CA1301766C - Process for the manufacture of 3-amino-5- methylisoxazole - Google Patents
Process for the manufacture of 3-amino-5- methylisoxazoleInfo
- Publication number
- CA1301766C CA1301766C CA000548923A CA548923A CA1301766C CA 1301766 C CA1301766 C CA 1301766C CA 000548923 A CA000548923 A CA 000548923A CA 548923 A CA548923 A CA 548923A CA 1301766 C CA1301766 C CA 1301766C
- Authority
- CA
- Canada
- Prior art keywords
- process according
- range
- hydroxyurea
- amino
- reaction
- 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 - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
An improved process for the manufacture of 3-amino-5-methylisoxazole is described. According to the process a nitrile compound selected from the group consisting of 2,3-dibromo-butyronitrile, 2-bromo-3-methoxybutyronitrile, 2-bromocrotono-nitrile and tetrolonitrile or mixtures thereof is reacted with hydroxyurea in the medium of an alkali metal hydroxide, wherein the pH during the reaction is maintained in the range of between 10.1 to 13 and preferably between 10.5 to 12.5. Optionally, an inert organic solvent is also present in the reaction system.
The hydroxyurea may be also prepared in-situ from alkyl carbamate and hydroxyamine in an aqueous alkali medium. The 3-amino-5-methylisoxazole derivatives are useful intermediates for the synthesis of sulfa drugs.
An improved process for the manufacture of 3-amino-5-methylisoxazole is described. According to the process a nitrile compound selected from the group consisting of 2,3-dibromo-butyronitrile, 2-bromo-3-methoxybutyronitrile, 2-bromocrotono-nitrile and tetrolonitrile or mixtures thereof is reacted with hydroxyurea in the medium of an alkali metal hydroxide, wherein the pH during the reaction is maintained in the range of between 10.1 to 13 and preferably between 10.5 to 12.5. Optionally, an inert organic solvent is also present in the reaction system.
The hydroxyurea may be also prepared in-situ from alkyl carbamate and hydroxyamine in an aqueous alkali medium. The 3-amino-5-methylisoxazole derivatives are useful intermediates for the synthesis of sulfa drugs.
Description
~3~
The present invention relates to a p~ocess for the manufacture of 3-amino-isoxazoles. More parti~ularly, the invention relates to an improved process ~or the manufac~ure of 3-amino-5-methylisoxazole (hereafter referred to as 3-AMI) at high yields.
EUCX~OUND oF ~HE DNUENTI
The compound 3-AMI is known aq an important raw material fo~
the preparation of sulfonamide derivatives which are widely used as antibacterical agents. Thus for example, by condensation of 3-AMI
with N-protected p-aminohenzenesulfonyl chloride, sulfamethoxazole is obtained which is one of the most effective sulfa drugs. 3-AMI
is mentioned as a new compound in the U.K. Patent No. 814,276 as a starting material for the manufacture of sulfa drugs. According to the patent, 3-AMI is obtained by the hydrolysis of ethyl-5-methyl-isoxazole-3-carbamate.
The literature is quite abundant with methods dealing with the manufacture of derivatives o~ 3-amino-isoxazoles having the formula:
- NH2 wherein: R represents: hydrogen, an I alkyl group containing l-S
R
~ O ~ carbon atoms and aryl groups.
The general scheme of these methods involves the reaction between a hydroxylamine, or derivatives thereof, with sultable nitrile compounds and the cyclization of the resulting intermediate product ~' ~3q~
usiny alkali hydroxide solutions. One of the maln disadvantages of the known methods is the relatively poor yields which are in the range of 50 - 76% only. Attempts to lmprove the yields of the methods, based on the above scheme, were unsuccessful and S accordingly other routes, which are more complicated or are requiring more expensive starting materials were suggested. Thus for instance accoxding to C.A. 98, 126062, it is suggested to cæry out this synthesis by starting with 3-carbamoyl-5-methylisoxazole and a mixture of sodium hydroxide and ~odium hypochlori~e.
It is an object of the present invention to provide an improved process for the manufacture of 3-amino-5-methylisoxazole.
It is another object of the present invention to provide an improved process for the manufacture of 3-amino-5~methylisoxazole at high yields. It is yet another object of the present invention to provide an improved process for the manu~acture of 3-amino-5-methyl-isoxazole (3-AMI) which is ot a high purity.
The invention consists of an improved process for the manufac~ure o~ 3-AMI, by reacting a nitrile compound selected from the group consisting of 2,3-dibromobutyronitrile (DBBN), 2-bromo-3-methoxybutyromtrile (BMBN), 2-bromocrotononitrile (2-BCN), tetrolonitrile (TN) and mixtures thereof with ~3~
hydroxyurea in an alkali metal hydroxide medium, the pH
during the reaction being maintained in the range o 10.1 - 13.
It was unexpectedly found that by carrying out the reaction of the nitrile-hydroxyurea compound under a controlled pH range, the most preferred being between 10.5 - 12.5, the yields obtained are considerably imp~oved being akove 90%. Moreover, the 3-AMI product is substantially fxee of the 5-amino-3-methylisoxazole (5-AMI) which is one of the main impurities present in the prior ar~ methods.
Another advantage of the process according to the pxesent invention, is the relatively short reaction time required in the cyclization step producing the 3-AMI. Whereas the prior art methods are mentioning long periods up to 24 hours, according to the present invention even less than 4 hours were found to be sufficient to obtain the high yields of 3-AMI. This enables to carry out the process even in a continuous manner.
According to a preferred embcdiment, the reaction in the alkali metal hydroxide mediu~, is carried out in the presence of an inert organic solvent for example primary alcohols, dioxane, tetrahydrofuran and the like or any mixture thereof. Spedfic examples of alcohols are methanol, ethanol etc.
~3~
Suitable alkali me~al hydroxides to be employed during the cyclization step are sod~um, potassium and lithium hydroxide, the first one being most preferable being also the less expensive. The alkali metal hydroxide is added generally in the form of an aqueous solution, the preferred concentration ran~e being ketween 30~ to 50% by wt.
The reaction temperature is not critical, generally being from about room temperature to the reflux temperature of the solvents utilized.
The first step of the process consists of the reaction between a nitrile, and hydroxyureaO This reaction is carried out under vigorous stirring. The nitrile is selected from DBBN, BMBN, 2-BCN and rLN or any mixture thereof, prepared according to the methods known in ~he art.
The sMBN see~s to be a new compound which is not described in the literature. It is Qbtained by the bromination o~ crotononitrile(CN) in methanol.
The hydroxyurea can be added either in its pure form or produced in-situ without any isolation or purification. Thus for instance, hydroxyurea can be prepared by mixing alkyl carbamates and hydroxylamine salts in basic aqueous medium. The hydroxylamine may be in the form of a free base or an acid addition salt such as hydrochloride, hydrosulfate and the like. In the latter case, the hydroxylamine will be formed in-situ, by reacting the acid salt with sodium hydroxide in the presence of alkyl carbamates as known in the art.
The main feature of the present lnvention, is the product:Lon of the 3-AMI by the reaction of the suitable nitriles and hy~roxyurea in the presence of alkali metal hydroxide in a critical narrow pH
range. It was found that the high yields are achieved only when the S reaction is produced under a pH ranging from 10.1 to 13 and most preferable at a pH range of between 10.5 to 12.5. When the F*l is below 10.1 or above 13, a sharp decrease occurs in the yield being accompanied by an increase o~ 5~AMI known as the main impurity.
This will cleæly appear from the Examples presented below. The inventors are not yet in a position to give a definite explanation of this phenomena.
The control o~ ~he ~H in the a~ove narrow range can be obtained by adding continuously small portions of alkaline metal hydroxide, using a conventional pH electrode as monitoring device.
Of course a person skilled in the art may utilize any other expedients for monitoring the pH at the above range.
The invention will be hereatter illustrated by the ~ollo~ing Examples without being limited thereto. A person skilled in the art after reading the specification, will be in a position ~o appreciate the gist o~ the invention and many variations might be conceivecl and incorporated therein~
~30:17~6 EXAMPLES 1 to 5 A solution contaimng 53.6 gr (0.8 moles) of crotononitrile and 42.5 ml of absolute methanol was mixed vigorously in a ~hree-necked flask. 128 gr (0.8 moles) o~ bromine were introduced dropwise into the solution. After the addition was completed the solution was lett for 24 hours aging and was ~ound to consist of about 79% DBBN.
o an amount o~ 130 mls of cold solution from the above resulted DBEN solution, it was added under vigorous stirring a solution consisting of 20 g sodium hydroxide dissolved in 75 ml water.
The solution was stirred ~or five minutes after the addition was completed, the organic layer was separated and dried over anhydrous MgS0 . 69.66 gr of a pale yellow mixture was obtained.
According to NMR spectrum, using tetrachloroethane as internal standard, the solution contained 85% of 2-BCN, 10.5% of B~EN and 1.1% of tetrolonitrile (TN).
Aqueous hydroxyurea (HXU) solution was prepared from 95 gr hydroxylammonium hydrochloride and 129 gr ot ethyl carbamate in a basic medium. 130 gr of the mixture ~repared above was introduced dropwise to the cold vigorously stirred HXU solution, while the pH
~3~
was kept between certain limits by occasional addition of 50% NaOH solution. After the addition was completed, the reaction mixture was mixed ~or 1 hr at room temperatur~ and then refluxed for about 3 hours.
The solution was cooled, filtered and extracted with 3 x 250 ml o~ ethyl acetate. The combined organic layer was dried over anhydrous MgS04 and evaporated.
The resulting oil was analyzed by HPLC using a Bio-Rad*, Aminex* HPX-72-0, 300 mm x 7 mm column; 0~01 ~ NaOH was used as eluant.
The experiment was repeated under the same conditions, the difference being the pH range maintained during the NaOH addition. The results are summarized in the following Table 1:
Table 1~ Yields of 3-AMI produced at various~ es usLnq crude 2-BCN as a nitrile s~Dxe ~1 Ex.2E~.3 Ex.4Ex.5 pH limits 9-10 10-1111-12 12-1313-14 3-AMI yield70.9 85.683.0 79.552.1 20 5-AMI yield3.4 2.1 1.5 1.1 2.0 -From the above Table 1, it appears clearly the improved results of the 3-AMI obtained according to the present invention. When the pH is kept in the range of 10.1-13, the yields are in the range of 79.5% to 85.6% compared with 70.9% and 52.1% when the pH ranges are between 9-10 and 13-14, i.e., below or above the optimal range * - Trademarks ,~ ..~, ~3~.1L'7~6 discovered acco~ding to the present invention. Also, the 3-AMI
product i5 purer than that obtained in the pH xanges outside the range of the present invention, containing less 5~AMI, which is the main impurity co-produced in the process.
EXA~PLES 6 to 8.
An amount of 214 mls of a methanolic solution of D~BW, obtained as in Examples 1 - 5, was added dropwise under vigorous stirring to an ice cooled solution of aqueous HXU (prepared as in Example 1 - 5) present in a 3 1 three-neclced flask. To the mixture, a solution of NaOH (50% concentration by wt.) was added, maintaining strictly the pH range. When the addi~ion was completed the crude mixture was worked up as described in Examples 1 - 5. Thxee experiments were repeated under the same conditions, the difference being the pH ranges kept during the sodium hydroxide addition.
The results are summarized in the following Table 2.
T~ELE 2 Yields of crude DBBN as a nitrile source.
Fx. 6 Ex. 7 Ex 8 pH ran~e 9-10 12-12.5 13.5-14 20 3-AMI yield 65.01 82.3% 21%
5-AMI yield 4.10 >0.1% not measured _ . . _ . . .. , .. .... _ ~3~
From the above Table 2, it again appears the improv~l resllts concerning yield ~nd purity of the 3-AMI produced according to the present invention.
F~UU~PLE 9, 2-~romocrotoni~rile ~2-ECN) was obtained by deh~drobromination of the DçæN obtained as in Examples 1-5, using a solution of NaOH.
The 2-~CN was distilled under vacuum ~50 degrees C/8 mm Rg). The procedure for obtaining the 3-A~I was the s~ne as in Examples 1-5, using ;~n amount o~ 147 g of the distilled 2-BCN. The pH during the reaction, was maintained by the addition of NaOH (50% concentration ~y wt.) in the range of 11 - 12~ An amount o~ 88.15 g of 3-AMI was produced ~Yield = 90%) the S-AMI impurity being less than 0.7%, as determaned by the ~.PLC analysls (as mentioned in Ex~nples 1 - 5).
It should be pointed out that Examples 1, 5, 6, 8 do not illustrate the present invention a~d are presented for ~omparison purposes only.
The present invention relates to a p~ocess for the manufacture of 3-amino-isoxazoles. More parti~ularly, the invention relates to an improved process ~or the manufac~ure of 3-amino-5-methylisoxazole (hereafter referred to as 3-AMI) at high yields.
EUCX~OUND oF ~HE DNUENTI
The compound 3-AMI is known aq an important raw material fo~
the preparation of sulfonamide derivatives which are widely used as antibacterical agents. Thus for example, by condensation of 3-AMI
with N-protected p-aminohenzenesulfonyl chloride, sulfamethoxazole is obtained which is one of the most effective sulfa drugs. 3-AMI
is mentioned as a new compound in the U.K. Patent No. 814,276 as a starting material for the manufacture of sulfa drugs. According to the patent, 3-AMI is obtained by the hydrolysis of ethyl-5-methyl-isoxazole-3-carbamate.
The literature is quite abundant with methods dealing with the manufacture of derivatives o~ 3-amino-isoxazoles having the formula:
- NH2 wherein: R represents: hydrogen, an I alkyl group containing l-S
R
~ O ~ carbon atoms and aryl groups.
The general scheme of these methods involves the reaction between a hydroxylamine, or derivatives thereof, with sultable nitrile compounds and the cyclization of the resulting intermediate product ~' ~3q~
usiny alkali hydroxide solutions. One of the maln disadvantages of the known methods is the relatively poor yields which are in the range of 50 - 76% only. Attempts to lmprove the yields of the methods, based on the above scheme, were unsuccessful and S accordingly other routes, which are more complicated or are requiring more expensive starting materials were suggested. Thus for instance accoxding to C.A. 98, 126062, it is suggested to cæry out this synthesis by starting with 3-carbamoyl-5-methylisoxazole and a mixture of sodium hydroxide and ~odium hypochlori~e.
It is an object of the present invention to provide an improved process for the manufacture of 3-amino-5-methylisoxazole.
It is another object of the present invention to provide an improved process for the manufacture of 3-amino-5~methylisoxazole at high yields. It is yet another object of the present invention to provide an improved process for the manu~acture of 3-amino-5-methyl-isoxazole (3-AMI) which is ot a high purity.
The invention consists of an improved process for the manufac~ure o~ 3-AMI, by reacting a nitrile compound selected from the group consisting of 2,3-dibromobutyronitrile (DBBN), 2-bromo-3-methoxybutyromtrile (BMBN), 2-bromocrotononitrile (2-BCN), tetrolonitrile (TN) and mixtures thereof with ~3~
hydroxyurea in an alkali metal hydroxide medium, the pH
during the reaction being maintained in the range o 10.1 - 13.
It was unexpectedly found that by carrying out the reaction of the nitrile-hydroxyurea compound under a controlled pH range, the most preferred being between 10.5 - 12.5, the yields obtained are considerably imp~oved being akove 90%. Moreover, the 3-AMI product is substantially fxee of the 5-amino-3-methylisoxazole (5-AMI) which is one of the main impurities present in the prior ar~ methods.
Another advantage of the process according to the pxesent invention, is the relatively short reaction time required in the cyclization step producing the 3-AMI. Whereas the prior art methods are mentioning long periods up to 24 hours, according to the present invention even less than 4 hours were found to be sufficient to obtain the high yields of 3-AMI. This enables to carry out the process even in a continuous manner.
According to a preferred embcdiment, the reaction in the alkali metal hydroxide mediu~, is carried out in the presence of an inert organic solvent for example primary alcohols, dioxane, tetrahydrofuran and the like or any mixture thereof. Spedfic examples of alcohols are methanol, ethanol etc.
~3~
Suitable alkali me~al hydroxides to be employed during the cyclization step are sod~um, potassium and lithium hydroxide, the first one being most preferable being also the less expensive. The alkali metal hydroxide is added generally in the form of an aqueous solution, the preferred concentration ran~e being ketween 30~ to 50% by wt.
The reaction temperature is not critical, generally being from about room temperature to the reflux temperature of the solvents utilized.
The first step of the process consists of the reaction between a nitrile, and hydroxyureaO This reaction is carried out under vigorous stirring. The nitrile is selected from DBBN, BMBN, 2-BCN and rLN or any mixture thereof, prepared according to the methods known in ~he art.
The sMBN see~s to be a new compound which is not described in the literature. It is Qbtained by the bromination o~ crotononitrile(CN) in methanol.
The hydroxyurea can be added either in its pure form or produced in-situ without any isolation or purification. Thus for instance, hydroxyurea can be prepared by mixing alkyl carbamates and hydroxylamine salts in basic aqueous medium. The hydroxylamine may be in the form of a free base or an acid addition salt such as hydrochloride, hydrosulfate and the like. In the latter case, the hydroxylamine will be formed in-situ, by reacting the acid salt with sodium hydroxide in the presence of alkyl carbamates as known in the art.
The main feature of the present lnvention, is the product:Lon of the 3-AMI by the reaction of the suitable nitriles and hy~roxyurea in the presence of alkali metal hydroxide in a critical narrow pH
range. It was found that the high yields are achieved only when the S reaction is produced under a pH ranging from 10.1 to 13 and most preferable at a pH range of between 10.5 to 12.5. When the F*l is below 10.1 or above 13, a sharp decrease occurs in the yield being accompanied by an increase o~ 5~AMI known as the main impurity.
This will cleæly appear from the Examples presented below. The inventors are not yet in a position to give a definite explanation of this phenomena.
The control o~ ~he ~H in the a~ove narrow range can be obtained by adding continuously small portions of alkaline metal hydroxide, using a conventional pH electrode as monitoring device.
Of course a person skilled in the art may utilize any other expedients for monitoring the pH at the above range.
The invention will be hereatter illustrated by the ~ollo~ing Examples without being limited thereto. A person skilled in the art after reading the specification, will be in a position ~o appreciate the gist o~ the invention and many variations might be conceivecl and incorporated therein~
~30:17~6 EXAMPLES 1 to 5 A solution contaimng 53.6 gr (0.8 moles) of crotononitrile and 42.5 ml of absolute methanol was mixed vigorously in a ~hree-necked flask. 128 gr (0.8 moles) o~ bromine were introduced dropwise into the solution. After the addition was completed the solution was lett for 24 hours aging and was ~ound to consist of about 79% DBBN.
o an amount o~ 130 mls of cold solution from the above resulted DBEN solution, it was added under vigorous stirring a solution consisting of 20 g sodium hydroxide dissolved in 75 ml water.
The solution was stirred ~or five minutes after the addition was completed, the organic layer was separated and dried over anhydrous MgS0 . 69.66 gr of a pale yellow mixture was obtained.
According to NMR spectrum, using tetrachloroethane as internal standard, the solution contained 85% of 2-BCN, 10.5% of B~EN and 1.1% of tetrolonitrile (TN).
Aqueous hydroxyurea (HXU) solution was prepared from 95 gr hydroxylammonium hydrochloride and 129 gr ot ethyl carbamate in a basic medium. 130 gr of the mixture ~repared above was introduced dropwise to the cold vigorously stirred HXU solution, while the pH
~3~
was kept between certain limits by occasional addition of 50% NaOH solution. After the addition was completed, the reaction mixture was mixed ~or 1 hr at room temperatur~ and then refluxed for about 3 hours.
The solution was cooled, filtered and extracted with 3 x 250 ml o~ ethyl acetate. The combined organic layer was dried over anhydrous MgS04 and evaporated.
The resulting oil was analyzed by HPLC using a Bio-Rad*, Aminex* HPX-72-0, 300 mm x 7 mm column; 0~01 ~ NaOH was used as eluant.
The experiment was repeated under the same conditions, the difference being the pH range maintained during the NaOH addition. The results are summarized in the following Table 1:
Table 1~ Yields of 3-AMI produced at various~ es usLnq crude 2-BCN as a nitrile s~Dxe ~1 Ex.2E~.3 Ex.4Ex.5 pH limits 9-10 10-1111-12 12-1313-14 3-AMI yield70.9 85.683.0 79.552.1 20 5-AMI yield3.4 2.1 1.5 1.1 2.0 -From the above Table 1, it appears clearly the improved results of the 3-AMI obtained according to the present invention. When the pH is kept in the range of 10.1-13, the yields are in the range of 79.5% to 85.6% compared with 70.9% and 52.1% when the pH ranges are between 9-10 and 13-14, i.e., below or above the optimal range * - Trademarks ,~ ..~, ~3~.1L'7~6 discovered acco~ding to the present invention. Also, the 3-AMI
product i5 purer than that obtained in the pH xanges outside the range of the present invention, containing less 5~AMI, which is the main impurity co-produced in the process.
EXA~PLES 6 to 8.
An amount of 214 mls of a methanolic solution of D~BW, obtained as in Examples 1 - 5, was added dropwise under vigorous stirring to an ice cooled solution of aqueous HXU (prepared as in Example 1 - 5) present in a 3 1 three-neclced flask. To the mixture, a solution of NaOH (50% concentration by wt.) was added, maintaining strictly the pH range. When the addi~ion was completed the crude mixture was worked up as described in Examples 1 - 5. Thxee experiments were repeated under the same conditions, the difference being the pH ranges kept during the sodium hydroxide addition.
The results are summarized in the following Table 2.
T~ELE 2 Yields of crude DBBN as a nitrile source.
Fx. 6 Ex. 7 Ex 8 pH ran~e 9-10 12-12.5 13.5-14 20 3-AMI yield 65.01 82.3% 21%
5-AMI yield 4.10 >0.1% not measured _ . . _ . . .. , .. .... _ ~3~
From the above Table 2, it again appears the improv~l resllts concerning yield ~nd purity of the 3-AMI produced according to the present invention.
F~UU~PLE 9, 2-~romocrotoni~rile ~2-ECN) was obtained by deh~drobromination of the DçæN obtained as in Examples 1-5, using a solution of NaOH.
The 2-~CN was distilled under vacuum ~50 degrees C/8 mm Rg). The procedure for obtaining the 3-A~I was the s~ne as in Examples 1-5, using ;~n amount o~ 147 g of the distilled 2-BCN. The pH during the reaction, was maintained by the addition of NaOH (50% concentration ~y wt.) in the range of 11 - 12~ An amount o~ 88.15 g of 3-AMI was produced ~Yield = 90%) the S-AMI impurity being less than 0.7%, as determaned by the ~.PLC analysls (as mentioned in Ex~nples 1 - 5).
It should be pointed out that Examples 1, 5, 6, 8 do not illustrate the present invention a~d are presented for ~omparison purposes only.
Claims (11)
1. A process for the manufacture of 3-amino-5-methylisoxazole, by reacting a nitrile compound selected from the group consisting of 2,3-dibromobutyronitrile,
2-bromo-3-methoxybutyronitrile, 2-bromocrotonotrile and tetrolonitrile, or a mixture thereof with hydroxyurea in an alkali metal hydroxide medium, the pH during the reaction being maintained in the range of 10.1 to 13.
2. A process according to claim 1, wherein the pH is maintained in the range of between 10.5 to 12.5.
2. A process according to claim 1, wherein the pH is maintained in the range of between 10.5 to 12.5.
3. A process according to claim 1, wherein an inert organic solvent is present during the reaction.
4. A process according to claim 3, wherein said solvent is selected from the group consisting of primary alcohols, dioxane, tetrahydrofuran or mixtures thereof.
5. A process according to claim 4, wherein said primary alcohol is methanol.
6. A process according to claim 5, wherein the alkali metal hydroxide is selected from sodium, potassium and lithium hydroxide.
7. A process according to claim 6, wherein the alkali metal hydroxide is added as an aqueous solution having a concentration in the range of 30% to 50% by weight.
8. A process according to claim 7, wherein the hydroxyurea is produced in-situ during the process.
9. A process according to claim 8, wherein the hydroxyurea is prepared from alkyl carbamate and hydroxylamine in an aqueous alkali medium.
10. A process according to claim 9, wherein said pH
range is monitored out by a pH electrode.
range is monitored out by a pH electrode.
11. A process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the process is carried out in a continuous manner.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL80260A IL80260A0 (en) | 1986-10-09 | 1986-10-09 | Process for the manufacture of 3-amino-5-methylisoxazole |
| IL80260 | 1986-10-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1301766C true CA1301766C (en) | 1992-05-26 |
Family
ID=11057193
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000548923A Expired - Fee Related CA1301766C (en) | 1986-10-09 | 1987-10-08 | Process for the manufacture of 3-amino-5- methylisoxazole |
Country Status (7)
| Country | Link |
|---|---|
| CA (1) | CA1301766C (en) |
| DE (1) | DE3731850A1 (en) |
| ES (1) | ES2005019A6 (en) |
| FR (1) | FR2605005B1 (en) |
| GB (1) | GB2196005B (en) |
| IL (1) | IL80260A0 (en) |
| ZA (1) | ZA876868B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1154482B (en) * | 1958-09-20 | 1963-09-19 | Shionogi & Co | Process for the preparation of 3-aminoisoxazoles |
| CH421963A (en) * | 1963-08-06 | 1966-10-15 | Hoffmann La Roche | Process for the preparation of aminoisoxazoles |
| NL132128C (en) * | 1962-08-24 | |||
| US3544582A (en) * | 1965-04-06 | 1970-12-01 | Hoffmann La Roche | Process for preparing aminoisoxazoles |
| JPS5927343B2 (en) * | 1977-06-08 | 1984-07-05 | 塩野義製薬株式会社 | Synthesis method of 3-aminoisoxazoles |
-
1986
- 1986-10-09 IL IL80260A patent/IL80260A0/en not_active IP Right Cessation
-
1987
- 1987-09-14 ZA ZA876868A patent/ZA876868B/xx unknown
- 1987-09-14 GB GB8721580A patent/GB2196005B/en not_active Expired - Fee Related
- 1987-09-22 DE DE19873731850 patent/DE3731850A1/en not_active Withdrawn
- 1987-09-28 ES ES8702765A patent/ES2005019A6/en not_active Expired
- 1987-10-08 CA CA000548923A patent/CA1301766C/en not_active Expired - Fee Related
- 1987-10-09 FR FR878714010A patent/FR2605005B1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| GB2196005B (en) | 1990-05-09 |
| GB8721580D0 (en) | 1987-10-21 |
| DE3731850A1 (en) | 1988-04-14 |
| ZA876868B (en) | 1988-03-15 |
| FR2605005B1 (en) | 1991-09-13 |
| FR2605005A1 (en) | 1988-04-15 |
| ES2005019A6 (en) | 1989-02-16 |
| GB2196005A (en) | 1988-04-20 |
| IL80260A0 (en) | 1987-01-30 |
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