WO2011098386A1 - Process for the preparation of an anthranilic acid derivative - Google Patents
Process for the preparation of an anthranilic acid derivative Download PDFInfo
- Publication number
- WO2011098386A1 WO2011098386A1 PCT/EP2011/051535 EP2011051535W WO2011098386A1 WO 2011098386 A1 WO2011098386 A1 WO 2011098386A1 EP 2011051535 W EP2011051535 W EP 2011051535W WO 2011098386 A1 WO2011098386 A1 WO 2011098386A1
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- sodium hydroxide
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- IGLWGHRTQOYFDV-UHFFFAOYSA-N NC(c(c(C(O)=O)ccc1)c1[N+]([O-])=O)=O Chemical compound NC(c(c(C(O)=O)ccc1)c1[N+]([O-])=O)=O IGLWGHRTQOYFDV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Definitions
- the present invention relates to the selective preparation of 6-nitro-anthranilic acid.
- 6-Nitro-anthranilic acid is a valuable intermediate for the preparation of benzonorbornene fungicides, as described for example in WO 2007/048556.
- 6-nitro-anthranilic acid (A) can be prepared according to the following scheme:
- 3-Nitro-phthalimide (E) is a useful starting material for the preparation of 6-nitro-anthranilic acid, in particular for large scale manufacturing which requires high safety standards.
- 6-nitrophthalamic acid (D) is then converted to 6-nitro-anthranilic acid (A).
- 6-nitrophthalamic acid may be reacted first with aqueous base, such as, for example, aqueous sodium hydroxide, and sodium hypochlorite, and then with aqueous acid, such as, for example, aqueous hydrochloric acid.
- aqueous base such as, for example, aqueous sodium hydroxide, and sodium hypochlorite
- aqueous acid such as, for example, aqueous hydrochloric acid.
- the disadvantage of this prior art process is the relatively low yield in each of the two steps (70-73%). Further, isolation is required to enrich the desired isomer with additional filtration which leads to high waste generation and higher cycle time (energy inefficient). Also, a two step synthesis is undesired for large scale production.
- the aim of the present invention is therefore to provide a novel process for the selective production of 6-nitro-anthranilic acid that avoids the disadvantages of the known process and makes it possible to prepare 6-nitro-anthranilic acid in high yields and good quality in an economically and ecologically advantageous way in a one-pot process with a high safety standard.
- the concentrated hydrochloric acid used in the process according to the invention has a concentration of 30 - 38 % by weight, preferably 30 - 35 % by weight.
- the reaction mass is acidified at a temperature of 5 to 10°C with concentrated hydrochloric acid to a pH of 1.5 to 2.0.
- the suspension of the compound of formula I I in sodium hydroxide can be prepared by charging an aqueous solution of sodium hydroxide (2 to 3 mol), cool the solution to a temperature of 20 to 30°C, in particular 25°C, and add portionwise 1 mol of the compound of formula II under stirring.
- the suspension of the compound of formula II in sodium hydroxide can be advantageously prepared by charging an aqueous solution of sodium hydroxide (preferably 2 mol), at a temperature of 5 to 60 °C, in particular 5 to 40°C, preferably of 25 to 30 °C, keep the temperature of the solution at 20 to 40°C, in particular 20 to 25°C, and add portionwise 1 mol of the compound of formula I I under stirring.
- concentration of sodium hydroxide is preferably 5 to 25%, more preferably 5 to 20%, in particular 15% by weight.
- the sodium hypochlorite (preferably in an amount of 1 .1 to 1 .2 mol) is added portionwise, preferably during 20 to 45 minutes.
- a preferred temperature range for the addition is from 5 to 60°C, in particu lar 5 to 40° C, preferably 25 to 30 ° C .
- the sodium hypochlorite concentration is preferably 8% to 15%, in particular 10 - 12 % by weight. It is preferred to stirr the reaction mass for 1 to 2 hours for complete conversion of the compound of formula II to the compound of formula I. It is advantageous to cool the reaction mass to a temperature from 5 to 10 °C before acidification to pH 1 .5 - 2.0 using concentrated HCI.
- a significant advantage of the process of this invention is the overall yield which is between 70% and 90%. Further, the process is carried out as a one-pot synthesis without isolation of intermediates. This qualifies the process of this invention in particular for large scale manufacturing of the compound of formula I.
- a further significant of the invention is the safety of the process (inherently safe process) due to the presence of a nitro group.
- alkaline solution of compound of formula II into NaOCI solution results in an accumulation and generation of the N-halo compound which is very high energetic and explosive compound.
- a lower mole ratio of NaOH as claimed with respect to compound of formula II results in undesired excessive gas evolution during acidification.
- Example 1 (best mode): A solution of NaOH (2.0 mole) having a strength of 1 5% by weight was cooled to a temperature of 25°C. Then 1 .0 mole of 3-nitro-phthalimide was added portionwise under stirring. While maintaining the temperature at 25-30°C, 1 .2 mole solution of 12% strength sodium hypochlorite was added portionwise. During addition, the pH of the reaction mass was kept at pH 12.0 with aqueous sodium hydroxide with a concentration of of 15% by weight. After stirring for 2 hours, the reaction mass was cooled down to 5-10 °C and acidified with 32% hydrochloric acid to a pH value of 1 .8. After stirring for another hour, the reaction mass was filtered with a suction filter. Then the cake was washed with cold water (8-10 °C) and dried under vacuum to yield 6-nitro-anthranilic acid in an amount of 88% of theory.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a novel a process for the preparation of a compound of formula (I) which process comprises adding 1 to 2 mol of sodium hypochlorite with a concentration of 8% to 15% by weight to a suspension of the compound of formula (II) in aqueous sodium hydroxide at a temperature of 5 to 60°C, wherein the concentration of sodium hydroxide in the suspension is from 5 to 25 % by weight; and acidifying the reaction mass with concentrated hydrochloric acid to a pH of 1.5 to 2.0 and wherein said process is carried out as a one-pot synthesis without isolation of intermediates.
Description
Process for the preparation of an anthranilic acid derivative
The present invention relates to the selective preparation of 6-nitro-anthranilic acid.
6-Nitro-anthranilic acid is a valuable intermediate for the preparation of benzonorbornene fungicides, as described for example in WO 2007/048556.
According to WO 2007/031323, 6-nitro-anthranilic acid (A) can be prepared according to the following scheme:
3-Nitro-phthalimide (E) is a useful starting material for the preparation of 6-nitro-anthranilic acid, in particular for large scale manufacturing which requires high safety standards.
However, an efficient process for the preparation of 6-nitro-anthranilic acid starting from 3- nitro-phthalimide has to avoid the form tion of the undesired regioisomer of formula (B)
which reduces yield and quality of the product. Therefore, the process according to WO 2007/031323 is performed in two separate steps. In the scheme above, 3-nitro-phthalimide (E) is converted in a first step by reaction with an aqueous base, and by subsequent reaction with an aqueous acid, into 6-nitrophthalamic acid (D). During the precipitation of the amido acid, the desired isomer (D) is enriched.
In a second step, 6-nitrophthalamic acid (D) is then converted to 6-nitro-anthranilic acid (A). In that step, 6-nitrophthalamic acid may be reacted first with aqueous base, such as, for example, aqueous sodium hydroxide, and sodium hypochlorite, and then with aqueous acid, such as, for example, aqueous hydrochloric acid.
The disadvantage of this prior art process is the relatively low yield in each of the two steps (70-73%). Further, isolation is required to enrich the desired isomer with additional filtration which leads to high waste generation and higher cycle time (energy inefficient). Also, a two step synthesis is undesired for large scale production.
The aim of the present invention is therefore to provide a novel process for the selective production of 6-nitro-anthranilic acid that avoids the disadvantages of the known process and makes it possible to prepare 6-nitro-anthranilic acid in high yields and good quality in an economically and ecologically advantageous way in a one-pot process with a high safety standard.
Thus, according to the present invention, there is provided a process for the preparation of a compound of formula I
adding 1 to 2 mol of sodium hypochlorite with a concentration of 8% to 15% by weight to a suspension of the compound of formula II
in aqueous sodium hydroxide at a temperature of 5 to 60°C, wherein the concentration of sodium hydroxide in the suspension is from 5 to 25 % by weight;
and acidifying the reaction mass with concentrated hydrochloric acid to a pH of 1 .5 to 2.0 and wherein said process is carried out as a one-pot synthesis without isolation of intermediates.
The concentrated hydrochloric acid used in the process according to the invention has a concentration of 30 - 38 % by weight, preferably 30 - 35 % by weight. In a preferred variant of the process of the invention, the reaction mass is acidified at a temperature of 5 to 10°C with concentrated hydrochloric acid to a pH of 1.5 to 2.0.
The suspension of the compound of formula I I in sodium hydroxide can be prepared by charging an aqueous solution of sodium hydroxide (2 to 3 mol), cool the solution to a temperature of 20 to 30°C, in particular 25°C, and add portionwise 1 mol of the compound of formula II under stirring.
The reaction is performed according to the shown reaction scheme with the in situ formation of the intermediates of formulae III, IV and V
The suspension of the compound of formula II in sodium hydroxide can be advantageously prepared by charging an aqueous solution of sodium hydroxide (preferably 2 mol), at a
temperature of 5 to 60 °C, in particular 5 to 40°C, preferably of 25 to 30 °C, keep the temperature of the solution at 20 to 40°C, in particular 20 to 25°C, and add portionwise 1 mol of the compound of formula I I under stirring. The concentration of sodium hydroxide is preferably 5 to 25%, more preferably 5 to 20%, in particular 15% by weight.
The sodium hypochlorite (preferably in an amount of 1 .1 to 1 .2 mol) is added portionwise, preferably during 20 to 45 minutes. A preferred temperature range for the addition is from 5 to 60°C, in particu lar 5 to 40° C, preferably 25 to 30 ° C . The sodium hypochlorite concentration is preferably 8% to 15%, in particular 10 - 12 % by weight. It is preferred to stirr the reaction mass for 1 to 2 hours for complete conversion of the compound of formula II to the compound of formula I. It is advantageous to cool the reaction mass to a temperature from 5 to 10 °C before acidification to pH 1 .5 - 2.0 using concentrated HCI. For the maximum product separation, it is preferred to stirr the resulting precipitate for another 30 minutes to 1 hour at a temperature of 5 to 10 °C. A significant advantage of the process of this invention is the overall yield which is between 70% and 90%. Further, the process is carried out as a one-pot synthesis without isolation of intermediates. This qualifies the process of this invention in particular for large scale manufacturing of the compound of formula I.
A further significant of the invention is the safety of the process (inherently safe process) due to the presence of a nitro group.
A lower temperature as claimed during sodium hypochlorite addition would lead to an accumulation of the intermediate of formula IV which is a high energetic intermediate which can go to runaway in the reaction vessel.
The addition of alkaline solution of compound of formula II into NaOCI solution (reverse mode of addition as in the process according to the invention) results in an accumulation and generation of the N-halo compound which is very high energetic and explosive compound.
A lower mole ratio of NaOH as claimed with respect to compound of formula II results in undesired excessive gas evolution during acidification.
Preparatory examples: Preparation of 6-nitro-anthranilic acid:
Example 1 (best mode):
A solution of NaOH (2.0 mole) having a strength of 1 5% by weight was cooled to a temperature of 25°C. Then 1 .0 mole of 3-nitro-phthalimide was added portionwise under stirring. While maintaining the temperature at 25-30°C, 1 .2 mole solution of 12% strength sodium hypochlorite was added portionwise. During addition, the pH of the reaction mass was kept at pH 12.0 with aqueous sodium hydroxide with a concentration of of 15% by weight. After stirring for 2 hours, the reaction mass was cooled down to 5-10 °C and acidified with 32% hydrochloric acid to a pH value of 1 .8. After stirring for another hour, the reaction mass was filtered with a suction filter. Then the cake was washed with cold water (8-10 °C) and dried under vacuum to yield 6-nitro-anthranilic acid in an amount of 88% of theory.
Example 2:
A solution of N aO H (3.0 mole) having a strength of 5% by weight was cooled to a temperature of 35° - 40°C. Then 1 .0 mole of 3-nitro-phthalimide was added portionwise under stirring. While maintaining the temperature at 35-40°C, 1 .2 mole solution of 8% strength sodium hypochlorite was added portionwise. During addition, the pH of the reaction mass was kept at pH 12.0 with aqueous sodium hydroxide with a concentration of of 15% by weight. After stirring for 2 hours, the reaction mass was cooled down to 5-10 °C and acidified with 32% hydrochloric acid to a pH value of 1 .8. After stirring for another hour, the reaction mass was filtered with a suction filter. Then the cake was washed with cold water (8-10 °C) and dried under vacuum to yield 6-nitro-anthranilic acid in an amount of 70% of theory.
Claims
1 . A process for the preparation of a compound of formula I
adding 1 to 2 mol of sodium hypochlorite with a concentration of 8% to 15% by weight to a suspension of the compound of formula II
in aqueous sodium hydroxide at a temperature of 5 to 60°C, wherein the concentration of sodium hydroxide in the suspension is from 5 to 25 % by weight;
and acidifying the reaction mass with concentrated hydrochloric acid to a pH of 1.5 to 2.0 and wherein said process is carried out as a one-pot synthesis without isolation of intermediates.
2. A process according to claim 1 which comprises
acidifying the reaction mass at a temperature of 5 to 10°C with concentrated hydrochloric acid to a pH of 1.5 to 2.0.
3. A process according to claim 1 which comprises adding 1 to 2 mol of sodium hypochlorite with a concentration of 8% to 15% by weight to a suspension of the compound of formula II in aqueous sodium hydroxide at a temperature of 5 to 40°C,
4. A process according to claim 3, comprises adding 1 to 2 mol of sodium hypochlorite with a concentration of 8% to 15% by weight to a suspension of the compound of formula II in aqueous sodium hydroxide at a temperature of 25 to 30°C,
5. A process according to claim 1 which comprises adding 1.1 to 1.2 mol of sodium
hypochlorite with a concentration of 8% to 15% by weight to a suspension of the compound of formula II.
6. A process according to claim 1 which process comprises
adding 1 .1 to 1.2 mol of sodium hypochlorite with a concentration of 10 - 12 % by weight to a suspension of the compound of formula II in aqueous sodium hydroxide at a temperature of 25 to 30°C, wherein the concentration of sodium hydroxide in the suspension is from 5 to 20% by weight; and acidifying the reaction mass with concentrated hydrochloric acid to a pH of 1 .5 to 2.0 and wherein said process is carried out as a one-pot synthesis without isolation of intermediates.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN276/DEL/2010 | 2010-02-09 | ||
| IN276DE2010 | 2010-02-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011098386A1 true WO2011098386A1 (en) | 2011-08-18 |
Family
ID=43983558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2011/051535 Ceased WO2011098386A1 (en) | 2010-02-09 | 2011-02-03 | Process for the preparation of an anthranilic acid derivative |
Country Status (4)
| Country | Link |
|---|---|
| AR (1) | AR080142A1 (en) |
| TW (1) | TW201136873A (en) |
| UY (1) | UY33220A (en) |
| WO (1) | WO2011098386A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11560384B2 (en) | 2017-05-04 | 2023-01-24 | University Of Utah Research Foundation | Benzonorbornadiene derivatives and reactions thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007031323A1 (en) | 2005-09-16 | 2007-03-22 | Syngenta Participations Ag. | Process for the production of amides |
| WO2007048556A1 (en) | 2005-10-25 | 2007-05-03 | Syngenta Participations Ag | Heterocyclic amide derivatives useful as microbiocides |
-
2011
- 2011-02-03 WO PCT/EP2011/051535 patent/WO2011098386A1/en not_active Ceased
- 2011-02-07 AR ARP110100392A patent/AR080142A1/en not_active Application Discontinuation
- 2011-02-08 TW TW100104081A patent/TW201136873A/en unknown
- 2011-02-09 UY UY0001033220A patent/UY33220A/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007031323A1 (en) | 2005-09-16 | 2007-03-22 | Syngenta Participations Ag. | Process for the production of amides |
| WO2007048556A1 (en) | 2005-10-25 | 2007-05-03 | Syngenta Participations Ag | Heterocyclic amide derivatives useful as microbiocides |
Non-Patent Citations (2)
| Title |
|---|
| HEINRICH SEIDEL, J. C. BITTNER: "Über Derivate der Nitrophtalsäuren", MONATSHEFTE FÜR CHEMIE, vol. 23, 1902, pages 415 - 436, XP002638261, DOI: 10.1007/BF01527262 * |
| ROBERT A SNOW ET AL: "Analysis of bridging regioselectivity operative in photorearrangement of ortho-substituted benzonorbornadienes", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, vol. 99, no. 11, 25 May 1977 (1977-05-25), pages 3734 - 3744, XP002271785, ISSN: 0002-7863, DOI: DOI:10.1021/JA00453A036 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11560384B2 (en) | 2017-05-04 | 2023-01-24 | University Of Utah Research Foundation | Benzonorbornadiene derivatives and reactions thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| UY33220A (en) | 2011-09-30 |
| AR080142A1 (en) | 2012-03-14 |
| TW201136873A (en) | 2011-11-01 |
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