. Naproxen can be recovered from the reaction mixture by known methods. For example, the reaction mixture containing naproxen can be poured into water and extracted using a suitable solvent such as methylene chloride. The organic layer is separated and washed with water to crystallize pure naproxen. In another variant, naproxen of general formula (1) (i
at least 2 molar equivalents, preferably 2 to 50 molar equivalents (calculated on aluminum) of a nickel-aluminum compound in the presence of ~50 molar equivalents of alkali metal hydroxide;
Kanamata Hakoha A Door A/ Miniram alloy and 5-no.
The reaction is allowed to proceed until four groups are removed. Preferred nickel-aluminum or cobalt-aluminum alloys have grain sizes of 1 millimeter or less and the aluminum concentration should be at least 10% by weight of the alloy. Suitable alkali metal hydroxides are sodium hydroxide, potassium hydroxide or lithium hydroxide. This reaction is carried out in an inert solvent. Preferred inert solvents are methanol, ethanol, solo/1i-nol, isoprono-9ol, tertiary-butanol, tetrahydrofuran or dioxane. The reaction temperature is between 0°C and the reflux temperature of the solvent, preferably at least 40°C. The reaction time is 15 minutes to 12 hours.

When the resolved general formula (I>05-halo compound is combined with a mixture of magnesium (preferably as a powder with a particle size of less than 1 millimeter), a lower alkanol and optionally a molar excess of an aliphatic amine, naproxen is produced.
can be obtained by direct reaction. The reaction is carried out at a temperature of 0°C to the reflux temperature of the reaction mixture, preferably at least 20°C, and under an inert atmosphere such as nitrogen. 5-
The time required for reduction of the halo group depends on the reaction temperature. Usually, 10 minutes to 12 hours is sufficient for this reaction. At reflux temperature, the reaction is complete within 1 hour.

Alternatively, a 5-halo compound represented by general formula (I),
lower alkanol, ethyl acetate, optionally under hydrogen.
The esters are treated in an inert organic solvent such as an ester having up to 2 carbon atoms or a lower alkanoic acid such as acetic acid or propionic acid. The reaction is at least 0°C,
Preferably, it is carried out at a temperature above 20°C for a period of 10 minutes to 24 hours. Reflux temperature is preferred.

In yet another method, the general formula (f)
79 radium on charcoal (palladium-on-cl+arcoal) using hydrogen.
.

Treat with platinum or platinum oxide. The reaction is carried out for a period of 10 minutes to 12 hours at a temperature from 0 DEG C. to the rapid flow temperature of the solvent, although room temperature is preferred.

The crude naproxen precursor of general formula CI), where R1 is hydrogen and n is 0, can be converted directly to naproxen. Similarly, this material can be refined to the desired optical rotation by crystallization and then converted to naproxen. Conversion to naproxen is carried out by treating the naproxen precursor with a suitable methylating agent.

Methylation involves the reaction of dimethyl sulfate, dimethyl carbonate or dimethyl halide with a naproxen precursor of general formula (I), ie a 6-hydroxy compound, in an alkaline medium. Water or lower aliphatic alcohols can be used as suitable solvents. To form an alkaline medium, sodium hydroxide, potassium hydroxide,
Sodium carbonate or potassium carbonate can be used. The reaction is carried out at a temperature ranging from 40°C to the reflux temperature of the reaction mixture. The optimum reaction temperature would be 40-70°C. Although the reaction time depends on the reaction temperature, the reaction is generally complete within 1 to 10 hours.

Isolation of naproxen can be accomplished by adding a solution of a strong organic or inorganic acid to the cooled and separated reaction mixture to acidify the mixture. The recovered precipitate is washed and then dried at low temperatures until the naproxen is affected by a drying operation. According to the above-mentioned method, a naproxen precursor of general formula (I) (wherein R
is hydrogen, X is halogen, and n is 1) can be methylated and then dehalogenated as described above.

In order to obtain a substance with an extremely excellent optical rotation, that is, [α':l, = 62-67° (chloroborm), the general formula (
Dehalogenation of the 5-halo compound of I) or general formula (I)
The naproxen obtained from either the methylation of the 6-hydroxy compound can be recrystallized.

naproxen with at least a slightly different organic or inorganic base;
The naproxen obtained by the process of the invention can be converted into a pharmaceutically acceptable salt, preferably by reaction with sodium hydroxide. The reaction is carried out in an inert solvent at a temperature between 0° C. and the reflux temperature of the solvent, optionally after removal of a portion or all of the solvent, and the naproxen salt is crystallized from the solvent. Crystalline salt materials can be recrystallized to increase purity.

Example 1 d,l-2-(s-hydroxy-2-naphthyl)propion v5 (l) with 215 ml of methanol and Toluev 1
The d,l-2-(6-hydroxy-2-naphthyl)propionic acid was dissolved by heating in 3.8 ml.

67.85' of N-n-octyl-D-glucamine was added, and the solution was cooled in a 40° C. trench to convert d-2-(6-hydroxy-2-naphthyl)furopionic acid into N-d-2- (
N-n of 6-hydroxy-2-naphthyl)progionic acid
-Octyl-D-glucamine salt was obtained. This salt has a specific rotation of 191.3° in chloroform after cleavage.
This yielded 11.55' of -2-(6-hydroxy-2-naphthyl)propionic acid. The yield was 23.0%.

6-Hydroxinaproxen precursor 10.5t was mixed with 60mJ of acetone and 1.5N hydrium hydroxide aqueous solution 1QQ.
mt, and 44% methyl iodide is added to this solution. was added. This solution was maintained at 0-20°C for 14 hours. The resulting naproxen methyl ester was hydrolyzed in situ to naproxen under basic reaction conditions. Conversion of 6-hydroxynaproxen precursor to naproxen is 90
A yield of 3 moss was achieved. The specific optical rotation of the naproxen obtained was +63.5° in chloroform.

Example 2 d,l -2-,(6-hydroxy-2-naphthyl)propionic acid 17. Of and N-methyl-D-glucami/
15.34f' was dissolved in 150+n/! of boiling methanol containing 2010 ml (10% by weight) of I.

? #The solution was filtered through a clearing tube, slowly stirred and carefully cooled to 45° C. to obtain the N-methyl-D-glucamine salt of 6-hydroxynaproxen precursor. The resulting salt was slurried three times from the same solvent system and after cleavage,
d-2-(6-hydroxy-2-naphthyl)zolopion 193.1r with a specific optical rotation of +91.7° in chloroborm was obtained with a yield of 18.3%.

After performing the operations described in Example 1, d-2-(6-
d-2-(6
-Medoxy (2-naphthyl) propionate.

Example 3 d,l -2-(5-bromo-6-medoxy-2-naphthyl)zolopionic acid 252, N-n-octyl-D-glucamine 23.7? and 10% in methanol) was refluxed to dissolve the crystalline material.

The reaction mixture was maintained at reflux for 20 minutes and then allowed to cool slowly. At 30°C, the N-
The seeds were prepared using 11-octyl-D-glucamine salt to promote crystallization. The reaction mixture was then left at room temperature overnight.

The precipitate was removed by filtration using yc and I-1, and washed with 30 mt of cold methanol to give d-2-(5-bromo-6-
A substance 16.74 enriched in the N-n-octyl-D-glucamine salt of medoxy-2-naphthyl)propionic acid was obtained.

Suspend 1.01 sample of this salt in 5 On 1 g of water? The mixture was boiled, heated to 80°C, and then fermented with concentrated iCl. The precipitate concentrated for d-2-(5-bromo-6-medox-7-2-naphthyl)propionic acid was isolated by one filtration at 50°C, washed with water and dried in a vacuum oven.

The obtained compound is [α):=+28.2°(C=CHC
0.5% in l1) e showed.

d-2-(5-bromo-6-medoxy-2-naphthyl)
The remaining 15.7 f of substances rich in propionic acid salts
As a solvent, add 2 ml of toluene and 1 ml of methanol at reflux temperature.
Dissolved in 8ml. The solution was cooled to 25°C and c+-
2-(5-Bromo6-Medoxy) was allowed to stand. The precipitate was isolated by filtration and washed with 20 ml of cold methanol.

The isolated material was suspended in 100 mJ of water, heated to 80° C. and acidified with I.Cl. The precipitate was separated to give substantially pure d-2-(5-bromo-6-methoxy-2
-naphthyl)zolopionic acid (Cα]”=+42.s°,
C=CHC1, 0.5%) 5.52 was obtained.

The resulting 5-promonazoloxene precursor ffJ was deodorized and concentrated to give, after operation as described above, a nazoloxene having a specific rotation of 64° in the chlorophonium.

Example 4 Triethylamine 2.42 f, d,l-2-(5-bromo-
15V of 6-medoxy (2-naphthyl)propionic acid was heated until reflux occurred. The reaction mixture was maintained at reflux for 20 minutes and then slowly cooled. At 30°C, a small amount of d-2-(5-bromo-6-medoxy-2-
Nn-octyl-D-glucamine salt of naphthyl)propionic acid was added to promote crystallization. The reaction mixture was then left at room temperature overnight. -X! 2 Isolate the precipitate by filtration and wash with 20 ml of cold methanol to remove the N
- Substances rich in n-octyl-D-glucamine salts 4.47
I got ft.

Substance 4 enriched in the salt of d-2-(5-bromo-6-medoxy-2-naftino)zolopionic acid at the reflux temperature of the solvent.
．． 47r was dissolved in 1μ of toluene and 9ml of methanol. The solution was cooled to 30°C, and the N-n
-Crystallization was promoted using octyl-D-glucamine salt, and the mixture was incubated overnight.

The precipitate was isolated by filtration and washed with 10 ml of cold methanol. The isolated material was suspended in 75 ml of water and heated to 80°C.
The precipitate was isolated and d-
A substance substantially enriched for 2-(5-bromo-6-medoxy-2-naphthyl)propionic acid ([α],=
+42°, (C=CH (J, middle 0.5 section)) 1.
Obtained 2y.

The prepared 5-promonaproxen precursor was debrominated to give nazoloxene after working up as previously described.

Example 5 d,l 5.30y of -2-(5-chloro-6-nodoxy-2-naphthynosy)solopionic acid was heated with isopropanol ♀ to around the reflux temperature of the solvent to dissolve d,1ffi. N-ethyl-D-glucamine 2092 (0,
5) and bring the solution to room temperature (i.e. about 20-23°C).
The mixture was cooled in a microwave oven to obtain Yumumasu 42, which is rich in the N-ethyl-D-glucamine salt of the nazoloxene precursor acid with a relatively small double angle and fIW. Seedlings were placed in rows 1/1 in water heated to about 80°C and treated with hydrochloric acid until they became acidic as naproxen-5I acid-rich substances precipitated from the bath solution. and recovered by filtration.

Reduction of solvent i1 + Ir, isopropanol 1
9.5rnt and 1.5p+/water. The solution was cooled to room temperature' to obtain -77J: crystalline salt 0.50r. This material was treated with hydrochloric acid as described in the previous section (Ragraff) to obtain a material that was further enriched for the nazoloxene precursor acid. )-2-(5-chloro-6-medoxy-2-naphthyl)propionic acid 11 was treated in small portions with nickel-anodized Miniram Alloy 32. The mixture was stirred for 2 hours, filtered once, diluted with excess dilute hydrochloric acid, and extracted with methylene chloride.

The organic layer was evaporated to dryness and the residue was recrystallized from methylene chloride-hexane to give 2-(6-medoxy-2-naphthyl)propionic acid ([α]o=6° in chloroporm).
I got it.

The above-mentioned operation was repeated using the corresponding 5-bromo compound to obtain [α]D-61.0 (chlorophonium) nazoloxene after recrystallization.

Example 6 6.22 d,l-2-(5-bromo-6-medoxy-2-naphthyl)propionic acid was added to 30 ml of Impropatool
and triethylamine/], 01f'(0
, 5) and heated to around the reflux temperature of the solvent,
d, l-acid was dissolved. N-ethyl-D-glucamine 2
．． 09F was added and the solution was cooled to room temperature to yield N-ethyl-D-glucamine salt enriched material 4.32r. A sample of this material was dissolved in approximately 25 ml of water heated to approximately 80°C, treated with hydrochloric acid until acidic as the nazoloxene precursor acid-rich material precipitated from solution, and recovered by filtration.

A substance rich in N-ethyl-D-glucamine salts, ooy, was dissolved in 20 ml of an aqueous solution of 5 polyisoprono(Nor/L) and 1.0 d of water near the reflux temperature of the solvent. The solution was cooled to room temperature 1 and initially 0.6? of recrystallized material was obtained. A sample of the recrystallized material was treated with hydrochloric acid as described in Section 7 (Ragraff) above, and 0.6?
Dissolved in 10ml of q6 Impropanol/L aqueous solution and 0.5ml of water. The solution was cooled to room temperature to obtain M2 recrystallized material of 0.437.

A sample of the recrystallized material was treated with hydrochloric acid as described in the first paragraph of this example to obtain more optically pure material.

The second recrystallized material from the previous paragraph 0.332
At around the reflux temperature of the solvent, add 12 rnl of a 5-thiisopropanol aqueous solution and 1. 'Dissolved in Oml. The solution was cooled to room temperature, yielding 0.271 of the third recrystallized material. This recrystallized material was treated with hydrochloric acid as described in the first paragraph of this example to obtain substantially pure 5
-Promonaproxen precursor was obtained.

Magnesium powder (6C1) was added to a 250 mJ flask equipped with a reflux condenser and nitrogen bubbler, followed by anhydrous methanol (50i+/) and triethylamine (ICI). The flask was flushed with nitrogen and a nitrogen atmosphere was maintained during the reaction.

5-promonaproxen precursor (0,1-E-nyl) in methanol (15r) was added slowly and the mixture was heated under reflux for another hour after the addition of 5-promonaproxen precursor was complete. The cooled mixture was mixed with 6N hydrochloric acid in the trench where the magnesium disappeared. The mixture was poured into water and extracted with methylene chloride. The organic layer was separated, washed with water, the solution was concentrated and crystallized by adding hexane. After recrystallization, the nazoloxene with a specific rotation [α]D-64° in chloroform was purified.

This procedure was repeated with the corresponding 5-chloro-naproxen precursor to obtain a specific rotation of 62° in chloroform.
Nazoloxene having the following properties was obtained.

Example 7 d,l -2-(5-chloro-6-medoxy-2-naphthyl)propionic acid 31 was dissolved in isopropyl alcohol 15
me and 0.5 f triethylamine in 0.5 ml water (
The zolopionic acid was molten by heating with 0,5 H()) near the R flow temperature of the solvent. 1.32 r (0,
5), a precipitate was immediately formed. Further Inzolo/Reel 15i+J and 1.5 rnl of water were added and the mixture was heated to near the reflux temperature of the solvent to dissolve the precipitate.

The solution was cooled to room temperature and the naproxen precursor was dissolved in the naproxen precursor acid. Treat with ln acid until acidic as the enriched material precipitates from solution and recover by υA filtration. - 1.00 ml of a substance rich in glucamine salts and 20 ml of 5-stroke insolono-9-14 aqueous solution
It was dissolved in 1. The solution was cooled to room temperature to obtain the first recrystallized material 0791. A sample of this recrystallized material was treated with hydrochloric acid as described in La Graff (previously) to obtain a material further enriched for the 5-chloro-naproxen precursor.

A solution containing 5 to 12 chloronazoloxene precursors in 10 ml of anhydrous methanol-A was mixed with 11 chloride-nickel and heated at reflux temperature for 12 hours. Filter the mixture;
The f solution was diluted with water. The precipitate was dried and recrystallized from acetone/hexane to obtain naproxen.

Repeat the above procedure with the corresponding 5-bromo-compound to determine the optical rotation [α] in chloroporum.

=60° naproxen was obtained.

The above procedure was repeated using N-methyl-D-glucamine and N-n-octyl-D-glucamine as resolving agents to obtain naproxen having a specific light extinction of 60 to 65° (chlorobosym).

Example 8 d,l -2-(5-bromo-6-medoxy-2-naphthyl)propionic acid 6.21 was converted to isoprono(nol 30
ml and triethylamine yl in 1.5 ml of water. o1
The d,l-acid was dissolved by heating with f (0.5 equivalents) to around the reflux temperature of the solvent. 2.93 f (0.5 eq.) of N-n-octyl-D-glucamine were added and the solution was cooled to room temperature to yield a material 4.51 enriched in the N-n-octyl-D-glucamine salt of the naproxen precursor. Ta. A sample of this material was dissolved in approximately 25 ml of water heated to approximately 80°C, treated with hydrochloric acid in a trench that became acidic as material rich in the naproxen precursor propionic acid precipitated from solution, and recovered by e-filtration. .

N-t>-octino L-D-glucamine salt-enriched naproxen precursor propionic acid near the reflux temperature of the solvent y1. oor inzolopanol 9.52111
and water Q, dissolved in 5 lnl. The solution was cooled to room temperature to obtain 0.85f of recrystallized salt. This material was treated with hydrochloric acid as described in the previous Q graph to obtain substantially pure product.

Equipped with a reflux condenser and nitrogen inlet! 200m1! In a flask, magnesium powder 602, anhydrous methanol, z5
0m/and triethylamine 10f were added.

The flask was kept under nitrogen during the entire reaction period.

0.1 mol of 5-promonaproxen precursor was added dropwise in the form of a solution in 15 r of methanol. After the addition of the 5-promonaproxen precursor under reflux was complete, the mixture was heated for an additional hour. The mixture was cooled to room temperature and 6N hydrochloric acid was added until the magnesium disappeared. The mixture was then diluted with water, methine chloride/methane was added and the mixture was treated with methylene chloride. Separate the i-layer,
Naproxen was crystallized by washing with water, concentrating the solution and adding hexane. After recrystallization naproxen was obtained with a melting point of 155° and [α]D-65°.

Repeating the above reaction sequentially using d, l-2-(5-chloro-6-medquin-2-naphthyl)propionic acid,
Melting point of 154°C and [α]D in chloroborum - 62°
Nazoloxene having the following properties was obtained.

Example 9 d, 7! -2-(6-Hydroxy-2-naphthyl)propionic acid 2.16F was heated to 90° C. with 0.50 r (0.5 eq.) of triethylamine in 30 m/s of ethylene glycol and d,l -2-( 6-hydroxy-
2-naphthyl)propionic acid was dissolved. Add 1.47 f of N-n-octyl-1)-glucamine and bring the solution to 40
The mixture was cooled to 0.degree. C., and crystallization was promoted using crystals of N-n-octyl-D-glucamine salt of d72-(6-hydroxy-2-nityl)propionic acid. The reaction mixture was stirred overnight at room temperature to yield 1.4'l of material enriched in the N-n-octyl-D-glucamine salt of d-2-(6-hydroxy-2-naphthyl)propionic acid. . A sample of this material was dissolved in about 25 +++, l of water heated to about 80°C and d
-2-(6-Hydroxy-2-naphthyl)propionic acid-rich material precipitated from solution by treatment with hydrochloric acid until acidic and recovered by filtration.

2v of 6-hydroxynazoloxene precursor was dissolved in 3Qmi of IN aqueous sodium hydroxide solution and 3.8F dimethysulfate/L was added to this solution. The solution was heated to 60° C. for 2 hours, cooled to room temperature, and then the reaction mixture was acidified by adding dilute hydrochloric acid. The obtained precipitate was filtered, washed with water until it became neutral, and after crystallization [α]D-
Nazoloxene 1.51 m'f4 with optical rotation of 62°
d, A! according to the bag rough method from 1° ago! -2-(6
-Hydroxy-5-bromo-2-naphthyl)fropionic acid was resolved, methylated and then dehalogenated according to the method of Example 4 to give nazoloxene exhibiting [α]D-60°.

Example 10 d, 3.1f of 7-2-(5-bromo-6-medoxy-2-naphthyl)propionic acid was added to 15 l of Impropatool.
and 0.50 f triethylamine in 0.75 ml water.
(0.5 i) and heated to around the reflux temperature of the solvent,
d,l -2-(5-bromo-6-medoxy-2-naphthino)zolopionic acid was dissolved. N-n-dodecy4-
1.759 (0.5 eq.) of D-glucamine was added and the solution was cooled to room temperature to dissolve the N-n of the nazoloxene precursor.
-Dodecyl-D-glucamine salt-rich substance 2.50f'
I got it. A sample of this salt was suspended in approximately 25 rnl of water at room temperature in the presence of 300 ml of potassium hydroxide and maintained at that temperature for 60 minutes. The precipitate was removed by one filtration. 5
- treating the P solution with hydrochloric acid until the promonaproxen premixed fX acid-rich material precipitates out of solution and becomes hostile;
Collected by filtration.

d-2-(,5-bromo-6
- Substance rich in N-n-dodecyl-D-glucamine salt of medoxy (2-naphthyl) propionic acid 1.0 Or 5%
It was dissolved in 20 wt of Inzoro IQ Sole aqueous solution. This solution was cooled to a constant temperature to obtain 0.88r of initial recrystallized material. A sample of this recrystallized material was treated with potassium hydroxide and then with hydrochloric acid as described in the previous paragraph to obtain a more concentrated material.

The first recrystallized material from the previous paragraph [i.e. d-2
- (Similarly concentrated substance for the N-n-dodecyl-D-glucamine salt of 5-bromo-6-medoxy-2-naphthi/I-)propionic acid] 0.62r was injected at 5% in the vicinity of the reflux temperature of the solvent. /QNol aqueous solution 1Srnl. The solution was cooled to room temperature to obtain a second recrystallized material 0.5F.

Magnesium 60? , anhydrous methanol)L 50 ml and triethylamine 10? 250 with reflux condenser containing
5-promonaproxen precursor in methanol (x5r) in a 1nl flask! Gradually add 0.1 mol,
After addition of the 5-prosonaproxen precursor, the mixture was heated at reflux for an additional hour. The flask was flushed for the entire duration of the reaction. After the 5-promonaproxen precursor addition was complete, the cooled mixture was mixed with 6N hydrochloric acid until the magnesium disappeared. The mixture was poured into ice and then extracted with methylene chloride. The organic layer was separated, washed with water, the solution was condensed and crystallized by adding hexane. After recrystallization, naproxen with [α), = 62° was obtained.

This operation was repeated with the corresponding 5-chloro-naproxen precursor to obtain naproxen with an optical rotation of 600.

Example 11 Sodium salt of d,/-2-(5-bromo-6-medoxy-2-naphthyl)propionic acid 135μ at 5%-r
:/ N-n-butyl-D-dalcamine hydrochloride 10 in 2' ml of an aqueous furopanol solution (heated with Iy to a solvent upstream temperature close to 1 μm. The reaction mixture was gradually cooled and a small amount of 5-promonazolkamine was added. N- of presen IvA substance
Promote crystallization using n-butyl-D-glucamine salt,
After subsequent cooling to room temperature, recovery by filtration and washing, 1.10r of material enriched in the N-n-butyl-D-glucamine salt of the 5-promonaproxen precursor was obtained. A sample of this material was dissolved in water, treated with hydrochloric acid until acidic as the d-2-(6-medoxy-2-naphthyl)propionic acid-rich material precipitated from solution, and collected by filtration.

A solution containing 12 of the 5-bromo precursor of naproxen in 40 mJ of anhydrous Methanol L was mixed with 2-N-11 and heated to reflux temperature for 14 hours while introducing hydrogen. This mixture was passed through, and the near P solution was diluted with water. The precipitate was dried and recrystallized from acetone-hexane to yield 65
Naproxen with an optical rotation of ° was obtained.

Example 12 d,7-2- (6-hydroxy-2-naphthi/L-)
2.12 kg of propionic acid was dissolved in 15 mJ of water and heated to about 80° C. with 1.46 F (0.55 eq.) of Kamine. Potassium hydroxide 0.1
7 f(O, 45 mL) was added and the pi of the solution was adjusted to 8 using potassium carbonate. Add a small amount of D-glucamine salt to promote crystallization, cool and prepare N-n-hexyl-D-glucamine salt-rich substance 1 of d-2-(6-hydroxy-2-naphthyl)zolopionic acid. I got .2!M.

The N-n-hexino, -p,, glucamine salt of d-2-(6-hydro-4-cy-2-naphthiA)propionic acid was dissolved in dioxane 15+n/, and 15 mg of an aqueous solution of sodium hydroxide (20%) was added. Add and heat the mixture,
Saturated with methyl bromide. It was then cooled to room temperature, whereby methyl bromide was continuously introduced. After cooling, the reaction mixture was acidified by adding IN aqueous hydrochloric acid and extracted with diethyl/L ether. The extracts were combined, washed with water, dried over sodium sulfate, filtered and evaporated to give Nazoloxe/ with an optical rotation of 58°.

Example 13 d, l-2-(6-hy1
4.60 y of Roxy-2-naphthyl)propionic acid was slurried. N-n-octyl-D-glucamine 3
．． 22F (0.55 eq.) was added and the solution was slowly cooled to 50°C. d-2-(6-hydroxy-
2-naphthi/I-)propio/N-n-octyl- of acid
After adding the D-glucamine salt and stirring the solution overnight, cooling to room temperature and recovering by filtration, the N-n-octyl-D of d-2-(6-hydroxy-2-naphthyl)propionic acid was added. - Substances rich in glucamine salts4. I got Of. N
A sample of this material was suspended in about 25 ml of water in the presence of 300 rng of potassium hydroxide at room temperature and maintained at that temperature for about 60 minutes. The resulting precipitate was removed by filtration.

until a substance rich in d-2-(6-hydroxy-2-naphthyl)propionic acid becomes acidic as it precipitates from solution.
The P solution was treated with hydrochloric acid and collected by filtration.

6-hy120x-naproxen precursor 21 in 1N7
1 (dissolved in 35 mt of aqueous sodium chloride solution and 4 v of dimethyl sulfate was added to this solution.The solution was then heated to 65°C.
The mixture was heated for 2.5 hours and cooled to room temperature. Then -t
The reaction mixture was acidified by adding ri hydrochloric acid. The precipitate formed after addition of further hydrochloric acid was washed with water until neutral, yielding naproxen 1.61 with an optical purity of 64° in chloroform.

Example 14 Racemic 2-(6-hydroxy-2-naphthenic)propionic acid 433F (2 mol) and N-methyl-D-glucamine 390. El (2 mol) was dissolved in 4 g of boiling methanol.

Filter the solution until clear and slowly stir i7 for 4 hours.
Carefully cooled to 5C. Next, 6-hi1! N-methyl-D-glucamine salt crystals of roxinaproxen precursor (obtained in preliminary tests by cooling, scraping with a glass rod, suction filtration, and washing with some methanol) 111", added A large amount of crystals was formed immediately after crystallization was promoted.

The temperature was maintained at 145 G and then gradually decreased to 15 iCt.

The precipitated crystals were separated and washed with a small amount of methanol.

The aggregation was (d)-6-hydroxynaproxen precursor N-methyl-D-glucamine 43 (10,F).

Dissolve the remainder of the precipitate in water and add dilute salt I! +12 was added to make the salt solution completely acidic. (d)-6-Hydroxinaproxen precursor was precipitated.

(d) -2-(6-hydroxy-2-naphthyl)propionic acid 200.9i 1N sodium hydroxide aqueous solution 350
4 (l) of dimethyl UiIJO was added to the solution. The solution was then heated to 60C for 2 hours, cooled to room temperature and the reaction mixture was made malleable by adding dilute hydrochloric acid. The resulting precipitate was separated, washed with water until it became neutral, and then recrystallized to form naproxen 175,118 with an optical rotation of 62°.

Example 15 Triethylamine in 20 mJ of 6% toluene in methanol 1. ．． 6.2 g of 2-(5-bromo-6-medoxy-2-naphthyl)propionic acid were heated to the reflux temperature of the solvent with 01.9, (o, 5 eq.).

and d, no acid was completely dissolved. 1.95 g (0.5 g) of N-methyl-D-glucamine was added and the solution was cooled to room temperature (i.e., about 20-23 C) to form the 5-bromo-naproxen precursor, N-methyl-D-glucamine. A substance 3.52.9 rich in glucamine salts was obtained. The salt was treated with hydroxy acid and collected by filtration.

5-promonaproxen precursor N-methyl-D-
Rich in glucamine salts'I//IJ% 1.00 g 2
It was recrystallized from 10 rne of methanol and 20 ml of ethanol, concentrated at reflux temperature to remove 5 ml of solvent, and cooled to obtain 0.85 g of recrystallized salt. This substance before, t!
Substantially pure 5-promonaproxen precursor was obtained by treatment with hydrochloric acid as described in Raguraf.

A bath solution containing 1y of 5-promonaproxen precursor in 10ml of anhydrous methanol was added to 100ml of palladium on charcoal.
g and stirred at room temperature under hydrogen atmosphere for 12 hours. The mixture was filtered, diluted with water and extracted with methylene chloride. The organic layer was evaporated to dryness and the residue was recrystallized from methyl chloride/hexane to give nazoloxene with an optical rotation of 58°.

In another variation, magnesium powder (60 g) was added to a 250 ml flask with a reflux condenser and a nitrogen bubbler.
Anhydrous methanol (5 (Ig) and triethylamine (Ig)
Og,) was added. The flask was filled with nitrogen and flushed with nitrogen to maintain a nitrogen atmosphere during the reaction.

The 5-promonaproxen precursor prepared in the first part of Example 11 was dissolved in 0.1 mole total methanol 15I and added slowly to the above reaction mixture, and after addition of the 5-promonaproxen precursor, the reaction mixture was It was heated under reflux for an additional hour. The cooled mixture was mixed with 6N hydrochloric acid until the magnesium disappeared. The mixture was then poured into water and extracted with methylene chloride. The organic layer was separated, washed with water, the solution was concentrated and crystallized by adding hexane. After recrystallization, naproxen with an optical rotation of 64° in chloroform was isolated.

These operations were repeated using the corresponding 5-chloro-naproxen pre-IK material to obtain [α]D- after recrystallization.
Naproxen with an angle of 62° was obtained.

Example 16 Aqueous methanol 500 as prepared in Example 1
A mixture prepared by adding 23.9 g of d-2-(6-medoxy-2-naphthyl)propionic acid to 4 g of sodium hydroxide in me was stirred at room temperature for 3 hours.

The mixture was then sonic evaporated to obtain sodium 2-(6-medquin-2-naphthyl)propionate. The product was then isolated by centrifugation in toluene and washed with hexane before drying. The product eluted with decomposition at about 2550, and the infrared spectrum of the product was 1260,16
00.1625 and 1725 on'''1 showed the maximum value. The yield was d-2-(6-medoxy-2-naphthyl)
It was 95% based on zolopionic acid.

+liA 'not tasuf 7-7. Uter cruise, 7-p59? lL °l+te/t

Claims (1)

Claims: (11d Characterized by the same propionic acid functionality as -2-(6-medoxy-2-naphthyl)propionic acid, and with substituents far from the chiral center p and d
- for d-2-(6-medoxy-2-su7tyl)propionic acid precursors characterized by having a substituent that can be converted to a substituent of 2-(6-medoxy-2-su7tyl)propionic acid N-R-D-glucamine (wherein R is methyl) or a salt thereof as a resolving agent. (2) characterized by the same propionic acid functional group as d-2-(6-medoxy-2-su7tyl)propionic acid;
In addition, in the substituent far from the chiral center, sb and d
-2-(6-medoxy-2-naphthyl)propio/acid; υ and n is 1, R' is aqueous or methyl, and when n is O, R1 is aqueous). N-R-D-glucamine (wherein R is methyl) or a salt thereof as a resolving agent for acid precursors. It is characterized by the same propionic acid functionality as (31d-'2-(,6-nimethoxy-2-naphthyl)propionic acid, and is also a substituent far from the chiral center with υ and d-2-(6-medoxy2-naphthyl) -naphthyl)propionic acid, characterized by having a substituent that can be converted into a substituent of
) N-R-D- as a resolving agent for propionic acid precursors
Glucamine (wherein R is alkyl having 2 to 18 carbon atoms or cycloalkyl having 3 to 8 carbon atoms) or salts thereof. (4) characterized by the same propionic acid functional group as d-2-(6-medoxy-2-naphthyl)propionic acid;
Also, if the substituent is far from the chiral center and d-
N as a resolving agent for d-2-(6-medoxy-2-naphthyl)propionic acid precursors characterized by having a substituent that can be converted into a substituent of 2-(6-medoxy-2-naphthyl)propionic acid -R-D-glucamine (wherein R is alkyl having 6 to 18 carbon atoms or cycloalkyl having 3 to 8 carbon atoms) or salts thereof. (5) General formula [wherein, X is a halogen selected from the group of chlorine and bromine, and when n is 1, R1 is hydrogen or methyl; or when n is 0, is R1 is hydrogen]
d compound shown by or! N-RD-glucamine (wherein R is methyl) salt of the compound. (6) General formula () [wherein, when X is a halogen selected from the group of chlorine or bromine and n is 1, R1 is hydrogen, or when n is O and R1 is hydrogen. (General formula [wherein, when X is a halogen selected from the group of chlorine and bromine and n is 1, R1 is hydrogen or methyl; or when n is 0, R1 is hydrogen]
d compound or one compound N-R-D-glucamine (R is alkyl of 2 to 18 carbon atoms or 3 to 8
cycloalkyl salts of 5 carbon atoms. (8) General formula [wherein, when X is a halogen selected from the group of chlorine and bromine and n is 1, R1 is hydrogen or methyl, or when n is O, R1 is hydrogen]
N-R-D-glucamine (wherein R is alkyl of 6 to 18 carbon atoms or cycloalkyl of 3 to 8 carbon atoms) salt of the compound or compounds represented by d. (9) N-R-D-glucamine salt O according to claim 1, 2, 5 or 6, wherein R is methyl and X is bromine. N-R-D-glucami/salt according to claim 3, 4, 7 or 8, characterized in that αO) R is n-octyl. QD(d)-2-(6-medoxy-2-naphthyl)propionic acid precursor and (A)-2-(6-medoxy-2-
A method for resolving mixtures of N-R-D-glucamine with (naphthyl)propionic acid precursors or mixtures of their salts into their enantiomers, wherein R is methyl.
or a salt thereof is used as a resolving agent. α21 (d)-2-(6-medoxy 2-su7til)
propionic acid precursor)-2-(6-medoxy2)
- A method for resolving a mixture with a naphthyl)propionic acid precursor or a mixture of salts thereof into their enantiomers, the method comprising: N-R-D-glucamine (wherein R is octyl) or a salt thereof A method that indicates that it is used as an agent. (131(d)-2-(6-medoxy-2-naphthyl)
A method for resolving a mixture of a propionic acid precursor and a (/ri-2-(6-medoxy-2-naphthyl)propionic acid precursor) or a mixture of their salts into their enantiomers, the method comprising: N-R-D - A process characterized in that glucamine (where R is alkyl of 2 to 18 carbon atoms or cycloalkyl of 3 to 8 carbon atoms) or a salt thereof is used as a resolving agent. )=2-(6-medoxy2-naphthyl)propionic acid precursor and (2))-2-(6-medoxy2
- Naphthyl)-propionic acid precursors or mixtures of their salts into their enantiomers, the process comprising: α51(d)-2-(6-medoxy-2-naphthyl)propionic acid precursor Claims characterized in that the body is characterized by the presence in the part of the molecule remote from the xyl center of a group that can be converted into a substituent of d-2-(6-medoxy-2-naphthyl)propionic acid. Chapter 11.12
．． The method according to any one of Items 13 and 14. (1G+ General formula () [wherein R1 is hydrogen or methyl, X is a halogen selected from the group of chlorine or bromine, p, and n is 1, or R1 is hydrogen, and Claims 11, 12, and 13, characterized in that a d-2-(6-medoxy-2-naphthyl)propionic acid precursor compound or a salt thereof represented by the formula [n is 0] is used. Section, No. 14
or the method described in paragraph 15. α71 -fv: Formula [wherein R1 is hydrogen, X is a halogen selected from the group of chlorine or bromine, and n is 1, or R' is hydrogen, and n is O] (d)
-& and C)-acid or a mixture of their salts is combined with N-R-D-glucamine (wherein R is methyl) or a salt thereof, and (d)-acid N-R-D 12. Process according to claim 11, characterized in that the product pairs of -glucamine salt and (2)-acid N-R-D-glucamine salt are separated by fractional crystallization. (X)+1 10- [wherein, X is a halogen selected from the group of chlorine and bromine, and when n is 1, R1 is hydrogen or methyl; or when n is O, R1 is hydrogen] A mixture of (d) -i and @)-acid or a mixture of these salts is combined with N-R-D-glucamine (wherein R is octyl) or a salt thereof. (d)-acid N-R
13. A method according to claim 12, characterized in that the production pair of -D-glucamine salt and (1)-acid N-R-D-glucamine salt is separated by fractional crystallization. (II) General formula () [wherein, X is a halogen selected from the group of chlorine and bromine, and n is 1, R1 is hydrogen or methyl, or n is O A mixture of (d)-acid and 0)-acid or a mixture of their salts is N-R-D-glucamine (wherein R is 2 to 1
is alkyl having 8 carbon atoms, or from 3 to 8
(d)-acid N-R-D-glucamine salt and 0)-acid N-R-D-glucamine salt are combined with a cycloalkyl compound having 4 carbon atoms or a salt thereof, and the resulting pair of (d)-acid N-R-D-glucamine salt and 0)-acid N-R-D-glucamine salt are fractionated crystallized. 16. A method according to claim 13 or claim 15, characterized in that the separation is carried out by extraction. (2α General formula () [wherein, X is a halogen selected from the group of chlorine and bromine, and when n is 1, R1 is hydrogen or methyl, or when n is 00, A mixture of (d)-acid and CI)-acid or a mixture of their salts represented by R1 is hydrogen is N-R-D-glucamine (wherein R is 6 to 18
(d)-acid N-R-D-glucamine salt)-
Process according to claim 14 or claim 15, characterized in that the producing pair of acid N-R-D-glucamine salts is separated by fractional crystallization. -D-glucamine (however,
R is methyl) or a salt thereof using the general formula () [wherein X is a halogen selected from the group of chlorine and bromine, and when n is 1, R1 is hydrogen or methyl; or when n is 00, R1 is hydrogen] or the salt of the compound represented by general formula (I), (b) the obtained d-2-(6-medoxy-2-naphthyl (d)-2-(6-medoxy-2-naphthyl)propionic acid or a pharmaceutically acceptable salt thereof, comprising converting a propionic acid precursor to d-2-(6-medoxy-2-naphthyl)propionic acid. manufacturing method. (33(a) Using N-R-D-glucamine (wherein R is methyl) or a salt thereof, the general formula [wherein X is a halogen selected from the group of chlorine and bromine, n When n is 1, R1 is hydrogen, or when n is 00, R1 is hydrogen] or the salt of the compound represented by general formula (1) is divided, and (b ) Obtained d-2-(6-medoxy 2-su7
(d)-2-(6-medoxy-2-naphthyl)propionic acid or a pharmaceutically acceptable thereof; Method of manufacturing salt. El! 3(a) N-R-D-glucamine (however,
R is alkyl of 2 to 18 carbon atoms, or 3 to
cycloalkyl of 8 carbon atoms) or a salt thereof, the general formula () [wherein X is a halogen selected from the group of chlorine and bromine, and when n is 1, R ' is hydrogen or methyl, or when n is 0, R1 is hydrogen] or the salt of the compound represented by general formula (1), and (b) the obtained d-2-(6-medoxy 2
(cl)-2-(6-medoxy-2-naphthyl), consisting of converting the -su7-tyl) propionic acid precursor to d-2-(6-medoxy-2-su7-tyl) propionic acid.
A method for producing propionic acid or a pharmaceutically acceptable salt thereof. (241(a) N-R-D-glucamine (However, R
is alkyl having 6 to 18 carbon atoms, or 3 to 8
of the general formula () [wherein X is a halogen selected from the group of chlorine or bromine, and when n is 1, R1 is hydrogen or methyl, or when n is 0, R' is hydrogen) or the salt of the compound of general formula (I), (b) the obtained d-2-(6- (d)-2-(6-medoxy-2-naphthyl/I/)propionic acid consisting of converting a medoxy-2-naphthyl)propionic acid precursor to d-2-(6-medoxy-2-naphthyl)propionic acid A method for producing an acid or a pharmaceutically acceptable salt thereof. (2!19 d-2-(6-hydroxy-2-naphthyl)propionic acid or its salt is converted into a-2-(6-medoxy-2-naphthyl)propionic acid) The method according to any one of Items 22, 23, 24, or 25. (2G d-2-(5-halo-2-naphthyl)propionic acid or a salt thereof is The method according to any one of claims 22, 23, 24, or 25, characterized in that the d-2-(2-naphthyl) propio/acid is converted into A process according to claim 26 or 27, characterized in that 6-medoxy (2-naphthyl) propionic acid is converted into its pharmaceutically acceptable salt. wherein, X is hydrogen selected from the group consisting of chlorine and bromine; when n is 1, R1 is hydrogen or methyl; when n is 0, R1 is hydrogen (d,)) acid N-R-D-glucamine (however, R
is methyl) a mixture of salts.翰 General formula [wherein, X is a halogen selected from the group consisting of chlorine and bromine, when n is 1, RI is hydrogen, and n
is 0, R1 is hydrogen] (d,)
) A mixture of N-R-D-glucamine (where R is methyl) acid salts. Go) General formula () [wherein, X is a halogen selected from the group consisting of chlorine and bromine, when n is 1, R1 is hydrogen or methyl, and when n is 00, R1 is N-R-D-glucamine of (d,)) acid represented by hydrogen, where R is alkyl having 2 to 18 carbon atoms or cycloalkyl having 3 to 8 carbon atoms; a) salt mixture. (31) General formula [wherein, is hydrogen] (d, N-R-D-glucamine of phosphoric acid, where R is alkyl having 6 to 18 carbon atoms or cycloalkyl having 3 to 8 carbon atoms) ) a mixture of salts.Oz general formula [wherein, ri is hydrogen] is shown as (
d. A splitting medium in which the solubility of the (naphthyl)propionic acid precursor salt is also significantly smaller than the solubility of the other diastereomeric salt at the splitting temperature. (c) General formula [wherein, X is a halogen selected from the group of chlorine and bromine, and when h is 1, RI is hydrogen, and n is O
(d,)) acid N-R-D-glucamine (wherein R is methyl)
a mixture of salts and a solvent in which the solubility of the corresponding d-2-(6-medoxy-2-naphthyl)propionic acid precursor salt is equal to that of the other diastereomeric salt at the splitting temperature. A small splitting medium with good solubility. 04) General formula [wherein X is a halogen selected from the group of chlorine and bromine, when n is 1, R1 is hydrogen or methyl, and when n is 0, RI is hydrogen ] is indicated by (
d,)) acid N-R-D-glucamine (where R is 2 to
is alkyl having 18 carbon atoms, or from 3 to
cycloalkyl having 8 carbon atoms) and a solvent, in which the corresponding d
- A splitting medium in which the solubility of the 2-(6-medoxy-2-su7tyl)propionic acid precursor salt is appreciably less than the solubility of the other diastereomer salt at the splitting temperature. C3■ General formula [wherein, X is a halogen selected from the group of chlorine and bromine, when n is 1, R1 is hydrogen or methyl, and when n is O, R1 is hydrogen ] (d,
)) acid N-R-D-glucamine (where R is 6 to 18
d-2-(6-
A splitting medium in which the solubility of the medoxy 2-naphthyl) propionic acid precursor salt is appreciably less than the solubility of the other diastereomeric salt at the splitting temperature. □□□ General formula () [In the formula, when X is a halogen selected from the group of chlorine and bromine, when n is 1, R1 is hydrogen or methyl, and when n is O is a d-isomer of a compound represented by R1 is hydrogen. C37) General formula () [wherein, X is a halogen selected from the group of chlorine and bromine, when n is 1, R1 is hydrogen or methyl, and when n is 0, R1 is hydrogen] is an isomer of the compound. The side d-2-(6-medoxy-2-naphthyl)propionic acid is characterized by the same propionic acid functional group as d-2-(6-medoxy-2-naphthyl), and also located away from the chiral center. General formula () characterized by having a substituent that can be converted into a substituent of propionic acid [wherein X is a halogen selected from the group of chlorine and bromine, and when n is 1, R1 is hydrogen, n is 0
d-2-(6
0N-R-D-glucamine (wherein R is methyl) or a salt thereof as a resolving agent for -Medoxy (2-naphthyl) propionic acid precursor. <3! J, (d)- and CI) A method for resolving -2-(6-medoxy-2-su7ter)propionic acid precursors or salts thereof into their enantiomers, comprising:
d) - N-R-D-glucamine (wherein R is alkyl having 1 to 18 carbon atoms or cycloalkyl having 3 to 8 carbon atoms) or these in order to isolate the acid precursor; Said method, characterized in that said G)-acid precursor is racemized and then resolved using a salt of G) as a resolving agent. (4G) characterized in that said precursor is characterized by the presence of a group that can be converted into a substituent of (d)-2-(6-medoxy-2-naphthyl)propionic acid in the part remote from the chiral center of the molecule. The method according to claim 39, wherein (4υ general formula [wherein R1 is hydrogen or methyl, X is chlorine or bromine, or R'' is hydrogen, 41. The method according to claim 40, characterized in that a precursor compound of the form hydrogen or a salt thereof is used. In order to release N-R-D-glucamine (R is 1 to 1
alkyl having 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms) or a salt of the glucamine described above, using the general formula [wherein, when X is chlorine or bromine, R1 is hydrogen or methyl, or when X is hydrogen, R1 is hydrogen] or a salt of the compound represented by general formula (I), (b) the above (d)- (d) converting the precursor compound to -2-(6-medoxy-2-naphthyl)propionic acid or a pharmaceutically acceptable salt thereof; and (c) racemizing the precursor compound in the (A)-form to obtain (d) A process for producing -2-(6-medoxy-2-naphthyl)propionic acid or a pharmaceutically acceptable form thereof, comprising resolving said precursor compound in racemic form. (43(dl- and II,g)-2-(6methoxy2
-Naphthyl)-propionic acid precursors or their salts into their enantiomers, the method comprising prepacking (a)-
To isolate the acid precursor, N-R-D-glucamine (where R is alkyl having 2 to 8 carbon atoms or 3 to
cycloalkyl having 8 carbon atoms) or a salt thereof as a resolving agent, the (A)-acid precursor is racemized and then resolved. (14) Located in the part of the molecule away from the chiral center. (d
) -2-(6-Medoxy-2-su7tyl)propionic acid. . (4) Precursors represented by the general formula [wherein R' is hydrogen or methyl and X is chlorine or bromine, or R1 is hydrogen and X is hydrogen] or salts thereof 45. A method according to claim 44, characterized in that (46) in order to isolate the precursor compound in the (a) (d)-form, , R is 2
- alkyl having 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms] or a salt of the glucamine, using the general formula [wherein, when X is chlorine or bromine, R1 is (b)
The (d)-form is (d)-2-(6-medoxy2
-naphthyl)propionic acid or a pharmaceutically acceptable salt thereof, and racemizing said precursor compound in the (C) U)- form;
A process for producing (cl>-2-(6-medoxy-2-naphthyl)propionic acid or a pharmaceutically acceptable salt thereof) comprising resolving said precursor compound in racemic form obtained.