CN102796044A - Chemical synthesis method for 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one derivatives - Google Patents
Chemical synthesis method for 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one derivatives Download PDFInfo
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- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 19
- WWQPGNZHJFFKRW-UHFFFAOYSA-N 2,3,4,5-tetrahydro-2-benzazepin-1-one Chemical class O=C1NCCCC2=CC=CC=C12 WWQPGNZHJFFKRW-UHFFFAOYSA-N 0.000 title claims abstract 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract 5
- 150000002148 esters Chemical class 0.000 claims abstract 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052705 radium Inorganic materials 0.000 claims description 2
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 4
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- 239000005457 ice water Substances 0.000 claims 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 150000001558 benzoic acid derivatives Chemical class 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- 238000000605 extraction Methods 0.000 description 12
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 229940095102 methyl benzoate Drugs 0.000 description 10
- 229920002554 vinyl polymer Polymers 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000006872 improvement Effects 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 5
- -1 substituted-phenyl Chemical group 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- GRUPMMBRLDBTDD-UHFFFAOYSA-N 3-[2-(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile Chemical compound S1C(C)=NC(C#CC=2C=C(C=CC=2)C#N)=C1 GRUPMMBRLDBTDD-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000008707 rearrangement Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CJYXCQLOZNIMFP-UHFFFAOYSA-N azocan-2-one Chemical group O=C1CCCCCCN1 CJYXCQLOZNIMFP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 150000005171 halobenzenes Chemical group 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- SWGQITQOBPXVRC-UHFFFAOYSA-N methyl 2-bromobenzoate Chemical class COC(=O)C1=CC=CC=C1Br SWGQITQOBPXVRC-UHFFFAOYSA-N 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004418 trolamine Drugs 0.000 description 2
- BNYFDICJYCBPRW-UHFFFAOYSA-N 2-bromo-6-methoxybenzoic acid Chemical compound COC1=CC=CC(Br)=C1C(O)=O BNYFDICJYCBPRW-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000006923 Schmidt rearrangement reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种2,3,4,5-四氢-1H-2-苯并氮杂卓-1-酮衍生物的化学合成方法，本发明的合成方法是以取代的邻卤苯甲酸为原料与醇反应，得到相应的取代酸酯；与丙烯腈反应得2-（2’-氰基烯基）苯甲酸酯衍生物中间体；在醇盐的条件下闭环得2,3,4,5-四氢-1H-2-苯并氮杂卓-1-酮衍生物。本方法具有反应步骤少、收率高的优点。The invention discloses a chemical synthesis method of 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one derivatives. The synthesis method of the invention is based on substituted o-halobenzoic acid React the raw material with alcohol to obtain the corresponding substituted ester; react with acrylonitrile to obtain the intermediate of 2-(2'-cyanoalkenyl) benzoate derivatives; and obtain 2,3, 4,5-tetrahydro-1H-2-benzazepin-1-one derivatives. The method has the advantages of less reaction steps and high yield.
Description
Technical field
The present invention relates to a kind of 2,3,4, the chemical synthesis process of 5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives.
Background technology
2,3,4,5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives is one type of important medicine intermediate, and very big demand is especially arranged in schizophrenia and neurasthenic medicine, therefore the synthetic of this compounds is had broad application prospects.
For 2,3,4, the chemical chemical synthesis process of 5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives mainly contains the Schmidt rearrangement and Beckmann resets two kinds of methods at present.It is with 3 that Schmidt resets, and 4-dihydro-1 (2H)-naphthalenone and hydrazoic acid are raw material, and it is with 3 that Beckmann resets, and 4-dihydro-1 (2H)-naphthalenone and azanol are raw material.Two kinds of building-up reactions formulas are following:
These two kinds of chemical synthesis process since in rearrangement process aryl migration on kinetics greater than alkyl, make that the rearrangement principal product of reaction is 1,3; 4; 5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives, and 2,3; 4,5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives is merely by product wherein.Generally speaking, these two kinds of routes are because the restriction of the Mechanism of rearrangement of reaction own makes 2,3,4, and 5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives is difficult to become the principal product of reaction.Cause reaction yield very low, simultaneously separation difficulty.
Summary of the invention
The objective of the invention is to overcome the defective of existing two kinds of rearrangement reaction compound methods, 2,3,4 of a kind of high yield is provided, the chemical synthesis process of 5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives.
Reaction formula of the present invention is following:
The chemical chemical synthesis process of said
is:
(A), get adjacent halobenzene carboxylic acid derivatives, in alcohol, pass through SOCl
2Carry out esterification under the reflux conditions, after reaction finished, concentration of reaction solution added entry afterwards, with the MTBE extraction, merged organic phase, and used saturated NaHCO
3Solution washing, the saturated common salt water washing, dry concentrate corresponding adjacent halobenzene manthanoate;
(B), get the adjacent halobenzene manthanoate that goes on foot gained, subsequently in strong polar aprotic solvent, under the condition of organic bases, palladium and catalyzer; Carry out heating reflux reaction with vinyl cyanide, be cooled to room temperature, join in the frozen water; Use petroleum ether extraction, organic phase is used 1M hydrochloric acid, saturated ammonium chloride; The saturated salt washing, dry concentrating, the adding silica decoloration is crossed post and is got 2-(2 '-cyanic acid thiazolinyl) benzoic ether midbody;
(C), get 2-(2 '-cyanic acid thiazolinyl) the benzoic ether midbody of step gained, under the condition of organic bases, alkoxide and catalyzer, carry out ring-closure reaction, the reaction after-filtration concentrates; Be added to the water, use petroleum ether extraction, organic phase is with 1M hydrochloric acid and saturated common salt washing; Dry concentrating with MTBE (MTEB) recrystallization, gets 2; 3,4,5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives.
Further improvement of the present invention is: adjacent halobenzene carboxylic acid derivatives
, R wherein
1, R
2And R
3Independently be selected from: hydrogen, C
1-6Alkyl, C
1-6Alkoxyl group or phenyl and substituted-phenyl; X is selected from F, Cl, Br, I.
Further improvement of the present invention is: the used alcohol of esterification is methyl alcohol or ethanol.
Further improvement of the present invention is: used organic bases is triethylamine, trolamine, pyridine or piperidines among the step B.
Further improvement of the present invention is: used strong polar aprotic solvent is N or DMSO 99.8MIN. among the step B.
Further improvement of the present invention is: used catalyzer is an acid chloride among the step B.
Further improvement of the present invention is: the alkoxide described in the ring-closure reaction among the step C is a kind of in sodium methylate, potassium methylate, sodium ethylate or the potassium ethylate.
Further improvement of the present invention is: the organic bases described in the ring-closure reaction among the step C is triethylamine, trolamine, pyridine or piperidines.
Further improvement of the present invention is: the catalyzer described in the ring-closure reaction among the step C is a nickel in the radium.
The present invention compared with prior art has the following advantages: of the present invention 2,3,4, and the chemical synthesis process of 5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives, its key point is that ring closure reaction makes the oenantholactam structure form.This route of synthesis directly closes ring, does not have isomerized defective, has improved the yield of reaction, is the efficient synthetic new way that provides of this compounds.
Embodiment:
In order to deepen to understanding of the present invention, will combine embodiment that the present invention is made further detailed description below, the following example only is used to explain the present invention, does not constitute the qualification to protection domain of the present invention.
Embodiment 1:
Synthesizing of o-bromobenzoic acid methyl esters:
20.0g o-bromobenzoic acid and 200ml methyl alcohol are added in three mouthfuls of round-bottomed flasks of 500ml, add SOCl under the stirring and dissolving, room temperature
217.8g, dripping and finish reaction 8h under refluxing, concentration of reaction solution adds 500ml water, and the MTBE extraction with 500ml merges organic phase, and uses saturated NaHCO
3Solution washing, the saturated common salt water washing, dry concentrate o-bromobenzoic acid methyl esters 22.5g, yield 98%.
Synthesizing of 2-(2 '-cyanic acid vinyl) oil of Niobe:
O-bromobenzoic acid methyl esters, 8.4g vinyl cyanide, 15.9g triethylamine, 0.3g acid chloride, 170ml DMF and the 0.8g triphenylphosphine of 18.0g are added in three mouthfuls of round-bottomed flasks of 500ml mechanical stirring, heating reflux reaction 10h successively; Be cooled to room temperature, join in the frozen water, use petroleum ether extraction; Organic phase is used 1M hydrochloric acid; Saturated ammonium chloride, saturated salt washing, dry concentrating; The adding silica decoloration is crossed post and is got 12.5g faint yellow solid 2-(2 '-cyanic acid vinyl) ethyl benzoate, yield 74%.
2,3,4,5-tetrahydrochysene-1H-2-benzazepine-1-ketone synthetic:
In the there-necked flask of 500ml, add 1.1g Re-Ni under the nitrogen protection magnetic agitation, add 10.0g 2-(2 '-cyanic acid vinyl) oil of Niobe, 1.0g TEA, 0.8g sodium methylate and 190ml methyl alcohol then successively; Be heated to 80 ℃, hydrogenation reaction 10h, filtering and concentrating; Be added to the water, use petroleum ether extraction, organic phase is with 1M hydrochloric acid and saturated common salt washing; Dry concentrating with MTBE (MTEB) recrystallization, gets 5.8g 2; 3,4,5-tetrahydrochysene-1H-2-benzazepine-1-ketone.Mother liquor adds the 2.6g off-white color solid that silica decoloration is crossed post, yield 67%.100.5 ℃ of fusing point 99.5 –.
1HNMR?in?CDCl
3：
δH?=?7.96?(1H,?NH),?7.67?(1H,?H9),7.35?(1H,?H7),?7.29?(1H,?H8),?7.14?(1H,?H6),?3.12?(2H,?H3),2.87?(2H,?H5),?2.04?(2H,?H4)。
Embodiment 2
Synthesizing of 2-bromo-6-methoxyl methyl benzoate:
23.1g 2-bromo-6-methoxybenzoic acid and 200ml methyl alcohol are added in three mouthfuls of round-bottomed flasks of 500ml, add SOCl under the stirring and dissolving, room temperature
217.8g, dripping and finish reaction 8h under refluxing, concentration of reaction solution adds 500ml water, and the MTBE extraction with 500ml merges organic phase, and uses saturated NaHCO
3Solution washing, the saturated common salt water washing, dry concentrate 2-bromo-6-methoxyl methyl benzoate 23.5g, yield 96%.
Synthesizing of 2-(2 '-cyanic acid vinyl)-6-methoxyl methyl benzoate:
2-bromo-6-methoxyl methyl benzoate, 8.4g vinyl cyanide, 15.9g triethylamine, 0.3g acid chloride, 170ml DMF and the 0.8g triphenylphosphine of 20.0g are added in three mouthfuls of round-bottomed flasks of 500ml mechanical stirring, heating reflux reaction 10h successively; Be cooled to room temperature, join in the frozen water, use petroleum ether extraction; Organic phase is used 1M hydrochloric acid; Saturated ammonium chloride, saturated salt washing, dry concentrating; The adding silica decoloration is crossed post and is got 12.9g yellow solid 2-(2 '-cyanic acid vinyl)-6-methoxybenzoic acid ethyl ester, yield 69%.
2,3,4,5-tetrahydrochysene-6-methoxyl group-1H-2-benzazepine-1-ketone synthetic:
In the there-necked flask of 500ml, add 1.1g Re-Ni under the nitrogen protection magnetic agitation, add 10.0g 2-(2 '-cyanic acid vinyl)-6-methoxyl methyl benzoate, 1.0g TEA, 0.8g sodium methylate and 200ml methyl alcohol then successively, be heated to 80 ℃; Hydrogenation reaction 10h, filtering and concentrating is added to the water; Use petroleum ether extraction, organic phase is with 1M hydrochloric acid and saturated common salt washing, dry concentrating; With MTBE (MTEB) recrystallization, get 5.5g yellow crystals 2,3; 4,5-tetrahydrochysene-6-methoxyl group-1H-2-benzazepine-1-ketone, yield 62.5%.106 ℃ of fusing point 104 –.
1HNMR?in?CDCl
3：
δH?=?7.31–7.24?(2H,?H8,?H9),?6.98?(1H,?H7),?6.51?(1H,?NH),3.84?(3H,OCH3),?3.10?(2H,?H3),?2.95?(2H,?H5),?1.95?(2H,?H4)。
Embodiment 3
Synthesizing of 2-bromo-7-methoxyl methyl benzoate:
23.1g 2-bromo-7-methoxybenzoic acid and 200ml methyl alcohol are added in three mouthfuls of round-bottomed flasks of 500ml, add SOCl under the stirring and dissolving, room temperature
217.8g, dripping and finish reaction 8h under refluxing, concentration of reaction solution adds 500ml water, and the MTBE extraction with 500ml merges organic phase, and uses saturated NaHCO
3Solution washing, the saturated common salt water washing, dry concentrate 2-bromo-7-methoxyl methyl benzoate 23.2g, yield 95%.
Synthesizing of 2-(2 '-cyanic acid vinyl)-7-methoxyl methyl benzoate:
2-bromo-7-methoxyl methyl benzoate, 8.4g vinyl cyanide, 15.9g triethylamine, 0.3g acid chloride, 170ml DMF and the 0.8g triphenylphosphine of 20.0g are added in three mouthfuls of round-bottomed flasks of 500ml mechanical stirring, heating reflux reaction 10h successively; Be cooled to room temperature, join in the frozen water, use petroleum ether extraction; Organic phase is used 1M hydrochloric acid; Saturated ammonium chloride, saturated salt washing, dry concentrating; The adding silica decoloration is crossed post and is got 13.1g 2-(2 '-cyanic acid vinyl)-7-methoxybenzoic acid ethyl ester, yield 70%.
2,3,4,5-tetrahydrochysene-7-methoxyl group-1H-2-benzazepine-1-ketone synthetic:
In the there-necked flask of 500ml, add 1.1g Re-Ni under the nitrogen protection magnetic agitation, add 10.0g 2-(2 '-cyanic acid vinyl)-6-methoxyl methyl benzoate, 1.0g TEA, 0.8g sodium methylate and 200ml methyl alcohol then successively, be heated to 80 ℃; Hydrogenation reaction 10h, filtering and concentrating is added to the water; Use petroleum ether extraction, organic phase is with 1M hydrochloric acid and saturated common salt washing, dry concentrating; With MTBE (MTEB) recrystallization, get 5.7g yellow crystals 2,3; 4,5-tetrahydrochysene-6-methoxyl group-1H-2-benzazepine-1-ketone, yield 65%.157 ℃ of fusing point 155 –.
1HNMR?in?CDCl
3：
δH?=?7.68?(1H,?H9),?6.89(1H,?NH),?6.84?(1H,?H8),?6.71?(1H,?H6),?3.84?(3H,?OCH3),?3.14?(2H,?H3),?2.84?(2H,?H5),?2.01?(2H,?H4)。
Of the present invention 2,3,4, the chemical synthesis process of 5-tetrahydrochysene-1H-2-benzazepine-1-ketone derivatives, its key point is that ring closure reaction makes the oenantholactam structure form.This route of synthesis directly closes ring, does not have isomerized defective, has improved the yield of reaction, is the efficient synthetic new way that provides of this compounds.
Claims (9)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110563652A (en) * | 2018-06-06 | 2019-12-13 | 新发药业有限公司 | intermediate compound, carbamazepine and derivatives thereof, and preparation method of oxcarbazepine and derivatives thereof |
| CN110563652B (en) * | 2018-06-06 | 2021-01-22 | 新发药业有限公司 | Intermediate compound, carbamazepine and derivatives thereof, and preparation method of oxcarbazepine and derivatives thereof |
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