CN102260233A - 3-butyl-1(3H)-isobenzofuranone derivatives and preparation method thereof - Google Patents
3-butyl-1(3H)-isobenzofuranone derivatives and preparation method thereof Download PDFInfo
- Publication number
- CN102260233A CN102260233A CN2011101145818A CN201110114581A CN102260233A CN 102260233 A CN102260233 A CN 102260233A CN 2011101145818 A CN2011101145818 A CN 2011101145818A CN 201110114581 A CN201110114581 A CN 201110114581A CN 102260233 A CN102260233 A CN 102260233A
- Authority
- CN
- China
- Prior art keywords
- butyl
- isobenzofuranone
- preparation
- derivatives
- silica gel
- 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.)
- Pending
Links
Abstract
The invention relates to 3-butyl-1(3H)-isobenzofuranone derivatives and a preparation method thereof. The derivatives have the structural formula shown as the specifications; and the preparation method comprises the following steps of: preparing an intermediate of 3-butyl-6-hydroxy-1(3H)-isobenzofuranone (II); (2) preparing an intermediate of 3-butyl-6-(brominated alkoxy)-1(3H)-isobenzofuranone (III); and (3) preparing the 3-butyl-1(3H)-isobenzofuranone derivatives. The compounds prepared by the method are derivatives of the 3-butyl-1(3H)-isobenzofuranone, and have various bioactivities, particularly antithrombotic and antihypertensive activities.
Description
Technical field
The invention belongs to 3-butyl-1 (3H)-isobenzofuranone technical field, be specifically related to a kind of 3-butyl-1 (3H)-derivatives of isobenzofaranone and preparation method thereof.
Background technology
3-butyl-1 (3H)-isobenzofuranone has another name called NBP, and its structure is shown below:
NBP is one of new drug of China recent years independent development, is mainly used in clinically to treat light, moderate cerebral infarction.The poorly water-soluble of NBP, and often need clinically and the medication combined use of anti-platelet aggregation.It is being carried out in the process of structure of modification, having its 6 of bibliographical informations to introduce derivatives such as amino, substituted-amino, fluorine, bromine and shown the biological activity (US6689808 that is better than NBP; Eur J Med Chem.2010., 45,1941-1946.).Therefore prepare 3-butyl-1 (3H)-isobenzofuranone 6 bit derivants, better effects if ground preventing angiocardiopathy or cerebrovascular diseases disease therapeuticing medicine is significant for seeking.
Summary of the invention
The purpose of this invention is to provide a kind of multiple bioactive 3-butyl-1 (3H)-derivatives of isobenzofaranone and preparation method thereof that has.
For achieving the above object, the technical solution used in the present invention is: the molecular structural formula of this derivative is as (I):
Wherein: n is 2～6 natural number;
R represents a kind of in Isopropylamine, TERTIARY BUTYL AMINE, cyclohexylamino, dimethylamine, diethylamine, pyrroles, piperidines, morpholine, piperazine, N methyl piperazine, N-ethyl piperazidine, N-sec.-propyl piperazine, N-phenylpiperazine, the N-benzyl diethylenediamine base.
The preparation process of 3-butyl-1 (3H)-derivatives of isobenzofaranone is as follows:
(1) preparation intermediate 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone
Under 0～5 ℃ of condition, it is in 30% the acidic aqueous solution that 3-butyl-6-amino-1 (3H)-isobenzofuranone is added volume percent, 3-butyl-6-amino-1 (3H)-isobenzofuranone and volume percent are that the mass ratio of 30% acidic aqueous solution is 1: (5～20), stir the ice bath cooling; To wherein slowly splashing into sodium nitrite solution, the mol ratio of 3-butyl-6-amino-1 (3H)-isobenzofuranone and Sodium Nitrite is 1 again: (1.0～1.2), insulated and stirred 0.5h gets yellow solution.
Will the volume percent identical be that 15～20% acidic aqueous solution is heated to 80～85 ℃ with the yellow solution volume, again above-mentioned yellow solution is slowly splashed into volume percent after the heating and be in 15～20% the acidic aqueous solution, stir 1～3h, naturally cooling; Ethyl acetate extraction then, separatory, drying is filtered, and concentrates, and lives chromatography through silica gel and gets 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone.
(2) preparation intermediate 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone
Earlier 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is dissolved in N, in the dinethylformamide, to wherein adding two bromoalkanes and acid binding agent, the mol ratio of two bromoalkanes that added and acid binding agent and 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is respectively (4～6) again: 1 and (1～2): 1; Under 70～90 ℃ of conditions, stir 3～5h then, be cooled to room temperature, filter, filtrate is poured in the mixture of ice and water, stir, ethyl acetate extraction, separatory merges organic layer, drying is filtered, and concentrates, and gets 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone through silica gel column chromatography;
(3) preparation 3-butyl-1 (3H)-derivatives of isobenzofaranone
Earlier 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone is dissolved in the acetone, to wherein adding triethylamine and amine, the mol ratio of triethylamine that is added and amine and 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone is respectively (1.5～2.5) again: 1 and (5～8): 1; Stirring and dissolving then, reflux 3～6h, concentrating under reduced pressure gets 3-butyl-1 (3H)-derivatives of isobenzofaranone through silica gel column chromatography.
The used eluent of described silica gel column chromatography is a methylene dichloride: the mixture of the volume ratio 10～20: 1 of methyl alcohol, or be sherwood oil: the volume ratio of ethyl acetate is 10～20: 1 mixture.
Described acidic aqueous solution is a kind of in aqueous sulfuric acid, aqueous hydrochloric acid and the phosphate aqueous solution; The preferably sulfuric acid aqueous solution.
Described acid binding agent is a kind of in salt of wormwood, cesium carbonate and the triethylamine; Preferred salt of wormwood.
Because technique scheme, the prepared compound of the present invention is the derivative of 3-butyl-1 (3H)-isobenzofuranone, has multiple biological activity, particularly antithrombotic and antihypertensive activity, for the exploitation cardiovascular medicament provides the foundation.
Embodiment
Giving further instruction below by embodiment to technology of the present invention, is not the restriction to its protection domain.
Implementation column 1
A kind of 3-butyl-1 (3H)-derivatives of isobenzofaranone and preparation method thereof.The molecular structural formula of this derivative is as (Ia):
The preparation process of this derivative is as follows:
(1) preparation intermediate 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II)
Under 0～5 ℃ of condition, it is in 30% the aqueous sulfuric acid that 3-butyl-6-amino-1 (3H)-isobenzofuranone is added volume percent, 3-butyl-6-amino-1 (3H)-isobenzofuranone and volume percent are that the mass ratio of 30% aqueous sulfuric acid is 1: (5～8), stir the ice bath cooling; To wherein slowly splashing into sodium nitrite solution, the mol ratio of 3-butyl-6-amino-1 (3H)-isobenzofuranone and Sodium Nitrite is 1 again: (1.0～1.08), insulated and stirred 0.5h gets yellow solution.
Will the volume percent identical be that 15～16% aqueous sulfuric acid is heated to 80～85 ℃, more above-mentioned yellow solution be slowly splashed in volume percent 15～16% aqueous sulfuric acids after the heating, stir 1～2h, naturally cooling with the yellow solution volume; Ethyl acetate extraction then, separatory, drying is filtered, and concentrates, and living chromatography (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is 10～20: 1 mixture) through silica gel must 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II).
(2) preparation intermediate 3-butyl-6-(2-bromine oxethyl)-1 (3H)-isobenzofuranone (IIIa)
Earlier 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is dissolved in N, in the dinethylformamide, again to wherein adding 1,2-ethylene dibromide and cesium carbonate, the mol ratio of glycol dibromide that is added and cesium carbonate and 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is respectively (4～4.2): 1 and (1～2): 1; Under 70～80 ℃ of conditions, stir 3～4h then, be cooled to room temperature, filter, filtrate is poured in the mixture of ice and water, stir, ethyl acetate extraction, separatory merges organic layer, dry, filter, concentrate, get 3-butyl-6-(2-bromine oxethyl)-1 (3H)-isobenzofuranone (IIIa) through silica gel column chromatography (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is 10～20: 1 mixture).
(3) oxyethyl group preparation 3-butyl-6-[(2-isopropylamine base)]-1 (3H)-isobenzofuranone (Ia)
Earlier 3-butyl-6-(2-bromine oxethyl)-1 (3H)-isobenzofuranone is dissolved in the acetone, to wherein adding triethylamine and Isopropylamine, the mol ratio of triethylamine that is added and Isopropylamine and 3-butyl-6-(2-bromine oxethyl)-1 (3H)-isobenzofuranone is respectively (1.5～1.8) again: 1 and (5～5.5): 1; Stirring and dissolving, reflux 3～5h, concentrating under reduced pressure is through silica gel column chromatography (the silica gel column chromatography eluent is a methylene dichloride: the volume ratio of methyl alcohol (10～20): 1 mixture) get 3-butyl-6-[(2-isopropylamine base) oxyethyl group]-1 (3H)-isobenzofuranone (Ia).
3-butyl-6-[(2-isopropylamine base that present embodiment 1 is prepared) oxyethyl group] constitutional features of-1 (3H)-isobenzofuranone (Ia) is: MS (ESI, m/z): 292[M+H]
+ 1H-NMR (DMSO, 400M) δ: 0.90 (t, J=7.2Hz, 3H, CH
3), 1.08 (d, J=6.0Hz, 6H, 2CH
3), 1.33-2.02 (m, 6H, 3CH
2), 2.69 (t, J=7.2Hz, 2H, NCH
2), 2.84 (m, 1H, CH), 4.03 (t, J=6.4Hz, 2H, OCH
2), 5.40-5.43 (m, 1H, CH), 7.19-7.22 (m, 1H, ArH), 7.27-7.31 (m, 2H, ArH); IR υ: 3452,2871,1718,1053,1065cm
-1
Implementation column 2
A kind of 3-butyl-1 (3H)-derivatives of isobenzofaranone and preparation method thereof.The molecular structural formula of this derivative is as (Ib):
The preparation process of this derivative is as follows:
(1) preparation intermediate 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II)
Under 0～5 ℃ of condition, it is in 30% the aqueous hydrochloric acid that 3-butyl-6-amino-1 (3H)-isobenzofuranone is added volume percent, 3-butyl-6-amino-1 (3H)-isobenzofuranone and volume percent are that the mass ratio of 30% aqueous hydrochloric acid is 1: (8～10), stir the ice bath cooling; To wherein slowly splashing into sodium nitrite solution, the mol ratio of 3-butyl-6-amino-1 (3H)-isobenzofuranone and Sodium Nitrite is 1 again: (1.08～1.12), insulated and stirred 0.5h gets yellow solution.
Will the volume percent identical be that 16～17% aqueous hydrochloric acid is heated to 80～85 ℃ with the yellow solution volume, again above-mentioned yellow solution is slowly splashed into volume percent after the heating and be in 16～17% the aqueous hydrochloric acid, stir 2～3h, naturally cooling; Ethyl acetate extraction then, separatory, drying is filtered, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II) to live chromatography through silica gel.
(2) preparation intermediate 3-butyl-6-(3-bromo propoxy-)-1 (3H)-isobenzofuranone (IIIb)
Earlier 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is dissolved in N, in the dinethylformamide, again to wherein adding 1,3-dibromopropane and salt of wormwood, added 1, the mol ratio of 3-dibromopropane and salt of wormwood and 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is respectively (4.2～4.5): 1 and (1.2～1.5): 1; Under 80～90 ℃ of conditions, stir 4～5h then, be cooled to room temperature, filter, filtrate is poured in the mixture of ice and water, stir, ethyl acetate extraction, separatory merges organic layer, dry, filter, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-(3-bromo propoxy-)-1 (3H)-isobenzofuranone (IIIb) through silica gel column chromatography.
(3) positive propoxy preparation 3-butyl-6-[(3-diethylin)]-1 (3H)-isobenzofuranone (Ib)
Earlier 3-butyl-6-(3-bromo propoxy-)-1 (3H)-isobenzofuranone is dissolved in the acetone, to wherein adding triethylamine and diethylamine, the mol ratio of triethylamine that is added and diethylamine and 3-butyl-6-(3-bromo propoxy-)-1 (3H)-isobenzofuranone is respectively (1.8～2.0) again: 1 and (5.5～6): 1; Stirring and dissolving then, reflux 4～6h, concentrating under reduced pressure is through silica gel column chromatography (the silica gel column chromatography eluent is a methylene dichloride: the volume ratio of methyl alcohol (10～20): 1 mixture) get 3-butyl-6-[(3-diethylin) positive propoxy]-1 (3H)-isobenzofuranone (Ib).
3-butyl-6-[(3-diethylin that this enforcement 2 example is prepared) positive propoxy] constitutional features of-1 (3H)-isobenzofuranone (Ib) is: MS (ESI, m/z): 320[M+H]
+ 1H-NMR (DMSO, 400M) δ: 0.91 (t, J=7.2Hz, 3H, CH
3), 1.03 (t, J=7.2Hz, 6H, 2CH
3), 1.33-1.49 (m, 4H, 2CH
2), 1.60-1.72 (m, 2H, CH
2), 1.96-2.03 (m, 2H, CH
2), 2.48-2.57 (m, 6H, 3NCH
2), 4.03 (t, J=6.4Hz, 2H, OCH
2), 5.40-5.43 (m, 1H, CH), 7.19-7.22 (m, 1H, ArH), 7.27-7.31 (m, 2H, ArH); IR υ: 3455,2867,1726,1054,1064cm
-1
Implementation column 3
A kind of 3-butyl-1 (3H)-derivatives of isobenzofaranone and preparation method thereof.The molecular structural formula of this derivative is as (Ic):
The preparation process of this derivative is as follows:
(1) preparation intermediate 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II)
Under 0～5 ℃ of condition, it is in 30% the phosphate aqueous solution that 3-butyl-6-amino-1 (3H)-isobenzofuranone is added volume percent, 3-butyl-6-amino-1 (3H)-isobenzofuranone and volume percent are that the mass ratio of 30% phosphate aqueous solution is 1: (10～12), stir the ice bath cooling; To wherein slowly splashing into sodium nitrite solution, the mol ratio of 3-butyl-6-amino-1 (3H)-isobenzofuranone and Sodium Nitrite is 1 again: (1.12～1.15), insulated and stirred 0.5h gets yellow solution.
Will the volume percent identical be that 17～18% phosphate aqueous solution is heated to 80～85 ℃ with the yellow solution volume, again above-mentioned yellow solution is slowly splashed into volume percent after the heating and be in 17～18% the phosphate aqueous solution, stir 1～2h, naturally cooling; Ethyl acetate extraction then, separatory, drying is filtered, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II) to live chromatography through silica gel.
(2) preparation intermediate 3-butyl-6-(4-bromo butoxy)-1 (3H)-isobenzofuranone (IIIc)
Earlier 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is dissolved in N, in the dinethylformamide, again to wherein adding 1,4-dibromobutane and triethylamine, added 1, the mol ratio of 4-dibromobutane and triethylamine and 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is respectively (4.5～5.0): 1 and (1.5～1.8): 1; Under 70～80 ℃ of conditions, stir 3～4h then, be cooled to room temperature, filter, filtrate is poured in the mixture of ice and water, stir, ethyl acetate extraction, separatory merges organic layer, dry, filter, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-(4-bromo butoxy)-1 (3H)-isobenzofuranone (IIIc) through silica gel column chromatography.
(3) n-butoxy preparation 3-butyl-6-[(4-piperidyl)]-1 (3H)-isobenzofuranone (Ic)
Earlier 3-butyl-6-(4-bromo butoxy)-1 (3H)-isobenzofuranone is dissolved in the acetone, to wherein adding triethylamine and piperidines, the mol ratio of triethylamine that is added and piperidines and 3-butyl-6-(4-bromo butoxy)-1 (3H)-isobenzofuranone is respectively (2.0～2.2) again: 1 and (6.0～7): 1; Stirring and dissolving then, reflux 3～6h, concentrating under reduced pressure is through silica gel column chromatography (the silica gel column chromatography eluent is a methylene dichloride: the volume ratio of methyl alcohol (10～20): 1 mixture) get 3-butyl-6-[(4-piperidyl) n-butoxy]-1 (3H)-isobenzofuranone (Ic).
3-butyl-6-[(4-piperidyl that present embodiment 3 is prepared) n-butoxy] constitutional features of-1 (3H)-isobenzofuranone (Ic) is: MS (ESI, m/z): 346[M+H]
+ 1H-NMR (DMSO, 400M) δ: 0.88 (t, J=7.2Hz, 3H, CH
3), 1.14-1.28 (m, 6H, 3CH
2), 1.61-2.03 (m, 10H, 5CH
2), 2.35-2.39 (m, 6H, 3NCH
2), 4.03 (t, J=6.4Hz, 2H, OCH
2), 5.40-5.43 (m, 1H, CH), 7.20-7.22 (m, 1H, ArH), 7.29-7.31 (m, 2H, ArH); IR υ: 3453,2868,1721,1056,1067cm
-1
Implementation column 4
A kind of 3-butyl-1 (3H)-derivatives of isobenzofaranone and preparation method thereof.The molecular structural formula of this derivative is as (Id):
The preparation process of 3-butyl-1 (3H)-derivatives of isobenzofaranone is as follows:
(1) preparation intermediate 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II)
Under 0～5 ℃ of condition, it is in 30% the aqueous sulfuric acid that 3-butyl-6-amino-1 (3H)-isobenzofuranone is added volume percent, 3-butyl-6-amino-1 (3H)-isobenzofuranone and volume percent are that the mass ratio of 30% aqueous sulfuric acid is 1: (12～15), stir the ice bath cooling; To wherein slowly splashing into sodium nitrite solution, the mol ratio of 3-butyl-6-amino-1 (3H)-isobenzofuranone and Sodium Nitrite is 1 again: (1.15～1.18), insulated and stirred 0.5h gets yellow solution.
Will the volume percent identical be that 18～19% aqueous sulfuric acid is heated to 80～85 ℃ with the yellow solution volume, again above-mentioned yellow solution is slowly splashed into volume percent after the heating and be in 18～19% the aqueous sulfuric acid, stir 1～3h, naturally cooling; Ethyl acetate extraction then, separatory, drying is filtered, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II) to live chromatography through silica gel.
(2) preparation intermediate 3-butyl-6-(5-bromo pentyloxy)-1 (3H)-isobenzofuranone (IIId)
Earlier 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is dissolved in N, in the dinethylformamide, again to wherein adding 1, pentamethylene bromide and salt of wormwood, the mol ratio of pentamethylene bromide that is added and salt of wormwood and 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is respectively (5.0～5.5): 1 and (1.8～1.9): 1; Under 80～90 ℃ of conditions, stir 4～5h then, be cooled to room temperature, filter, filtrate is poured in the mixture of ice and water, stir, ethyl acetate extraction, separatory merges organic layer, dry, filter, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-(5-bromo pentyloxy)-1 (3H)-isobenzofuranone (IIId) through silica gel column chromatography.
(3) n-pentyloxy preparation 3-butyl-6-[(5-morpholinyl)]-1 (3H)-isobenzofuranone (Id)
Earlier 3-butyl-6-(5-bromo pentyloxy)-1 (3H)-isobenzofuranone is dissolved in the acetone, to wherein adding triethylamine and morpholine, the mol ratio of triethylamine that is added and morpholine and 3-butyl-6-(5-bromo pentyloxy)-1 (3H)-isobenzofuranone is respectively (2.2～2.3) again: 1 and (7.0～7.5): 1; Stirring and dissolving then, reflux 4～6h, concentrating under reduced pressure is through silica gel column layer (the silica gel column chromatography eluent is a methylene dichloride: the volume ratio of methyl alcohol (10～20): 1 mixture) analyse 3-butyl-6-[(5-morpholinyl) n-pentyloxy]-1 (3H)-isobenzofuranone (Id).
3-butyl-6-[(5-morpholinyl that present embodiment 4 is prepared) n-pentyloxy] constitutional features of-1 (3H)-isobenzofuranone (Id) is: MS (ESI, m/z): 362[M+H]
+ 1H-NMR (DMSO, 400M) δ: 0.91 (t, J=7.2Hz, 3H, CH
3), 1.65-2.03 (m, 8H, 4CH
2), 2.39-2.45 (m, 6H, 3NCH
2), 3.72 (t, J=4.4Hz, 4H, 2OCH
2), 4.04 (t, J=6.4Hz, 2H, OCH
2), 5.40-5.43 (m, 1H, CH), 7.20-7.23 (m, 1H, ArH), 7.29-7.32 (m, 2H, ArH); IR υ: 3457,2871,1723,1056,1064cm
-1
Implementation column 5
A kind of 3-butyl-1 (3H)-derivatives of isobenzofaranone and preparation method thereof.The molecular structural formula of this derivative is as (Ie):
The preparation process of this derivative is as follows:
(1) preparation intermediate 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II)
Under 0～5 ℃ of condition, it is in 30% the aqueous sulfuric acid that 3-butyl-6-amino-1 (3H)-isobenzofuranone is added volume percent, 3-butyl-6-amino-1 (3H)-isobenzofuranone and volume percent are that the mass ratio of 30% aqueous sulfuric acid is 1: (15～20), stir the ice bath cooling; To wherein slowly splashing into sodium nitrite solution, the mol ratio of 3-butyl-6-amino-1 (3H)-isobenzofuranone and Sodium Nitrite is 1 again: (1.18～1.2), insulated and stirred 0.5h gets yellow solution.
Earlier will the volume percent identical be that 19～20% aqueous sulfuric acid is heated to 80～85 ℃ with the yellow solution volume, again above-mentioned yellow solution is slowly splashed into volume percent after the heating and be in 19～20% the aqueous sulfuric acid, stir 2～3h, naturally cooling; Ethyl acetate extraction then, separatory, drying is filtered, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone (II) to live chromatography through silica gel.
(2) preparation intermediate 3-butyl-6-(6-bromo hexyloxy)-1 (3H)-isobenzofuranone (IIIe)
Earlier 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is dissolved in N, in the dinethylformamide, again to wherein adding 1,6-dibromo-hexane two bromoalkanes and salt of wormwood, added 1, the mol ratio of 6-dibromo-hexane and salt of wormwood and 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is respectively (5.5～6.0): 1 and (1.9～2.0): 1; Under 70～80 ℃ of conditions, stir 3.5～4.5h then, be cooled to room temperature, filter, filtrate is poured in the mixture of ice and water, stir, ethyl acetate extraction, separatory merges organic layer, dry, filter, concentrate, (the silica gel column chromatography eluent is a sherwood oil: the volume ratio of ethyl acetate is (10～20): 1 mixture) get 3-butyl-6-(6-bromo hexyloxy)-1 (3H)-isobenzofuranone (IIIe) through silica gel column chromatography.
(3) positive hexyloxy preparation 3-butyl-6-[(6-N-methylpiperazine base)]-1 (3H)-isobenzofuranone (Ie)
Earlier 3-butyl-6-(6-bromo hexyloxy)-1 (3H)-isobenzofuranone is dissolved in the acetone, to wherein adding triethylamine and N methyl piperazine, the mol ratio of triethylamine that is added and N methyl piperazine and 3-butyl-6-(6-bromo hexyloxy)-1 (3H)-isobenzofuranone is respectively (2.3～2.5) again: 1 and (7.5～8.0): 1; Stirring and dissolving then, reflux 3～5h, concentrating under reduced pressure is through the positive hexyloxy of silica gel column chromatography (the silica gel column chromatography eluent is a methylene dichloride: the volume ratio of methyl alcohol (10～20): 1 mixture) get 3-butyl-6-[(6-N-methylpiperazine base)]-1 (3H)-isobenzofuranone (Ie).
3-butyl-6-[(6-N-methylpiperazine base that present embodiment is prepared) positive hexyloxy] constitutional features of-1 (3H)-isobenzofuranone (Ie) is: MS (ESI, m/z): 389[M+H]
+ 1H-NMR (DMSO, 400M) δ: 0.91 (t, J=7.2Hz, 3H, CH
3), 1.37-1.48 (m, 4H, 2CH
2), 1.65-2.04 (m, 10H, 5CH
2), 2.29 (s, 3H, NCH
3), 2.39-2.47 (m, 10H, 5NCH
2), 4.04 (t, J=6.4Hz, 2H, OCH
2), 5.40-5.43 (m, 1H, CH), 7.20-7.22 (m, 1H, ArH), 7.29-7.31 (m, 2H, ArH); IR υ: 3457,2872,1723,1056,1069cm
-1
The prepared compound of this embodiment is the derivative of 3-butyl-1 (3H)-isobenzofuranone, has multiple biological activity, particularly antithrombotic and antihypertensive activity, provides the foundation for developing new cardiovascular medicament.
Claims (4)
1. a 3-butyl-1 (3H)-derivatives of isobenzofaranone, the molecular structural formula that it is characterized in that this derivative are as (I):
Wherein: n is 2～6 natural number;
R represents a kind of in Isopropylamine, TERTIARY BUTYL AMINE, cyclohexylamino, dimethylamine, diethylamine, pyrroles, piperidines, morpholine, piperazine, N methyl piperazine, N-ethyl piperazidine, N-sec.-propyl piperazine, N-phenylpiperazine, the N-benzyl diethylenediamine base.
2. the preparation method of a kind of 3-butyl-1 as claimed in claim 1 (3H)-derivatives of isobenzofaranone is characterized in that preparation process is as follows:
(1) preparation intermediate 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone
Under 0～5 ℃ of condition, it is in 30% the acidic aqueous solution that 3-butyl-6-amino-1 (3H)-isobenzofuranone is added volume percent, 3-butyl-6-amino-1 (3H)-isobenzofuranone and volume percent are that the mass ratio of 30% acidic aqueous solution is 1: (5～20), stir the ice bath cooling; To wherein slowly splashing into sodium nitrite solution, the mol ratio of 3-butyl-6-amino-1 (3H)-isobenzofuranone and Sodium Nitrite is 1 again: (1.0～1.2), and insulated and stirred 0.5h gets yellow solution;
Will the volume percent identical be that 15～20% acidic aqueous solution is heated to 80～85 ℃ with the yellow solution volume, again above-mentioned yellow solution is slowly splashed into volume percent after the heating and be in 15～20% the acidic aqueous solution, stir 1～3h, naturally cooling; Ethyl acetate extraction then, separatory, drying is filtered, and concentrates, and lives chromatography through silica gel and gets 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone;
(2) preparation intermediate 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone
Earlier 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is dissolved in N, in the dinethylformamide, to wherein adding two bromoalkanes and acid binding agent, the mol ratio of two bromoalkanes that added and acid binding agent and 3-butyl-6-hydroxyl-1 (3H)-isobenzofuranone is respectively (4～6) again: 1 and (1～2): 1; Under 70～90 ℃ of conditions, stir 3～5h then, be cooled to room temperature, filter, filtrate is poured in the mixture of ice and water, stir, ethyl acetate extraction, separatory merges organic layer, drying is filtered, and concentrates, and gets 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone through silica gel column chromatography;
(3) preparation 3-butyl-1 (3H)-derivatives of isobenzofaranone
Earlier 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone is dissolved in the acetone, to wherein adding triethylamine and amine, the mol ratio of triethylamine that is added and amine and 3-butyl-6-(bromo-oxyl)-1 (3H)-isobenzofuranone is respectively (1.5～2.5) again: 1 and (5～8): 1; Stirring and dissolving then, reflux 3～6h, concentrating under reduced pressure gets 3-butyl-1 (3H)-derivatives of isobenzofaranone through silica gel column chromatography;
The used eluent of described silica gel column chromatography is a methylene dichloride: the mixture of the volume ratio 10～20: 1 of methyl alcohol, or be sherwood oil: the volume ratio of ethyl acetate is 10～20: 1 mixture.
3. the preparation method of 3-butyl-1 as claimed in claim 2 (3H)-derivatives of isobenzofaranone is characterized in that described acidic aqueous solution is a kind of in aqueous sulfuric acid, aqueous hydrochloric acid and the phosphate aqueous solution; The preferably sulfuric acid aqueous solution.
4. the preparation method of 3-butyl-1 as claimed in claim 2 (3H)-derivatives of isobenzofaranone is characterized in that described acid binding agent is a kind of in salt of wormwood, cesium carbonate and the triethylamine; Preferred salt of wormwood.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101145818A CN102260233A (en) | 2011-05-04 | 2011-05-04 | 3-butyl-1(3H)-isobenzofuranone derivatives and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101145818A CN102260233A (en) | 2011-05-04 | 2011-05-04 | 3-butyl-1(3H)-isobenzofuranone derivatives and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102260233A true CN102260233A (en) | 2011-11-30 |
Family
ID=45007099
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101145818A Pending CN102260233A (en) | 2011-05-04 | 2011-05-04 | 3-butyl-1(3H)-isobenzofuranone derivatives and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102260233A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418596A (en) * | 2015-12-02 | 2016-03-23 | 武汉科技大学 | 1-[3-butyl-1(3H)-isobenzofuranone-6-yl]-1H-pyrazol-5(4H)-one derivative as well as preparation method and pharmaceutical application |
| WO2023001164A1 (en) * | 2021-07-21 | 2023-01-26 | 江苏正大丰海制药有限公司 | Compound for treating ischemic brain injury-related disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1440398A (en) * | 2000-06-28 | 2003-09-03 | 中国医学科学院药物研究所 | Substituted phthalides as anti-convulsive drugs |
| CN101073567A (en) * | 2006-05-19 | 2007-11-21 | 何瑞恒 | Butylbenzene phthalein concentrated solution for injection and its making method |
-
2011
- 2011-05-04 CN CN2011101145818A patent/CN102260233A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1440398A (en) * | 2000-06-28 | 2003-09-03 | 中国医学科学院药物研究所 | Substituted phthalides as anti-convulsive drugs |
| CN101073567A (en) * | 2006-05-19 | 2007-11-21 | 何瑞恒 | Butylbenzene phthalein concentrated solution for injection and its making method |
Non-Patent Citations (1)
| Title |
|---|
| 庞素华: "《1.酪氨酸蛋白激酶抑制剂的设计与合成 2.正丁苯酞类似物的合成及重排反应》", 15 December 2006, article "正丁苯酞类似物的合成及重排反应" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418596A (en) * | 2015-12-02 | 2016-03-23 | 武汉科技大学 | 1-[3-butyl-1(3H)-isobenzofuranone-6-yl]-1H-pyrazol-5(4H)-one derivative as well as preparation method and pharmaceutical application |
| WO2023001164A1 (en) * | 2021-07-21 | 2023-01-26 | 江苏正大丰海制药有限公司 | Compound for treating ischemic brain injury-related disease |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2587903T3 (en) | Imidazolidinedione compounds and their uses | |
| CN103965120B (en) | Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application | |
| ES2585221T3 (en) | A process for the preparation of 6- (7 - ((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -n-methyl-1-naphthamide and synthetic intermediates thereof | |
| CZ20001621A3 (en) | Indazole bioisostere replacement of catechol in therapeutically active compounds | |
| WO2007088462A1 (en) | Spirochromane antagonists of the h-3 receptor | |
| CN1422260A (en) | 2-guanidino-4-arylchinazolines as NHE-3 inhibitors | |
| BRPI0715872A2 (en) | COMPOUND; PHARMACEUTICAL COMPOSITION; Compost preparation method; COMPOUND PREPARED BY THE METHOD; AND METHOD OF TREATMENT OF A DISORDER IN A MAMMALIAN NEEDED | |
| BR112019024376A2 (en) | compound of general formula (i), or pharmaceutically acceptable salts thereof, pharmaceutical composition and use of the compounds or pharmaceutically acceptable salts thereof | |
| JP6713472B2 (en) | Chromenone monocarboxylic acid transporter inhibitor | |
| CN105481869B (en) | A kind of pyrans simultaneously [3,2- α] phenazene derivative and its preparation method and application | |
| AU2008209672B2 (en) | Chromene S1P1 receptor antagonist | |
| CN102260233A (en) | 3-butyl-1(3H)-isobenzofuranone derivatives and preparation method thereof | |
| CN105622546A (en) | Preparation method for vortioxetine | |
| Liu et al. | Synthesis and anti-hepatitis B virus evaluation of novel ethyl 6-hydroxyquinoline-3-carboxylates in vitro | |
| CN102234285B (en) | Preparation method of olanzapine | |
| CN112745237B (en) | 2-arylamine compound and preparation method and application thereof | |
| CN101085779A (en) | Substituted indole-3-oxalylepipodophyllotoxin derivative, salt and application thereof | |
| CN102311398A (en) | Triazole compounds, preparation method thereof, and application thereof in preparing histone deacetylase I inhibitor | |
| ES2527011T3 (en) | Piperazine derivatives to block calcium channels Cav2.2 | |
| CA2704649C (en) | Tetracyclic dipyrano-coumarin compounds with anti-hiv and anti-mycobacterium tuberculosis activities | |
| CN105801577B (en) | A kind of methyl substituted pyrroles of polyfluoro [3,2 c] and the preparation method of quinolines | |
| JPS62145073A (en) | Quinazoline derivative | |
| KR102204267B1 (en) | Substituted (r)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-ene-carboxylic acid(variants) and ester thereof, method for producing and using same | |
| Xi et al. | Synthesis and Blocking Activities of a New Class of α1‐Adrenoceptor Antagonists | |
| CN102086197B (en) | Protoberberine derivative with insulin-sensitizing activity and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20111130 |