CN102746211B - Method for preparing substituted indole-3-methanal compound - Google Patents
Method for preparing substituted indole-3-methanal compound Download PDFInfo
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- CN102746211B CN102746211B CN201210216628.6A CN201210216628A CN102746211B CN 102746211 B CN102746211 B CN 102746211B CN 201210216628 A CN201210216628 A CN 201210216628A CN 102746211 B CN102746211 B CN 102746211B
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- 238000000034 method Methods 0.000 title claims abstract description 20
- -1 indole-3-methanal compound Chemical class 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000010992 reflux Methods 0.000 claims abstract description 14
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims abstract description 12
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 11
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000002475 indoles Chemical class 0.000 claims abstract description 10
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical class CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 claims abstract description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical class [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052698 phosphorus Chemical class 0.000 claims abstract description 7
- 239000011574 phosphorus Chemical class 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical class C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000002808 molecular sieve Substances 0.000 claims description 14
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 9
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000013019 agitation Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 4
- 238000002386 leaching Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 6
- WPGQNNNGFHRGPT-UHFFFAOYSA-N n,n-dimethyl-2-(2-nitrophenyl)ethenamine Chemical compound CN(C)C=CC1=CC=CC=C1[N+]([O-])=O WPGQNNNGFHRGPT-UHFFFAOYSA-N 0.000 abstract 2
- 239000011259 mixed solution Substances 0.000 abstract 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 11
- 238000010792 warming Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000005311 nuclear magnetism Effects 0.000 description 10
- CTNIXLBHXMSZKL-UHFFFAOYSA-N 6-chloro-1h-indole-3-carbaldehyde Chemical compound ClC1=CC=C2C(C=O)=CNC2=C1 CTNIXLBHXMSZKL-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YUAJKGBLPVLADK-UHFFFAOYSA-N 5-fluoro-1h-indole-3-carbaldehyde Chemical compound FC1=CC=C2NC=C(C=O)C2=C1 YUAJKGBLPVLADK-UHFFFAOYSA-N 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- TUWARWGEOHQXCO-UHFFFAOYSA-N 5-methoxyindole-3-carbaldehyde Chemical compound COC1=CC=C2NC=C(C=O)C2=C1 TUWARWGEOHQXCO-UHFFFAOYSA-N 0.000 description 4
- CWCYUOSLRVAKQZ-UHFFFAOYSA-N 6-fluoro-1h-indole-3-carbaldehyde Chemical compound FC1=CC=C2C(C=O)=CNC2=C1 CWCYUOSLRVAKQZ-UHFFFAOYSA-N 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 0 Cc1c(*)cccc1 Chemical compound Cc1c(*)cccc1 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005679 Batcho-Leimgruber synthesis reaction Methods 0.000 description 2
- 238000010715 Leimgruber–Batcho indole synthesis reaction Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 2
- DMCPFOBLJMLSNX-UHFFFAOYSA-N indole-3-acetonitrile Chemical compound C1=CC=C2C(CC#N)=CNC2=C1 DMCPFOBLJMLSNX-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- KMAQZIILEGKYQZ-UHFFFAOYSA-N 1-chloro-3-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC(Cl)=C1 KMAQZIILEGKYQZ-UHFFFAOYSA-N 0.000 description 1
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000006783 Fischer indole synthesis reaction Methods 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- CHIFTAQVXHNVRW-UHFFFAOYSA-N Nitrile-1H-Indole-3-carboxylic acid Natural products C1=CC=C2C(C#N)=CNC2=C1 CHIFTAQVXHNVRW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical class C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000430 tryptophan group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Abstract
The invention relates to the field of organic synthesis and medical intermediate preparation and especially relates to a method for preparing a substituted indole-3-methanal compound. The method comprises the following steps that N,N-dimethylformamidodimethylacetal or N,N-methylformamidodiethylacetal and substituted 2-nitrotoluene undergo a reflux reaction to produce beta-dimethylamino-2-nitrostyrene; beta-dimethylamino-2-nitrostyrene and a mixed solution of hydrazine and alcohol undergo a reaction to produce a substituted indole; and the substituted indole, dimethylformamide (DMF) and phosphorus oxyhalogen undergo a reaction to produce the substituted indole-3-methanal compound. Yields of all processes of the method provided by the invention are more than 90%. A total yield of the method is more than 80%.
Description
Technical field
The present invention relates to organic synthesis and medicine intermediate preparation field, be specially a kind of preparation method of substituted indole-3-carboxaldehyde compounds.
Background technology
Substituted indole-3-carboxaldehyde compounds is the intermediate that in Synthetic Organic Chemistry, a class is important, as very extensive in indole-3-formaldehyde (CAS 487-89-8), 5-fluoro indole-3-formaldehyde (CAS 2338-71-8), 6-fluoro indole-3-formaldehyde (CAS2795-41-7), 6-chloro-indole-3-formaldehyde (CAS 703-82-2), 5-methoxyindole-3-carboxaldehyde (CAS10601-19-1), purposes: tryptamines class and the derivative thereof for the synthesis of some with pharmaceutical activity; Synthesize some tryptophane compounds; Synthesize some plant-growth regulator, as indole-3-acetonitrile and indole-3-acetic acid compounds; Synthesize and various there is bioactive medicine intermediate.Therefore the synthetic method of substituted indole-3-carboxaldehyde is the important topic that people study always.
About the synthesis of indole ring, bibliographical information mainly contains 3 kinds of methods: (1) Fischer indole synthesis; (2) Reisert indole synthesis; (3) Leimgruber-Batcho indole synthesis.2 of indole ring synthesized by first two method are connected with a carboxyl, and the carboxyl on 2 will be sloughed the very high temperature of needs (general more than 200 DEG C), more difficult in operation, and give certain difficulty to band in industrialization.
Summary of the invention
The present invention aims to provide a kind of preparation method of substituted indole-3-carboxaldehyde compounds.
The present invention selects Leimgruber-Batcho indole synthesis.This synthetic method with the Ortho Nitro Toluene compounds of various replacement for raw material, utilize the strong sucting electronic effect of nitro, methyl on nitro ortho position is made to have certain acidity, can with DMFDMA(N, dinethylformamide dimethylacetal) or DMFDEA(N, dinethylformamide dimethyl ethyl acetal) condensation in polar solvent, generate the β-dimethylin-2-nitrostyrolene replaced; Products therefrom reductive agent reduces and obtains relevant indole product.Introduce the method for aldehyde radical about indoles 3, this patent mainly adopts Vilsmeier method.The method is: be dissolved in polar solvent by related indoles compound and DMF according to certain ratio, drips three oxyhalogen phosphorus under condition of ice bath.Be warming up to 90 DEG C after dropwising, react 4 hours, namely reacted.
Whole reaction process is divided into three steps, and reaction expression is as follows:
The method of substituted indole-3-carboxaldehyde compounds shown in preparation formula (I), wherein R is hydrogen, or 5 or 6 halogens or C1 ~ C4 alkoxyl group replaced; Step comprises:
(1) N, dinethylformamide dimethylacetal (DMFDMA) or N, replacement 2-nitrotoluene and the organic solvent I of dinethylformamide diethyl acetal (DMFDEA) and formula (II) structure mix, back flow reaction 4 ~ 8 hours, R in formula (II) is hydrogen, or 4 or 5 halogens or C1 ~ C4 alkoxyl group replaced;
Remove organic solvent I, washing obtains the β-dimethylin-2-nitrostyrolene with formula (III) structure, and the R in formula (III) is hydrogen, or 4 or 5 halogens or C1 ~ C4 alkoxyl group replaced;
DMF dimethylacetal (DMFDMA) or DMF diethyl acetal (DMFDEA) are 4 ~ 6:1 with the mol ratio of replacement 2-nitrotoluene, are preferably 4.8 ~ 5.2; Organic solvent I is polar solvent, is preferably acetonitrile or dimethyl formamide DMF; Especially be acetonitrile, reflux temperature is 80 ~ 95 DEG C;
(2) formula (III) compound joins in the mixing solutions of hydrazine and methyl alcohol, and the mol ratio of formula (III) compound and hydrazine is 1:6 ~ 12; 45 ~ 60 DEG C are reacted 6 ~ 12 hours, and remove the substituted indole that solvent obtains formula (IV), the R in formula (IV) is hydrogen, or 5 or 6 halogens or C1 ~ C4 alkoxyl group replaced;
In the mixing solutions of described hydrazine and methyl alcohol or ethanol, the content of hydrazine is 8wt% ~ 15wt%;
(3) substituted indole of step (2) is dissolved in organic solvent II I, maintains the temperature at less than 15 DEG C, is added drop-wise in the organic solvent II I containing dimethylformamide DMF and molecular sieve and three oxyhalogen phosphorus, continues to react 3 ~ 6 hours at 10 ~ 35 DEG C; In reaction solution, add potassium hydroxide or sodium hydroxide solution (concentration 2 ~ 8mol/L) again, back flow reaction 10 ~ 15 hours, cooled and filtered, under agitation filtrate is poured in-5 ~ 0 DEG C of frozen water, cross leaching precipitation; Organic solvent II I is polar solvent, and being preferably acetonitrile or dimethyl formamide, is especially acetonitrile;
Molecular sieve is preferably 4A molecular sieve;
Substituted indole is 1mol: 3 ~ 6mol: 1.5 ~ 3mol: 50 ~ 100g:4 ~ 12mol with dimethylformamide, three oxyhalogen phosphorus, molecular sieve and potassium hydroxide or sodium hydroxide concentration ratio, is preferably 1mol:3.8 ~ 4.5mol:1.5 ~ 2.5mol:70 ~ 95g:9.5 ~ 11mol;
Obtain target product substituted indole-3-carboxaldehyde compounds after the precipitation recrystallization of step (3), preferably use petrol ether/ethyl acetate system recrystallization.
This patent has carried out corresponding improvement to traditional method, makes the yield of each step all reach more than 90%, overall yield more than 80%.Concrete improvement is as follows:
(1) the first step reaction, have employed the method for acetonitrile as solvent refluxing, temperature controls at about 80 DEG C, changes the method needing control temperature 130 DEG C ~ 140 DEG C over, reduces energy waste and environmental protection pressure; Simultaneously by controlling the ratio of Ortho Nitro Toluene compounds and DMFDMA and DMFDEA replaced, the productive rate of post-reaction treatment recrystallization is made greatly to bring up to more than 95%.
(2) second step reaction, have employed the mixing solutions of methyl alcohol and hydrazine as reductive agent, changes and adopts iron powder/acetic acid as the traditional method of reductive agent in the past.Both decreased the generation of side reaction, and additionally reduced the absorption of solid opposing product, improve reaction yield.
(3) three-step reactions, add 4A molecular sieve and dewater, and adopt acetonitrile as solvent, make yield reach more than 90%.
Accompanying drawing explanation
Fig. 1 is the nuclear-magnetism figure of indoles-3 formaldehyde
Fig. 2 is the nuclear-magnetism figure of 5-fluoro indole-3 formaldehyde
Fig. 3 is the nuclear-magnetism figure of 6-chloro-indole-3-formaldehyde
Fig. 4 is the nuclear-magnetism figure of 5-methoxyindole-3-carboxaldehyde
Fig. 5 is the nuclear-magnetism figure of 6-fluoro indole-3-formaldehyde
Embodiment
The synthesis of embodiment 1 indoles-3 formaldehyde
Join in 80ml acetonitrile by 5.6 grams of 2-nitrotoluenes (compound 1a, 0.041mol), 24.3 grams of DMFDMA (0.205mol), temperature of reaction rises to 85 DEG C ~ 95 DEG C, refluxes 5 hours.Cooled by reaction solution, solvent is spin-dried for, and washs to obtain 7.7 grams of crude material 2a (0.0402mol, yield 98.0%) through water and micro ethanol.
Gained compound 2a is joined 130ml containing in the methyl alcohol (content 0.4mol, the 10eq of hydrazine) of 10wt% hydrazine, and be warming up to 50 DEG C, react 8 hours, be cooled to room temperature.Be spin-dried for solvent and obtain product 3a (4.5 grams, 0.0385mol, yield 96.1%), be dissolved in 20ml acetonitrile.
By 11.2 grams of DMF(0.154mol, 4eq) and 3 grams of 4A molecular sieves join in 100ml acetonitrile, and reaction is cooled to 0 DEG C ~ 5 DEG C, under condition of ice bath, slowly drips 11.6 grams of POCl
3(0.0769mol, 2eq).Drip and finish, continue stirring 30 minutes, drip the acetonitrile solution 20ml containing 3a compound in less than 15 DEG C, after dropwising, reaction solution is warming up to room temperature (25 DEG C), reacts 4 hours.
100ml potassium hydroxide solution (3.8mol/L, 10eq) is dropped in reaction solution, after dropwising, by reaction solution reflux 12 hours, is cooled to room temperature.Filter and filtrate is slowly poured in the frozen water of 0 DEG C under agitation, separating out faint yellow solid.Filter, filter cake petrol ether/ethyl acetate system recrystallization obtains target product 5.1 grams, nuclear-magnetism figure as shown in Figure 1, yield 92.5%.
Overall yield of reaction is 87.1%.
The synthesis of embodiment 2 5-fluoro indole-3-formaldehyde
Join in 80ml acetonitrile by 7.2 grams of 5-fluorine-2-nitro methylbenzenes (compound 1b, 0.046mol), 27.4 grams of DMFDMA (0.232mol), temperature of reaction rises to 85 DEG C ~ 95 DEG C, refluxes 5 hours.Reaction cooled, solvent is spin-dried for, and washs to obtain 9.3 grams of crude material 2b (0.0443mol, yield 96.2%) through water and micro ethanol.
Gained intermediate 2b is joined 147ml containing in the methyl alcohol (content 0.45mol, the 10eq of hydrazine) of 10wt% hydrazine, and be warming up to 50 DEG C, react 8 hours, be cooled to room temperature.Be spin-dried for solvent and obtain 5.7 grams of product 3b (0.0424mol, yield 95.8%), be dissolved in 20ml acetonitrile.
By 12.3 grams of DMF(0.168mol, 4eq) and 3.3 grams of 4A molecular sieves join in 100ml acetonitrile, and reaction is cooled to 0 DEG C ~ 5 DEG C, under condition of ice bath, slowly drips 12.8 grams of POCl
3(0.084mol).Drip and finish, continue stirring 30 minutes, drip the acetonitrile solution 20ml containing 3b in less than 15 DEG C, after dropwising, reaction solution is warming up to room temperature (25 DEG C), reacts 4 hours.Be that 3.8mol/L potassium hydroxide solution (, 10eq) drops in reaction solution by 112ml concentration, after dropwising, by reaction solution reflux 12 hours, be cooled to room temperature.Filter and filtrate is slowly poured in frozen water under agitation, separating out faint yellow solid.Filter, filter cake petrol ether/ethyl acetate system recrystallization obtains target product 6.3 grams, nuclear-magnetism figure as shown in Figure 2, yield 92.2%.
Overall yield of reaction is 84.9%.
The synthesis of embodiment 3 6-chloro-indole-3-formaldehyde
Join in acetonitrile (80ml) by 6.6 grams of 4-Chloro-2-Nitrobenzenes (compound 1c, 0.039mol), 23.0 grams of DMFDMA (0.193mol, 5eq), temperature of reaction rises to 85 DEG C ~ 95 DEG C, refluxes 5 hours.Reaction cooled, solvent is spin-dried for, and washs to obtain 8.4 grams of crude material 2c (0.0369mol, yield 94.6%) through water and micro ethanol.
Gained intermediate 2c is joined 118ml containing in the methyl alcohol (content 0.36mol, the 10eq of hydrazine) of 10wt% hydrazine, and be warming up to 50 DEG C, react 8 hours, be cooled to room temperature.Be spin-dried for solvent and obtain 5.4 grams of product 3c (0.0355mol, yield 96.3%), be dissolved in 20ml acetonitrile.
By 10.4 grams of DMF(0.142mol, 4eq) and 3 grams of 4A molecular sieves join in acetonitrile (100ml), and reaction is cooled to 0 DEG C ~ 5 DEG C, under condition of ice bath, slowly drips 10.8 grams of POCl
3(0.084mol, 2eq).Drip and finish, continue stirring 30 minutes, drip the acetonitrile solution 20ml containing 3c in less than 15 DEG C, after dropwising, reaction solution is warming up to room temperature (25 DEG C), reacts 4 hours.95ml potassium hydroxide solution (3.8mol/L, 10eq) is dropped in reaction solution, after dropwising, by reaction solution reflux 12 hours, is cooled to room temperature.Filter and filtrate is slowly poured in frozen water under agitation, separating out faint yellow solid.Filter, filter cake petrol ether/ethyl acetate system recrystallization obtains target product 5.8 grams, nuclear-magnetism figure as shown in Figure 3, yield 90.5%.
Overall yield of reaction is 82.4%.
The synthesis of embodiment 4 5-methoxyindole-3-carboxaldehyde
Join in 80ml acetonitrile by 5.8 grams of 5-methoxyl group-2-nitrotoluenes (compound 1d, 0.035mol), 20.7 grams of DMFDMA (0.174mol, 5eq), temperature of reaction rises to 85 DEG C ~ 95 DEG C, refluxes 5 hours.Reaction cooled, solvent is spin-dried for, and washs to obtain crude material 8.6 grams of 2d (0.0335mol, yield 95.7%) through water and micro ethanol.
Gained intermediate 2d is joined 107ml containing in the methyl alcohol (content 0.33mol, the 10eq of hydrazine) of 10wt% hydrazine, and be warming up to 50 DEG C, react 8 hours, be cooled to room temperature.Be spin-dried for solvent and obtain 5.9 grams of product 3d (0.0324mol, yield 96.6%), be dissolved in 20ml acetonitrile.
By 9.4 grams of DMF(0.129mol, 4eq) and 3 grams of 4A molecular sieves join in 100ml acetonitrile, and reaction is cooled to 0 DEG C ~ 5 DEG C, under condition of ice bath, slowly drips 9.8 grams of POCl
3(0.065mol, 2eq).Drip and finish, continue stirring 30 minutes, drip the acetonitrile solution 20ml containing 3d in less than 15 DEG C, after dropwising, reaction solution is warming up to room temperature (25 DEG C), reacts 4 hours.85ml potassium hydroxide solution (3.8mol/L, 10eq) is dropped in reaction solution, after dropwising, by reaction solution reflux 12 hours, is cooled to room temperature.Filter and filtrate is slowly poured in frozen water under agitation, separating out faint yellow solid.Filter, filter cake petrol ether/ethyl acetate system recrystallization obtains target product 6.2 grams, yield 91.6%, and nuclear-magnetism figure as shown in Figure 4.Overall yield of reaction is 84.6%.
The synthesis of embodiment 5 6-fluoro indole-3-formaldehyde
Join in acetonitrile (80ml) by 6.8 grams of 4-fluorine-2-nitro methylbenzenes (0.044mol), 26.1 grams of DMFDMA (0.219mol, 5eq), temperature of reaction rises to 85 DEG C ~ 95 DEG C, refluxes 5 hours.Reaction cooled, solvent is spin-dried for, and washs to obtain 8.9 grams of crude material 2e (0.0423mol, yield 96.2%) through water and micro ethanol.
Gained intermediate 2e is joined 135ml containing in the methyl alcohol (content 0.42mol, the 10eq of hydrazine) of 10wt% hydrazine, and be warming up to 50 DEG C, react 8 hours, be cooled to room temperature.Be spin-dried for solvent and obtain 5.4 grams of product 3e (0.0403mol, yield 95.2%), be dissolved in 20ml acetonitrile.
By 11.8 grams of DMF(0.161mol, 4eq) and 3 grams of 4A molecular sieves join in 100ml acetonitrile, and reaction is cooled to 0 DEG C ~ 5 DEG C, under condition of ice bath, slowly drips 12.2 grams of POCl
3(0.08mol, 2eq).Drip and finish, continue stirring 30 minutes, drip the acetonitrile solution of 20ml containing 3e in less than 15 DEG C, after dropwising, reaction solution is warming up to room temperature (25 DEG C), reacts 4 hours.107ml potassium hydroxide solution (3.8mol/L, 10eq) is dropped in reaction solution, after dropwising, by reaction solution reflux 12 hours, is cooled to room temperature.Filter and filtrate is slowly poured in frozen water under agitation, separating out faint yellow solid.Filter, filter cake petrol ether/ethyl acetate system recrystallization obtains target product 6.0 grams, nuclear-magnetism figure as shown in Figure 5, yield 91.3%.Overall yield of reaction is 83.6%.
Embodiment 6
Embodiment 1 ~ 5 product is used to synthesize further for raw material:
(1) indole-3-formaldehyde of embodiment 1:
According to US2011/294781A1,2011 record, and the compd A 1 that the indole-3-formaldehyde (embodiment 1) as one of starting material generates has and acts on immune pharmaceutical activity.
(2) synthesis of the 5-fluoro indole-3-formaldehyde of embodiment 2
According to WO2006/62465A1,2006 record, and generate compd A 2 have the pharmaceutical activity acting on cardiovascular disorder by 5-fluoro indole-3-formaldehyde.
(3) the 6-chloro-indole-3-formaldehyde of embodiment 3
Record according to US2011/313167A1, by 6-chloro-indole-3-formaldehyde through Ugi Reactive Synthesis compound A-13, there is good antitumour activity.
(4) the 5-methoxyindole-3-carboxaldehyde of embodiment 4
According to WO2008/55994A1, the record of 2008, by 5-methoxyl group-3-formaldehyde synthetic compound A4, has the activity for the treatment of enteron aisle relative disease.
(5) the 6-fluoro indole-3-formaldehyde of embodiment 5
The compound A-45 synthesized by the fluoro-3-formaldehyde of 6-is a kind of intermediate synthesizing multi-medicament.
Claims (4)
1. prepare the method for substituted indole-3-carboxaldehyde compounds for one kind, described substituted indole-3-carboxaldehyde compounds structural formula is such as formula (I), and wherein R is hydrogen, or 5 or 6 halogens or C1 ~ C4 alkoxyl group replaced, it is characterized in that, step comprises:
(1) N, dinethylformamide dimethylacetal or N, replacement 2-nitrotoluene and the organic solvent I of dinethylformamide diethyl acetal and formula (II) structure mix, back flow reaction 4 ~ 8 hours, R in formula (II) is hydrogen, or 4 or 5 halogens or C1 ~ C4 alkoxyl group replaced;
Remove organic solvent I, washing obtains the β-piperidyl-2-nitrostyrolene with formula (III) structure, and the R in formula (III) is hydrogen, or 4 or 5 halogens or C1 ~ C4 alkoxyl group replaced;
DMF dimethylacetal or DMF diethyl acetal are 4 ~ 6:1 with the mol ratio of replacement 2-nitrotoluene; Organic solvent I is acetonitrile, and reflux temperature is 80 ~ 95 DEG C;
(2) formula (III) compound joins in the mixing solutions of hydrazine and methyl alcohol or ethanol, and the mol ratio of formula (III) compound and hydrazine is 1:6 ~ 12; 45 ~ 60 DEG C are reacted 6 ~ 12 hours, and remove the substituted indole that solvent obtains formula (IV), the R in formula (IV) is hydrogen, or 5 or 6 halogens or C1 ~ C4 alkoxyl group replaced;
In the mixing solutions of described hydrazine and methyl alcohol or ethanol, the content of hydrazine is 8wt% ~ 15wt%;
(3) substituted indole of step (2) is dissolved in organic solvent II I, maintains the temperature at less than 15 DEG C, is added drop-wise in the organic solvent II I containing dimethylformamide and molecular sieve and three oxyhalogen phosphorus, continues to react 3 ~ 6 hours at 10 ~ 35 DEG C; Potassium hydroxide or sodium hydroxide solution is added again in reaction solution, back flow reaction 10 ~ 15 hours, cooled and filtered, under agitation filtrate is poured in-5 ~ 0 DEG C of frozen water, cross leaching precipitation, obtain target product substituted indole-3-carboxaldehyde compounds with after petrol ether/ethyl acetate system recrystallization precipitation;
Organic solvent II I is acetonitrile;
Substituted indole is 1mol:3 ~ 6mol:1.5 ~ 3mol:50 ~ 100g:4 ~ 12mol with dimethylformamide, three oxyhalogen phosphorus, molecular sieve and potassium hydroxide or sodium hydroxide concentration ratio.
2. a kind of method preparing substituted indole-3-carboxaldehyde compounds described in claim 1, it is characterized in that, in step (1), N, dinethylformamide dimethylacetal or DMF diethyl acetal are 4.8 ~ 5.2 with the mol ratio of replacement 2-nitrotoluene.
3. a kind of method preparing substituted indole-3-carboxaldehyde compounds described in claim 1, is characterized in that, step (3) Middle molecule sieve is 4A molecular sieve.
4. a kind of method preparing substituted indole-3-carboxaldehyde compounds described in claim 1, it is characterized in that, in step (3), substituted indole is 1mol:3.8 ~ 4.5mol:1.5 ~ 2.5mol:70 ~ 95g:9.5 ~ 11mol with dimethylformamide, three oxyhalogen phosphorus, molecular sieve and potassium hydroxide or sodium hydroxide concentration ratio; Potassium hydroxide or concentration of sodium hydroxide solution are 2 ~ 8mol/L.
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| CN102924359B (en) * | 2012-10-30 | 2015-03-11 | 中国科学院烟台海岸带研究所 | Method for synthesizing substituted indole compounds through one-pot method |
| CN103351327A (en) * | 2013-07-27 | 2013-10-16 | 上海泰坦科技股份有限公司 | Preparation method of fluorate indolal |
| CN104130174A (en) * | 2014-07-30 | 2014-11-05 | 天津市斯芬克司药物研发有限公司 | Indazole derivative and preparation method thereof |
| CN108329249B (en) * | 2018-02-09 | 2020-11-24 | 盐城锦明药业有限公司 | Method for synthesizing indole-3-formaldehyde compound |
| CN114573496B (en) * | 2022-04-08 | 2023-11-07 | 贵州大学 | Preparation method of 4-chloroindole-3-acetic acid |
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