CN105294562A - Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine - Google Patents
Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine Download PDFInfo
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- 0 [*+]c(c(C=O)c1)ccc1Cl Chemical compound [*+]c(c(C=O)c1)ccc1Cl 0.000 description 2
- UGQRECYDRHOMIS-UHFFFAOYSA-N C=CCN(C1[U]C2CC1)c(cc1)c2cc1Cl Chemical compound C=CCN(C1[U]C2CC1)c(cc1)c2cc1Cl UGQRECYDRHOMIS-UHFFFAOYSA-N 0.000 description 1
- PSBRDXVGBVRCLD-UHFFFAOYSA-N C=CCN(CCC1)c(ccc(Cl)c2)c2C1=O Chemical compound C=CCN(CCC1)c(ccc(Cl)c2)c2C1=O PSBRDXVGBVRCLD-UHFFFAOYSA-N 0.000 description 1
- AHESNFIUAHTYGS-UHFFFAOYSA-N O=C1c2cc(Cl)ccc2NCCC1 Chemical compound O=C1c2cc(Cl)ccc2NCCC1 AHESNFIUAHTYGS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of a key intermediate, namely, 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine, of Tolvaptan. The synthetic method comprises four steps of A, the synthesis of 5-chloro-2-(di-allyl amino)-benzaldehyde, B, the synthesis of 1-allyl-7-chloro-2,3,4,5-tetrahydro-1H-2,5-epoxy benzo[b]azepine, C, the synthesis of 1-allyl-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine, and D, the synthesis of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine. According to the process route, the key intermediate of Tolvaptan is synthesized through four reactions of substitution, cyclization, ring-opening and deprotection, the synthetic steps are less, the operation is easy and convenient, the equipment requirement is low, the yield in each step is relatively high, column chromatography separation is not needed in the four reactions, and the synthetic method has the advantages that the technology is simple, the industrial scale production is facilitated, and the cost is low.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to the synthetic method of a kind of tolvaptan key intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine.
Background technology
7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine is the key intermediate preparing tolvaptan.Tolvaptan is arginine vasopressin (AVP) antagonist of a kind of high-efficiency low-toxicity researched and developed by Japanese great Zhong drugmaker, the research of AVPReceptorAgonists is taken to from nineteen eighty-three, and FDA the most finally in May, 2009 ratifies tolvaptan sheet treatment hyponatremia, is the oral type selectivity vasopressin antagonists of uniquely getting permission to treat this disease.Its English commodity are called Samsa (Tolvaptan), chemistry N-[4-[(7-chloro-2 by name, 3,4,5-tetrahydrochysene-1-benzo is mixed nitrogen Zhuo-1-base) carbonyl]-3-aminomethyl phenyl]-2-methyl benzamide, English language Chemical is called N-(4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo [b] azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide.Molecular structural formula is as follows:
Tolvaptan can reduce the concentration level of arginine vasopressin in blood circulation (AVP), therefore may be used for treating the heavy body that causes due to liver cirrhosis, heart failure, SIADH and etc. hypovolemic hyponatremia, and the heavy body situation of patient can be improved.Tolvaptan can obviously alleviate weight in patients and oedema, and does not destroy electrolyte balance.Its better tolerance, need not limit the intake of water, good market prospects in treatment.The synthesis of tolvaptan generally passes through key intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine acylations, more obtained through reducing.But there is the problems such as synthetic route is long, yield is low, starting material are expensive, aftertreatment purification difficult in several schemes of synthesis key intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine at present.
The people such as KazumiKondo develop with 3-chloro-6-nitrobenzoic acid for starting raw material adopts route as follows obtained (see Bioorganic & amp through 7 steps reactions; MedicinalChemistry1999,7 (8), 1743-1754).This method processing step is numerous and diverse, and total recovery is low.And the method needs the material that toxicity such as use tindichloride, methyl-sulfate etc. is higher, also will use DMF, acetic acid, the contour polar solvent of polyphosphoric acid, pollution discharge amount is very big, easily causes environmental pollution.React as follows:
SamirZ.Zard research group utilizes Beckmann to be rearranged to committed step and achieves the structure of seven-membered ring (see Bioorganic & amp; MedicinalChemistry2006,14 (18), 6165-6173).But the method has following shortcoming: expensive and that environmental pollution is larger xanthate (stink, poisonous) must be used, also will use inflammable, to have severe toxicity borine, make material cost higher, and overall yield be too low.Reaction formula is as follows:
ShitalK.Chattopadhyay group closes ring metathesis with alkene and closes ring for committed step, is obtained by reacting benzazepine ketone compound (see Synlett2008, (19), 3011-3015) through seven steps.But the method also has following shortcoming: reaction scheme is long, overall yield is low and need in reaction to use expensive Grubbs catalyzer, limits the application of this method.
Summary of the invention
The technical problem to be solved in the present invention is for prior art present situation, provides one to prepare the chloro-5-oxo-2,3 of 7-, the novel method of 4,5-tetrahydrochysene-1H-1-benzazepine, its object is to shorten reaction scheme, improve overall yield, finally reduce production cost, increase the performance of enterprises.
The technical scheme that the present invention solves the problems of the technologies described above is to provide the synthetic method of a kind of 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine, comprises the following steps:
The synthesis of the chloro-2-of A, 5-(diallylamine base)-phenyl aldehyde: the fluoro-5-chlorobenzaldehyde of 2-to be dissolved in solvent in the basic conditions with diallylamine generation substitution reaction, obtain the chloro-2-of 5-(diallylamine base)-phenyl aldehyde;
B, 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2, the synthesis of 5-epoxy benzene [b] azatropylidene: chloro-for above-mentioned 5-2-(diallylamine base)-phenyl aldehyde is dissolved in solvent and carbonyl Ene occurs reacts under the condition of heating, obtain 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2,5-epoxy benzene [b] azatropylidene;
The chloro-5-oxo-2,3,4 of C, 1-allyl group-7-, the synthesis of 5-tetrahydrochysene-1H-1-benzazepine: by above-mentioned 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2,5-epoxy benzene [b] azatropylidene is dissolved in solvent, there is open loop selfoxidation-reduction reaction under acidic conditions, obtain the chloro-5-oxo-2,3 of 1-allyl group-7-, 4,5-tetrahydrochysene-1H-1-benzazepine;
The synthesis of D, 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine: described step D comprises two kinds of methods:
(1) the chloro-5-oxo-2,3,4 of .1-allyl group-7-, there is alkene migration and obtain enamine intermediates in the dissolving of 5-tetrahydrochysene-1H-1-benzazepine, then remove allyl group through the effect of acid in a solvent under the effect of alkali, obtains the chloro-5-oxo-2 of 7-, 3,4,5-tetrahydrochysene-1H-1-benzazepine.
(2) .1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine dissolves de-allyl group under the effect of palladium catalyst, part and acid in a solvent, obtains 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine.
Wherein, in the preparation method of above-mentioned 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine:
Solvent in described steps A be selected from acetonitrile, water, dioxane, propyl carbinol, DMF, methyl-sulphoxide one or more, the more preferably mixed solvent of water and acetonitrile; Alkali in described steps A is selected from triethylamine, diisopropyl ethyl amine, salt of wormwood, sodium carbonate, potassium tert.-butoxide, sodium tert-butoxide, cesium carbonate, cesium fluoride, sodium methylate, more preferably salt of wormwood; The fluoro-5-chlorobenzaldehyde of described 2-is 1:1.05 ~ 5, more preferably 1:1.05 ~ 2 with the ratio of the molar weight of diallylamine; The fluoro-5-chlorobenzaldehyde of described 2-is 1:1.05 ~ 5, more preferably 1:1.5 ~ 2 with the ratio of the molar weight of alkali; Temperature of reaction in room temperature to solvent reflux temperature, more preferably 60 DEG C ~ 100 DEG C; Reaction time range 5-75 hour, has reacted usually in 10-48 hour.
Solvent in described step B be selected from sulfoxide type solvents, alcoholic solvent, aromatic hydrocarbon solvent and amide solvent one or more, more preferably aromatic hydrocarbon solvent, the preferred dimethylbenzene of described aromatic hydrocarbon solvent; Temperature of reaction 100 DEG C ~ 200 DEG C, more preferably 120 DEG C ~ 150 DEG C; Reaction time range 5-72 hour, has reacted usually in 10-48 hour; The chloro-2-of described 5-(diallylamine base)-phenyl aldehyde reaction density is 0.1 ~ 2mol/L, more preferably 0.25 ~ 1mol/L.
In described step C, acid is selected from one or more in hydrochloric acid, sulfuric acid, formic acid, acetic acid, methylsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, more preferably sulfuric acid; Solvent in described step C be selected from halogenated hydrocarbon solvent, alcoholic solvent, aromatic hydrocarbon solvent and esters solvent one or more, more preferably water; Temperature of reaction room temperature to solvent reflux temperature, more preferably 80 DEG C ~ 110 DEG C; Reaction time range 1-30 hour, has reacted usually in 2-8 hour.
In method (1) in described step D, alkene migration step alkali is selected from potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, more preferably potassium tert.-butoxide; In the method (1) of described step D, the solvent of alkene migration step is selected from sulfoxide type solvents and amide solvent, more preferably sulfoxide type solvents, the preferred methyl-sulphoxide of described sulfoxide type solvents; Temperature of reaction 80 DEG C ~ 120 DEG C, more preferably 90 DEG C ~ 110 DEG C; In 0.5 ~ 6 hour reaction times, usually react in 1-3 hour; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:1.5 ~ 5, more preferably 1:1.5 ~ 3 with the ratio of the molar weight of alkali; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine reaction density is 0.1 ~ 2mol/L, more preferably 0.2 ~ 1mol/L.
In method (1) in described step D, the de-allyl group step acid of acid is selected from one or more in hydrochloric acid, sulfuric acid, formic acid, acetic acid, more preferably hydrochloric acid;
In method (2) in described step D, palladium catalyst is selected from Pd (PPh
3)
4, Pd (dba)
2, Pd (AcO)
2, more preferably Pd (AcO)
2; In the method (2) of described step D, part is selected from PPh
3, DPPB, more preferably PPh
3; Described acid is selected from 2-Thiosalicylic acid, formic acid, N, N-dimethyl barbituric acid, tosic acid, more preferably N, N-dimethyl barbituric acid; Described solvent is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, more preferably methylene dichloride; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:0.01 ~ 1, more preferably 1:0.01 ~ 0.05 with the ratio of the molar weight of palladium catalyst; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:0.05 ~ 1, more preferably 1:0.05 ~ 0.2 with the ratio of the molar weight of part; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:1 ~ 5, more preferably 1:1.5 ~ 3 with the ratio of the molar weight of acid.
The present invention relates to benzo to mix the synthetic method of nitrogen Zhuo, specifically refer to the synthetic method of key intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine; This operational path adopts replacement, cyclization, open loop, deprotection four-step reaction synthesis tolvaptan key intermediate, and synthesis step is few, easy and simple to handle, equipment requirements is low, the higher four-step reaction of each step yield does not need column chromatography for separation.There is technique simple, be convenient to commercial scale production and the low advantage of cost.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1
The synthesis of the chloro-2-of A, 5-(diallylamine base)-phenyl aldehyde: by chloro-for fluoro-for 2-5-phenyl aldehyde (0.948g, 6mmol) be dissolved in acetonitrile/water (V:V=1:1) mixed solvent (6mL), add potassium carbonate powder (1.24g, 9mmol), diallylamine (3.7mL, 30mmol).Reaction mixture is warming up to back flow reaction 60h.Reaction solution is cooled to room temperature, water (30mL) is added in reaction solution, extraction into ethyl acetate (3 × 30mL), merge organic phase, saturated common salt water washing (30mL), anhydrous sodium sulfate drying, filters evaporate to dryness and quantitatively obtains the chloro-2-of pale yellowish oil 5-(diallylamine base)-phenyl aldehyde (1.34g, 95%).
1HNMR(300MHz,CDCl
3)δ10.29(s,1H),7.75(d,J＝2.7Hz,1H),7.40(dd,J＝8.7,2.7Hz,1H),7.05(d,J＝8.7Hz,1H),5.93–5.69(m,2H),5.27–5.16(m,4H),3.76(dt,J＝6.0,1.2Hz,4H)。
B, 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2, the synthesis of 5-epoxy benzene [b] azatropylidene: chloro-for 5-2-(diallylamine base)-phenyl aldehyde (1.3g, 5.5mmol) is joined in steel reactor, add dimethylbenzene (30mL) to dissolve, after being screwed by reactor, oil bath is warming up to 175 DEG C, reaction 18h.After reacting completely, reactor is cooled to room temperature, reactor of outwarding winding.Büchner funnel loads silica gel, by reacting liquid filtering, sherwood oil (150mL) eccysis dimethylbenzene, ethyl acetate (150mL) is washed again, filtrate evaporate to dryness is obtained 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2,5-epoxy benzene [b] azatropylidene (1.21g, 93%).
1HNMR(300MHz,CDCl
3)δ7.04(dd,J＝8.7,2.7Hz,1H),6.87(d,J＝2.7Hz,1H),6.54(d,J＝8.7Hz,1H),5.95–5.82(m,1H),5.35–5.20(m,1H),5.20–5.14(m,2H),5.03–4.90(m,1H),3.98–3.89(m,1H),3.87–3.75(m,1H),2.26–2.09(m,3H),2.07–1.96(m,1H).
The synthesis of C, 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine: chloro-2,3,4, the 5-tetrahydrochysene-1H-2 of 1-allyl group-7-, 5-epoxy benzene [b] azatropylidene (1.2g, 5.1mmol) adds in reaction flask, adds 10%H
2sO
4aq (12mL), is warming up to 90 DEG C of reaction 11h.Reaction solution is cooled to room temperature, adds water (25mL), extraction into ethyl acetate (3 × 30mL), merge organic phase, saturated sodium bicarbonate solution (25mL) washing once, washes (25mL) once, saturated common salt water washing (30mL), anhydrous sodium sulfate drying, filter evaporated under reduced pressure solvent and obtain the chloro-5-oxo-2,3,4 of light tan solid 1-allyl group-7-, 5-tetrahydrochysene-1H-1-benzazepine (1.08g, 90%).M.P.86-88℃。
1HNMR(300MHz,CDCl
3)δ7.69(d,J＝2.7Hz,1H),7.21(dd,J＝8.7,2.7Hz,1H),6.80(d,J＝8.7Hz,1H),5.96–5.82(m,1H),5.28–5.22(m,1H),5.28–5.13(m,1H),4.07(dt,J＝4.8,1.8Hz,2H),3.28(t,J＝6.6Hz,2H),2.78(t,J＝7.2Hz,2H),2.32–2.18(m,2H).
The chloro-5-oxo-2 of D, 7-; 3; 4; the synthesis of 5-tetrahydrochysene-1H-1-benzazepine: by chloro-for 1-allyl group-7-5-oxo-2,3,4; 5-tetrahydrochysene-1H-1-benzazepine (1g; 4.25mmol) add in reactor, add methylene dichloride (12mL) and dissolve, add 1 subsequently; 3-dimethyl barbituric acid (2.8g; 18mmol), palladium (27mg, 0.12mmol); triphenylphosphine (142mg; 0.54mmol), nitrogen protection, is warming up to back flow reaction 8h.Reaction solution is cooled to room temperature, add water (30mL), extraction into ethyl acetate (3 × 30mL), merge organic phase, saturated sodium bicarbonate solution (30mL) washs three times, wash (30mL) once, saturated common salt water washing (30mL), anhydrous sodium sulfate drying.Büchner funnel loads silica gel (2cm is thick), and filtered by extraction liquid, ethyl acetate (100mL) is washed, and filtrate decompression evaporate to dryness is obtained brown oil.Brown oil be again dissolved in ethyl acetate (3mL), ice-water bath stirs, and constantly passes into hydrogen chloride gas (be added drop-wise in sodium-chlor by the vitriol oil and prepare), separates out until no longer include solid.Filtered on buchner funnel, cold ethyl acetate (30mL) is washed, and obtains light yellow solid 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine hydrochloride, 883mg.The chloro-5-oxo-2 of 7-will be obtained, 3,4,5-tetrahydrochysene-1H-1-benzazepine hydrochloride adds in round-bottomed flask, adds water (10mL), and saturated sodium bicarbonate solution regulates pH to neutral, extraction into ethyl acetate (3 × 15mL), once, saturated aqueous common salt (15mL) washs, anhydrous sodium sulfate drying in washing (15mL).Filter evaporated under reduced pressure and obtain 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine (745mg, 90%).M.P.97-99℃。
1HNMR(300MHz,CDCl
3)δ7.68(d,J＝2.4Hz,1H),7.18(dd,J＝8.4,2.4Hz,1H),6.71(d,J＝8.4Hz,1H),4.78(brs,1H),3.25(t,J＝6.6Hz,2H),2.83(t,J＝7.2Hz,2H),2.22–2.12(m,2H).
Embodiment 2
The synthesis of the chloro-2-of A, 5-(diallylamine base)-phenyl aldehyde: by compound 1, chloro-phenyl aldehyde (the 0.948g of the fluoro-5-of 2-, 6mmol) be dissolved in acetonitrile/water (V:V=1:1) mixed solvent (6mL), add potassium carbonate powder (1.24g, 9mmol), diallylamine (3.7mL, 30mmol).Reaction mixture is warming up to back flow reaction 60h.Reaction solution is cooled to room temperature, water (30mL) is added in reaction solution, extraction into ethyl acetate (3 × 30mL), merge organic phase, saturated common salt water washing (30mL), anhydrous sodium sulfate drying, filters evaporate to dryness and quantitatively obtains the chloro-2-of pale yellowish oil 5-(diallylamine base)-phenyl aldehyde (1.36g, 96%).
B, 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2, the synthesis of 5-epoxy benzene [b] azatropylidene: chloro-for 5-2-(diallylamine base)-phenyl aldehyde (1.3g, 5.5mmol) is joined in steel reactor, add dimethylbenzene (30mL) to dissolve, after being screwed by reactor, oil bath is warming up to 175 DEG C, reaction 18h.After reacting completely, reactor is cooled to room temperature, reactor of outwarding winding.Büchner funnel loads silica gel, by reacting liquid filtering, sherwood oil (150mL) eccysis dimethylbenzene, ethyl acetate (150mL) is washed again, filtrate evaporate to dryness is obtained 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2,5-epoxy benzene [b] azatropylidene (1.23g, 95%).
The synthesis of C, 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine: chloro-2,3,4, the 5-tetrahydrochysene-1H-2 of 1-allyl group-7-, 5-epoxy benzene [b] azatropylidene (1.2g, 5.1mmol) adds in reaction flask, adds 10%H
2sO
4aq (12mL), is warming up to 90 DEG C of reaction 11h.Reaction solution is cooled to room temperature, adds water (25mL), extraction into ethyl acetate (3 × 30mL), merge organic phase, saturated sodium bicarbonate solution (25mL) washing once, washes (25mL) once, saturated common salt water washing (30mL), anhydrous sodium sulfate drying, filter evaporated under reduced pressure solvent and obtain the chloro-5-oxo-2,3,4 of light tan solid 1-allyl group-7-, 5-tetrahydrochysene-1H-1-benzazepine (1.07g, 89%).M.P.86-88℃。
The chloro-5-oxo-2 of D, 7-, the synthesis of 3,4,5-tetrahydrochysene-1H-1-benzazepine: by chloro-for 1-allyl group-7-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine (940mg, 4.0mmol) adds in reactor, add methyl-sulphoxide (40mL), potassium tert.-butoxide (670mg, 6mmol), 100 DEG C are reacted 1 hour.Reaction solution is cooled to room temperature, and add water (400mL) in reaction solution, dichloromethane extraction (3 × 50mL), merges organic phase, washing (3 × 30mL), anhydrous sodium sulfate drying.Extraction liquid is filtered evaporate to dryness, adds 1NHCl (50mL), reflux 2 hours.Reaction solution is cooled to room temperature, in reaction solution, adds saturated sodium bicarbonate solution, regulate pH to alkalescence, extraction into ethyl acetate (3 × 30mL), merge organic phase, saturated common salt water washing (30mL), anhydrous sodium sulfate drying.Filter evaporate to dryness extraction liquid and obtain brown oil, brown oil is dissolved in again in ethyl acetate (3mL), ice-water bath stirs, and constantly passes into hydrogen chloride gas (be added drop-wise in sodium-chlor by the vitriol oil and prepare), separates out until no longer include solid.Filtered on buchner funnel, cold ethyl acetate (30mL) is washed, and obtains light yellow solid 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine hydrochloride, 693mg.The chloro-5-oxo-2 of 7-will be obtained, 3,4,5-tetrahydrochysene-1H-1-benzazepine hydrochloride adds in round-bottomed flask, adds water (10mL), and saturated sodium bicarbonate solution regulates pH to neutral, extraction into ethyl acetate (3 × 15mL), once, saturated aqueous common salt (15mL) washs, anhydrous sodium sulfate drying in washing (15mL).Filter evaporated under reduced pressure and obtain 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine (569mg, 73%).
Claims (13)
1. the preparation method of 7-chloro-5-oxo-2,3,4, a 5-tetrahydrochysene-1H-1-benzazepine, it is characterized in that, its preparation process comprises the following steps:
The synthesis of the chloro-2-of A, 5-(diallylamine base)-phenyl aldehyde: the fluoro-5-chlorobenzaldehyde of 2-to be dissolved in solvent in the basic conditions with diallylamine generation substitution reaction, obtain the chloro-2-of 5-(diallylamine base)-phenyl aldehyde;
B, 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2, the synthesis of 5-epoxy benzene [b] azatropylidene: chloro-for above-mentioned 5-2-(diallylamine base)-phenyl aldehyde is dissolved in solvent and carbonyl Ene occurs reacts under the condition of heating, obtain 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2,5-epoxy benzene [b] azatropylidene;
The chloro-5-oxo-2,3,4 of C, 1-allyl group-7-, the synthesis of 5-tetrahydrochysene-1H-1-benzazepine: by above-mentioned 1-allyl group-7-chloro-2,3,4,5-tetrahydrochysene-1H-2,5-epoxy benzene [b] azatropylidene is dissolved in solvent, there is open loop selfoxidation-reduction reaction under acidic conditions, obtain the chloro-5-oxo-2,3 of 1-allyl group-7-, 4,5-tetrahydrochysene-1H-1-benzazepine;
D, 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine: the chloro-5-oxo-2 of 1-allyl group-7-, 3,4,5-tetrahydrochysene-1H-1-benzazepine is dissolved in the effect of solvent neutralization reaction reagent and removes allyl group, obtains the chloro-5-oxo-2 of 7-, 3,4,5-tetrahydrochysene-1H-1-benzazepine.
2. the chloro-5-oxo-2 of a kind of 7-according to claim 1, the preparation method of 3,4,5-tetrahydrochysene-1H-1-benzazepine, it is characterized in that: the solvent described in steps A be selected from acetonitrile, water, dioxane, propyl carbinol, DMF, methyl-sulphoxide one or more; Alkali in described steps A is selected from triethylamine, diisopropyl ethyl amine, salt of wormwood, sodium carbonate, potassium tert.-butoxide, sodium tert-butoxide, cesium carbonate, cesium fluoride, sodium methylate.
3. the preparation method of a kind of 7-according to claim 1 chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: the fluoro-5-chlorobenzaldehyde of the 2-described in steps A is 1:1.05 ~ 5 with the ratio of the molar weight of diallylamine; The fluoro-5-chlorobenzaldehyde of 2-is 1:1.05 ~ 5 with the ratio of the molar weight of alkali; Temperature of reaction in room temperature to solvent reflux temperature; Reaction time range 5-75 hour.
4. the chloro-5-oxo-2 of a kind of 7-according to claim 1,3, the preparation method of 4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: the solvent described in step B be selected from sulfoxide type solvents, alcoholic solvent, aromatic hydrocarbon solvent and amide solvent one or more; Temperature of reaction 100 DEG C ~ 200 DEG C; Reaction time range 5-72 hour.
5. the preparation method of a kind of 7-according to claim 1 chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: the chloro-2-of the 5-described in step B (diallylamine base)-phenyl aldehyde reaction density is 0.1 ~ 2mol/L.
6. the chloro-5-oxo-2 of a kind of 7-according to claim 1,3, the preparation method of 4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: the acid described in step C be selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, methylsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid one or more; Solvent in described step C be selected from halogenated hydrocarbon solvent, alcoholic solvent, aromatic hydrocarbon solvent and esters solvent one or more; Temperature of reaction room temperature is to solvent reflux temperature; Reaction time range 1-30 hour.
7. the chloro-5-oxo-2,3,4 of a kind of 7-according to claim 1, the preparation method of 5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: the 1-allyl group-7-chloro-2,3 described in step C, 4,5-tetrahydrochysene-1H-2,5-epoxy benzene [b] azatropylidene is 1:5 ~ 50 with the ratio of the molar weight of acid; Chloro-2,3,4, the 5-tetrahydrochysene-1H-2 of described 1-allyl group-7-, 5-epoxy benzene [b] azatropylidene reaction density is 0.1 ~ 2mol/L.
8. the preparation method of a kind of 7-according to claim 1 chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: described step D comprises two kinds of methods:
(1) the chloro-5-oxo-2,3,4 of .1-allyl group-7-, there is alkene migration and obtain enamine intermediates in the dissolving of 5-tetrahydrochysene-1H-1-benzazepine, then remove allyl group through the effect of acid in a solvent under the effect of alkali, obtains the chloro-5-oxo-2 of 7-, 3,4,5-tetrahydrochysene-1H-1-benzazepine.
(2) .1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine dissolves de-allyl group under the effect of palladium catalyst, part and acid in a solvent, obtains 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine.
9. the chloro-5-oxo-2 of a kind of 7-according to claim 8,3, the preparation method of 4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: in the method (1) of described step D, alkene migration step alkali is selected from potassium tert.-butoxide, sodium tert-butoxide, sodium methylate; In described method (1), the solvent of alkene migration step is selected from sulfoxide type solvents and amide solvent; Temperature of reaction 80 DEG C ~ 120 DEG C; 0.5 ~ 6 hour reaction times.
10. the chloro-5-oxo-2 of a kind of 7-according to claim 8,3,4, the preparation method of 5-tetrahydrochysene-1H-1-benzazepine, it is characterized in that: the chloro-5-oxo-2 of alkene migration step 1-allyl group-7-in the method (1) of described step D, 3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:1.5 ~ 5 with the ratio of the molar weight of alkali; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine reaction density is 0.1 ~ 2mol/L.
The chloro-5-oxo-2 of 11. a kind of 7-according to claim 8,3, the preparation method of 4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: in the method (1) of described step D, the de-allyl group step acid of acid is selected from one or more in hydrochloric acid, sulfuric acid, formic acid, acetic acid.
The preparation method of 12. a kind of 7-according to claim 8 chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine, is characterized in that: in the method (2) of described step D, palladium catalyst is selected from Pd (PPh
3)
4, Pd (dba)
2, Pd (AcO)
2; In the method (2) of described step D, part is selected from PPh
3, DPPB; In the method (2) of described step D, acid is selected from 2-Thiosalicylic acid, formic acid, N, N-dimethyl barbituric acid, tosic acid; In described step D method (2), solvent is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane.
The chloro-5-oxo-2 of 13. a kind of 7-according to claim 8,3,4, the synthetic method of 5-tetrahydrochysene-1H-1-benzazepine, it is characterized in that: the chloro-5-oxo-2 of 1-allyl group-7-in the method (2) of described step D, 3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:0.01 ~ 1 with the ratio of the molar weight of palladium catalyst; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:0.05 ~ 1 with the ratio of the molar weight of part; Described 1-allyl group-7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine is 1:1 ~ 5 with the ratio of the molar weight of acid.
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