IE850695L - Preparation of d-alpha-(6-methoxy-2-naphthyl) propionic acid. - Google Patents
Preparation of d-alpha-(6-methoxy-2-naphthyl) propionic acid.Info
- Publication number
- IE850695L IE850695L IE69585A IE69585A IE850695L IE 850695 L IE850695 L IE 850695L IE 69585 A IE69585 A IE 69585A IE 69585 A IE69585 A IE 69585A IE 850695 L IE850695 L IE 850695L
- Authority
- IE
- Ireland
- Prior art keywords
- naphthyl
- methoxy
- propionic acid
- ester
- process according
- Prior art date
Links
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 55
- 235000019260 propionic acid Nutrition 0.000 claims description 26
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- -1 alkali metal bicarbonate Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical group 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- 239000003513 alkali Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Description
59288 - i - Process for preparing d-ot- ( 6-methoxy-2-naphthyl )propionic acid This invention relates to a novel process for preparing d-a-(6-methoxy-2-naphthyl)propionic acid.
The d-a-(6-methoxy-2-naphthyl)propionic acid or its salt is useful as, for example, anti-flammatory or analgesic agents.
As processes for preparing d-ot- ( 6-inethoxy-2-naphthyl )-propionic acid, there have been heretofore known (i) a process in which racemic modification of a-(6-methoxy-2-naphthyl)propionic acid is optically resolved, (ii) a process in which an ester of d-a-(6-methoxy-2-naphthyl)-propionic acid is hydrolyzed in the presence of an acid catalyst, and the like.
The process in which racemic modification of a-(6-methoxy-2-naphthyl)propionic acid is optically resolved, however, can not be said to be a satisfactory one from an §9288 economical view point because it is necessary to repeat the crystallization several times or more and to use expensive agents for the optical resolution. 1 • In the process in which an ester of d-a-(6-methoxy- "l 5 2-naphthyl)propionic acid is hydrolyzed in the presence of an acid catalyst, the methoxy group at the 6-position in the naphthyl group of the carboxylic acid which is a desired product or of the unreacted starting ester tends to be partially converted to a hydroxy group by 10 hydrolysis to form d-a-(6-hydroxy-2-naphthyl)propionic acid or its ester as a by-product, requiring treatment for purification after completion of the hydrolysis, and therefore the above process also can not be said to be a fully satisfactory one for an industrial application.
Further, there is known a process in which an ester of d-a-(6-methoxy-2-naphthyl)propionic acid is hydrolyzed in an organic solvent containing an alkali catalyst. In this process, however, racemization reaction occurs simultaneously with hydrolysis to result in remarkable 20 decrease in the optical purity of the resulting product (see U.S. Patent No.4,417,070, Table 2 on page 4), and the process can be said not to be of a good efficiency.
The present inventors have made extensive studies in 25 order to eliminate the drawbacks in the processes described above, and as a result, have found a fact that a process in which the hydrolysis is effected in an aqueous alkali catalyst solution is unexpectedly accompanied with little racemization reaction, and have 30 accomplished this invention.
More specifically, in hydrolysing an ester such as the ester of d-a-(6-methoxy-2-naphthyl)propionic acid, which is hardly soluble in water, there have been usually used water-soluble organic solvents such as ethanol, methanol and the like, which are capable of dissolving the ester 5 of d-a-(6-methoxy-2-naphthyl)propionic acid but do not participate in the reaction, in order to enhance the rate of reaction.
Opposed to the above, the present inventors have used water as a solvent, and as a result, have found that 10 hydrolysis of the ester group unexpectedly proceeds while remarkably suppressing the racemization, and have accomplished this invention.
The present inventors have further found that in the present process there does not occur a side reaction that 15 the methoxy group at the 6-position on the naphthyl group of the carboxylic acid or of the unreacted starting ester is converted to a hydroxy group by hydrolysis to form a by-product d-a-(6-hydroxv-2-naphthyl)propionic acid or its ester, whereas such a side reaction is observed in 20 the acid-catalyzed hydrolysis as mentioned above.
Accordingly, this invention is to provide a novel process for preparing d-a-(6-methoxy-2-naphthyl)propionic acid, which is characterized by hydrolyzing an ester of d-a-(6-methoxy-2-naphthyl)propionic acid in an aqueous alkali 25 (basic) catalyst solution.
The present invention will be described in more detail below.
The ester of d-a-(6-methoxy-2-naphthyl)propionic acid 30 which is used as a starting material may be a lower alkyl ester excluding t-butyl ester of said acid, or an ester of said acid with a phenyl group unsubstituted or substituted with an electron attracting group such as CI, N02 and Br, preferably methyl ester or ethyl ester, and 5 most preferably methyl ester.
The alkali catalyst to be used in this invention includes, for example, an alkali hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide; ammonia; an alkali metal carbonate such as sodium 10 carbonate and potassium carbonate; an alkali metal bicarbonate such as sodium bicarbonate and potassium bicarbonate; an alkali metal salt of an organic acid such as sodium acetate and potassium acetate, a salt of d-a-(6-methoxy-2-naphthyl)propionic acid or a-(6-methoxy-15 2-naphthyl)propionic acid such as potassium, sodium and ammonium salt of said acid, and the like.
The concentration of the alkali catalyst in the aqueous solution may be in the range from 0.01 to 4 0 % by weight, preferably from 0.1 to 25 % by weight. The higher the 20 concentration of the solution is, the faster the reaction proceeds.
The reaction temperature may be in the range from 0°C to a temperature at which the reaction solution is refluxed, i.e., from 0°C to 100°C.
With respect to the ratio of the ester of d-a-(6-methoxy-2-naphthyl)propionic acid which is used as a starting material to the water which is used as a solvent (ester/water), the smaller the ratio is, the faster the reaction proceeds. On the contrary, the greater the 30 ratio is, the higher volumetric efficiency is.
The ratio may be usually in the range from 10 to 0.001, preferably 1.0 to 0.001.
The reaction time is not limitative so long as it is enough to carry out the reaction completely and maintains the degree of retention of the configuration in an asymmetric carbon of the product at the desired level or 5 higher. Although the desired reaction time may be varied depending upon the degree of optical purity to be maintained or the concentrations of the catalyst and/or the substrate (ester), it may be usually in the range from approximately 30 minutes to 100 hours. It is 10 possible to shorten or extend the reaction time to any degree depending upon the desired degrees of optical purity and hydrolysis or the reaction conditions.
As the hydrolysis reaction proceeds, an alcohol is produced from .the ester group of the starting ester. An 15 aqueous alkali catalyst solution containing the alcohol thus produced or an alcohol in a ratio (by weight or by volume) corresponding to that of the alcohol thus produced is included in the "aqueous alkali catalyst solution" defined in this invention.
The process according to this invention will be described in more detail by the following Examples and Comparative Example.
Example 1 1 g of methyl ester of d-a-(6-methoxy-2-naphthyl)-25 propionic acid ([a]^ + 78.7° (c = 1, Chloroform); optical purity 100 %) suspended in 40 g of 1 % aqueous potassium carbonate solution was heated at 100°C for 6 hours and then cooled. To the resulting reaction mixture, 10 ml of toluene and 5 ml of 5 % aqueous sodium 30 hydroxide solution were added to conduct partition. The aqueous layer was neutralized with hydrochloric acid and a solid deposited was extracted with 10 ml of ethyl acetate. After the organic layer was washed with water, concentrated by distilling the solvent away and dried to obtain 0.72 g of white crystal of d-a-(6-methoxy-2-naphthyl)propionic acid. Yield: 76 %; [a]^5 + 64.8° (c = 1.0, Chloroform); optical, purity 94 %.
Comparative Example 1 (a conventionally available process utilizing alkali-catalyzed hydrolysis) After 2.3 g of ethyl ester of d-a-(6-methoxy-2-naphthyl)-10 propionic acid ([a]^5 + 48.6°; optical purity 100 % ), 7.3g of ethanol, 2.5 g of water and 0.5 g of sodium hydroxide were combined, the resulting reaction mixture was heated under reflux for 4 hours, cooled, acidified with hydrochloric acid and thereafter partitioned between 15 water and toluene. The toluene layer thus obtained was washed with water and concentrated to obtain 1.9 g of d-a-(6-methoxy-2-naphthyl)propionic acid. The optical purity was 45 %.
Examples 2 to 8 Experiments for Examples 2 to 8 were carried out under the same reaction conditions and post treatment conditions as in Example 1 except that the kinds of the ester of d-a-( 6-methoxy-2-naphthyl) propionic acid and the catalyst to be used, reaction time and reaction 25 temperature were varied. The results are shown in the following. Table. In the experiments for Examples 2 to 8, used were 1 g of the ester of d-a-(6-methoxy-2-naphthyl)-propionic acid and 40 g of the aqueous catalyst solution.
Table Example No.
Ester Aqueous catalyst Solution Reaction conditions Temperature Time ( C) (hr) Conversion (%) Degree of retention of optical activity in carboxylic acid(%) 2 Methyl 0.l%NaOH 100 8 93 3 Methyl %NaOH - 25 6 8 93 4 Methyl %Na2C03 100 4 99 89 Ethyl 3%NaHC03 100 16 31 90 6 Methyl i%nh3 100 6 27 91 7 Methyl i%k2co3 100 6 76 94 8* ;Methyl ;5%K-C0, ;100 ;7 ;39 ;94 ;i i ;* For this Example only, the ester and the aqueous alkali catalyst solution as starting material were used in an amount of lg and 4 g, respectively.
Claims (10)
1. A process for preparing d- a-(6-methoxy-2-naphthyl)propionic acid, by hydrolysis of an ester of d- a-(6-methoxy-2-naphthyl)propionic acid 5 with a basic catalyst characterized in that said hydrolysis is carried out under aqueous conditions.
2. A process according to Claim 1, characterized in that the ester is derived from a lower alkanol having 1 to 3 carbon atoms. 10
3. A process according to Claim 2, characterized in that the lower alkanol is methanol or ethanol.
4. A process according to any preceding claim, characterized in that 15 the basic catalyst is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal acetate or a salt of d-a -(6-methoxy-2-naphthyl)propionic acid.
5. A process according to Claim 4, characterized in that the basic 20 catalyst is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
6. A process according to any preceding claim, the concentration of the basic catalyst in aqueous solution is in the range from 0.01 to 40% 25 by weight.
7. A process according to Claim 6, characterized in that the concentration is in the ranged from 0.1 to 25% by weight. 30
8. A process according to any preceding claim characterized in that the hydrolysis is carried out at a temperature from 0 to 100°C.
9. A process according to Claim 1 for preparing a d-a -(6-methoxy-2-naphthyl)propionic acid, substantially as hereinbefore 35 described by way of Example.
10. A d- a-(6-methoxy-2-naphthyl)propionic acid whenever prepared by a method as claimed in any of the preceding claims. T0MKINS & CO.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE69585A IE59288B1 (en) | 1985-03-19 | 1985-03-19 | Process for preparing d-alpha-(6-methoxy-2-naphthyl) propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE69585A IE59288B1 (en) | 1985-03-19 | 1985-03-19 | Process for preparing d-alpha-(6-methoxy-2-naphthyl) propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE850695L true IE850695L (en) | 1986-09-19 |
| IE59288B1 IE59288B1 (en) | 1994-02-09 |
Family
ID=11016935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE69585A IE59288B1 (en) | 1985-03-19 | 1985-03-19 | Process for preparing d-alpha-(6-methoxy-2-naphthyl) propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE59288B1 (en) |
-
1985
- 1985-03-19 IE IE69585A patent/IE59288B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE59288B1 (en) | 1994-02-09 |
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| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |