CN102558083B - 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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- CN102558083B CN102558083B CN201010599362.9A CN201010599362A CN102558083B CN 102558083 B CN102558083 B CN 102558083B CN 201010599362 A CN201010599362 A CN 201010599362A CN 102558083 B CN102558083 B CN 102558083B
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- Prior art keywords
- isoxazole
- methyl alcohol
- reaction
- double substitution
- compound
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- 238000000034 method Methods 0.000 title abstract description 12
- 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 12
- 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 8
- 238000003756 stirring Methods 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 5
- 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
- 150000001412 amines Chemical class 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
- 229940125782 compound 2 Drugs 0.000 abstract 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 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
- 238000004090 dissolution Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 238000000926 separation 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
- 239000003814 drug Substances 0.000 description 2
- 150000002545 isoxazoles Chemical class 0.000 description 2
- 241000219061 Rheum Species 0.000 description 1
- 239000003905 agrochemical 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
- 238000005516 engineering process Methods 0.000 description 1
- 239000002360 explosive Substances 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
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
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- 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 shown in the description, the amine compound 2 is one of pyrrolidine, piperidine and 4-methylpiperidine.
Description
Technical field
The present invention relates to a kind of synthesis N, N
-the method of two replacement-3-An isoxazole-5-carbinol compound.
Background technology
Isoxazole derivative is the compound that a class has pharmaceutical use, its derivative 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 sterilant precursor (
jpn. Kokai Tokkyo Koho jP 79 09, 278), in medicine and agricultural chemicals etc., there is huge value of exploiting and utilizing.3-An isoxazole-5-methyl alcohol as a kind of important Isoxazole derivative, due to its potential pharmaceutical use receiving much attention in recent years (
pCT Int. Appl.,
2008036653).Regrettably, only have a small amount of document to report its synthetic method, and these method synthesis steps are long, severe reaction conditions, and employ the tetracol phenixin of severe toxicity and the reagent such as explosive sodium azide (
j. Org. Chem
., 1985, 50 (26), 5723-5727).These methods significantly limit this type of reaction in medical research and the application in producing.Present method has prepared a series of N, N from raw material simple and easy to get in comparatively gentle next step reaction of condition
-two replacement-3-An isoxazole-5-methyl alcohol is the very big breakthrough to such compou nd synthesis method.
Summary of the invention
The object of this invention is to provide one and under cesium fluoride effect, under condition of no solvent, directly substitution reaction occurs with aminated compounds by 3-Xiu isoxazole-5-methyl alcohol, generate N, N
-the method of two replacement-3-An isoxazole-5-carbinol compound.The step mainly solving the existence of existing synthetic method is long, severe reaction conditions, and uses the technical problems such as poisonous reagent.
The invention provides N, N
-the synthetic method of two replacement-3-An isoxazole-5-carbinol compound, comprises the following steps: 3-Xiu isoxazole-5-methyl alcohol
1with aminated compounds under cesium fluoride effect
2under condition of no solvent, directly there is substitution reaction generate N, N
-two replacement-3-An isoxazole-5-carbinol compound
3, reaction formula is as follows:
Aminated compounds 2 is the one in tetramethyleneimine, piperidines or 4-methyl piperidine.
Concrete synthesis step is:
3-Xiu isoxazole-5-methyl alcohol stirs in vexed tank with the one in tetramethyleneimine, piperidines or 4-methyl piperidine under cesium fluoride effect, is heated to 100 ~ 120
oc, stirs 18 ~ 72 hours, and cooling, is spin-dried for, chromatographic separation, obtains N, and N-is two replaces-3-An isoxazole-5-methyl alcohol.
The present invention is without the need to reaction solvent.
3-Xiu isoxazole-5-methyl alcohol of the present invention 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.
Instant invention overcomes the drawback of traditional method, have the following advantages: 1) reaction conditions is gentle; 2) catalyzer using costliness is avoided; 3) reactions steps is simple; 4) avoiding with an organic solvent, is solvent-free reaction, is easy to amplify; 5) universality of reacting is good, can introduce multiple amine and replace; 6) substituting group can be introduced in multiple site and carry out further derivatize.Innovative point of the present invention is to have developed the two novel method replacing-3-An isoxazole-5-methyl alcohol of a kind of synthesis N, N-.The two productive rate replacing-3-An isoxazole-5-methyl alcohol of corresponding N, the N-of present method gained is 60 ~ 77 %.
Embodiment
Following examples contribute to understanding the present invention, but are not limited to content of the present invention.
Embodiment 1
3apreparation: in the vexed tank of 100 mL tetrafluoro of drying, add 3-bromine-isoxazole-5-methyl alcohol (25 g, 140 mmol) successively, cesium fluoride (42 g, 280 mmol) and tetramethyleneimine (20 mL), to be added complete, by vexed for tetrafluoro tank sealing, 100
ostir 18 hours under C.After having reacted, vexed tank is cooled to room temperature, product to be transferred in the round-bottomed flask of 100 mL and to be spin-dried for, and then in flask, adds 100 mL water dissolution, with methylene dichloride (three times, 50 mL are each) extraction, merge organic phase, with anhydrous sodium sulfate drying one hour, filter, concentrated, pillar layer separation (developping agent: sherwood oil is 2:1 than ethyl acetate volume ratio) obtain product 3-pyrrolidyl-isoxazole-5-methyl alcohol (
3a) 16.4 g, productive rate is 70%.Product is 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 the vexed tank of 100 mL tetrafluoro of drying, add 3-bromine-isoxazole-5-methyl alcohol (15 g, 84 mmol) successively, cesium fluoride (32 g, 210 mmol) and 4-methyl piperidine (15 mL), to be added complete, by vexed for tetrafluoro tank sealing, 100
ostir 36 hours under C.After having reacted, vexed tank is cooled to room temperature, product to be transferred in the round-bottomed flask of 100 mL and to be spin-dried for, and then in flask, adds 100 mL water dissolution, with methylene dichloride (three times, 50 mL are each) extraction, merges organic phase.With anhydrous sodium sulfate drying one hour, filter, concentrated, pillar layer separation (developping agent: sherwood oil is 2:1 than ethyl acetate volume ratio) obtains product 3-(4-methyl piperidine base)-isoxazole-5-methyl alcohol (
3b) 9.8 g, productive rate is 60%.Product is 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 the vexed tank of 100 mL tetrafluoro of drying, add 3-bromine-isoxazole-5-methyl alcohol (20 g, 112 mmol) successively, cesium fluoride (17 g, 112 mmol) and piperidines (30 mL), to be added complete, by the sealing of vexed for tetrafluoro tank, 120
ostir 72 hours under C.After having reacted, vexed tank is cooled to room temperature, product to be transferred in the round-bottomed flask of 100 mL and to be spin-dried for, and then in flask, adds 100 mL water dissolution, with methylene dichloride (three times, 50 mL are each) extraction, merges organic phase.With anhydrous sodium sulfate drying one hour, filter, concentrated, pillar layer separation (developping agent: sherwood oil is 1:1 than ethyl acetate volume ratio) obtain product 3-piperidyl-isoxazole-5-methyl alcohol (
3c) 16 g, productive rate is 77 %.Product is 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 (1)
1.N, N
-the synthetic method of two replacement-3-An isoxazole-5-carbinol compound, comprises the following steps: 3-Xiu isoxazole-5-methyl alcohol
1with aminated compounds under cesium fluoride effect
2under condition of no solvent, directly there is substitution reaction generate N, N
-two replacement-3-An isoxazole-5-carbinol compound
3, reaction formula is as one of the following:
，
，
Aminated compounds 2 is tetramethyleneimine, the one in piperidines or 4-methyl piperidine; 3-Xiu isoxazole-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; Reaction stirring 18 ~ 72 hours; Reaction is carried out in vexed tank.
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