CN111454192A - Efficient synthesis process of medical intermediate 5-bromoindole - Google Patents
Efficient synthesis process of medical intermediate 5-bromoindole Download PDFInfo
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- CN111454192A CN111454192A CN201910057181.4A CN201910057181A CN111454192A CN 111454192 A CN111454192 A CN 111454192A CN 201910057181 A CN201910057181 A CN 201910057181A CN 111454192 A CN111454192 A CN 111454192A
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- bromoindole
- acylindoline
- indoline
- bromoindoline
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- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000008569 process Effects 0.000 title claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 19
- -1 indole compound Chemical class 0.000 claims abstract description 49
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 46
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 239000002994 raw material Substances 0.000 claims abstract description 29
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 24
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 230000010933 acylation Effects 0.000 claims abstract description 7
- 238000005917 acylation reaction Methods 0.000 claims abstract description 7
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- 230000020176 deacylation Effects 0.000 claims abstract description 6
- 238000005947 deacylation reaction Methods 0.000 claims abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000007791 liquid phase Substances 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 114
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 238000001035 drying Methods 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- 238000005406 washing Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical group BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000001263 acyl chlorides Chemical class 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical group CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 238000006386 neutralization reaction Methods 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000012047 saturated solution Substances 0.000 claims description 6
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
- 229940045803 cuprous chloride Drugs 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- 150000002475 indoles Chemical class 0.000 claims description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 4
- QEDCHCLHHGGYBT-UHFFFAOYSA-N 5-bromo-2,3-dihydro-1h-indole Chemical compound BrC1=CC=C2NCCC2=C1 QEDCHCLHHGGYBT-UHFFFAOYSA-N 0.000 claims description 3
- 238000007171 acid catalysis Methods 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 150000002476 indolines Chemical class 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 5
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 2
- 230000021615 conjugation Effects 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 7
- 230000001276 controlling effect Effects 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- UVPIVHVTWLIDNY-UHFFFAOYSA-N 5-(1h-imidazol-2-yl)-1h-indole Chemical class C1=CNC(C=2C=C3C=CNC3=CC=2)=N1 UVPIVHVTWLIDNY-UHFFFAOYSA-N 0.000 description 1
- UNGXXMDQBJHCMQ-UHFFFAOYSA-N 5-cyanoindole-1-carboxylic acid Chemical compound N#CC1=CC=C2N(C(=O)O)C=CC2=C1 UNGXXMDQBJHCMQ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 210000004560 pineal gland Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- RPZBRGFNBNQSOP-UHFFFAOYSA-N vilazodone hydrochloride Chemical compound Cl.C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 RPZBRGFNBNQSOP-UHFFFAOYSA-N 0.000 description 1
- 229960003381 vilazodone hydrochloride Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a high-efficiency synthesis process of a medical intermediate 5-bromoindole, wherein an indole compound is used as a raw material, and the five-membered ring conjugation of the indole is destroyed through low-pressure liquid-phase hydrogenation to obtain an indoline compound; reacting the indoline compound with an acylation reagent to protect nitrogen to obtain an N-acyl indoline compound; bromizing the N-acyl indoline compound to obtain a 5-bromo-N-acyl indoline compound; the 5-bromo-N-acylindoline compound is protected by deacylation to obtain a 5-bromoindoline compound; the 5-bromoindoline compound is subjected to oxidative dehydrogenation by oxygen or air under the action of a cuprous catalyst and a nitrogen oxide to obtain the target compound 5-bromoindole. The steps involved in the invention are convenient to operate, the conditions are mild, and the environmental pollution is reduced; the final product has high yield, high purity and low energy consumption.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a high-efficiency synthesis process of a medical intermediate 5-bromoindole.
Background
5-bromoindole with the molecular formula C8H6BrN is an important pharmaceutical chemical intermediate. Indole compounds widely exist in nature, and many indoles containing substituent groups on benzene rings have physiological activity. The 5-substituted indole compound is an intermediate which is widely applied to medicaments for preventing and treating cardiovascular diseases, neurological diseases, tumors, enhancing immunity and the like; for example, the pineal gland element is also called brain platinum, is mainly prepared from 5-methoxyindole, and is directly acted on hypothalamus, thereby having various physiological functions of promoting sleep, regulating endocrine, enhancing immunity and the like; 5-cyano-substituted indoles for the production of vasoconstrictors for the treatment of migraineIs also an important intermediate of antidepressant drug vilazodone hydrochloride; 5-furan or thiophene substituted tryptamines useful as 5-HTIDAgonists of the receptor; 5-Imidazolyl indoles are thrombin inhibitors and are obtained by reacting 5-cyanoindole-1-carboxylic acid with 4-phenylpiperidine. The 5-bromoindole is an important intermediate for synthesizing compounds such as 5-cyanoindole and 5-methoxyindole, and therefore, the 5-bromoindole is necessary for the research and development of a synthetic process of the 5-bromoindole.
At present, the preparation of 5-bromoindole mainly adopts a process of sulfonating indole firstly and then brominating indole, i.e. adding indole and sodium sulfite, then protecting 1-position of indole with acetyl, then brominating, and finally removing sodium sulfinate and acetyl. However, the production process has the defects of large solvent consumption, high cost, environmental friendliness and the like, and the product obtained by the production process has high sulfur content, dark color and poor purity.
Therefore, the development of an efficient synthesis process of a medical intermediate 5-bromoindole, which is environment-friendly, easily available in raw materials, high in yield, good in purity, low in cost and suitable for industrial production, is urgently needed.
Disclosure of Invention
In order to solve the problems in the background art, the invention provides an efficient synthesis process of a medical intermediate 5-bromoindole, which has the advantages of simple preparation process, easily available raw materials, high yield, good purity and low energy consumption, and ensures the product quality.
In order to achieve the purpose, the invention adopts the following technical scheme:
a high-efficiency synthesis process of a medical intermediate 5-bromoindole comprises the following steps:
s1: indole compounds are used as raw materials, and the conjugate of indole five-membered rings is destroyed through low-pressure liquid-phase hydrogenation to obtain indoline compounds;
s2: reacting the indoline compound prepared in the step S1 with an acylation reagent to protect nitrogen to obtain an N-acyl indoline compound;
s3: brominating the N-acylindoline compound prepared in the step S2 to obtain a 5-bromo-N-acylindoline compound;
s4: performing deacylation protection on the 5-bromo-N-acylindoline compound prepared in the step S3 to obtain a 5-bromoindoline compound;
s5: carrying out oxidative dehydrogenation on the 5-bromoindoline compound prepared in the step S4 by using oxygen or air under the action of a cuprous catalyst and a nitrogen oxide to obtain a target compound 5-bromoindole;
wherein, the acylating reagent in the step S2 is acid anhydride, acyl chloride or carboxylic acid; in the step S3, the bromization reagent is dibromohydantoin; in the step S4, deacylation is carried out under the action of acid catalysis or alkali hydrolysis, wherein acid is hydrochloric acid or sulfuric acid, and alkali is sodium hydroxide or potassium carbonate; in the step S5, the cuprous catalyst is cuprous chloride or cuprous bromide, and the nitrogen oxide is 2,2,6, 6-tetramethylpiperidine-N-oxide.
Further, the method comprises the following specific steps:
s1: adding indole, a metal catalyst platinum carbon and an organic solvent toluene into a high-pressure reaction kettle, introducing nitrogen to fully displace the air in the high-pressure reaction kettle, introducing hydrogen, controlling the pressure of the hydrogen in the reaction kettle to be 1.5-2Mpa and the temperature to be 90-130 ℃, reacting for a period of time to obtain a hydrogenation mixture, and filtering and distilling under reduced pressure to obtain an indoline compound;
s2: dissolving the indoline compound prepared in the step S1 in dichloromethane, then dropwise adding an acylation reagent, reacting at 0-20 ℃ until the raw material disappears, and then concentrating, extracting, concentrating, crystallizing and drying to obtain an N-acyl indoline compound;
s3: dissolving the N-acylindoline compound prepared in the step S2 in dichloromethane, adding a bromization reagent, reacting at 0-10 ℃ until the raw material disappears, washing by using a saturated solution of sodium bisulfite, washing by using water, concentrating, crystallizing and drying to obtain a 5-bromo-N-acylindoline compound;
s4: dissolving the 5-bromo-N-acylindoline compound prepared in the step S3 in methanol, adding a sodium hydroxide solution, heating to 40-60 ℃ for reaction until the raw materials disappear, adding an acid solution for neutralization, standing for layering, recovering an upper organic solution, concentrating, extracting with dichloromethane, concentrating, crystallizing, and drying to obtain a product 5-bromoindoline compound;
s5: and (4) dissolving the 5-bromoindoline compound prepared in the step (S4) in toluene, adding a cuprous catalyst and a nitrogen oxide, introducing air, reacting at 60-100 ℃ until the raw materials disappear, filtering to remove solids, washing the obtained organic layer with water, washing with saturated brine, concentrating, crystallizing, filtering, and drying to obtain the 5-bromoindoline.
Further, the mol ratio of the indole to the platinum carbon to the toluene in the step 1 is 1 (0.1-0.6): (2-10).
Further, in the step S2, the mol ratio of the indoline compound, the dichloromethane and the acylating agent is 1: (10-20): (1-1.5).
Further, in the step S3, the molar ratio of the N-acylindoline compound, the dichloromethane and the brominating agent is 1: (10-30): (0.5-1).
Further, in the step S4, the molar ratio of the 5-bromo-N-acylindoline compound to the methanol to the sodium hydroxide solution is 1: (15-30): (0.8-1.2).
Further, in the step S5, the molar ratio of the 5-bromoindoline compound, the toluene, the cuprous catalyst and the nitrogen oxide is 1: (5-10): (0.01-0.05): (0.01-0.05).
Compared with the prior art, the invention has the following beneficial effects:
the method has the advantages that the steps are convenient to operate, the conditions are mild, and the simple and easily-obtained solvents such as methanol, toluene, dichloromethane and the like are used as reaction systems, so that the requirements on equipment in industrial production are reduced, and the environmental pollution is reduced; the final product has high yield, high purity and low energy consumption.
Drawings
FIG. 1 is a flow chart of a high-efficiency synthesis process of a medical intermediate 5-bromoindole in the invention.
Detailed Description
The invention is described in further detail below with reference to specific embodiments and with reference to the following drawings.
The high-efficiency synthesis process of the medical intermediate 5-bromoindole comprises the following specific steps:
s1: adding indole, a metal catalyst platinum carbon and an organic solvent toluene into a high-pressure reaction kettle, introducing nitrogen to fully displace the air in the high-pressure reaction kettle, introducing hydrogen, controlling the pressure of the hydrogen in the reaction kettle to be 1.5-2Mpa and the temperature to be 90-130 ℃, reacting for a period of time to obtain a hydrogenated mixture, and filtering and distilling under reduced pressure to obtain an indoline compound for destroying the conjugation of the five-membered ring of the indole; wherein the mol ratio of indole to platinum carbon to toluene is 1 (0.1-0.6): (2-10).
S2: dissolving the indoline compound prepared in the step S1 in dichloromethane, then dropwise adding an acylation reagent, reacting at 0-20 ℃ until the raw material disappears, and then concentrating, extracting, concentrating, crystallizing and drying to obtain an N-acyl indoline compound; wherein the mol ratio of the indoline compound to the dichloromethane to the acylation agent is 1: (10-20): (1-1.5).
S3: dissolving the N-acylindoline compound prepared in the step S2 in dichloromethane, adding a bromization reagent, reacting at 0-10 ℃ until the raw material disappears, washing by using a saturated solution of sodium bisulfite, washing by using water, concentrating, crystallizing and drying to obtain a 5-bromo-N-acylindoline compound; wherein the mol ratio of the N-acylindoline compound to the dichloromethane to the brominating agent is 1: (10-30): (0.5-1).
S4: dissolving the 5-bromo-N-acylindoline compound prepared in the step S3 in methanol, adding a sodium hydroxide solution, heating to 40-60 ℃ for reaction until the raw materials disappear, adding an acid solution for neutralization, standing for layering, recovering an upper organic solution, concentrating, extracting with dichloromethane, concentrating, crystallizing, and drying to obtain a product 5-bromoindoline compound; wherein the molar ratio of the 5-bromo-N-acylindoline compound to the methanol to the sodium hydroxide solution is 1: (15-30): (0.8-1.2).
S5: dissolving the 5-bromoindoline compound prepared in the step S4 in toluene, adding a cuprous catalyst and a nitrogen oxide into the toluene, introducing air, carrying out oxidative dehydrogenation reaction at 60-100 ℃ until the raw materials disappear, filtering to remove solids, washing an organic layer with water, washing with saturated salt water, concentrating, crystallizing, filtering and drying to obtain 5-bromoindoline; wherein the mol ratio of the 5-bromoindoline compound to the toluene to the cuprous catalyst to the nitrogen oxide is 1: (5-10): (0.01-0.05): (0.01-0.05).
Wherein, the acylating reagent in the step S2 is acid anhydride, acyl chloride or carboxylic acid; in the step S3, the bromization reagent is dibromohydantoin; in the step S4, deacylation is carried out under the action of acid catalysis or alkali hydrolysis, wherein acid is hydrochloric acid or sulfuric acid, and alkali is sodium hydroxide or potassium carbonate; in the step S5, the cuprous catalyst is cuprous chloride or cuprous bromide, and the nitrogen oxide is 2,2,6, 6-tetramethylpiperidine-N-oxide.
Example 1
A high-efficiency synthesis process of a medical intermediate 5-bromoindole comprises the following specific steps:
s1: adding indole, platinum carbon and toluene into a high-pressure reaction kettle, wherein the molar ratio of the indole to the platinum carbon to the toluene is 1:0.3:6, introducing nitrogen to fully displace air in the high-pressure reaction kettle, introducing hydrogen, controlling the pressure of the hydrogen in the reaction kettle to be 1.5-2Mpa and the temperature to be 90-130 ℃, reacting for a period of time to obtain a hydrogenated mixture, and filtering and distilling under reduced pressure to obtain the indoline compound capable of destroying the indole five-membered ring conjugation.
S2: dissolving the indoline compound prepared in the step S1 in dichloromethane, then dropwise adding acid anhydride into the dichloromethane, wherein the molar ratio of the indoline compound to the dichloromethane to the acyl chloride is 1:16:1, reacting at 0-20 ℃ after dropwise adding until the raw materials disappear, and then concentrating, extracting, concentrating, crystallizing and drying the mixture to obtain the N-acyl indoline compound.
S3: dissolving the N-acyl indoline compound prepared in the step S2 in dichloromethane, adding dibromohydantoin into the dichloromethane, wherein the molar ratio of the N-acyl indoline compound to the dichloromethane to the dibromohydantoin is 1:18:0.8, reacting at 0-10 ℃ until the raw materials disappear, washing with a saturated solution of sodium bisulfite, washing with water, concentrating, crystallizing, and drying to obtain the 5-bromo-N-acyl indoline compound.
S4: dissolving the 5-bromo-N-acylindoline compound prepared in the step S3 in methanol, adding a sodium hydroxide solution into the methanol, wherein the molar ratio of the 5-bromo-N-acylindoline compound to the methanol to the sodium hydroxide solution is 1:21:1, heating to 40-60 ℃, reacting until the raw materials disappear, then adding an acid solution for neutralization, standing for layering, recovering an upper organic solution, concentrating, extracting with dichloromethane, concentrating, crystallizing, and drying to obtain the product 5-bromoindoline compound.
S5: dissolving the 5-bromoindoline compound prepared in the step S4 in toluene, adding cuprous chloride and 2,2,6, 6-tetramethylpiperidine-N-oxide into the toluene, wherein the molar ratio of the 5-bromoindoline compound to the toluene to the cuprous catalyst to the nitric oxide is 1:8:0.02:0.01, introducing air, carrying out oxidative dehydrogenation reaction at 60-100 ℃ until the raw material disappears, filtering to remove solids, washing the obtained organic layer with water, washing with saturated brine, concentrating, crystallizing, filtering and drying to obtain the 5-bromoindole (the purity is 99.7%).
Example 2
A high-efficiency synthesis process of a medical intermediate 5-bromoindole comprises the following specific steps:
s1: adding indole, platinum carbon and toluene into a high-pressure reaction kettle, wherein the molar ratio of the indole to the platinum carbon to the toluene is 1:0.1:2, introducing nitrogen to fully displace air in the high-pressure reaction kettle, introducing hydrogen, controlling the pressure of the hydrogen in the reaction kettle to be 1.5-2Mpa and the temperature to be 90-130 ℃, reacting for a period of time to obtain a hydrogenated mixture, and filtering and distilling under reduced pressure to obtain the indoline compound capable of destroying the indole five-membered ring conjugation.
S2: dissolving the indoline compound prepared in the step S1 in dichloromethane, then dropwise adding acyl chloride into the dichloromethane, wherein the molar ratio of the indoline compound to the dichloromethane to the acyl chloride is 1:20:1.5, reacting at 0-20 ℃ after dropwise adding until the raw materials disappear, and then concentrating, extracting, concentrating, crystallizing and drying to obtain the N-acyl indoline compound.
S3: dissolving the N-acyl indoline compound prepared in the step S2 in dichloromethane, adding dibromohydantoin into the dichloromethane, wherein the molar ratio of the N-acyl indoline compound to the dichloromethane to the dibromohydantoin is 1:10:0.5, reacting at 0-10 ℃ until the raw materials disappear, washing with a saturated solution of sodium bisulfite, washing with water, concentrating, crystallizing, and drying to obtain the 5-bromo-N-acyl indoline compound.
S4: dissolving the 5-bromo-N-acylindoline compound prepared in the step S3 in methanol, adding a concentrated hydrochloric acid solution, wherein the molar ratio of the 5-bromo-N-acylindoline compound to the methanol to the sodium hydroxide solution is 1:15:1.2, heating to 40-60 ℃, reacting until the raw materials disappear, then adding an alkali solution for neutralization, standing for layering, recovering an upper organic solution, concentrating, extracting with dichloromethane, concentrating, crystallizing, and drying to obtain the product 5-bromoindoline compound.
S5: dissolving the 5-bromoindoline compound prepared in the step S4 in toluene, adding cuprous chloride and 2,2,6, 6-tetramethylpiperidine-N-oxide into the toluene, wherein the molar ratio of the 5-bromoindoline compound to the toluene to the cuprous catalyst to the nitric oxide is 1:5:0.0.05:0.05, introducing air, carrying out oxidative dehydrogenation reaction at 60-100 ℃ until the raw materials disappear, filtering to remove solids, washing the obtained organic layer with water, washing with saturated brine, concentrating, crystallizing, filtering and drying to obtain the 5-bromoindole (the purity is 99.2%).
Example 3
A high-efficiency synthesis process of a medical intermediate 5-bromoindole comprises the following specific steps:
s1: adding indole, platinum carbon and toluene into a high-pressure reaction kettle, wherein the molar ratio of the indole to the platinum carbon to the toluene is 1:0.6:10, introducing nitrogen to fully displace air in the high-pressure reaction kettle, introducing hydrogen, controlling the pressure of the hydrogen in the reaction kettle to be 1.5-2Mpa and the temperature to be 90-130 ℃, reacting for a period of time to obtain a hydrogenated mixture, and filtering and distilling under reduced pressure to obtain the indoline compound capable of destroying the indole five-membered ring conjugation.
S2: dissolving the indoline compound prepared in the step S1 in dichloromethane, then dropwise adding acyl chloride into the dichloromethane, wherein the molar ratio of the indoline compound to the dichloromethane to the acyl chloride is 1:10:1, reacting at 0-20 ℃ after dropwise adding until the raw materials disappear, and then concentrating, extracting, concentrating, crystallizing and drying to obtain the N-acyl indoline compound.
S3: dissolving the N-acylindoline compound prepared in the step S2 in dichloromethane, adding dibromohydantoin into the dichloromethane, wherein the molar ratio of the N-acylindoline compound to the dichloromethane to the dibromohydantoin is 1:30:1, reacting at 0-10 ℃ until the raw materials disappear, and then washing with a saturated solution of sodium bisulfite, washing with water, concentrating, crystallizing and drying to obtain the 5-bromo-N-acylindoline compound.
S4: dissolving the 5-bromo-N-acylindoline compound prepared in the step S3 in methanol, adding a sodium hydroxide solution into the methanol, wherein the molar ratio of the 5-bromo-N-acylindoline compound to the methanol to the sodium hydroxide solution is 1:30:0.8, heating to 40-60 ℃, reacting until the raw materials disappear, adding an acid solution for neutralization, standing for layering, recovering an upper organic solution, concentrating, extracting with dichloromethane, concentrating, crystallizing, and drying to obtain the product 5-bromoindoline compound.
S5: dissolving the 5-bromoindoline compound prepared in step S4 in toluene, and then adding cuprous bromide and 2,2,6, 6-tetramethylpiperidine-N-oxide thereto, wherein the molar ratio of the 5-bromoindoline compound, toluene, cuprous catalyst and nitrogen oxide is 1:10: 0.01: 0.01, then introducing air, carrying out oxidative dehydrogenation reaction at 60-100 ℃ until the raw materials disappear, filtering to remove solids, washing the obtained organic layer with water, washing with saturated saline, concentrating, crystallizing, filtering and drying to obtain the 5-bromoindole (the purity is 99.4%).
The method has the advantages that the steps are convenient to operate, the conditions are mild, and the simple and easily-obtained solvents such as methanol, toluene, dichloromethane and the like are used as reaction systems, so that the requirements on equipment in industrial production are reduced, and the environmental pollution is reduced; the final product has high yield, high purity and low energy consumption.
The present invention has been described in terms of specific examples, which are provided to aid understanding of the invention and are not intended to be limiting. For a person skilled in the art to which the invention pertains, several simple deductions, modifications or substitutions may be made according to the idea of the invention.
Claims (7)
1. A high-efficiency synthesis process of a medical intermediate 5-bromoindole is characterized by comprising the following steps:
s1: indole compounds are used as raw materials, and the conjugate of indole five-membered rings is destroyed through low-pressure liquid-phase hydrogenation to obtain indoline compounds;
s2: reacting the indoline compound prepared in the step S1 with an acylation reagent to protect nitrogen to obtain an N-acyl indoline compound;
s3: brominating the N-acylindoline compound prepared in the step S2 to obtain a 5-bromo-N-acylindoline compound;
s4: performing deacylation protection on the 5-bromo-N-acylindoline compound prepared in the step S3 to obtain a 5-bromoindoline compound;
s5: carrying out oxidative dehydrogenation on the 5-bromoindoline compound prepared in the step S4 by using oxygen or air under the action of a cuprous catalyst and a nitrogen oxide to obtain a target compound 5-bromoindole;
wherein, the acylating reagent in the step S2 is acid anhydride, acyl chloride or carboxylic acid; in the step S3, the bromization reagent is dibromohydantoin; in the step S4, deacylation is carried out under the action of acid catalysis or alkali hydrolysis, wherein acid is hydrochloric acid or sulfuric acid, and alkali is sodium hydroxide or potassium carbonate; in the step S5, the cuprous catalyst is cuprous chloride or cuprous bromide, and the nitrogen oxide is 2,2,6, 6-tetramethylpiperidine-N-oxide.
2. The efficient synthesis process of the medical intermediate 5-bromoindole as claimed in claim 1, which comprises the following steps:
s1: adding indole, a metal catalyst platinum carbon and an organic solvent toluene into a high-pressure reaction kettle, introducing nitrogen to fully displace the air in the high-pressure reaction kettle, introducing hydrogen, controlling the pressure of the hydrogen in the reaction kettle to be 1.5-2Mpa and the temperature to be 90-130 ℃, reacting for a period of time to obtain a hydrogenation mixture, and filtering and distilling under reduced pressure to obtain an indoline compound;
s2: dissolving the indoline compound prepared in the step S1 in dichloromethane, then dropwise adding an acylation reagent, reacting at 0-20 ℃ until the raw material disappears, and then concentrating, extracting, concentrating, crystallizing and drying to obtain an N-acyl indoline compound;
s3: dissolving the N-acylindoline compound prepared in the step S2 in dichloromethane, adding a bromization reagent, reacting at 0-10 ℃ until the raw material disappears, washing by using a saturated solution of sodium bisulfite, washing by using water, concentrating, crystallizing and drying to obtain a 5-bromo-N-acylindoline compound;
s4: dissolving the 5-bromo-N-acylindoline compound prepared in the step S3 in methanol, adding a sodium hydroxide solution, heating to 40-60 ℃ for reaction until the raw materials disappear, adding an acid solution for neutralization, standing for layering, recovering an upper organic solution, concentrating, extracting with dichloromethane, concentrating, crystallizing, and drying to obtain a product 5-bromoindoline compound;
s5: and (4) dissolving the 5-bromoindoline compound prepared in the step (S4) in toluene, adding a cuprous catalyst and a nitrogen oxide, introducing air, reacting at 60-100 ℃ until the raw materials disappear, filtering to remove solids, washing the obtained organic layer with water, washing with saturated brine, concentrating, crystallizing, filtering, and drying to obtain the 5-bromoindoline.
3. The efficient synthesis process of the medical intermediate 5-bromoindole as claimed in claim 2, wherein the molar ratio of indole, platinum carbon and toluene in step 1 is 1 (0.1-0.6): (2-10).
4. The efficient synthesis process of a medical intermediate 5-bromoindole as claimed in claim 2, wherein the molar ratio of indoline compound, dichloromethane and acylating agent in step S2 is 1: (10-20): (1-1.5).
5. The efficient synthesis process of the pharmaceutical intermediate 5-bromoindole according to claim 2, wherein the molar ratio of the N-acylindoline compound, the dichloromethane and the brominating agent in step S3 is 1: (10-30): (0.5-1).
6. The efficient synthesis process of a pharmaceutical intermediate 5-bromoindole as claimed in claim 2, wherein the molar ratio of the 5-bromo-N-acylindoline compound, methanol and sodium hydroxide solution in step S4 is 1: (15-30): (0.8-1.2).
7. The efficient synthesis process of the medical intermediate 5-bromoindole as claimed in claim 2, wherein the molar ratio of the 5-bromoindoline compound, the toluene, the cuprous catalyst and the nitrogen oxide in step S5 is 1: (5-10): (0.01-0.05): (0.01-0.05).
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| CN106966950A (en) * | 2017-04-17 | 2017-07-21 | 兰州大学 | A kind of preparation method of the bromo indole of pharmaceutical intermediate 5 |
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