CN106083653A - The synthetic method of Ormetoprim intermediate cinnamonitrile - Google Patents
The synthetic method of Ormetoprim intermediate cinnamonitrile Download PDFInfo
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- CN106083653A CN106083653A CN201610395428.XA CN201610395428A CN106083653A CN 106083653 A CN106083653 A CN 106083653A CN 201610395428 A CN201610395428 A CN 201610395428A CN 106083653 A CN106083653 A CN 106083653A
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- Prior art keywords
- cinnamonitrile
- ormetoprim
- synthetic method
- acrylonitrile
- dimethoxy
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- ZWKNLRXFUTWSOY-QPJJXVBHSA-N (e)-3-phenylprop-2-enenitrile Chemical compound N#C\C=C\C1=CC=CC=C1 ZWKNLRXFUTWSOY-QPJJXVBHSA-N 0.000 title claims abstract description 28
- KEEYRKYKLYARHO-UHFFFAOYSA-N 5-[(4,5-dimethoxy-2-methylphenyl)methyl]pyrimidine-2,4-diamine Chemical compound C1=C(OC)C(OC)=CC(C)=C1CC1=CN=C(N)N=C1N KEEYRKYKLYARHO-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229960003068 ormetoprim Drugs 0.000 title claims abstract description 18
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 42
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 26
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 dimethoxy 2 tolyl aldehydes Chemical class 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 210000003608 fece Anatomy 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- OOWFYDWAMOKVSF-UHFFFAOYSA-N 3-methoxypropanenitrile Chemical compound COCCC#N OOWFYDWAMOKVSF-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 2
- 235000019082 Osmanthus Nutrition 0.000 description 2
- 241000333181 Osmanthus Species 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 229930016911 cinnamic acid Natural products 0.000 description 2
- 235000013985 cinnamic acid Nutrition 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- RMIZEUOAFVZZJG-UHFFFAOYSA-N 4,5-dimethoxy-2-methylbenzaldehyde Chemical compound COC1=CC(C)=C(C=O)C=C1OC RMIZEUOAFVZZJG-UHFFFAOYSA-N 0.000 description 1
- NWYRNCMKWHKPAI-UHFFFAOYSA-N C(=O)=O.[Na] Chemical compound C(=O)=O.[Na] NWYRNCMKWHKPAI-UHFFFAOYSA-N 0.000 description 1
- 241000522254 Cassia Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- POCUPXSSKQAQRY-UHFFFAOYSA-N hydroxylamine;hydrate Chemical compound O.ON POCUPXSSKQAQRY-UHFFFAOYSA-N 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides the synthetic method of a kind of Ormetoprim intermediate cinnamonitrile, with acrylonitrile and 4,5 dimethoxy 2 tolyl aldehydes are raw material, and in methanol solution of sodium methylate, direct single step reaction obtains cinnamonitrile.Use one kettle way of the present invention to prepare Ormetoprim intermediate cinnamonitrile, production operation can be simplified, reduce labour intensity, raise labour productivity, improve production quality.
Description
Technical field
The present invention relates to the synthetic method of a kind of Ormetoprim intermediate cinnamonitrile.
Background technology
Ormetoprim, chemical name 2,4-diaminourea-5-(4,5-dimethoxy-2-methyl-benzyl) pyrimidine, molecular formula
C14H18N4O3.Ormetoprim is conventional Trimethoprim in animal husbandry and aquatic products industry.4,5-dimethoxy-2-methyl-2 '-
(methoxyl methyl)-cinnamonitrile is a step important intermediate of synthesis Ormetoprim, and the synthesis with regard to cinnamonitrile is mainly acrylonitrile
Reaction in methanol solution of sodium methylate generates 3-methoxypropionitrile, 3-methoxypropionitrile again with 4,5-dimethoxy-2-methylbenzene
Formaldehyde is condensed cinnamonitrile in methanol solution of sodium methylate.This kind of method is because to be divided into 2 steps, and owing to acrylonitrile has play
Poison, operation inconvenience, cost is high.
Notification number is the preparation method that the patent of invention of CN101230017B discloses a kind of cinnamonitrile, first by Carbon Dioxide
Sodium, hydroxylamine hydrochloride and water are mixed and made into the aqueous solution of hydroxylamine hydrochloride and sodium carbonate, then water-soluble by hydroxylamine hydrochloride and sodium carbonate
Drop is added in the solution of cinnamic acid and ethanol or methyl alcohol, then stands, then pour reactant mixture into ice after stirring fully
In water, until separating out white precipitate, filtering out white precipitate and washing with water, after being dried, i.e. preparing Chinese cassia tree aldoxime.To cinnamic acid
Dripping the acetic anhydride of 2～2.5 times (mol ratios) in oxime, stirring carries out cooling after dehydration, and then reduce pressure Distillation recovery acetic acid
The acetic acid that acid anhydride and reaction generate, further vacuum decompression distillation, collect 130～132 DEG C/1064Pa or 151.0 DEG C/5330Pa
Under stable cut, obtain cinnamonitrile.Preparation method described in this patent of invention, has complex steps, cycle length, one-tenth equally
This high problem.
Content of the invention
For Shortcomings in prior art, the invention provides the synthesis side of a kind of Ormetoprim intermediate cinnamonitrile
Method, with acrylonitrile and 4,5-dimethoxy-2-tolyl aldehyde is raw material, and in methanol solution of sodium methylate, single step reaction obtains meat
Osmanthus nitrile, with simplify production operation, improve product quality, reduce labour intensity, raise labour productivity, the present invention has cost
Advantage low, that technique is simple, the cycle is short.
The present invention realizes above-mentioned technical purpose by techniques below means.
The synthetic method of Ormetoprim intermediate cinnamonitrile, it is characterised in that comprise the following steps:
(1) by 4,5-dimethoxy-2-tolyl aldehyde puts in methanol solution of sodium methylate, and mixes, by propylene
Nitrile is added drop-wise in solution, carries out condensation reaction；
(2) by the product cooling of gained in step (1), filter, obtain filter cake, wash filter cake post-drying, obtain 4,5-bis-
Methoxyl group-2-methyl-2 '-(methoxyl methyl)-cinnamonitrile.
Preferably, the mol ratio of described 4,5-dimethoxy-2-tolyl aldehyde and acrylonitrile be 1.0～1.3:1.7～
1.9
Preferably, the mol ratio of described 4,5-dimethoxy-2-tolyl aldehyde and acrylonitrile is 1.1:1.8
Preferably, in described step (1), reaction temperature is 25～35 DEG C, and the reaction time is 3～7h.
Preferably, described step (1) reaction temperature is 28～32 DEG C, and the reaction time is 4～6h.
Preferably, in described step (2), the temperature of cooling is 0 DEG C.
Preferably, the concentration of described methanol solution of sodium methylate is 26～28%.
The synthetic method of Ormetoprim intermediate cinnamonitrile of the present invention, by with 4,5-dimethoxy-2-methyl
Benzaldehyde is raw material, carries out a step condensation reaction in methanol solution of sodium methylate with acrylonitrile, i.e. can get 4,5-dimethoxy-
2-methyl-2 '-(methoxyl methyl)-cinnamonitrile.Simplify production operation step, reduce labour intensity, raise labour productivity, change
Entering product quality, product qualified rate reaches 99.2%, and yield reaches 85%, and the present invention has the prospect of large-scale industrial application.
Brief description
Fig. 1 is the gas chromatogram of synthetic method synthetic product of the present invention.
Fig. 2 (a), (b) are respectively the cinnamonitrile of described synthetic method synthesis1H-NMR figure and13C-NMR schemes.
Fig. 3 (a), (b) are respectively molecular ion peak and the fragment ion of the cinnamonitrile MS spectrogram of described synthetic method synthesis
Peak.
Detailed description of the invention
Below in conjunction with the accompanying drawings and specific embodiment the present invention is further illustrated, but protection scope of the present invention is simultaneously
It is not limited to this.
Embodiment 1
By 4,5-dimethoxy-2-tolyl aldehyde (180g, 1.0mol) puts in 28% methanol solution of sodium methylate, dropping
Acrylonitrile (95.4g, 1.8mol), is incubated 25～35 DEG C of droppings, after dropping finishes, reacts 5 hours, be cooled to 0 DEG C, filter, filter
Cake obtains cinnamonitrile (185.2g), yield 85.7%, white solid, content 99.22% with a small amount of washing, product after drying.
Embodiment 2
By 4,5-dimethoxy-2-tolyl aldehyde (216g, 1.2mol) puts in 28% methanol solution of sodium methylate, dropping
Acrylonitrile (100.7g, 1.9mol), is incubated 25～35 DEG C of droppings, after dropping finishes, reacts 5 hours, be cooled to 0 DEG C, filter, filter
Cake obtains cinnamonitrile (185.6g), yield 85.9%, white solid, content 99.26% with a small amount of washing, product after drying.
Embodiment 3
By 4,5-dimethoxy-2-tolyl aldehyde (198g, 1.1mol) puts in 28% methanol solution of sodium methylate, dropping
Acrylonitrile (95.4g, 1.8mol), is incubated 25～35 DEG C of droppings, after dropping finishes, reacts 5 hours, be cooled to 0 DEG C, filter, filter
Cake obtains cinnamonitrile (186.5g), yield 86.3%, white solid, content 99.28% with a small amount of washing, product after drying.
Embodiment 4
By 4,5-dimethoxy-2-tolyl aldehyde (198g, 1.1mol) puts in 28% methanol solution of sodium methylate, dropping
Acrylonitrile (95.4g, 1.8mol), is incubated 28～32 DEG C of droppings, after dropping finishes, reacts 5 hours, be cooled to 0 DEG C, filter, filter
Cake obtains cinnamonitrile (187.1g), yield 86.6%, white solid, content 99.30% with a small amount of washing, product after drying.
The nmr spectrum of synthetic method synthetic product of the present invention and MS collection of illustrative plates are distinguished as shown in Figure 2 and Figure 3, Fig. 2
A (), (b) are cinnamonitrile1H-NMR、13C-NMR schemes, as seen from the figure, and 4,5-dimethoxy-2-methyl-2 '-(methoxyl methyl)-meat
Osmanthus nitrile structural analysis is:1HNMR(500MHz,δ):7.62(s,1H),7.32(s,1H),6.69(s,1H),4.16(s,2H),
3.90(s,3H),3.88(s,3H),3.43(s,3H),2.30(s,3H)；13CNMR(500MHz,δ):150.4,146.9,
142.7,131.1,123.8,118.1,113.1,110.3,106.3,73.6,58.0,55.8,55.6,18.9.Accompanying drawing 3 (a),
B () is molecular ion peak and the fragment ion peak of cinnamonitrile MS figure, have figure to understand, MS:(ES+) 270.1 (M+23).Schemed by NMR
With MS collection of illustrative plates, it is known that this product is really 4,5-dimethoxy-2-methyl-2 '-(methoxyl methyl)-cinnamonitrile.Synthesis shown in Fig. 1 is produced
The gas-chromatography spectrogram of thing, it is known that this product productivity more than 99%.
Described embodiment be the present invention preferred embodiment, but the present invention is not limited to above-mentioned embodiment, not
In the case of deviating from the flesh and blood of the present invention, any conspicuously improved, replacement that those skilled in the art can make
Or modification belongs to protection scope of the present invention.
Claims (7)
1. the synthetic method of Ormetoprim intermediate cinnamonitrile, it is characterised in that comprise the following steps:
(1) by 4,5-dimethoxy-2-tolyl aldehyde puts in methanol solution of sodium methylate, and mixes, and drips acrylonitrile
It is added in solution, carry out condensation reaction；
(2) by the product cooling of gained in step (1), filter, obtain filter cake, wash filter cake post-drying, obtain 4,5-dimethoxy
Base-2-methyl-2 '-(methoxyl methyl)-cinnamonitrile.
2. the synthetic method of Ormetoprim intermediate cinnamonitrile according to claim 1, it is characterised in that: described 4,5-bis-
The mol ratio of methoxyl group-2-tolyl aldehyde and acrylonitrile is 1.0～1.3:1.7～1.9.
3. the synthetic method of Ormetoprim intermediate cinnamonitrile according to claim 1, it is characterised in that: described 4,5-bis-
The mol ratio of methoxyl group-2-tolyl aldehyde and acrylonitrile is 1.1:1.8.
4. the synthetic method of Ormetoprim intermediate cinnamonitrile according to claim 1, it is characterised in that: described step
(1) in, reaction temperature is 25～35 DEG C, and the reaction time is 3～7h.
5. the synthetic method of Ormetoprim intermediate cinnamonitrile according to claim 1, it is characterised in that: described step
(1) reaction temperature is 28～32 DEG C, and the reaction time is 4～6h.
6. the synthetic method of Ormetoprim intermediate cinnamonitrile according to claim 1, it is characterised in that: described step
(2) in, the temperature of cooling is 0 DEG C.
7. the synthetic method of Ormetoprim intermediate cinnamonitrile according to claim 1, it is characterised in that: described sodium methoxide
The concentration of methanol solution is 26～28%.
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| CN201610395428.XA CN106083653A (en) | 2016-06-06 | 2016-06-06 | The synthetic method of Ormetoprim intermediate cinnamonitrile |
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| CN201610395428.XA CN106083653A (en) | 2016-06-06 | 2016-06-06 | The synthetic method of Ormetoprim intermediate cinnamonitrile |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107311938A (en) * | 2017-08-29 | 2017-11-03 | 湖北龙翔药业科技股份有限公司 | A kind of synthetic method of Ormetoprim |
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|---|---|---|---|---|
| US3341541A (en) * | 1964-11-12 | 1967-09-12 | Hoffmann La Roche | Processes and intermediates for pyrimidine derivatives |
| US4033962A (en) * | 1975-06-26 | 1977-07-05 | Hoffman-La Roche Inc. | 2,4-Diamino-pyrimidine derivatives and processes |
| US20050209260A1 (en) * | 2004-03-05 | 2005-09-22 | Roche Palo Alto Llc | Diaminopyrimidines as P2X3 and P2X2/3 antagonists |
| CN101230017A (en) * | 2008-01-09 | 2008-07-30 | 武汉市合中生化制造有限公司 | Method for preparing cinnamonitriles |
| CN103214326A (en) * | 2013-04-18 | 2013-07-24 | 陕西师范大学 | Synthesis method of cinnamate, cinnamonitrile, cinnamamide and derivative thereof |
-
2016
- 2016-06-06 CN CN201610395428.XA patent/CN106083653A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3341541A (en) * | 1964-11-12 | 1967-09-12 | Hoffmann La Roche | Processes and intermediates for pyrimidine derivatives |
| US4033962A (en) * | 1975-06-26 | 1977-07-05 | Hoffman-La Roche Inc. | 2,4-Diamino-pyrimidine derivatives and processes |
| US20050209260A1 (en) * | 2004-03-05 | 2005-09-22 | Roche Palo Alto Llc | Diaminopyrimidines as P2X3 and P2X2/3 antagonists |
| CN101230017A (en) * | 2008-01-09 | 2008-07-30 | 武汉市合中生化制造有限公司 | Method for preparing cinnamonitriles |
| CN103214326A (en) * | 2013-04-18 | 2013-07-24 | 陕西师范大学 | Synthesis method of cinnamate, cinnamonitrile, cinnamamide and derivative thereof |
Non-Patent Citations (1)
| Title |
|---|
| PERCY S. MANCHAND等: "Syntheses of Antibacterial 2,4-Diamino-5-benzylpyrimidines. Ormetoprim and Trimethoprim", 《J. ORG. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107311938A (en) * | 2017-08-29 | 2017-11-03 | 湖北龙翔药业科技股份有限公司 | A kind of synthetic method of Ormetoprim |
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