CN101812010A - Isoindolinylcarboxylic ester derivative and preparation method - Google Patents
Isoindolinylcarboxylic ester derivative and preparation method Download PDFInfo
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Abstract
The invention discloses an isoindolinylcarboxylic ester derivative and a preparation method. The isoindolinylcarboxylic ester derivative is characterized in that the derivative is a compound with a structure of general formula (I). The isoindolinylcarboxylic ester derivative can be used as an active structural unit of a novel angiotensin converting enzyme inhibitor, a novel diuretic and a novel multi-medicament resistance inhibitor in the field of medicaments, and also can be used as a parent structure of novel isoindolinyl organic pigments in the coating industry. The preparation method has the advantages of cheap and easily obtained raw reaction materials, mild reaction condition, simple operation, higher yield, lower cost and environmental friendliness.
Description
Technical field
The present invention relates to a kind of isoindoline carboxylates derivatives and preparation method.
Background technology
The isoindoline carboxylates derivatives has important use value and Research Significance at medicine and chemical field.
Hypertension can be divided into essential hypertension and secondary hypertension.The pathogeny of essential hypertension is very complicated, and up to the present its pathogenesis also fails to illustrate fully, discovers that it relates to comprise all multifactor of heredity, environment, internal secretion, nervus centralis etc.But what gain universal acceptance is that the pathogeny of renin-angiotensin-aldosterone system and essential hypertension, the regulation and control of blood pressure all have very close getting in touch.According to the difference at mechanism of action position, can will be divided into following several types as the hypertension class medicine of target target: renin inhibitor, angiotensin-convertion enzyme inhibitor, angiotensin II receptor antagonists, neutral endopeptidase-angiotensin-converting enzyme double inhibitor, chymase inhibitor with renin-angiotensin-aldosterone system.Wherein the angiotensin-convertion enzyme inhibitor antihypertensive effect is definite; in addition owing to selection type is good, adverse reaction rate is low and to remarkable concern and the favor that enjoys the world of medicine of the provide protection of target organ, be widely used in hypertensive treatment field at present.
Captopril and enalapril are the representatives that contains sulfydryl and non-sulfydryl vasotonia converting enzyme inhibitor, have higher inhibitory enzyme activity and better pharmacokinetic property and the L-proline(Pro) structural unit in their structures is replaced the Trolaprilat and the quinapril that derive, become new angiotensin converting enzyme inhibitors.Studies show that the L-proline(Pro) structure in the captopril structure is replaced with the isoindoline carboxylic acid structure, and formed derivative can be used as a kind of new angiotensin converting enzyme inhibitors, its pharmacodynamics, pharmacokinetics character have obtained the research that deepens continuously
[1]
Indapamide (4-chloro-3-sulfahydantoin-N-(2,3-dihydro-2-Methyl-1H-indole) benzamide) is the weak diuretic(s) of imitating of a kind of novel sulfamido.Studies show that it not only has the diuresis effect but also tangible hypotensive effect is arranged, in general, low dose just can reach the ideal effect.Find by the structure of indapamide and other 4-chloro-3-sulfoamido benzamide indole derivatives diuretic(s) and the research contrast of medicine efficacy relation: indole structure may not be that active receptors must an obligato part.Therefore, more derivative is synthesized and is used for screening, the compound that particularly contains the isoindoline carboxylic acid structure, result of study is found, the ion excretion rate of this compounds is higher, antihypertensive effect is better, and diuretic properties is better, and this mainly is because the isoindoline carboxylic acid structure is replaced indole structure unit role
[2]
Multidrug resistance is meant in tumor therapeutic procedure, tumour cell also produces cross resistance to other hydrophobic drug that many functions are different, structure is different simultaneously to a kind of antitumour drug deposits yields is chemical sproof, this comprises taxol, vinealeucoblastine(VLB), Zorubicin, mitoxantrone, etoposide and bisantrene etc., the phenomenon that causes the result of treatment of medicine to reduce gradually.Its generation mechanism is quite complicated, thinks that at present the mechanism that multidrug resistance produces is mainly concerned with: MDR
1The increase of gene expression product causes the concentration of antitumor drug constantly to reduce; The change of tumour cell membrane structure makes antitumor drug not enter into smoothly in the cell; The change of glutathione transfers enzyme activity makes the medicine that enters in the tumour cell lose activity; Thereby the lethal effect of medicine has been escaped in the reinforcement of the transformation of dna structure and reparation.
Clinical study shows, a series of compounds can both be at the multidrug resistance of external reversing drug, thereby the level of recovering cancer therapy drug in the cell is in cytotoxicity concentration.The different compound of these structures is generally hydrophobic compound, comprising calcium-channel antagonists such as verapamil, and dihydropyridine, pyridine analogs, vinca alkaloids is like thing; Anti-arrhythmic such as Quinidine; Immunosuppressor such as ciclosporin A; Calmodulin such as dihydroketoacridine acid amides and piperidine carboxylic acid.There have been at present many groups to carry out the synthetic of dihydropyridine, verapamil and ciclosporin A derivative, to optimize its multidrug resistance activity.The isoindoline carboxylates derivatives is the analogue of verapamil, and its pharmacologically active is similar to verapamil, can be used as the agent of novel multiple reversal of drug resistance, and containing the isoindoline structural unit in this and the structure has confidential relation
[3]Therefore, just may develop and have more highly active multidrug resistance reversal agent by this compounds being carried out structural modification.
In coatings industry, organic dye is of a great variety, and chromatogram is complete, and is bright in luster.Because of it has good stability, resistance to acids and bases and fastness to weathering excellence, tinting strength is good and be subjected to common concern, has been applied to increasing occasion, particularly when condition is relatively harsher.Make a general survey of pigment industry development in recent years, the output of world's pigment dyestuff does not have growth by a relatively large margin, but the demand of high-performance pigment dyestuff is but had significantly raising.The application of the particularly high-grade pigment dyestuff of pigment dyestuff in coatings industry such as building coating, car paint, coil coating etc. is increasingly extensive, and its shared share ratio is also constantly soaring.Along with the continuous progress of science and technology, seek low-carbon (LC), environmental protection, energy-conservation target and the trend that has become industrial development.Progressively replace mineral dye, the high-performance pigment dyestuff of development structure novelty becomes the focus of research, and the high-grade pigment dyestuff that contains the isoindoline structure is one of them
[4]
About the synthetic method and the activity research of isoindoline carboxylates derivatives, existing a series of relevant reports now exemplify as follows:
[1]Sylvester，K.；John，B.；Robert，W.F.，et?al.J.Med.Chem.1986，29，1953-1961
[2]Blankley，C.J.；Kaltenbronn，J.S.，DeJohn，D.E.，et?al.J.Med.Chem.1987，30，992-998.
[3]Giorgio，C.and?Paolo，S.J.Med.Chem.1981，24，1003-1006.
[4] Ceng Zhuo, Lin Yuanbin, dyestuffs industries, 2001,38 (1): 10-11
[5]Oliver，G?and?Stephen，L.B.，J.Org.Chem.2002，67，465-475.
[6]Yoshihiro，S.，Toyoki，N.，Miwako，M.J.Org.Chem.1994，59，6133-6135.
[7]Axel，C.；Eric，D.；Dumitru，I.，et?al.Tetrahedron?Lett.1998，39，2319-2320.
[8]Daniel?S.，Olga?S.Org.Biomol.Chem.2009，7，3382-3384.
The synthetic method of above-mentioned existing isoindoline carboxylates derivatives is all existing limitation in varying degrees, and low as productive rate, product is difficult for separation and purification, and reaction raw materials be difficult for to obtain, and is less economical, and is unfriendly etc. to environment.At present, be that starting raw material prepares the synthetic method of isoindoline carboxylates derivatives both at home and abroad also less than report with the 2-tolyl aldehyde.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of isoindoline carboxylates derivatives is provided.
Second purpose of the present invention provides a kind of preparation method of isoindoline carboxylates derivatives.
Technical scheme of the present invention is summarized as follows:
A kind of isoindoline carboxylates derivatives, the compound with general formula (I) structure
Wherein: R
1Be sec.-propyl, 2-methoxy ethyl, benzyl or p-methoxyphenyl; R
2Be methyl or ethyl.
The compound of described general formula (I) structure is preferably:
N-benzyl isoindoline-1-carboxylate methyl ester, N-isopropyl indoline-1-carboxylic acid, ethyl ester, N-(2-methoxy ethyl) isoindoline-1-carboxylic acid, ethyl ester, N-benzyl isoindoline-1-carboxylic acid, ethyl ester or N-p-methoxyphenyl isoindoline-1-carboxylic acid, ethyl ester.
A kind of preparation method of isoindoline carboxylates derivatives comprises the following steps:
(a) be starting raw material with 2-tolyl aldehyde (II) and methenyl bromide, in solvent, under the inorganic strong alkali effect, under the condition that lithium chloride exists, react, obtain midbody compound (III), be further purified through recrystallization again;
(b) with compound (III) and methyl alcohol or ethanol under the acid catalysis condition, through esterification, generate midbody compound (IV);
(c) with compound (IV) separation and purification, with Methanesulfonyl chloride in solvent, under the condition that triethylamine exists,, generate compound (V) through condensation reaction;
(d) compound (V) and inorganic bromide reagent are substituted reaction in solvent, generate midbody compound (VI);
(e) compound (VI) is substituted reaction with sodium bromate-sodium hydrogen sulfite system in solvent, generates midbody compound (VII);
(f) with compound (VII) and isopropylamine, 2-methoxy ethyl amine, benzylamine or P-nethoxyaniline in solvent under the microwave irradiation effect through the N-heterocyclization, generate isoindoline-1-carboxylates derivatives (I).
Solvent described in the step (a) be volume ratio be 1: 11,4-dioxane/water or tetrahydrofuran (THF)/water, described inorganic strong alkali are sodium hydroxide or potassium hydroxide.
Solvent is exsiccant methyl alcohol or ethanol described in the step (b), and described acid is the vitriol oil, concentrated hydrochloric acid or tosic acid.
Solvent is exsiccant methylene dichloride or 1 described in the step (c), the 2-ethylene dichloride.
Solvent is acetone or tetrahydrofuran (THF) described in the step (d), and described inorganic bromide reagent is anhydrous lithium bromide or anhydrous Sodium Bromide.
Solvent described in the step (e) is that volume ratio is ethyl acetate/water of 4: 3, and the mol ratio of described sodium bromate-sodium bisulfite is 1: 1, and reaction conditions is to react under solar light irradiation.
Solvent described in the step (f) is water, acetonitrile, 1,4-dioxane or N, and dinethylformamide, the power of described microwave radiation are 700W, temperature of reaction is 140 ℃.
Isoindoline carboxylates derivatives of the present invention can be used as the active structure unit application of new angiotensin converting enzyme inhibitors, novel diuretic(s), novel multidrug resistance inhibitor in field of medicaments, and the precursor structure that also can be used as novel isoindoline class pigment dyestuff is applied to coatings industry.
The invention has the advantages that: reaction raw materials is cheap and easy to get, the reaction conditions gentleness, and simple to operate, productive rate is higher, and cost is lower, and is environmentally friendly.
Embodiment
Isoindoline carboxylates derivatives synthetic reaction equation of the present invention is:
Embodiment 1
The preparation of N-benzyl isoindoline-1-carboxylic acid, ethyl ester:
(a) preparation of 2-methyl-Alpha-hydroxy toluylic acid (III)
In the dry there-necked flask of the 500mL that magnetic agitation and thermometer are housed, add lithium chloride (14.1g successively, 0.34mol), potassium hydroxide (38g, 0.67mol), water 160mL adds 1 of 160mL more successively in this mixing solutions, the 4-dioxane, the 2-tolyl aldehyde (20g, 0.17mol) and methenyl bromide (42.1g, 0.17mol); This reaction solution is constantly stirred under ice-water bath, slowly rise to room temperature, rise to 40 ℃ again, the pH value of monitoring reaction liquid makes it to remain on 12, then adds solid potassium hydroxide if be lower than; The TLC detection reaction needs 48 hours approximately to fully; Reaction solution is cooled to room temperature and adds concentrated hydrochloric acid to regulate that pH value makes it be 2, uses ethyl acetate (100mL * 3) extraction again, the saturated common salt water washing, and the merging organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains dope; Thick product recrystallization in 30% ethyl acetate-petroleum ether solvent obtains white solid compound 2-methyl-Alpha-hydroxy toluylic acid 18g, productive rate 65%; Fusing point: 102-105 ℃ (literature value: 105-106 ℃);
1H-NMR (CDCl
3, 400MHz) δ: 7.19-7.34 (m, 4H), 5.47 (s, 1H), 2.44 (s, 3H). (b) preparation of 2-methyl-Alpha-hydroxy Phenylacetic acid ethylester (IV)
To magnetic agitation is housed, add compound 2-methyl-Alpha-hydroxy toluylic acid (compound (III)) (2g in the dry round-bottomed flask of the 100mL of prolong, 0.012mol), add 25mL exsiccant ethanol again and make it dissolving, reflux, disposable adding p-methyl benzenesulfonic acid (0.42g, 0.0024mol), constantly stir down, the TLC detection reaction needs 4 hours approximately to fully; Reaction solution is cooled to room temperature, concentrating under reduced pressure; With the ethyl acetate dilution, successively with saturated aqueous common salt, saturated sodium bicarbonate solution washing, merge organic phase again, anhydrous sodium sulfate drying, concentrating under reduced pressure gets yellow liquid 2-methyl-Alpha-hydroxy Phenylacetic acid ethylester (IV) 2.3g, yield 98% again;
1H-NMR(CDCl
3，400MHz)δ：7.17-7.30(m，4H)，5.36(s，1H)，4.17-4.27(q，2H，J＝7.2Hz)，2.44(s，3H)，1.20-1.24(t，3H，J＝7.2Hz).
(c) preparation of compound (V)
In the dry there-necked flask of the 100mL that magnetic agitation and thermometer are housed, add 2-methyl-Alpha-hydroxy Phenylacetic acid ethylester (2.3g, 0.012mol), adding methylene dichloride (15mL) makes it to dissolve fully, under constantly stirring, ice-water bath adds triethylamine (2.4g again, 0.024mol), slowly drip Methanesulfonyl chloride (2.8g, dichloromethane solution 0.024mol) (10mL); The TLC detection reaction needs 6 hours approximately to fully; Add saturated aqueous common salt then, dichloromethane extraction (20mL * 3); Merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure gets yellow liquid (compound (V)) 3.2g again, and productive rate 98% does not have purifying directly to carry out next step reaction;
(d) preparation of 2-methyl-alpha-brominated Phenylacetic acid ethylester 2.6g (VI)
In the dry round-bottomed flask of the 100mL that magnetic agitation and prolong are housed, add previous step products therefrom compound (V) (3.2g, 0.012mol), add acetone (24mL) and make it dissolving, be warming up to backflow under constantly stirring, add again anhydrous lithium bromide (2.1g, 0.024mol); The TLC detection reaction needs 8 hours approximately to fully, and reaction solution is cooled to room temperature, concentrating under reduced pressure.With ethyl acetate dilution (2 * 25mL), and then wash with water, merge organic phase, anhydrous sodium sulfate drying gets yellow oily liquid 2-methyl-alpha-brominated Phenylacetic acid ethylester 2.6g (compound (VI)), productive rate 87% at concentrating under reduced pressure;
1H-NMR(CDCl
3，400MHz)δ：7.18-7.62(m，4H)，5.62(s，1H)，4.24-4.28(q，2H，J＝7.2Hz)，2.44(s，3H)，1.26-1.30(t，3H，J＝7.2Hz).
(e) preparation of 2-brooethyl-alpha-brominated Phenylacetic acid ethylester (VII)
To magnetic agitation is housed, add 2-methyl-alpha-brominated Phenylacetic acid ethylester (2.6g successively in the dry there-necked flask of the 100mL of thermometer, 0.02mol), ethyl acetate (12mL), sodium bromate (3.0g, 0.06mol), water (8mL), and then (2.1g, 0.06mol) 8mL behind the dropping aqueous solution of sodium bisulfite.This reaction solution constantly stirs under the room temperature solar radiation then, and the TLC detection reaction needs 15 hours approximately to fully.Use the ethyl acetate dilute reaction solution, separate organic layer, use 20% hypo solution, saturated common salt water washing more successively, organic phase is at anhydrous sodium sulfate drying, concentrating under reduced pressure, with 3%-5% ethyl acetate/petroleum ether system, obtain yellow liquid 2-brooethyl-alpha-brominated Phenylacetic acid ethylester (VII) 3.2g, productive rate 92% by column chromatography purification;
1H-NMR(CDCl
3，400MHz)δ：7.33-7.75(m，4H)，5.81(s，1H)，4.56-4.63(m，2H)，4.25-4.29(q，2H，J＝5.2Hz)，1.27-1.31(t，3H，J＝7.2Hz).
(f) preparation of isoindoline carboxylates derivatives (I)
With mol ratio is 1: 1.1 ratio, and step (e) gained compound and benzylamine are added in the distilled water, is heated to 140 ℃ under the microwave radiation condition, reaction 40min, and described microwave irradiation power is 700W.TLC detects to the reaction end.Reaction is cooled to room temperature with reaction solution after finishing, and separates out solid and carries out suction filtration, thicker product recrystallization is obtained target product isoindoline carboxylates derivatives; (if can not separate out solid then uses the organic solvent ethyl acetate extraction, concentrating under reduced pressure passes through column chromatography separating purification with thick product more again); Obtain N-benzyl isoindoline-1-carboxylic acid, ethyl ester (weak yellow liquid, productive rate 84%)
1H-NMR(CDCl
3，400MHz)δ：7.16-7.44(m，9H)，4.75(s，1H)，4.16-4.30(m，4H)，3.87-3.92(m，2H)，1.27-1.30(t，3H，J＝7.2Hz).
Embodiment 2
The preparation of N-isopropyl indoline-1-carboxylic acid, ethyl ester:
Step (a)-(e) is with embodiment 1
(f) preparation of isoindoline carboxylates derivatives (I)
With mol ratio is 1: 1.1 ratio, and step (e) gained compound and isopropylamine are added in the distilled water, is heated to 140 ℃ under the microwave radiation condition, reaction 40min, and described microwave irradiation power is 700W.TLC detects to the reaction end.Reaction is cooled to room temperature with reaction solution after finishing, and separates out solid and carries out suction filtration, thicker product recrystallization is obtained target product isoindoline carboxylates derivatives; (if can not separate out solid then with the organic solvent dichloromethane extraction, concentrating under reduced pressure passes through column chromatography separating purification with thick product more again; ) obtain N-isopropyl indoline-1-carboxylic acid, ethyl ester (weak yellow liquid, productive rate 91%)
1H-NMR(CDCl
3，400MHz)δ：7.18-7.28(m，4H)，4.81(s，1H)，4.37-4.40(d，1H，J＝12.8Hz)，4.21-4.27(q，2H，J＝7.2Hz)，4.01-4.04(d，1H，J＝12.8Hz)，3.06-3.16(m，1H，J＝6.4Hz)，1.27-1.31(t，3H，J＝7.2Hz)，1.16-1.18(t，6H，J＝6.0Hz).
Embodiment 3
The preparation of N-(2-methoxy ethyl) isoindoline-1-carboxylic acid, ethyl ester:
Step (a)-(e) is with embodiment 1
(f) preparation of isoindoline carboxylates derivatives (I)
With mol ratio is 1: 1.1 ratio, and step (e) gained compound and 2-methoxy ethyl amine are added in the distilled water, is heated to 140 ℃ under the microwave radiation condition, reaction 40min, and described microwave irradiation power is 700W.TLC detects to the reaction end.Reaction is cooled to room temperature with reaction solution after finishing, and separates out solid and carries out suction filtration, thicker product recrystallization is obtained target product isoindoline carboxylates derivatives; (separate out solid organic solvent ethyl acetate extraction, concentrating under reduced pressure passes through column chromatography separating purification with thick product more again; ) obtain N-(2-methoxy ethyl) isoindoline-1-carboxylic acid, ethyl ester (weak yellow liquid, productive rate 86%)
1H-NMR(CDCl
3，400MHz)δ：7.21-7.33(m，4H)，4.73(s，1H)，4.47-4.50(d，1H，J＝12.8Hz)，4.22-4.29(q，2H，J＝7.2Hz)，3.96-3.99(d，1H，J＝12.8Hz)，3.60-3.63(m，2H，J＝4.8Hz)，3.35(s，3H)，3.06-3.10(m，2H)，1.30-1.34(t，3H，J＝7.2Hz).
Embodiment 4
The preparation of N-benzyl isoindoline-1-carboxylate methyl ester:
(a) preparation of 2-methyl-Alpha-hydroxy toluylic acid (III)
With 1 in tetrahydrofuran (THF) alternate embodiment 1 step (a) of 160mL, 4-dioxane, with hydroxide instead of hydrogen potassium oxide, other obtains white solid compound 2-methyl-Alpha-hydroxy toluylic acid (III) with embodiment 1 step (a);
(b) preparation of 2-methyl-Alpha-hydroxy methyl phenylacetate (IV)
Tosic acid with in the vitriol oil (also can use concentrated hydrochloric acid) alternate embodiment 1 step (b) replaces ethanol with methyl alcohol, and other obtains 2-methyl-Alpha-hydroxy methyl phenylacetate (IV), productive rate 92% with embodiment 1 step (b);
(c) preparation of compound (V)
With the 2-methyl-Alpha-hydroxy Phenylacetic acid ethylester in 2-methyl-Alpha-hydroxy methyl phenylacetate alternate embodiment 1 step (c), with 1,2-ethylene dichloride instead of methylene chloride, other is with embodiment 1 step (c), and obtaining compound (V) productive rate is 97%;
(d) 2-methyl-alpha-brominated Phenylacetic acid ethylester 2.6g (compound (VI))
The compound (V) that compound (V) alternate embodiment 1 step (c) for preparing with present embodiment step (c) prepares, substitute acetone with tetrahydrofuran (THF), substitute anhydrous lithium bromide with anhydrous Sodium Bromide, other is with embodiment 1 step (d), obtain 2-methyl-alpha-brominated methyl phenylacetate (VI) 2.6g, productive rate 83%;
(e) preparation of 2-brooethyl-alpha-brominated methyl phenylacetate
With the 2-methyl-alpha-brominated Phenylacetic acid ethylester of 2-methyl-alpha-brominated methyl phenylacetate alternate embodiment 1 step (e) preparation, other obtains 2-brooethyl-alpha-brominated methyl phenylacetate, productive rate 90% with embodiment 1 step (e);
(f) preparation of isoindoline carboxylates derivatives (I)
With mol ratio is 1: 1.1 ratio, and step (e) gained compound and benzylamine are added in the acetonitrile, is heated to 140 ℃ under the microwave radiation condition, reaction 40min, and described microwave irradiation power is 700W.TLC detects to the reaction end.Reaction is cooled to room temperature with reaction solution after finishing, and separates out solid and carries out suction filtration, thicker product recrystallization is obtained target product isoindoline carboxylates derivatives; (if can not separate out solid then with the organic solvent dichloromethane extraction, concentrating under reduced pressure passes through column chromatography separating purification with thick product more again; ) obtain N-benzyl isoindoline-1-carboxylate methyl ester (weak yellow liquid, productive rate 78%)
1H-NMR(CDCl
3，400MHz)δ：7.17-7.43(m，4H)，4.76(s，1H)，4.27-4.30(d，1H，J＝12.8Hz)，4.12-4.15(d，1H，J＝12.8Hz)，3.85-3.91(m，2H)，3.71(s，1H).
Embodiment 5
N-p-methoxyphenyl isoindoline-1-carboxylate methyl ester preparation:
Step (a)-(e) is with embodiment 4
(f) preparation of isoindoline carboxylates derivatives (I)
With mol ratio is 1: 1.1 ratio, and step (e) gained compound and P-nethoxyaniline are added 1, in the 4-dioxane, is heated to 140 ℃ under the microwave radiation condition, reaction 40min, and described microwave irradiation power is 700W.TLC detects to the reaction end.Reaction is cooled to room temperature with reaction solution after finishing, if separating out solid then carries out suction filtration, thicker product recrystallization is obtained target product isoindoline carboxylates derivatives; (if can not separate out solid then uses the organic solvent ethyl acetate extraction, concentrating under reduced pressure passes through column chromatography separating purification with thick product more again; ) N-p-methoxyphenyl isoindoline-1-carboxylate methyl ester (faint yellow solid, productive rate 87%, M.p.95-97 ℃)
1H-NMR(CDCl
3，400MHz)δ：7.30-7.47(m，4H)，6.88-6.90(d，2H)，6.60-6.62(d，2H)，5.45(s，1H)，4.85-4.88(d，1H，J＝12.8Hz)，4.63-4.66(d，1H，J＝12.8Hz)，4.14-4.20(q，2H，J＝7.2Hz)，3.77(s，3H)，1.17-1.21(t，3H，J＝7.2Hz).
Embodiment 6
Use N, the P-nethoxyaniline in dinethylformamide alternate embodiment 5 steps (f), other is with embodiment 5.
The above, only being part embodiment of the present invention, is not that the present invention is done any pro forma restriction, any simple modification that every foundation technical spirit of the present invention is done the foregoing description, equivalent variations and modification all belong in the technical solution of the present invention scope.
Claims (9)
1. isoindoline carboxylates derivatives, the compound of (I) structure that it is characterized in that having general formula
Wherein: R
1Be sec.-propyl, 2-methoxy ethyl, benzyl or p-methoxyphenyl; R
2Be methyl or ethyl.
2. a kind of isoindoline carboxylates derivatives according to claim 1 is characterized in that the compound of described general formula (I) structure is:
N-benzyl isoindoline-1-carboxylate methyl ester, N-isopropyl indoline-1-carboxylic acid, ethyl ester, N-(2-methoxy ethyl) isoindoline-1-carboxylic acid, ethyl ester, N-benzyl isoindoline-1-carboxylic acid, ethyl ester or N-p-methoxyphenyl isoindoline-1-carboxylic acid, ethyl ester.
3. the preparation method of claim 1 or 2 isoindoline carboxylates derivatives is characterized in that comprising the following steps:
(a) be starting raw material with 2-tolyl aldehyde (II) and methenyl bromide, in solvent, under the inorganic strong alkali effect, under the condition that lithium chloride exists, react, obtain midbody compound (III), be further purified through recrystallization again;
(b) with compound (III) and methyl alcohol or ethanol under the acid catalysis condition, through esterification, generate midbody compound (IV);
(c) with compound (IV) separation and purification, with Methanesulfonyl chloride in solvent, under the condition that triethylamine exists,, generate compound (V) through condensation reaction;
(d) compound (V) and inorganic bromide reagent are substituted reaction in solvent, generate midbody compound (VI);
(e) compound (VI) is substituted reaction with sodium bromate-sodium hydrogen sulfite system in solvent, generates midbody compound (VII);
(f) with compound (VII) and isopropylamine, 2-methoxy ethyl amine, benzylamine or P-nethoxyaniline in solvent under the microwave irradiation effect through the N-heterocyclization, generate isoindoline-1-carboxylates derivatives (I).
4. the preparation method of a kind of isoindoline carboxylates derivatives according to claim 3, it is characterized in that solvent described in the described step (a) be volume ratio be 1: 11,4-dioxane/water or tetrahydrofuran (THF)/water, described inorganic strong alkali are sodium hydroxide or potassium hydroxide.
5. the preparation method of a kind of isoindoline carboxylates derivatives according to claim 3 is characterized in that the solvent that uses in the step (b) is methyl alcohol or ethanol, and described acid is the vitriol oil, concentrated hydrochloric acid or tosic acid.
6. the preparation method of a kind of isoindoline carboxylates derivatives according to claim 3 is characterized in that solvent is exsiccant methylene dichloride or 1 described in the described step (c), the 2-ethylene dichloride.
7. the preparation method of a kind of isoindoline carboxylates derivatives according to claim 3 is characterized in that solvent is acetone or tetrahydrofuran (THF) described in the described step (d), and described inorganic bromide reagent is anhydrous lithium bromide or anhydrous Sodium Bromide.
8. the preparation method of a kind of isoindoline carboxylates derivatives according to claim 3, it is characterized in that, solvent described in the step (e) is that volume ratio is ethyl acetate/water of 4: 3, the mol ratio of described sodium bromate-sodium bisulfite is 1: 1, and reaction conditions is to react under solar light irradiation.
9. the preparation method of a kind of isoindoline carboxylates derivatives according to claim 3, it is characterized in that solvent described in the step (f) is water, acetonitrile, 1,4-dioxane or N, dinethylformamide, the power of described microwave radiation is 700W, and temperature of reaction is 140 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104105760A (en) * | 2011-12-14 | 2014-10-15 | 爱克发印艺公司 | Surface modified pigments and non-aqueous inks therewith |
| CN111718290A (en) * | 2020-07-22 | 2020-09-29 | 苏州爱玛特生物科技有限公司 | Synthesis method of multi-configuration isoindoline-1-carboxylic acid amino acid compound |
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| CN1085546A (en) * | 1992-07-20 | 1994-04-20 | E·R·斯奎布父子公司 | Aminediol protease inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1085546A (en) * | 1992-07-20 | 1994-04-20 | E·R·斯奎布父子公司 | Aminediol protease inhibitors |
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| 《化工科技市场》 20011231 沈永嘉等 异吲哚啉酮和异吲哚啉有机颜料 7-11,71 , 第9期 2 * |
| 《染料工业》 20010228 曾卓等 异吲哚基体高档有机颜料 10-11 第38卷, 第1期 2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104105760A (en) * | 2011-12-14 | 2014-10-15 | 爱克发印艺公司 | Surface modified pigments and non-aqueous inks therewith |
| CN104105760B (en) * | 2011-12-14 | 2016-08-24 | 爱克发印艺公司 | Surface-modified pigments and non-aqueous inks thereof |
| CN111718290A (en) * | 2020-07-22 | 2020-09-29 | 苏州爱玛特生物科技有限公司 | Synthesis method of multi-configuration isoindoline-1-carboxylic acid amino acid compound |
| CN111718290B (en) * | 2020-07-22 | 2022-11-25 | 苏州爱玛特生物科技有限公司 | Synthesis method of multi-configuration isoindoline-1-carboxylic acid amino acid compound |
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