GB1596032A - Resolution of optically active 2-arylpropionic acids - Google Patents

Resolution of optically active 2-arylpropionic acids Download PDF

Info

Publication number
GB1596032A
GB1596032A GB9697/77A GB969777A GB1596032A GB 1596032 A GB1596032 A GB 1596032A GB 9697/77 A GB9697/77 A GB 9697/77A GB 969777 A GB969777 A GB 969777A GB 1596032 A GB1596032 A GB 1596032A
Authority
GB
United Kingdom
Prior art keywords
process according
acid
salt
ethylamine
diluent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB9697/77A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boots Co PLC
Original Assignee
Boots Co PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boots Co PLC filed Critical Boots Co PLC
Priority to GB9697/77A priority Critical patent/GB1596032A/en
Priority to PT67743A priority patent/PT67743A/en
Priority to GR55617A priority patent/GR64816B/en
Priority to CS781413A priority patent/CS222255B2/en
Priority to BG7838943A priority patent/BG28567A3/xx
Priority to AT163478A priority patent/AT360508B/en
Priority to DE19782809794 priority patent/DE2809794A1/en
Priority to CH249378A priority patent/CH638482A5/en
Priority to SE7802603A priority patent/SE436422B/en
Priority to HU78BO1703A priority patent/HU178810B/en
Priority to SU782588501A priority patent/SU784759A3/en
Priority to YU540/78A priority patent/YU41472B/en
Priority to NO780785A priority patent/NO146197C/en
Priority to IT48320/78A priority patent/IT1202818B/en
Priority to CA298,426A priority patent/CA1105942A/en
Priority to IN241/CAL/78A priority patent/IN147834B/en
Priority to FI780738A priority patent/FI66828C/en
Priority to IE467/81A priority patent/IE46476B1/en
Priority to DK100878A priority patent/DK154418C/en
Priority to ES467606A priority patent/ES467606A1/en
Priority to AU33977/78A priority patent/AU521708B2/en
Priority to DD78204036A priority patent/DD136261A5/en
Priority to JP2644878A priority patent/JPS53112841A/en
Priority to FR7806692A priority patent/FR2383155A1/en
Priority to PL1978205161A priority patent/PL110888B1/en
Priority to ZA00781369A priority patent/ZA781369B/en
Priority to LU79186A priority patent/LU79186A1/en
Priority to BE185750A priority patent/BE864671A/en
Priority to NLAANVRAGE7802520,A priority patent/NL189126C/en
Priority to NZ186644A priority patent/NZ186644A/en
Priority to EG161/78A priority patent/EG13345A/en
Priority to PH20873A priority patent/PH13333A/en
Priority to US05/945,481 priority patent/US4209638A/en
Publication of GB1596032A publication Critical patent/GB1596032A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

(54) RESOLUTION OF OPTICALLY ACTIVE 2-ARYLPROPIONIC ACIDS (71) We, THE BOOTS COMPANY LIMITED, a British Company, of 1 Thane Road West, Nottingham, NG2 3AA, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to the preparation of optically active 2-arylpropionic acids.
Certain 2-arylpropionic acids are known to have valuable biological properties and in particular anti-inflammatory properties.
It is believed that, with some 2-arylpropionic acids, biological activity of one of the optical isomers is greater than that of its enantiomer and it is desirable that a simple method of obtaining a preponderance of one enantiometer be achieved.
Conventional resolution techniques involving separation of a mixture of diastereoisomeric salts of an acid are usually very tedius since they often require several recrystallisation stages and also racemisation of the unwanted enantiomer to improve yields.
We have now found that a desired enantiomer of a 2-arylpropionic acid can be obtained from a mixture of diastereoisomeric salts in a simple manner in which generally fewer stages are involved than in conventional resolution techniques. The acids which can be used include those claimed in British Patents Nos. 1,091,403; 1,200,204 and 1,359,987.
According to the invention there is provided a process for increasing the proportion of a desired enantiomer of a 2-arylpropionic acid which comprises heating at a temperature of at least 80"C. a mixture comprising a salt of the 2-arylpropionic acid with an enantiomer of a chiral organic nitrogenous base and an inert liquid organic diluent in which the salt of the racemic acid has a solubility of 0.1 to 10% w/v in the diluent at the operating temperature, and in which the amount of the salt is such that a proportion thereof is undissolved in the diluent, continuing the heating until a portion of one optical isomer of the acid component of the salt is converted into its enantiomer, and recovering the solid salt of which the acid component now has an increased and preponderant proportion of that enantiomer.
The 2-arylpropionic acid is generally one in which the aryl group is of formula
in which n is an integer of 1 to 4, preferably 1 or 2, and Q is the same or different and is selected from C1 < alkyl, e.g. methyl; aralkyl, e.g. benzyl; cycloalkyl, e.g. of three to seven carbon atoms, and especially cyclohexyl; alkyl substituted cycloalkyl, e.g. monomethyl and monoethyl substituted cyclohexyl; aryl, e.g. phenyl and phenyl substituted with, for example 1 or 2 alkyl, preferably C1 alkyl, alkoxy, preferably C1 ffi alkoxy, alkylthio preferably C14 alkylthio, cyano or halogen; alkoxy, preferably C1+ alkoxy; cycloalkoxy, e.g. cyclohexyloxy; aryloxy, e.g. phenoxy and phenoxy substituted with, for example 1 or 2 halogen atoms especially chlorine or fluorine; alkylthio, preferably C1 alkylthio; aralkylthio; cycloalkylthio; arylthio, e.g. phenylthio; arylcarbonyl, e.g. benzoyl and thenoyl; cycloalkenyl e.g. cyclohexenyl; trifluoromethyl; halogen, e.g. fluorine or chlorine; furyl; pyrrolidinyl; pyrrolyl; pyrrolinyl; thienyl; or 1-oxo-2-isoindolinyl; or two Q groups together form a carbocyclic or heterocyclic ring, which rings may be aromatic and may be substituted. Examples of groups formed by two Q groups together with the benzene to which they are attached include naphthyl and substituted naphthyl, especially alkoxynaphthyl, fluorenyl, benzoxazolyl, optionally substituted e.g. by p-chlorophenyl, carbazolyl, optionally substituted by chIoro, benzothiazolyl, optionally substituted by phenyl, phenothiazinyl, optionally substituted by alkoxy and alkyl, benzofuranyl optionally substituted by phenyl, benzopyrano [2,3-b]-pyridinyl, and 9-oxoxanthenyl.
Instead of being a substituted phenyl the aryl group may be a heteroaryl group e.g. benzothiazolyl, pyrrolyl, or thienyl, which groups may be substituted by groups designated for Q above.
Particularly preferred compounds are those in which the aryl group is of the formula:
in which m is 0 or 1, and R3, R4 and Rs may be the same or different and are selected from hydrogen, chlorine, fluorine, hydroxy and methoxy. Especially preferred are those compounds in which m is 0.
Other preferred aryl groups include 2 - (6 - methoxy - 2 - naphthyl) and those in which n is 1 and Q is in the 3-position and is benzoyl or phenoxy or is in the 4position and is 1 - oxo - 2 - isoindolinyl.
The invention is particularly applicable to 2 - (2 - fluoro - 4 - biphenylyl)propionic acid and especially in obtaining a preponderance of the (+ )-isomer.
The invention can be carried out by using a racemic 2-arylpropionic acid, either enantiomer of a 2-arylpropionic acid, or mixtures containing a preponderance of either enantiomer. Depending on the particular salts involved the process may result in an increase of either enantiomer of the acid. The use of racemic acid results in formation of a salt containing a preponderance of one enantiomer of the acid. The process does not convert material to give salt of one enantiomer of the acid exclusively in all cases so it is often desirable to treat the material obtained to a minimal number, generally not more than two, conventional recrystallisation stages or other means of purification.
The desired acid may be recovered from the salt by conventional means, e.g. by acidification of the salt with a dilute mineral acid followed by extraction from the aqueous mixture with a suitable organic solvent Recrystallisation of the acid may increase the optical purity still further.
It will be appreciated that the choice of base will depend on the 2-arylpropionic acid. The choice of diluent will depend on the 2-arylpropionic acid and the base.
Generally the base is an a-monosubstituted alkylamine, and preferably an amonosubstituted ethylamine, especially an a - phenylethylamine in which the phenyl ring may be substituted by one or more groups such as alkyl e.g. C1 < alkyl, especially isopropyl, halogen, e.g. chlorine or fluorine, alkoxy e.g. C1 < alkoxy, especially methoxy.
Particularly prefe'rred bases are (-) - r -methylbenzylamine, especially when used to resolve 2 - (2 - fluoro - 4 - biphenylyl)propionic acid, and (-) - a - (2 - methoxyphenyl)ethylamine. Other suitable bases include (-) - a - (4 - isopropylphenyl)ethylamine, (-) - a - (3 - chlorophenyl )ethylamine, (-) - a - (4 - fluorophenyl)ethylamine (-) - a - (3 - fluorophenyl)ethylamine, (-) - a - (2 - fluorophenyl)ethylamine, (-) - a - (2 - chlorophenyl)ethylamine, (+) - xr - (2 - methoxyphenyl)ethylamine, (-) - a - (2,6 - dimethoxyphenylzethylamine and also (+) - a - cyclohexylethylamine. The base (-) - a - (2,6 - dimethylphenyl)ethylamine is claimed in Application No. 16197/78 (Serial No. 1 596033).
Preferably the mixture of diluent and salt is heated at a temperature of 9O-1500C e.g. 95-1300C. The heating is usually carried out for at least 1 hour e.g. 8-96 hours.
It is preferred that the ratio of the salt to the diluent is from 1:1 to 1:100 w/v, e.g. 1:5 to 1:15 w/v.
Preferably the solubility of the salt of the racemic acid in the diluent at the operating temperature is from 0.5 to 20% w/v.
Preferably 50 to 98% by weight of the salt e.g. 8095%, is undissolved in the diluent at the operating temperature.
The inert diluent is a liquid at the temperature at which the mixture is heated and may comprise one or more organic compounds. Usually the diluent is of low polarity and for example may comprise one or more hydrocarbons. The diluent is preferably a mixture of hydrocarbons which are predominantly aliphatic and it preferably has a boiling point in the range 110--135"C. Polar compounds, in amounts of e.g. up to 1% may be included in the diluent.
It is preferable that the diluent is such that the reaction can be carried out under reflux conditions.
It may be desirable, to avoid by-product formation, that heating is carried out under an inert atmosphere, e.g. nitrogen.
The invention is illustrated in the following Examples in which flurbiprofen is (+) - 2 - (2 - fluoro - 4 - biphenylyl)propionic acid. Unless otherwise stated specific rotations were measured in ethanol at a concentration of 1% w/v and at ambient temperature.
Examples 1 to 31.
Various mixtures comprising an amine salt of a 2-arylpropionic acid and a diluent consisting of one or more liquid organic compounds were stirred and heated. On completion of the heating, the hot mixtures were filtered through a steam heated Buchner funnel, the salts were washed with a hot diluent dried in vacuo, acidified with dilute sulphuric or hydrochloric acid and the acid mixtures extracted with ether.
The ether extracts were washed with water, dried and evaporated to give 2-arylpropionic acids having a different optical activity from the acid component of the salt from the start of the experiment The details and results of various Examples are given in Table I.
TABLE I
Solubility of salt of (#) acid in diluent at [&alpha;]D of Diluent per reaction Reaction Reaction Yield acid g. of salt temperature Temperature Time of salt recovered Ex. No. Acid Amine Diluent (ml) (ml/g) ( C) (hours) (%) ( ) 1 A2 G R 10 110 115 24 58.0 +23.6 2 A2 G R 10 110 115 72 71.0 +35.3 3 A1 G R 10 110 115 72 80.0 +31.3 4 A1 H R 10 85 115 72 61.2 +34.2 5 A1 J R 10 100 115 72 61.3 +29.3 6 B G R 10 100 115 72 71.0 +34.9 7 C G R 10 90 115 72 69.0 +27.9 8 A1 G S 10 26 117 72 73.3 +33.4 9 A1 G T 10 15.5 117 72 74.5 +33.0 10 A1 G U1 10 68.4 113 72 75.3 +33.4 11 A1 G R 10 186 108 72 76.5 +25.5 12 A1 G R 10 352 97 72 77.0 +15.8 13 A3 G V 10 72 115 72 66.5 +27.6 14 A1 K R 10 33 115 72 49.0 +37.0 TABLE I (Continued)
Solubility of salt of (#) acid in diluent at [&alpha;]D of acid Diluent per reaction Reaction Reaction Yield recovered g. of salt temperature Temperature Time of salt ( ) Ex. No. Acid Amine Diluent (ml) (ml/g) ( C) (hours) (%) 15 A1 G W 10 124 125 8 71.0 +22.5 16 A1 G W 10 124 125 96 73.5 +33.6 17 A1 G X 10 57 126 72 70.0 +35.4 18 A1 G Y 10 114 115 72 76.0 +32.4 19 A1 L1 R 14.4 160 115 72 84.3 -41.45 20 A1 M R 9.4 94 115 72 64.0 +37.3 21 A4 G R 10 110 115 72 80.5 +35.0 22 A1 G U2 10 57 112 72 66.0 +32.4 23 D G R 6.7 58 115 72 67.7 +27.3 24 A1 G T 3 15.5 117 72 87.0 +33.3 25 A1 G S 5 26 117 72 79.0 +35.4 26 A1 N R 6 66 115 72 69.5 -35.2 27 A1 L2 R 15.2 160 115 72 80.1 +42.1 28 A1 O R 4 40 115 72 57.6 +37.6 29 A1 P R 6 59 115 72 58.0 +34.9 30 E G R 3 28 115 72 65.4 +12.6 31 F G Z 7 90 115 72 57.7 +32.3 KEY TO TABLE I 2-arylpropionic acids
A1 = (#)-2-(2-fluoro-4-biphenylyl)propionic acid A2 = 2-(2-fluoro-4-biphenylyl)propionic acid, having [&alpha;]D-30 # Optically pure isomers A3 = 2-(2-fluoro-4-biphenylyl)propionic acid, having [&alpha;]D-44.7 have [&alpha;]D of + or -44.7 A4 = 2-(2-fluoro-4-biphenyl)propionic acid, having [&alpha;]D+8.9 B = (#)-2-(2'-fluoro-biphenylyl)propionic: Optically pure (+)-isomer has [&alpha;]D+50.3 C = (#)-2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid: Optically pure (+)-isomer has [&alpha;]D+35.9 D* = (#)-2-(6-methoxy-2-naphthyl)propionic acid: Optically pure (+)-isomer has [&alpha;]D+66 E = (#)-2-[4-(2-fluorophenoxy)phenyl]propionic acid: Optically pure (+)-isomer has [&alpha;]D+42.0 F = (#)-2-(2-hydroxy-4-biphenylyl)propionic acid: Optically pure (+)-isomer has [&alpha;]D+47.6 * Specific rotations of this acid were measured in chloroform at a concentration of 1% w/v Amines Solvents G = (-)-&alpha;-methylbenzylamine R = Petroleum fraction, initial b.p. 112 C H = (-)-&alpha;-(4-isopropylphenyl)ethylamine S = (-)-&alpha;-pinene J = (+)-&alpha;-cyclohexylethylamine T = myrcene K = (-)-&alpha;-(3-chlorophenyl)ethylamine U1 = 85% R + 15% toluene L1= (+)-&alpha;-(2-methoxyphenyl)ethylamine U2=67% R + 33% toluene L2= (-)-&alpha;-(2-methoxyphenyl)ethylamine V = Petroleum fraction, b.p. range 120 C-160 C M = (-)-&alpha;-(4-fluorophenyl)ethylamine W = Petroleum fraction, initial b.p. 125 C N = (+)-&alpha;-(2-fluorophenyl)ethylamine X = Octane O = (-)-&alpha;-(2-chlorophenyl)ethylamine Y = Petroleum fraction, initial b.p. 115 C, containing 1% n-butanol P = (-)-&alpha;-(3-fluorophenyl)ethylamine Z = Toluene Example 32.
Flurbiprofen (4.75 kg.) was mixed with a petroleum fraction b.p. 1250 C (48 litres) and the mixture stirred under nitrogen and heated to form a solution. (-) - a- Methylbenzylamine (2.35 kg.) in the same petrol (23 litres) was added with stirring and the mixture then heated under reflux under nitrogen for 72 hours. The internal temperature was 12500. The mixture was then filtered, and the salt was washed with the hot petrol and dried to give the (-) - xe - methylbenzylamine salt of 2 - (2 - fluoro4 - biphenylyl)propionic acid (5.4 k.g.) in 76% yield. A small portion of this was acidified to give 2 - (2 - fluoro - 4 - biphenylyl)propionic acid having [fz]D + 330.
The remainder was recrystallised from isopropanol and a portion acidified to give 2 - (2 - fluoro - 4 - biphenylyl)propionic acid having [a], + 410.
The remainder of the recrystallised salt (4.3 kg.) was mixed with light petroleum (b.p. 102-120"C; 35 litres) and water (37 litres), and the mixture stirred under nitrogen. Concentrated hydrochloric acid (1 kg.) was added and the mixture refluxed for 1 hour. The hot organic layer was separated, washed wtih water, filtered, cooled and the product collected by filtration, washed with hexane and dried to give 2 - (2fluoro - 4 - biphenylyl)propionic acid, having [a]D + 43.7 representing 98% optical purity.
The filtrate after the initial 72 hour heating of the salt together with solid recovered from mother liquors from the isopropanol recrystallisation of salt and the petrol crystallisation of the acid were all recycled for treatment with a further quantity of flurbiprofen.
The amine salt of the racemic acid has a solubility in the petroleum fraction of 124 ml/g. at 12500.
Example 33.
The (-) - a - methylbenzylammonium salt (1 part by weight) of flurbiprofen was mixed with light petroleum (b.p. 4e600C; 10 parts by volume) and heated at 116"C in a sealed autoclave for 72 hours. The mixture was then cooled and filtered and the salt was washed with light petroleum and dried in vacuo to give a 93.5% yield of salt which gave 2 - (2 - fluoro - 4 - biphenylyl)propionic acid having [a]D + 21.90.

Claims (22)

WHAT WE CLAIM IS:
1. A process for increasing the proportion of a desired enantiomer of a 2-arylpropionic acid, which comprises heating at a temperature of at least 80"C a mixture comprising a salt of the 2-arylpropionic acid with an enantiomer of a chiral organic nitrogeneous base and an inert liquid organic diluent in which the salt of the racemic acid has a solubility of 0.1 to 10% w/v at the operating temperature, and in which the amount of the salt is such that proportion thereof is undissolved in the diluent, continuing the heating until a portion of one optical isomer of the acid component of the salt is converted into its enantiomer, and recovering the solid salt of which the acid component now has an increased and preponderant proportion of that enantiomer.
2. A process according to claim 1 in which the 2-arylpropionic acid is one in which the aryl group is of the formula:
in which m is 0 or 1, and R3, R4 and R; may be the same or different and are selected from hydrogen, chlorine, fluorine, hydroxy and methoxy.
3. A process according to claim 2 in which the 2 - arylpropionic acid is selected from 2 - (2 - fluoro - 4 - biphenylyl) propionic acid, 2 - (2' - fluoro - 4 - biphenylyl)propionic acid, 2 - (2,2',4' - trifluoro - 4 - biphenylyl)propionic acid, 2 - (2 - hydroxy4 - biphenylyl )propionic acid and 2 - [4 - (2 - fluorophenoxy)phenyl]propionic acid.
4. A process according to claim 1 in which the 2-arylpropionic acid is 2 - (6methoxy - 2 - naphthyl)propionic acid.
5. A process according to any one of the preceding claims in which the chiral organic nitrogenous base is an a-monosubstituted alkylamine.
6. A process according to claim 5 in which the &alpha; monosubstituted alkylamine is an a-monosubstituted ethylamine.
7. A process according to claim 6 in which the a-monosubstituted ethylamine is an a-phenylethylamine in which the phenyl ring may be substituted by one or more C1-4 alkyl, C1-4 alkoxy or halogen groups.
8. A process according to claim 7 in which the enantiomer of the &alpha;-phenylethyl- amine is selected from (-) ( - methylbenzylamine, (-) - a - (2 - methoxyphenyl)ethylamine, (-) - a - 4 - isopropylphenyl)ethylamine, (-) - 3 - (chlorophenyl)ethylamine, (-) - a - (4 - fluorophenyl)ethylamine, (-) - a - (3 - fluorophenyl)ethylamine, (-) - a - (2 - fluorophenyl)ethylamine and (-) - a - (2 - chlorophenyl)ethylamine.
9. A process according to any one of the preceding claims in which the heating is conducted at a temperature of 90-1500C.
10. A process according to claim 9 in which the temperature is 95-1300C.
11. A process according to any one of the preceding claims in which the heating is conducted for 8-96 hours.
12. A process according to any one of the preceding claims in which the ratio of the salt to the diluent is from 1:1 to 1:100 w/v.
13. A process according to claim 12 in which the ratio is from 1:5 to 1:15 w/v.
14. A process according to any one of the preceding claims in which the solubility of the salt of the racemic acid in the diluent is from 0.5 to 2% w/v.
15. A process according to any one of the preceding claims in which 50 to 98% by weight of the salt is undissolved in the diluent at the operating temperature.
16. A process according to claim 15 in which 80 to 95% by weight of the salt is undissolved.
17. A process according to any one of the preceding claims in which the diluent is a liquid at the temperature at which the mixture is heated and is of low polarity.
18. A process according to claim 17 in which the diluent is a mixture of hydrocarbons which are predominantly aliphatic and has a boiling point in the range 110--1350C.
19. A process according to claim 1 in which the 2-arylpropionic acid is 2 - (2fluoro - 4 - biphenylyl)propionic acid and the base is (-) - a - methylbenzylamine.
20. A process according to claim 1 substantially as described in any of the Examples.
21. A salt of a 2-arylpropionic acid with an optically active organic nitrogenous base when obtained by a process according to any one of the preceding claims.
22. A 2-arylpropionic acid having a preponderance of one enantiomer when obtained from a salt as claimed in claim 21.
GB9697/77A 1977-03-08 1977-03-08 Resolution of optically active 2-arylpropionic acids Expired GB1596032A (en)

Priority Applications (33)

Application Number Priority Date Filing Date Title
GB9697/77A GB1596032A (en) 1977-03-08 1977-03-08 Resolution of optically active 2-arylpropionic acids
PT67743A PT67743A (en) 1977-03-08 1978-03-06 Preparation of therapeutic agents
GR55617A GR64816B (en) 1977-03-08 1978-03-06 Resolution of flurbiprofen ii/iii
CS781413A CS222255B2 (en) 1977-03-08 1978-03-06 Method of increasing the portion of the deisred anantiometer in the acid component of the 2-arylpropion acid
BG7838943A BG28567A3 (en) 1977-03-08 1978-03-07
AT163478A AT360508B (en) 1977-03-08 1978-03-07 METHOD FOR PRODUCING 2-ARYLPROPIONIC ACIDS WITH INCREASED PART IN A DESIRED ENANTIOMER
DE19782809794 DE2809794A1 (en) 1977-03-08 1978-03-07 PROCESS FOR INCREASING THE PROPORTION OF A DESIRED ENANTIOMER OF A 2-ARYLPROPIONIC ACID
CH249378A CH638482A5 (en) 1977-03-08 1978-03-07 Process for enlarging an enantiomeric portion of the acid constituent of a salt of a 2-arylpropionic acid
SE7802603A SE436422B (en) 1977-03-08 1978-03-07 PROCEDURE FOR OKING THE PROPORTION OF AN INJURED ENANTIOMES OF A 2-ARYL PROPIONIC ACID
HU78BO1703A HU178810B (en) 1977-03-08 1978-03-07 Process for the enrichment of one of the enantiomers of 2-aryl-propionic acid
SU782588501A SU784759A3 (en) 1977-03-08 1978-03-07 Method of preparing 2-arylpropionic acid enanthiomer
YU540/78A YU41472B (en) 1977-03-08 1978-03-07 Process for the resolution of enonthiomers of 2-arby propionic acid
NO780785A NO146197C (en) 1977-03-08 1978-03-07 PROCEDURE FOR THE MANUFACTURE OF OPTICALLY ACTIVE 2-ARYL PROPIONIC ACIDS
IT48320/78A IT1202818B (en) 1977-03-08 1978-03-07 PROCEDURE FOR PREPARING 2-ARIL-PROPIONIC COMPOUNDS WITH INCREASED PROPORTION OF ENANTIOMER
CA298,426A CA1105942A (en) 1977-03-08 1978-03-07 Preparation of therapeutic agents
IN241/CAL/78A IN147834B (en) 1977-03-08 1978-03-07
FI780738A FI66828C (en) 1977-03-08 1978-03-07 SAETT ATT OEKA ANDELEN AV EN SAODAN ENATIOMER VILKEN HAR EN HOG BIOLOGISK ACTIVITIES
IE467/81A IE46476B1 (en) 1977-03-08 1978-03-07 Resolution of optically active 2-arylpropionic acids
DK100878A DK154418C (en) 1977-03-08 1978-03-07 PROCEDURE FOR INCREASING THE QUANTITY SHARE OF A DESIRED ENANTIOMER OF A 2-ARYL PROPIC ACID
ES467606A ES467606A1 (en) 1977-03-08 1978-03-07 Method for preparation of potically active 22aryle propionic acid
AU33977/78A AU521708B2 (en) 1977-03-08 1978-03-08 Increasing proportion of desired 2-aryl propionic acid enantiomers
DD78204036A DD136261A5 (en) 1977-03-08 1978-03-08 METHOD FOR INCREASING THE SHARING OF A DESIRED ENANTIOMER OF A 2-ARYLPROPIONIC ACID
JP2644878A JPS53112841A (en) 1977-03-08 1978-03-08 Method for preparation of potically active 22aryle propionic acid
FR7806692A FR2383155A1 (en) 1977-03-08 1978-03-08 PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 2-ARYLPROPIONIC ACIDS
PL1978205161A PL110888B1 (en) 1977-03-08 1978-03-08 Method of increasing the contents of desired enantiomerof 1-arylpropionic acid
ZA00781369A ZA781369B (en) 1977-03-08 1978-03-08 Preparation of therapeutic agents
LU79186A LU79186A1 (en) 1977-03-08 1978-03-08 PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 2-ARYL-PROPIONIC ACIDS
BE185750A BE864671A (en) 1977-03-08 1978-03-08 PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 2-ARYLPROPIONIC ACIDS
NLAANVRAGE7802520,A NL189126C (en) 1977-03-08 1978-03-08 PROCESS FOR PREPARING OPTICALLY ACTIVE 2-ARYLPROPION ACIDS.
NZ186644A NZ186644A (en) 1977-03-08 1978-03-08 Increasing the proportion of desired enantiomer of a 2-arylpropionic acid
EG161/78A EG13345A (en) 1977-03-08 1978-03-11 Preparation of a 2-arylpropionic acid has a therapeutic effect
PH20873A PH13333A (en) 1977-03-08 1978-03-13 Preparation of optical isomers of 2-arylpropionic acid
US05/945,481 US4209638A (en) 1977-03-08 1978-09-25 Preparation of therapeutic agents

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB9697/77A GB1596032A (en) 1977-03-08 1977-03-08 Resolution of optically active 2-arylpropionic acids

Publications (1)

Publication Number Publication Date
GB1596032A true GB1596032A (en) 1981-08-19

Family

ID=9877029

Family Applications (1)

Application Number Title Priority Date Filing Date
GB9697/77A Expired GB1596032A (en) 1977-03-08 1977-03-08 Resolution of optically active 2-arylpropionic acids

Country Status (3)

Country Link
BE (1) BE864671A (en)
GB (1) GB1596032A (en)
ZA (1) ZA781369B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004065344A1 (en) * 2003-01-23 2004-08-05 Nagase & Co., Ltd. Process for producing optically active flurbiprofen

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004065344A1 (en) * 2003-01-23 2004-08-05 Nagase & Co., Ltd. Process for producing optically active flurbiprofen
US7214820B2 (en) 2003-01-23 2007-05-08 Nagase & Co., Ltd. Process for producing optically active flurbiprofen

Also Published As

Publication number Publication date
ZA781369B (en) 1979-02-28
BE864671A (en) 1978-09-08

Similar Documents

Publication Publication Date Title
US4209638A (en) Preparation of therapeutic agents
Blomquist et al. Unsaturated nitriles as dienophiles in the diene synthesis
EP0146080B1 (en) Process for the racemic separation of bicyclic alpha-imino carboxylic-acid esters
US3739019A (en) Preparation of optically active trans chrysanthemic acid
CA1105942A (en) Preparation of therapeutic agents
JPH05208978A (en) Method for aroylating 5-position of 1,2-dihydro-3h-pyrrolo(1,2-alpha)pyrrole-1-carboxyic ester
US3166571A (en) 1-phenyl-1, 2-cyclopropane dicarboximides
KR860001228B1 (en) Process for the optical resolution of mixtures of d-and-l- -(6-methoxy- -naphtyhl)-propionic acids
EP0169688B1 (en) Process for preparing anti-inflammatory cycloalkylidenemethylphenylacetic acid derivatives
GB1596032A (en) Resolution of optically active 2-arylpropionic acids
KR810000954B1 (en) Process for the preparation of 2-arylpropionic acid
JPH0236142A (en) Production of 4-disubstituted phenyl-1- tetralones
Jian et al. Facile preparation of some highly hindered chiral 1, 2-diphenyl-2-(N-monoalkyl) amino alcohols and N-benzylbornamine
CA1058173A (en) Process for production of 8-bromothienotriazolo-1,4-diazepines
DE2362687C3 (en) Process for the preparation of the optical isomers of penicillamine
DE2258985A1 (en) PROCESS FOR THE MANUFACTURING OF 2- (3BENZOYLPHENYL) -PROPIONIC ACID AND ANALOGUE PRODUCTS
DE2248525A1 (en) PROCESS FOR THE DECARBOXYLATION OF ORTHO- OR PARA-HYDROXYARYLCARBONIC ACIDS
US3636093A (en) Resolution of 2-methylene cyclopropane carboxylic acid
AT330181B (en) PROCESS FOR THE PRODUCTION OF NEW QUINOLINESSIC ACID DERIVATIVES AND THEIR SALT
Sandin et al. The Synthesis of Some 9, 10-Dialkylanthracenes and 4, 9-Dialkylbenzthiophanthrenes
US4451658A (en) Process for producing substituted pyrroles
JPS63152336A (en) Crystalline complex compound of propargyl alcohols and tertiary diamines and separation and purification of propargyl alcohols using said compound
FR2530236A1 (en) NOVEL AMINOALKYL NAPHTHALENIC DERIVATIVES, THEIR ACID ADDITION SALTS AND THE PREPARATION METHOD THEREOF AND THE THERAPEUTIC USE OF THESE DERIVATIVES AND SALTS
JPH0710822A (en) Separation of optical isomer of amino acid ester
JPH03261743A (en) Optical resolution of jasmonic acid and dihydrojasmonic acid

Legal Events

Date Code Title Description
PS Patent sealed
PE20 Patent expired after termination of 20 years

Effective date: 19980306