GB2236318A - Process for preparing pure N-methyl-anthranilic acid methylester - Google Patents
Process for preparing pure N-methyl-anthranilic acid methylester Download PDFInfo
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- GB2236318A GB2236318A GB8921692A GB8921692A GB2236318A GB 2236318 A GB2236318 A GB 2236318A GB 8921692 A GB8921692 A GB 8921692A GB 8921692 A GB8921692 A GB 8921692A GB 2236318 A GB2236318 A GB 2236318A
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- acid
- antranilic
- methyl
- meth
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- Organic Chemistry (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing pure N-methyl-anthranilic acid methylester in which anthranilic acid is methylated in an aqueous medium, then the desired N-methyl-anthranilic acid methylester is separated in a way that the methylated reaction mixture is poured on water and the mixture is extracted with an aromatic hydrocarbon or halogenated aromatic hydrocarbon and thus obtained organic extract is further extracted with diluted hydrochloric acid, thereafter the solvent is distilled off and the desired product is isolated. Isolation of N,N-dimethyl anthranilic acid methylester from the reaction product by the present method is also claimed.
Description
I 4 - 1 PROCESS FOR PREPARING PURE N-,n2TlrlL-Al.,"TRALTILIC ACID
lflETHYLESTER 2 The invention relates to the preparation of Nmeth-yl-antranilic acid methjlester b-y meth.ylation of antranilic acid and b:y.processing the reaction mixture obtained.
It is known that N-meth:yl-antranilic acid meth.ylester can be found in tangerine. tuberose, orange flower oil. h7acinth and jasmine oil as scenting component.
Asa scenting com-ponent,it is used in detergents, soaps and cosmetic compositions. N-m--th.yl-antranilic meth.ylester is. however. suitable for flavouring foodstuffs and drinks and is a popular p--oduct b7 the production of artifical essence of tangerine.
On the basis of the above it is obvious that the preparation of lT-methylantranilic acid meth.ylester is an important technical task.
According to the method of Vernin G. (La France et ses Parfums i. 51, page 429-448 /1966/) antranilic acid methylester is meth.ylated in an aqueous medium in thep?esence of NaHCO 3 at 85 0 C with dimeth-71 sulphate and reacted for 30 hours. The mixture is extracted with ether and after the-ether is removed the product is distilled at 126 OC in vacuo. Yield of N-meth-:yl-antranilic acid methylester is 51.3 %, the starting material can be recovered in 23 %,-the residue is loss and the dimethyl derivative. resp. Yield does not change either in the case if methylation is carried out with methyl iodide or meth:yl tosjlate.-The separation of the products obtained did not succeed bj preparative chromatographv 3 either because the physical characteristics of the three compounds are fast identical. This is illustrated in Table 1.
Table 1
Compound Melting Boiling K (25 00) point p8int 00 c Antranilic acid meth71- 24-35 132/2 kPa 1.7x10 -12 ester N-meth71-antranilic 19 135/2 kPa 3.36x10 -11 acid meth71ester N9N-dimeth-yl-antranilic 18.5 139/2 kPa 6.05x10-11 acid methylester The physical charac-teris tics which the separation is based on are fast identical, so separation cannot be solved on this basis.
Among.recent.processes concerning the preparation of N-methjl-antranilic acid meth:ylester US-PS 495829922 can be mentioned, according to which antranilic acid methylester is reacted with aqueous formaldehyde,solution in a molar ratio of 1:1 in the presence of Rane.y-nickel catalyst b:y hydrogenation under pressure. At the end of the catalytic reaction the product is extracted with toluene and purified b:y vacuum distillation. Though formation of dimeth:yl - 4 derivative can be avoided., it is disadvantageous that the:yield does not exceed 69 % and an expensive apparatus under pressure is necessarj for the process, the product should be purified b-y vacuum distillation and the yield is low.
Object of the invention is to prepare N-methylantranilic acid meth7lester bj an economic process, b.7 using simple apparatus and b.y selective separation of the desired product.
The process of the invention for preparing pure N-meth.71-antranilic acid methylester b7 meth71ating antranilic acid methjlester while using dimethjl sulphate or methyl iodide in an aqueous medium then selectively separating the desired lT-methjl-antranilic acid meth.ylester can be characterized b7 extracting the organic phase after pouring on water with aromatic hjdrocarbon or halogenated aromatic h-ydrocarbon from product mixtures methjIated with dimethyl sulphate or meth:yl iodide in an aqueous organic solvent medium, and b:y extracting the solvent extract(s) with aqueous hydrochloi-ic acid, preferabl-y with aqueous solution containing 1-10 weight% of h:ydrochloric acid. then distillingthe extracted solx-,nt extract after dr:ying. and obtaining the desired lT- meth:ylantranilic acid methTlester..and if-desired, after neutralisation and solvent extraction the starting material and/or dialk:ylated product is recovered.
Surprisingl_y it was found that N-methjl-antranilic acid meth.-ylester is suitable for the formation of intramolecular h. ydrogen bridge and for the formation of a stabile six-membered ring, while the starting material and the dimethjl derivative Is not suitable for the formation of the same. Accordingl-y on the basis of our experiments antranilic acid meth.ylester and N,VTdime th-yl-antrani lie acid meth-ylester form a water soluble salt with liquid h-ydrochloric acid and can be extracted from organic solvent solution, while the h- ydrogen bridge structure of N-meth71-antranilic acid meth.ylester does not decompose, salt will not be formed. the product remains in the solvent phase.
Separation is carried out in a wa.y that from the benzene. toluene or xylene solution of the mixture containing the three compounds the side product is selectivel-7 separated b7 1-5 % aqueous h.ydrochloric acid in a non continuous or continuous equipment.
If the isolation of Nj-dimeth71-antranilic acid meth.7lester is important, then alk.71ation is continued until the reaction of all the starting materials and thedialk-71-ated product is selectivel-y separated according to the invention.
Alk.ylation is expedientl.7 carried out in a homogeneous reaction medium, water soluble organic solvent, such as acetone, dioxane or methanol is added to the aqueous medium, thus antranilic acid meth71ester is dissolved, so the alk71ation can be - 6 carried out during an hour.
Example 1
151.17 g (1 mole) of antranilic acid methylester is dissolved in 400 cm3 of dioxane. 400 cm3 of water and 126 g (1.5 mole) of NaHOO 3 are added. Under good stirring 126 g = 95 cm 3 (1 mole) of dimeth71su:k-,ate are added dropwise during an hour at 60 OC. It is stirred at 60 0 C for a further hour. then dioxane is distilled off and cooled to room temperature it is poured to 3 dm3 of water. The aqueous emulsion is extracted with -3x500 cm 3 of benzene. The combined benzene solutions are extracted with 10x200 cm3 of diluted hydrochloric acid (dilution ratio 1:10).
After extraction the benzene solution is dried over Na 2 so 4 and the benzene is distilled off. The residue is 89.2 g, of 99.2 % Ni-methjlantranilic acid meth.ylester, yield: 54 %, calculated for antranillic acid meth-7lester.
The aqueous hydrochloric acidic extracts are combined. neutralized with Na 2 CO 3 until pH = 7-8. then the aqueous suspension is. extracted with 3x200 CM3 of benzene. The benzene extractions are combined and benzene is distilled off. The residual 61.7 g of product mixture contains antranilic acid ester in 56.4 % (0.23 mole, 34.8 g) its remaining part is dialk-yl derivative (0.15 mole, 26.9 g).
Total yield: 23 % of unchanged starting antranilic acid meth.ylester, 54 % of N-meth.yl-antranilic acid meth. VIestE,- 15 % of N N-dimeth.yl-antranilic acid meth-ylester.
The anal.ysis was carried out b-y gas chromatoc,.raph of t:ype Carlo Erba 4160 on a capillar.y column.
Example 2
75.6 9 (0.5 mole) of antranilic acid meth.ylester is dissolved in 300 cm3 of methanol and 45 g (0.42 mole) Na 2 CO 3 is added. Stirring is started and the mixture is heated on water bath until reflux. then 94.6 g (0.75 mole) of dimeth71 sulphate is added dropivise during an hour under mild boiling. After addition is finished the reaction mixture is stirred for an hour under reflux. then 200 cm3 of benzene are added and cooled to 0 0 C. The precipitated cr-ystals are filtered, washed with 50 em 3 of benzene and processed according to the method described in Example 1.
Yield: 57 9 of 99.5 % of N-methjl-antranilic acid meth.7lester (60 Example 3
For the simultaneous preparation of N-methyl_ antranilic acid meth:ylester and N,N-dimet'b,.y 1-antrani lie acid meth-ylester 151.17 g (1 mole) of antranilic acid meth:yleeter is dissolved in 400 cm3 of dioxane, 400 cm3 of water is added and 252 g (3 mole) NaHCO 3 is added 8 dropwise at 60 0 C during an hour under good stirring, 250 g = 188 cm3 (1. 98 mole) of dimethyl sulphate and stirred at this temperature for an hour. The mixture is cooled to room temperature and poured on 3 dm3 of water. The aqueous suspension is extracted with 3x500 em 3 of benzene. The benzene solutions are combined and extracted with 10x200 cm3 of diluted hydrochloric acid (dilution 1:10). The benzene solution is dried over Na 2 so 4 and benzene is distilledcff. the residue is 8549 g of 99 % N-metl-. Lyl-antranilic acid meth71ester, -yield: 52 %.
The aqueous hydrochloric acidic extracts are combined and extracted with 100 cm3 of benzene. This benzene extract is used again during the production of the next charge. by the first benzene extraction. The hydrochloric acidic solution is neutralized with Na 2 CO 3 (until pH 7-8), then.the aqueous suspension is extracted with 3x200 ml of benzene. The benzene extractions are combined. dried on Na 2 so 4 and benzene is distilled off. The residue contains 68 g of 95.15 % N,1-dimeth:ylantranilic acid methylester (38 %)s 1.5 % of N-methjl-antranilic acid meth71ester and 3 % of antranilic acid meth:ylester. Yield of the two products altogether is 90 9
Claims (8)
1. A process for preparing pure N-methyl-antranilic acid metl-.Lyleste2? b.y meth:ylating antranilic acid meth-ylester while using dimethyl sulphate or meth.yl iodide in an aqueous medium then selectively separating the desired N-meth.yl-antranilic acid metli-ylester characterized b-y extracting the organic phase, after pouring on water. with-aromatic hydrocarbon or halogenated aromatic h.ydrocarbon from product mixtures methylated with dimeth.yl sulphate or meth--yl iodide in an aqueous organic solvent medium, and b.y extracting the solvent extract(s) obtained with aqueous h..ydrochloi-ic acid, preferabl..y with aqueous solution containingl-10 weight% of h-.ydrochloric acid. then distilling the solvent extract after dr.Ving it and isolating the desired N-methyl-antranilic acid meth.ylester; and, if desired. recovering after neutralization and solvent extraction the starting material and/or the dialk.ylated product.
2. A process of preparing N-methyl-antranilic acid methyl ester comprising methylating antranilic acid methyl ester in a polar solvent using dimethyl sulphate or methyl iodide, adding water to the reaction product, extracting the organic phase of the product using an aromatic hydrocarbon andjor.a halogenated aromatic hydrocarbon, contacting the resulting organic phase with aqueous hydrochloric acid and isolating the N-methyl antranilic acid methyl ester from the remaining organic.phase.
3. A process as claimed in claim 2, wherein the N-methyl antranilic acid methyl ester is isolated from the organic phase by drying and distillation of the organic solvent.
4. A process as claimed in claim 2 or claim 3, wherein the aqueous hydrochloric acid is a solution containing 1 to 10 weight % of hydrochloric acid.
5. A process as claimed in any one of claims 2 to 4, which further comprises neutralising the aqueous hydrochloric acid phase and extracting the starting material and the dimethylated product therefrom by means of solvent extraction.
6. A process of preparing N-methyl-antranilic acid methyl ester which is substantially as hereinbefore described in any one of Examples 1 to 3.
7. N-methyl-antranilic acid methyl ester produced by a process as claimed in any one of claims 1 to 4 or 6.
8. N,N-dimethyl antranilic acid methyl ester produced by a process as claimed in claim 5 or claim 6.
Published 1991 atThe Patent Office, State House. 66171 HghHolbom. London WC1R47P. Further copies may be obtained from Sales Branch. Unit 6. Nine Mile Point cwmrclinfach. Cross Keys. Nrt NP1 7HZ. Printed by Multiplex techniques lid. St Mary Cray. Kent.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8921692A GB2236318A (en) | 1989-09-26 | 1989-09-26 | Process for preparing pure N-methyl-anthranilic acid methylester |
| FR8913763A FR2653428A1 (en) | 1989-09-26 | 1989-10-20 | PROCESS FOR THE PREPARATION OF METHYL ESTER OF PURE N-METHYL-ANTHRANILIC ACID |
| DE19893936229 DE3936229A1 (en) | 1989-09-26 | 1989-10-31 | METHOD FOR PRODUCING PURE N- (METHYL) -ANTHRANILE ACID METHYL ESTER |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8921692A GB2236318A (en) | 1989-09-26 | 1989-09-26 | Process for preparing pure N-methyl-anthranilic acid methylester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8921692D0 GB8921692D0 (en) | 1989-11-08 |
| GB2236318A true GB2236318A (en) | 1991-04-03 |
Family
ID=10663624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8921692A Withdrawn GB2236318A (en) | 1989-09-26 | 1989-09-26 | Process for preparing pure N-methyl-anthranilic acid methylester |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE3936229A1 (en) |
| FR (1) | FR2653428A1 (en) |
| GB (1) | GB2236318A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7368592B1 (en) | 2000-10-04 | 2008-05-06 | Prom Limited | Process for the preparation of alkyl n-alkylanthranilate |
| US8865742B2 (en) | 2010-11-28 | 2014-10-21 | Mapi Pharma Ltd. | Intermediate compounds and processes for the preparation of quinoline derivatives such as Laquinimod sodium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4582922A (en) * | 1985-02-01 | 1986-04-15 | National Starch And Chemical Corporation | Process for the preparation of methyl N-methylanthranilate |
-
1989
- 1989-09-26 GB GB8921692A patent/GB2236318A/en not_active Withdrawn
- 1989-10-20 FR FR8913763A patent/FR2653428A1/en active Pending
- 1989-10-31 DE DE19893936229 patent/DE3936229A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| La France et ses parfumes. By G. Vernin pages 429-448 (1966) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7368592B1 (en) | 2000-10-04 | 2008-05-06 | Prom Limited | Process for the preparation of alkyl n-alkylanthranilate |
| US8865742B2 (en) | 2010-11-28 | 2014-10-21 | Mapi Pharma Ltd. | Intermediate compounds and processes for the preparation of quinoline derivatives such as Laquinimod sodium |
| US9102592B2 (en) | 2010-11-28 | 2015-08-11 | Mapi Pharma Ltd. | Intermediate compounds and processes for the preparation of quinoline derivatives such as laquinimod sodium |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8921692D0 (en) | 1989-11-08 |
| DE3936229A1 (en) | 1991-05-02 |
| FR2653428A1 (en) | 1991-04-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |