CN110229115A - The method for synthesizing 4- methyl oxazole -5- formamide - Google Patents
The method for synthesizing 4- methyl oxazole -5- formamide Download PDFInfo
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- CN110229115A CN110229115A CN201910284529.3A CN201910284529A CN110229115A CN 110229115 A CN110229115 A CN 110229115A CN 201910284529 A CN201910284529 A CN 201910284529A CN 110229115 A CN110229115 A CN 110229115A
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- Prior art keywords
- reaction
- oxa
- method described
- catalyst
- ammonium hydroxide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
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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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to synthesis 4- methyl-oxazole -5- formamide (OXA) methods, including reacting the compound of structure formula (I) with high concentration ammonium hydroxide: where R1It is H or C1‑10Alkyl.
Description
It is on April 24th, 2013 that the application, which is the applying date, application No. is 201380016902.8, entitled " synthesis
The divisional application of the application for a patent for invention of the method for 4- methyl oxazole -5- formamide ".
Invention field
The present invention relates to synthesis 4- methyl-oxazole -5- formamide new method, which is synthesis pyridoxol (vitamin
B6 valuable intermediate).
Background of invention
Several methods for preparing pyridoxol known.The summary of these most important methods can be for example, Liv Ullmann chemical industry
Encyclopaedical (Ullmann ' s Encyclopedia of Industrial Chemistry), the 5th edition, 1996, vol.A
27, p.533-537 in find.For commercial synthesis pyridoxol, Kondratyeva, G.Y. are almost used only now,
Khim.Nauka Promst.2, the method for 666 (1957), this method are carried out by oxazole and maleic acid or derivatives thereof
Diels-Alder reaction obtains pyridine ring.Especially preferred oxazole is 5- cyano -4- methyl-oxazole (OXN) in route of synthesis.
US 5910594, which is described, manufactures 5- cyano -4- low alkyl group-oxazole method by dehydration, wherein non-proton
In organic solvent, under amine existence condition, 5- carbamyl -4- low alkyl group oxazole is reacted with silicon tetrachloride.According to US
5502212 disclosures, using N, N, in polar non-proton organic solvent, OXA is dehydrated to be formed for-disubstituted formamide and cyanuric chloride
Corresponding OXN.Theoretically, the yield of the OXN obtained in the corresponding OXA is 99.4%.
Unfortunately, without the disclosure of OXA preparation method.Although above-mentioned Liv Ullmann chemical encyclopedia the 533rd
Page mentions 4- methyl-oxazole -5- carboxylic acid, ethyl ester and is converted to OXA, but does not provide any reaction condition, including yield and pure
Degree.
The side of OXA is prepared the purpose of the present invention is finding high yield under conditions of attractive for commercial synthesis
Method.
Summary of the invention
Present invention discover that 4- methyl-oxazole -5- carboxylate is reacted by the ammonium hydroxide with high concentration, it can high yield (90% He
It is even higher) it is converted to OXA.
Therefore, the present invention provides synthesis 4- methyl-oxazole -5- formamide (OXA) methods, including make structure formula (I)
Compound reacted with high concentration ammonium hydroxide:
Wherein R1It is H or C1-10Alkyl.
Detailed description of the invention
" the C used in the present invention1-10Alkyl " refers to branch or non-branched, cyclic annular or non-annularity, saturation
Alkyl comprising 1-10 carbon atom.Preferably, " C1-10Alkyl " is C1-4Alkyl, including but not limited to methyl, ethyl, third
Base, isopropyl, cyclopropyl, butyl, isobutyl group, tert-butyl, methylcyclopropyl groups and cyclobutyl.More preferably " C1-10Alkyl " is
Methyl or ethyl.
The present invention provides synthesis 4- methyl-oxazole -5- formamide (OXA) method, the chemical combination including making structure formula (I)
Object is reacted with high concentration ammonium hydroxide:
Wherein R1It is H or C1-10Alkyl.
The ammonium hydroxide for the high concentration used in reaction can be the aqueous solution of ammonia, and the minimum 15wt% of concentration is at least preferably
28wt%, more preferably minimum 30wt%, most preferably minimum 31wt%, 32wt%, 33wt%, 34wt%, 35wt%,
36wt%, 37wt%, 38wt%, 39wt%, 40wt%, 42wt%, 45wt%, 48wt%, 50wt%, 52wt% or
55wt%.In one embodiment of this method, the concentration for the ammonium hydroxide used in reaction is more excellent between 28wt% to 50wt%
Choosing between 30wt% to 45wt%, further it is more preferred between 30wt% to 40wt%.
The amount for the ammonium hydroxide used in reaction be not it is crucial, can change in a wide range.Preferably, ammonium hydroxide is used
Amount is the compound relative to every 1mol structure formula (I), and the range of the amount of ammonia is between 1mol to 10mol, preferred range
Between 2mol to 8mol, most preferred range is between 5mol to 8mol.
Preferably, reaction existing for the catalyst under the conditions of carry out, wherein catalyst is selected from ammonium salt, quaternary ammonium salt and alkali gold
Belong to the group of phosphate composition.
The example of ammonium salt is that structural formula is NH4Those of X salt, wherein X is inorganic anion, such as hydrochloric acid, sulfuric acid, phosphorus
Strong organic acid sour or well known to those skilled in the art, for example, carboxylic acid (it is mono-, double-, three-, polynary), such as formic acid,
Acetic acid, trifluoroacetic acid, citric acid.
The structural formula of quaternary ammonium salt as catalyst is by [N (R1)3R2] X indicates, wherein R1It is C1-C10Alkyl, R2Be hydrogen or
Person C1-C10Alkyl, X are the anion of above-mentioned inorganic acid or organic acid.
Alkali metal phosphate can be unitary, binary, (the MeH of ternary2PO4,Me2HPO4,Me3PO4), metal is preferred
Sodium or potassium.
The catalyst used in reaction is preferably ammonium halide, and most preferred catalyst is ammonium chloride.
The amount of reacting middle catalyst be not it is crucial, can change in a wide range.Relative to structure formula (I)
Compound, the mole of preferably catalyst are at least 0.01 to 0.05, and preferred range is 0.025 to 0.2.
The reaction can be in pressure and temperature typical for the reaction in ammonium hydroxide and well-known to those having ordinary skill in the art
Under the conditions of easily carry out.Preferably, under atmospheric pressure, 10 DEG C to 25 DEG C at a temperature of, at a temperature of preferred 20 DEG C into
Row reaction.
Optionally, which can carry out in a solvent.Solvent can be any solvent known in the art, including but
It is to be not limited only to alcohol such as methanol, ethyl alcohol, isopropanol and their mixture.
Optionally, reaction can carry out in inert gas, such as nitrogen, argon gas or their mixture.Reaction
It can be completed in less than 20 hours, usually 5 to 15 hours.It, can be by crystallizing the OXA for being easy to generate after reaction
It is isolated from reaction mixture.The OXA (optionally after further purification) isolated can be according to side well known in the art
Method is converted to the addition salts of pyridoxol and pyridoxol.
As the raw material of this reaction, the compound of structure formula (I) can obtain by methods known in the art, than
Such as the method described in patent publications US3538110, IN177708, US4026901 and US2009143346.
Method of the invention is very simple, its advantage is that yield height (up to 97%), the reaction time is short (about 10 hours),
The time that the OXA of generation is crystallized out from reaction mixture is short (about 2 hours).
Following examples further describe the present invention.These implementations are not intended to limit the invention in any way.
Embodiment
Embodiment 1: OXA is prepared using 25% ammonium hydroxide
Into 1000ml stainless steel autoclave, 155.15g 4- methyl-oxazole -5- carboxylate (OXE) is added
(1.0mol) and 340g ammonia solution (5mol, 25% aqueous solution) and in 20 DEG C of stirring 11h.Product OXA is precipitated in the reaction.It will
Suspension cools to -16 DEG C, and stirring 7h obtains 123g canescence to flaxen crystallization, and purity is 96.4% (± 1.2) (GC),
Yield is 94% (± 1.7).
Embodiment 2: OXA is prepared using 30% ammonium hydroxide
Into 1000ml stainless steel autoclave, be added 155.15g OXE (1.0mol) and 382g ammonia solution (6.7mol,
30% aqueous solution) and in 20 DEG C of stirring 12h.Product OXA is precipitated in the reaction.Suspension is cooled to -16 DEG C, stirring
15min obtains 123.7g canescence to flaxen crystallization, and purity is 96.5% (± 0.7) (GC), yield be 94.7% (±
1.2)。
Embodiment 3: OXA is prepared using 35% ammonium hydroxide
Into 1000ml stainless steel autoclave, be added 155.15g OXE (1.0mol) and 365g ammonia solution (7.5mol,
35% aqueous solution) and in 20 DEG C of stirring 12h.Product OXA is precipitated in the reaction.Suspension is cooled to -16 DEG C, stirring
30min obtains 122.1g canescence to flaxen crystallization, and purity is 98.2% (± 0.7) (GC), yield be 95.1% (±
1.2)。
Embodiment 4: OXA is prepared using 45% ammonium hydroxide
Into 1000ml stainless steel autoclave, be added 155.15g OXE (1.0mol) and 337g ammonia solution (10mol, 45%
Aqueous solution) and in 20 DEG C of stirring 10h.Product OXA is precipitated in the reaction.Suspension is cooled to -16 DEG C, stirring 7h is obtained
126.1g canescence is to flaxen crystallization, and purity is 97.2% (± 2) (GC), and yield is 97.2% (± 2.5).
Embodiment 5: OXA is prepared using 55% ammonium hydroxide
Into 250ml stainless steel autoclave, be added 38.8g OXE (0.25mol) and 96.4g ammonia solution (3.12mol,
55% aqueous solution) and in 20 DEG C of stirring 10h.Product OXA is precipitated in the reaction.Suspension is cooled to -16 DEG C, stirring 7h is obtained
To 31.3g canescence to flaxen crystallization, purity is 98.3% (± 1) (GC), and yield is 97.6% (± 1.5).
Embodiment 6: start to prepare OXA in ethanol with the OXE purified using 35% ammonium hydroxide
It is equipped with to 500ml in the stainless steel autoclave of blender, pressure controller, temperature controller, by 17.3g ammonia
(100%, 1020mmol) 500rpm in 20min is added with stirring 21.9g OXE (96.3%, 136mmol), 31.1g water
In (1728mmol) and the mixture of 20.8g ethyl alcohol (99.9%, 357mmol).Internal temperature during reactant is added
It is maintained at 5 DEG C.Reaction mixture is heated to 30 DEG C, internal temperature is maintained at 30 DEG C of 20h at 9.0bars.Reaction is mixed
Object cools to -20 DEG C of stirring (300rpm) 10h.Filtering for crystallizing object is simultaneously dried overnight at 50 DEG C, 20mbar.The evaporation of mother liquor low pressure
(15mbar, 50 DEG C), residue are dry at 50 DEG C, 20mbar.Obtain 17.2g purity be 98.7% (1H NMR) OXA.Base
It is 87.6% in the thick yield of OXE, is selectively 87.9%.Separating yield is 74%.
Embodiment 7: start to prepare OXA in ethanol with thick OXE using 35% ammonium hydroxide
It is equipped with to 500ml in the stainless steel autoclave of blender, pressure controller, temperature controller, by 17.3g ammonia
(100%, 1020mmol) 500rpm in 20min is added with stirring 24.0g OXE (87.8%, 136mmol), 31.1g water
In (1728mmol) and the mixture of 20.8g ethyl alcohol (99.9%, 357mmol).Internal temperature during reactant is added
It is maintained at 5 DEG C.Reaction mixture is heated to 30 DEG C, internal temperature is maintained at 30 DEG C of 20h at 9.0bars.Reaction is mixed
Object cools to -20 DEG C of stirring (300rpm) 10h.Filtering for crystallizing object is simultaneously dried overnight at 50 DEG C, 20mbar.The evaporation of mother liquor low pressure
(15mbar, 50 DEG C), residue are dry at 50 DEG C, 20mbar.Obtain 17.2g purity be 99.9% (1H NMR) OXA.Base
It is 92.3% in the thick yield of OXE, is selectively 92.5%.Separating yield is 68.2%.
Embodiment 8: being started with the OXE of purifying, is catalyzed preparation OXA through ammonium chloride in the mixture of ammonium hydroxide and ethyl alcohol
It is equipped with to 500ml in the stainless steel autoclave of blender, pressure controller, temperature controller, by 17.3g ammonia
(100%, 1020mmol) 500rpm in 20min is added with stirring 21.9g OXE (96.3%, 136mmol), 0.4g chlorination
In the mixture of ammonium (7mmol, 99.5%), 31.1g water (1728mmol) and 20.8g ethyl alcohol (99.9%, 357mmol).Adding
Internal temperature is maintained at 5 DEG C during entering reactant.Reaction mixture is heated to 30 DEG C, internal temperature is at 9.0bars
It is maintained at 30 DEG C of 20h.Reaction mixture is cooled into -20 DEG C of stirring (300rpm) 10h.Filtering for crystallizing object and 50 DEG C,
It is dried overnight under 20mbar.Mother liquor low pressure evaporates (15mbar, 50 DEG C), and residue is dry at 50 DEG C, 20mbar.It obtains
17.2g purity be 98.9% (1H NMR) OXA.Thick yield based on OXE is 94.2%, is selectively 98.3%.Separation produces
Rate is 87.4%.
Embodiment 9: being started with the OXE of purifying, is catalyzed preparation OXA through ammonium chloride in the mixture of ammonium hydroxide and ethyl alcohol
It is equipped with to 500ml in the stainless steel autoclave of blender, pressure controller, temperature controller, by 17.3g ammonia
(100%, 1020mmol) 500rpm in 20min is added with stirring 21.9g OXE (96.3%, 136mmol), 0.7g chlorination
In the mixture of ammonium (99.5%, 14mmol), 31.1g water (1728mmol) and 20.8g ethyl alcohol (99.9%, 357mmol).Adding
Internal temperature is maintained at 5 DEG C during entering reactant.Reaction mixture is heated to 30 DEG C, internal temperature is at 9.0bars
It is maintained at 30 DEG C of 20h.Reaction mixture is cooled into -20 DEG C of stirring (300rpm) 10h.Filtering for crystallizing object and 50 DEG C,
It is dried overnight under 20mbar.Mother liquor low pressure evaporates (15mbar, 50 DEG C), and residue is dry at 50 DEG C, 20mbar.It obtains
17.2g purity be 99.9% (1H NMR) OXA.Thick yield based on OXE is 96.6%, is selectively 97.7%.Separation produces
Rate is 85.4%.
Claims (9)
1.4- methyl-oxazole -5- formamide synthetic method comprising the compound and concentration for making structure formula (I) are at least
The ammonium hydroxide of 30wt% reacts:
Wherein R1It is H or C1-10Alkyl.
2. according to the method described in claim 1, wherein the concentration of the ammonium hydroxide is at least 35%.
3. according to the method described in claim 1, wherein the dosage of the ammonium hydroxide is, the change relative to every 1mol structure formula (I)
Object is closed, the amount of ammonia is in 2mol to 8mol range.
4. being carried out under the conditions of according to the method described in claim 1, wherein reaction is existing for the catalyst.
5. according to the method described in claim 4, wherein the catalyst is selected from quaternary ammonium salt.
6. according to the method described in claim 4, wherein the catalyst is ammonium halide.
7. according to the method described in claim 6, wherein the catalyst is ammonium chloride.
8. method according to any one of claims 4 to 7, wherein the compound relative to structure formula (I), is added to
The molar range of catalyst in reaction is 0.01 to 0.5.
9. being carried out at a temperature of 10 DEG C to 25 DEG C under atmospheric pressure according to the method described in claim 1, wherein reacting.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12165425 | 2012-04-25 | ||
| EP12165425.5 | 2012-04-25 | ||
| CN201380016902.8A CN104203930A (en) | 2012-04-25 | 2013-04-24 | Process for synthesis of 4-methyloxazole-5-carboxamide |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380016902.8A Division CN104203930A (en) | 2012-04-25 | 2013-04-24 | Process for synthesis of 4-methyloxazole-5-carboxamide |
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| Publication Number | Publication Date |
|---|---|
| CN110229115A true CN110229115A (en) | 2019-09-13 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910284529.3A Pending CN110229115A (en) | 2012-04-25 | 2013-04-24 | The method for synthesizing 4- methyl oxazole -5- formamide |
| CN201380016902.8A Pending CN104203930A (en) | 2012-04-25 | 2013-04-24 | Process for synthesis of 4-methyloxazole-5-carboxamide |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201380016902.8A Pending CN104203930A (en) | 2012-04-25 | 2013-04-24 | Process for synthesis of 4-methyloxazole-5-carboxamide |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP2841424A1 (en) |
| CN (2) | CN110229115A (en) |
| WO (1) | WO2013160322A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4772718A (en) * | 1985-11-01 | 1988-09-20 | Hoffmann-La Roche Inc. | Process for preparing 5-cyano-4-methyl-oxazole |
| CN1104213A (en) * | 1993-02-25 | 1995-06-28 | 弗·哈夫曼-拉罗切有限公司 | Method for the production of oxazole derivatives |
| CN1193016A (en) * | 1997-02-13 | 1998-09-16 | 弗·哈夫曼-拉罗切有限公司 | Production of oxazole derivative |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3538110A (en) | 1966-11-12 | 1970-11-03 | Basf Ag | Production of 4-methyloxazole-5-carboxylic esters |
| US4026901A (en) | 1975-04-30 | 1977-05-31 | Hoffmann-La Roche Inc. | Conversion of 4-lower alkyloxazole-5-carboxamide to 4-lower alkyl-5-cyanooxazoles |
| US8067583B2 (en) | 2006-12-26 | 2011-11-29 | Trustees Of Dartmouth College | Method for synthesizing furanosteroids |
-
2013
- 2013-04-24 EP EP13719475.9A patent/EP2841424A1/en not_active Withdrawn
- 2013-04-24 WO PCT/EP2013/058426 patent/WO2013160322A1/en active Application Filing
- 2013-04-24 CN CN201910284529.3A patent/CN110229115A/en active Pending
- 2013-04-24 CN CN201380016902.8A patent/CN104203930A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4772718A (en) * | 1985-11-01 | 1988-09-20 | Hoffmann-La Roche Inc. | Process for preparing 5-cyano-4-methyl-oxazole |
| CN1104213A (en) * | 1993-02-25 | 1995-06-28 | 弗·哈夫曼-拉罗切有限公司 | Method for the production of oxazole derivatives |
| CN1193016A (en) * | 1997-02-13 | 1998-09-16 | 弗·哈夫曼-拉罗切有限公司 | Production of oxazole derivative |
Non-Patent Citations (6)
| Title |
|---|
| DAVID D. DAVEY: ""Synthesis of 6-Phenylimidazo[1,2-a]pyrazin-8-one and 1-Methyl-6-phenylimidazo[1,5-a]pyrazin-8-one via Quaternary Intermediates"", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| S.V.STEPANOVA等: ""SYNTHESIS OF 4-METHYL-5-CYANOOXAZOLE AND ITS REACTION"", 《PHARMACEUTICAL CHEMISTRY JOURNAL》 * |
| TH. RINDERSPACHER等: ""Ueber Dipyridyl-Aehnliche Thiazolyl-Oxazole"", 《HELVETICA CHIMICA ACTA》 * |
| 张祥麟: "《无机化学（下册）》", 30 September 1983, 湖南教育出版社 * |
| 曾昭琼: "《有机化学.下册》", 30 November 2004, 高等教育出版社 * |
| 郭书好: "《有机化学》", 31 July 2004, 广东科技出版社 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104203930A (en) | 2014-12-10 |
| EP2841424A1 (en) | 2015-03-04 |
| WO2013160322A1 (en) | 2013-10-31 |
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