CN108892648A - A kind of Lizakuputan benzoate intermediate process for solid phase synthesis - Google Patents
A kind of Lizakuputan benzoate intermediate process for solid phase synthesis Download PDFInfo
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- CN108892648A CN108892648A CN201810767119.XA CN201810767119A CN108892648A CN 108892648 A CN108892648 A CN 108892648A CN 201810767119 A CN201810767119 A CN 201810767119A CN 108892648 A CN108892648 A CN 108892648A
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- nitrobenzyl
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- triazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The present invention relates to a kind of Lizakuputan benzoate intermediate process for solid phase synthesis, 4- nitrobenzyl halogen and the direct solid state grinding reaction of triazole, it is added in solvent after reaction and dissolves catalyst, then obtain 4- nitrobenzyl triazole or its derivative through being separated by solid-liquid separation；The catalyst is one or more of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide；The solid phase reaction temperature is room temperature.Compared with prior art, the present invention does not use organic solvent, has the characteristics that energy consumption is lower, pollutant discharge amount is less, is a kind of green, clean and environmental protection and efficient method, has good industrial development application value.
Description
Technical field
The invention belongs to technical field of fine, especially a kind of Lizakuputan benzoate intermediate synthesis in solid state work
Skill.
Background technique
Lizakuputan benzoate (Rizatriptan Benzoate), assumed name：N, N- dimethyl -5- (1H-1,2,4- tri-
Azoles -1- ylmethyl) -1H- indoles -3- ethamine list benzoate, structure is for example shown below.
Lizakuputan benzoate is second generation triptan class (triptans) the migraine treatment drug developed in recent years.
There is high affinity to people 5-HT1B and 5-HT1D, it is lower to other 5-HT1 and 5-HT7 receptor affinities, to 5-HT2,5-
HT3, adrenaline, DA, histamine, choline or BZ receptor are without obvious activity.For treating Acute Migraine Attacks, has and work
Fastly, the advantages of good effect, safe ready.The medicine is developed by Merck (Merck) company, and in June, 1998 lists in the U.S., and 2000
Application of import, the Japanese approval of import in 2003 are proposed to China.
From the point of view of the data of report (such as US7786156 B2, CN102030740A, 2008075163 A2 of WO,
CN103664901A, IN 755/CHE/2005 etc.), the synthesis of Lizakuputan benzoate mainly has following three routes：
1, using to nitrobenzyl bromine as starting material, through with 1, its change of N alkane under 2,4- triazole phase transfer catalysis (PTC)s, using normal pressure
Hydrogenating reduction, sodium sulfite restores after diazotising, and 1- (4- Hydrazino-phenyl) methyl-1,2,4- triazole sulfonic acid two are generated under highly basic
Sodium, then it is cyclic with 4- (N, TMSDMA N dimethylamine base) butyraldehyde dimethyl acetal, benzoic acid obtains Lizakuputan benzoate at salt.
2, using to nitrobenzyl bromine as starting material, through with 4- amino -1,2, its change of N alkane under 4- triazole phase transfer catalysis (PTC),
Diazotising deamination, then atmospheric hydrogenation restore, and sodium sulfite restores after diazotising, and 1- (4- Hydrazino-phenyl) first is generated under highly basic
Base -1,2,4- triazole disodium sulfonate, then it is cyclic with 4- (N, TMSDMA N dimethylamine base) butyraldehyde dimethyl acetal, benzoic acid obtains benzene first at salt
Sour rizatriptan.
3, it using indoline as starting material, methylates through triazole, dehydrogenation, upper side chain restores, and obtains benzoic acid benefit at salt
Prick triptan.
Main production is that method 1 and method 2 carry out, but are required to leave using a large amount of organic solvents at present
Energy consumption height, heavy-polluted defect.
Summary of the invention
The technical problem to be solved by the present invention is to overcome drawbacks described above in the prior art and deficiencies, provide a kind of technique letter
Single, the lower Lizakuputan benzoate intermediate process for solid phase synthesis of energy consumption.
The principle of the present invention is found in the course of the research based on us, with to nitrobenzyl bromine or to nitro benzyl chloride and 1,2,
4- triazole or 4- amino-1,2,4-triazol are that raw material reacts synthetic intermediate 4- nitrobenzyl triazole or its derivative
When, solid phase reaction being carried out under condition of no solvent grinding and generating target compound, reaction equation is as follows：
The present invention is achieved through the following technical solutions above-mentioned purpose：
The present invention's first is that give the synthesis in solid state work of Lizakuputan benzoate intermediate 4- nitrobenzyl triazole
Skill, technical solution are：4- nitrobenzyl halogen and 1,2,4- triazoles direct solid state grinding reaction under the effect of the catalyst, reaction
After be added stirring solvent inorganic salts are dissolved, then through be separated by solid-liquid separation obtain solid phase i.e. 4- nitrobenzyl triazole；It is described
Catalyst is one or more of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide；The solid state grinding reaction temperature is
Room temperature.
Further, the 4- nitrobenzyl halogen and 1,2,4- triazole molar ratio of material examples are 1：1-1.5；The catalyst
Dosage be 4- nitrobenzyl halogen 1-1.5 times of molar equivalent.
Further, the solvent of the addition is water.
Further preferred preferred plan：Weigh 0.1mol to 1,2,4- triazoles of nitrobenzyl bromine, 0.15mol and
0.15mol potassium carbonate is added in mortar, and solid abrasive 10 minutes, are then allowed to stand half an hour at room temperature；100mL is added in solid
Water stirring, and boil, it is filtered after being cooled to room temperature, obtains 4- nitrobenzyl triazole.
The present invention's second is that gives Lizakuputan benzoate intermediate 1- (4- nitrobenzyl) -4- amino -4H-1,2,
The process for solid phase synthesis of 4- triazole halide, technical solution are：4- nitrobenzyl halogen and 4- amino -4H-1,2,4- triazoles
Stirring solvent is added after reaction and dissolves inorganic salts, then obtains solid phase i.e. through being separated by solid-liquid separation for direct solid state grinding reaction
1- (4- nitrobenzyl) -4- amino -4H-1,2,4- triazole halide；The solid state grinding reaction temperature is room temperature.
Further, the 4- nitrobenzyl halogen and 4- amino -4H-1,2,4- triazole molar ratio of material examples are 1：1-1.5.
Further, the solvent of the addition is methanol.
Further preferred preferred plan：0.4mol is weighed to the 4- amino -4H-1,2,4 three of nitrobenzyl bromine and 0.42mol
Nitrogen azoles is added in mortar, at room temperature solid abrasive 30 minutes, after being then allowed to stand 1 hour；The stirring of 300mL methanol is added in solid
It 30 minutes, then filters, filter cake is washed with a small amount of methanol, and drying obtains target compound 1- (4- nitrobenzyl) -4- amino -
4H-1,2,4- triazole bromide.
Above-mentioned Lizakuputan benzoate intermediate 4- nitrobenzyl triazole and 1- (4- nitrobenzyl) -4- amino -4H-
In the process for solid phase synthesis of 1,2,4- triazole halide, the 4- nitrobenzyl halogen is to nitrobenzyl bromine or to nitro benzyl chloride；
It is both needed to heating in the whipping process to boil, solid phase then is obtained by filtration by being cooled to room temperature.
Compared with prior art, the present invention does not use organic solvent, has the spies such as energy consumption is lower, pollutant discharge amount is less
Point is a kind of green, clean and environmental protection and efficient method, has good industrial development application value.
Specific embodiment
Below by embodiment the present invention is described in detail, it should be understood that these embodiments are only used for the purpose of illustration,
It is never limited in protection scope of the present invention.It will be understood by those skilled in the art that without departing from spirit of the invention and outside
Can be with the details and forms of the technical scheme of the invention are modified or replaced under enclosing, but these modifications or substitutions each fall within this hair
In bright protection scope.
Embodiment 1：The synthesis in solid state of 4- nitrobenzyl triazole
22g (0.1mol) is weighed to nitrobenzyl bromine, 1,2,4- triazole of 10g (0.15mol), 20.7g (0.15mol) carbonic acid
Potassium is added in mortar, at room temperature solid abrasive 10 minutes, after being then allowed to stand half an hour, solid color burn, through HPLC (methanol：
Water=7：3, C18 columns, flow velocity 1mL/min, similarly hereinafter) analysis, nitrobenzyl bromine is converted completely, the stirring of 100mL water is added in solid,
And boil, it is filtered after being cooled to room temperature, obtains 4- nitrobenzyl triazole 17g, yield 85%, HPLC purity assay 98.5%
(HPLC analysis condition：C18 column；278nm；Mobile phase, methanol/water=4/7；Flow velocity, 1mL/min.Similarly hereinafter).Fusing point：100~
102℃。
Embodiment 2：The synthesis in solid state of 4- nitrobenzyl triazole
18g (0.1mol) is weighed to nitro benzyl chloride, 1,2,4- triazole of 10g (0.15mol), 16g (0.15mol) carbonic acid
Sodium is added in mortar, at room temperature solid abrasive 10 minutes, and after being then allowed to stand half an hour, solid color burn is analyzed through HPLC,
Completely to the conversion of nitro benzyl chloride, the stirring of 100mL water is added in solid, and boiled, filtered after being cooled to room temperature, obtain 4- nitrobenzyl
Base triazole 16g, yield 80%, HPLC purity assay 99%.Fusing point：100~102 DEG C.
Embodiment 3：The synthesis in solid state of 4- nitrobenzyl triazole
86g (0.5mol) is weighed to nitro benzyl chloride, 1,2,4- triazole of 42g (0.6mol), 65g (0.6mol) sodium carbonate,
It is added in mortar, at room temperature solid abrasive 30 minutes, after being then allowed to stand 1 hour, solid color burn is analyzed through HPLC, to nitre
The stirring of 300mL water is added completely, by solid in the conversion of base benzyl chloride, and boils, and filters after being cooled to room temperature, obtains 4- nitrobenzyl three
Nitrogen azoles 78g, yield 78%, HPLC purity assay 98.4%.Fusing point：100~102 DEG C.
Embodiment 4：The synthesis in solid state of 4- nitrobenzyl triazole
22g (0.1mol) is weighed to nitrobenzyl bromine, 1,2,4- triazole of 8.5g (0.12mol), 5g (0.125mol) hydrogen-oxygen
Change sodium, is added in mortar, at room temperature solid abrasive 10 minutes, after being then allowed to stand 1 hour, solid color burn is analyzed through HPLC,
Completely to the conversion of nitrobenzyl bromine, the stirring of 100mL water is added in solid, and boiled, filtered after being cooled to room temperature, obtain 4- nitrobenzyl
Base triazole 13.4g, yield 66%, HPLC purity assay 98%.Fusing point：100~102 DEG C.
Embodiment 5：The synthesis of 1- (4- nitrobenzyl) -4- amino -4H-1,2,4- triazole chloride
86g (0.5mol) is weighed to nitro benzyl chloride, 50g (0.6mol) 4- amino -4H-1,2,4 triazoles, addition mortar
In, solid abrasive 30 minutes are analyzed after being then allowed to stand 1 hour through HPLC at room temperature, convert nitro benzyl chloride completely, by solid
300mL methanol is added to stir 30 minutes, then filters, filter cake is washed with a small amount of methanol, and drying obtains target compound 115g,
Yield 89%, HPLC purity assay 99.2%.Fusing point：186-188℃.
Embodiment 6：The synthesis of 1- (4- nitrobenzyl) -4- amino -4H-1,2,4- triazole bromide
86g (0.4mol) is weighed to nitrobenzyl bromine, 35g (0.42mol) 4- amino -4H-1,2,4 triazoles, addition mortar
In, solid abrasive 30 minutes are analyzed after being then allowed to stand 1 hour through HPLC at room temperature, convert nitrobenzyl bromine completely, by solid
300mL methanol is added to stir 30 minutes, then filters, filter cake is washed with a small amount of methanol, and drying obtains target compound 110g,
Yield 91%, HPLC purity assay 99.4%.Fusing point：218-221℃.
Embodiment 7：The synthesis of 1- (4- nitrobenzyl) -4- amino -4H-1,2,4- triazole chloride
86g (0.5mol) is weighed to nitro benzyl chloride, 42g (0.5mol) 4- amino -4H-1,2,4 triazoles, addition mortar
In, solid abrasive 30 minutes are analyzed after being then allowed to stand 1 hour through HPLC at room temperature, convert nitro benzyl chloride completely, by solid
300mL methanol is added to stir 30 minutes, then filters, filter cake is washed with a small amount of methanol, and drying obtains target compound 97g, is received
Rate 75.2%, HPLC purity assay 99.2%.Fusing point：186-188℃.
Embodiment 8：The synthesis of 1- (4- nitrobenzyl) -4- amino -4H-1,2,4- triazole bromide
86g (0.4mol) is weighed to nitrobenzyl bromine, 50g (0.6mol) 4- amino -4H-1,2,4 triazoles, addition mortar
In, solid abrasive 30 minutes are analyzed after being then allowed to stand 1 hour through HPLC at room temperature, convert nitrobenzyl bromine completely, by solid
300mL methanol is added to stir 30 minutes, then filters, filter cake is washed with a small amount of methanol, and drying obtains target compound 112g,
Yield 92.2%, HPLC purity assay 98.4%.Fusing point：218-221℃.
Above-described embodiment is only used to illustrate the technical scheme of the present invention and not to limit it, and those of ordinary skill in the art are to this hair
Other modifications or equivalent replacement that bright technical solution is made, as long as it does not depart from the spirit and scope of the technical scheme of the present invention,
It is intended to be within the scope of the claims of the invention.
Claims (10)
1. a kind of Lizakuputan benzoate intermediate process for solid phase synthesis, which is characterized in that 4- nitrobenzyl halogen and 1,2,4- tri-
Stirring solvent is added after reaction and dissolves inorganic salts, then for nitrogen azoles direct solid state grinding reaction under the effect of the catalyst
Solid phase i.e. 4- nitrobenzyl triazole is obtained through being separated by solid-liquid separation；The catalyst is sodium carbonate, potassium carbonate, sodium hydroxide or hydrogen-oxygen
Change one or more of potassium；The solid state grinding reaction temperature is room temperature.
2. a kind of Lizakuputan benzoate intermediate process for solid phase synthesis, which is characterized in that 4- nitrobenzyl halogen and 4- amino-
4H-1, the direct solid state grinding reaction of 2,4- triazoles are added stirring solvent and dissolve inorganic salts, after reaction then through solid-liquid
Isolated solid phase, that is, 1- (4- nitrobenzyl) -4- amino -4H-1,2,4- triazole halide；The solid state grinding reaction temperature
Degree is room temperature.
3. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 1, which is characterized in that the 4-
Nitrobenzyl halogen and 1,2,4- triazole molar ratio of material examples are 1：1-1.5；The dosage of the catalyst is the 1- of 4- nitrobenzyl halogen
1.5 times of molar equivalents.
4. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 2, which is characterized in that the 4-
Nitrobenzyl halogen and 4- amino -4H-1,2,4- triazole molar ratio of material examples are 1：1-1.5.
5. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 1, which is characterized in that described to add
The solvent entered is water.
6. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 2, which is characterized in that described to add
The solvent entered is methanol.
7. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 1-6, feature exist
In the 4- nitrobenzyl halogen is to nitrobenzyl bromine or to nitro benzyl chloride.
8. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 1-6, feature exist
In needing heating to boil in the whipping process, solid phase then be obtained by filtration by being cooled to room temperature.
9. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 1, which is characterized in that weigh
1,2, the 4- triazoles and 0.15mol potassium carbonate of nitrobenzyl bromine, 0.15mol are added in mortar, at room temperature solid in 0.1mol
Grinding 10 minutes, is then allowed to stand half an hour；The stirring of 100mL water is added in solid, and is boiled, filters, obtains after being cooled to room temperature
4- nitrobenzyl triazole.
10. Lizakuputan benzoate intermediate process for solid phase synthesis according to claim 2, which is characterized in that weigh
4- amino -4H-1 of the 0.4mol to nitrobenzyl bromine and 0.42mol, 2,4 triazoles are added in mortar, at room temperature solid abrasive 30
Minute, after being then allowed to stand 1 hour；300mL methanol is added in solid to stir 30 minutes, is then filtered, filter cake is washed with a small amount of methanol
It washs, drying obtains target compound 1- (4- nitrobenzyl) -4- amino -4H-1,2,4- triazole bromides.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028458A (en) * | 2019-05-09 | 2019-07-19 | 广东广康生化科技股份有限公司 | A kind of new method preparing metconazole |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007054979A1 (en) * | 2005-11-14 | 2007-05-18 | Matrix Laboratories Ltd | Process for the large scale production of rizatriptan benzoate |
| WO2008075163A2 (en) * | 2006-12-15 | 2008-06-26 | Aurobindo Pharma Limited | An improved process for the preparation of rizatriptan |
| CN103936683A (en) * | 2014-03-06 | 2014-07-23 | 陕西科技大学 | 4-amino-5-substituted-1,2,4-triazole-3-thione Schiff base and preparation method thereof |
| CN108129405A (en) * | 2018-02-09 | 2018-06-08 | 绍兴新东泽化工有限公司 | A kind of preparation method of Lizakuputan benzoate intermediate |
-
2018
- 2018-07-13 CN CN201810767119.XA patent/CN108892648A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007054979A1 (en) * | 2005-11-14 | 2007-05-18 | Matrix Laboratories Ltd | Process for the large scale production of rizatriptan benzoate |
| WO2008075163A2 (en) * | 2006-12-15 | 2008-06-26 | Aurobindo Pharma Limited | An improved process for the preparation of rizatriptan |
| CN103936683A (en) * | 2014-03-06 | 2014-07-23 | 陕西科技大学 | 4-amino-5-substituted-1,2,4-triazole-3-thione Schiff base and preparation method thereof |
| CN108129405A (en) * | 2018-02-09 | 2018-06-08 | 绍兴新东泽化工有限公司 | A kind of preparation method of Lizakuputan benzoate intermediate |
Non-Patent Citations (3)
| Title |
|---|
| AUDREY BEILLARD ET AL.: "Expedient Mechanosynthesis of N,N-Dialkyl Imidazoliums and Silver(I)–Carbene Complexes in a Ball-Mill", 《CHEMISTRY A EUROPEAN JOURNAL》 * |
| MUTHUVEL RAMANATHAN EZHILARASI ET AL.: "Green Synthesis, 1D and 2D NMR spectral characterization of imidazole fused with pyrimidine nucleus by using grinding techniques", 《JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARCH》 * |
| NISHA CHANDNA ET AL.: "Pyrazolylbenzyltriazoles as cyclooxygenase inhibitors: synthesis and biological evaluation as dual anti-inflammatory and antimicrobial agents", 《NEW JOURNAL OF CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028458A (en) * | 2019-05-09 | 2019-07-19 | 广东广康生化科技股份有限公司 | A kind of new method preparing metconazole |
| CN110028458B (en) * | 2019-05-09 | 2022-10-11 | 广东广康生化科技股份有限公司 | Novel method for preparing metconazole |
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