CN102558083A - Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound - Google Patents
Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound Download PDFInfo
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- CN102558083A CN102558083A CN2010105993629A CN201010599362A CN102558083A CN 102558083 A CN102558083 A CN 102558083A CN 2010105993629 A CN2010105993629 A CN 2010105993629A CN 201010599362 A CN201010599362 A CN 201010599362A CN 102558083 A CN102558083 A CN 102558083A
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- China
- Prior art keywords
- isoxazole
- compound
- replacements
- methyl alcohol
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 7
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 229940126214 compound 3 Drugs 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- 230000000694 effects Effects 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 150000001412 amines Chemical class 0.000 abstract description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
- -1 amine compound Chemical class 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 229940125782 compound 2 Drugs 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 150000002545 isoxazoles Chemical class 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 241000219061 Rheum Species 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a synthesizing method for an N, N-double substitution-3-amino isoxazole-5-methanol compound, and mainly solves the technical problems of long procedure, rigorous reaction conditions, toxic reagent using and the like in the conventional synthesis method. The synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound in the invention comprises the steps as follows: under the action of cesium fluoride, 3-bromine isoxazole-5-methenol 1 and an amine compound 2 are directly subjected to substitution reaction on a solvent-free condition to generate the N, N-double substitution-3-amino isoxazole-5-methanol compound 3. The reaction formula is as follows: the amine compound in one of pyrrolidine, piperidine and 4-methylpiperidine.
Description
Technical field
The present invention relates to a kind of synthetic N, N
-The method of two replacements-3-An isoxazole-5-carbinol compound.
Background technology
Isoxazole derivative is one type of compound with pharmaceutical use, its verivate as antarthritic medicine be applied to clinical (
J. A. Clzn. Rheum. Dis. 1984 , 10,385
.), also can be used as diuretic(s) (
J. Indian Chem. Soc. 1946,
23, 189.;
Jpn. Kokai.Tokkyo Koho. JP79 14, 968 etc.) and the precursor of sterilant (
Jpn. Kokai Tokkyo Koho JP 79 09, 278), at aspects such as medicine and agricultural chemicals huge value of exploiting and utilizing is arranged.3-An isoxazole-5-methyl alcohol is as a kind of important De Isoxazole derivative and since its potential pharmaceutical use receive much attention in recent years (
PCT Int. Appl.,
2008036653).Regrettably, have only a small amount of document that its compound method is reported, and these method synthesis steps are long, severe reaction conditions, and used hypertoxic tetracol phenixin and explosive reagent such as sodium azide (
J. Org. Chem
., 1985, 50 (26), 5723-5727).These methods have greatly limited this type of and have been reflected at the application in medical research and the production.Present method from the raw material that simply is easy to get in comparatively gentle next step prepared in reaction of condition a series of N, N
-Two replacements-3-ammonia isoxazole-5-methyl alcohol are the very quantum jumps to the synthetic method of such compound.
Summary of the invention
The purpose of this invention is to provide a kind of 3-Xiu isoxazole-5-methyl alcohol that passes through with aminated compounds substitution reaction taking place directly under condition of no solvent under the cesium fluoride effect, generate N, N
-The method of two replacements-3-An isoxazole-5-carbinol compound.It is long mainly to solve the step that existing compound method exists, severe reaction conditions, and technical problem such as use poisonous reagent.
The present invention provides N, N
-The compound method of two replacements-3-An isoxazole-5-carbinol compound may further comprise the steps: 3-Xiu isoxazole-5-methyl alcohol
1Under the cesium fluoride effect and aminated compounds
2Substitution reaction directly takes place under condition of no solvent generate N, N
-Two replacements-3-An isoxazole-5-carbinol compound
3, reaction formula is following:
Aminated compounds 2 is a kind of in tetramethyleneimine, piperidines or the 4-methyl piperidine.
Concrete synthesis step is:
A kind of in vexed jar the stirring of 3-Xiu isoxazole-5-methyl alcohol under the cesium fluoride effect and in tetramethyleneimine, piperidines or the 4-methyl piperidine is heated to 100 ~ 120
oC stirred 18 ~ 72 hours, and cooling is revolved driedly, and chromatographic separation obtains N, the two replacement-3-An isoxazoles of N--5-methyl alcohol.
The present invention need not reaction solvent.
3-Xiu isoxazole of the present invention-5-methyl alcohol is 1: 10 with the amount of substance ratio of aminated compounds 2; 3-Xiu isoxazole-5-methyl alcohol is 1: 3 with the amount of substance ratio of additive cesium fluoride.
The present invention has overcome the drawback of traditional method, has the following advantages: 1) reaction conditions is gentle; 2) avoided the use expensive catalysts; 3) reactions step is simple; 4) avoid the use of organic solvent, be solvent-free reaction, be easy to amplify; 5) universality of reaction is good, can introduce various kinds of amine and replace; 6) can introduce substituting group in a plurality of sites and carry out further derivatize.Innovative point of the present invention is to have developed a kind of synthetic N, the novel method of the two replacement-3-An isoxazoles of N--5-methyl alcohol.The corresponding N of present method gained, the productive rate of the two replacement-3-An isoxazoles of N--5-methyl alcohol is 60～77 %.
Embodiment
Following examples help to understand the present invention, but are not limited to content of the present invention.
Embodiment 1
3aPreparation: in exsiccant 100 mL tetrafluoros are vexed jar, add 3-bromine-isoxazoles-5-methyl alcohol (25 g, 140 mmol) successively, cesium fluoride (42 g, 280 mmol) and tetramethyleneimine (20 mL), to be added finishing seals tetrafluoro for vexed jar, 100
oC stirred 18 hours down.After reaction is accomplished, vexed jar is cooled to room temperature, product is transferred in the round-bottomed flask of 100 mL and revolves dried; In flask, add 100 mL water dissolution then, extract with methylene dichloride (three times, 50 mL are each); Merge organic phase, with anhydrous sodium sulfate drying one hour, filtration; Concentrate, column chromatography separate (developping agent: sherwood oil is 2:1 than ETHYLE ACETATE volume ratio) obtain product 3-pyrrolidyl-isoxazoles-5-methyl alcohol (
3a) 16.4 g, productive rate is 70%.Product is a white solid.
1H?NMR?(400?MHz,?
d-DMSO)?δ?5.90?(s,?1?H),?5.48?(t,?
J?=?6.0?Hz,?1?H),?4.38?(d,?
J?=?6.0?Hz,?2?H),?3.19-3.16?(m,?4?H),?1.89-1.83?(m,?4?H)；MS?(m/z):168.8?(M
++1,?100)。
Embodiment 2
3bPreparation: in exsiccant 100 mL tetrafluoros are vexed jar, add 3-bromine-isoxazoles-5-methyl alcohol (15 g, 84 mmol) successively, cesium fluoride (32 g, 210 mmol) and 4-methyl piperidine (15 mL), to be added finishing seals tetrafluoro for vexed jar, 100
oC stirred 36 hours down.After reaction is accomplished, vexed jar is cooled to room temperature, product is transferred in the round-bottomed flask of 100 mL and revolves driedly, in flask, adds 100 mL water dissolution then, with methylene dichloride (three times, 50 mL are each) extraction, and the merging organic phase.With anhydrous sodium sulfate drying one hour, filter, concentrate, column chromatography separate (developping agent: sherwood oil is 2:1 than ETHYLE ACETATE volume ratio) obtain product 3-(4-methyl piperidine base)-isoxazoles-5-methyl alcohol (
3b) 9.8 g, productive rate is 60%.Product is a white solid.
1H?NMR?(400?MHz,?
d-DMSO)?δ?6.11?(s,1?H),?5.50-5.47?(t,?
J?=?6.0?Hz,?1?H),?4.36?(d,?
J?=?6.0?Hz,?2?H)?3.59-3.56?(m,?2?H),?2.74-2.67?(m,2?H)?,?1.59-1.56?(m,?2?H)?,?1.50-1.47?(m,?1?H)?,?1.16-1.05?(m,?2?H),?0.87-0.86?(d,?
J?=?6.0?Hz,?3?H)；MS?(m/z):?196.8?(M
++1,?100)。
Embodiment 3
3cPreparation: in exsiccant 100 mL tetrafluoros are vexed jar, add 3-bromine-isoxazoles-5-methyl alcohol (20 g, 112 mmol) successively, cesium fluoride (17 g, 112 mmol) and piperidines (30 mL), to be added finishing seals tetrafluoro for vexed jar, 120
oC stirred 72 hours down.After reaction is accomplished, vexed jar is cooled to room temperature, product is transferred in the round-bottomed flask of 100 mL and revolves driedly, in flask, adds 100 mL water dissolution then, with methylene dichloride (three times, 50 mL are each) extraction, and the merging organic phase.With anhydrous sodium sulfate drying one hour, filter, concentrate, column chromatography separate (developping agent: sherwood oil is 1:1 than ETHYLE ACETATE volume ratio) obtain product 3-piperidyl-isoxazoles-5-methyl alcohol (
3c) 16 g, productive rate is 77 %.Product is a white solid.
1H?NMR?(400?MHz,?
d-DMSO)?δ?6.14?(s,?1?H),?5.53-5.52?(t,
?J?=?5.6?Hz,?1?H),?4.39-4.38?(d,?
J?=?6.0?Hz,?2?H),?3.15-3.14?(m,?4?H),?1.54-1.53?(m,?6?H)；MS?m/z):182.8?(M
++1,?100)。
Claims (4)
1.N, N
-The compound method of two replacements-3-An isoxazole-5-carbinol compound may further comprise the steps: 3-Xiu isoxazole-5-methyl alcohol
1Under the cesium fluoride effect and aminated compounds
2Substitution reaction directly takes place under condition of no solvent generate N, N
-Two replacements-3-An isoxazole-5-carbinol compound
3, reaction formula is following:
Aminated compounds 2 is a tetramethyleneimine, a kind of in piperidines or the 4-methyl piperidine.
2. N according to claim 1, N
-The compound method of two replacements-3-An isoxazole-5-carbinol compound is characterized in that the 3-Xiu isoxazole-5-methyl alcohol and the amount of substance ratio of aminated compounds 2 are 1: 10; 3-Xiu isoxazole-5-methyl alcohol is 1: 3 with the amount of substance ratio of additive cesium fluoride.
3. N according to claim 1, N
-The compound method of two replacements-3-An isoxazole-5-carbinol compound is characterized in that temperature of reaction 100 ~ 120
oC stirred 18 ~ 72 hours.
4. N according to claim 1, N
-The compound method of two replacements-3-An isoxazole-5-carbinol compound is characterized in that being reflected in vexed jar and carries out.
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Cited By (1)
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|---|---|---|---|---|
| CN112574097A (en) * | 2020-12-21 | 2021-03-30 | 杭州仟源保灵药业有限公司 | Preparation method of Ebastine and fumarate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008036653A2 (en) * | 2006-09-19 | 2008-03-27 | Incyte Corporation | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
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2010
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| WO2008036653A2 (en) * | 2006-09-19 | 2008-03-27 | Incyte Corporation | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
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| CN112574097A (en) * | 2020-12-21 | 2021-03-30 | 杭州仟源保灵药业有限公司 | Preparation method of Ebastine and fumarate thereof |
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