CN116621761A - Tertiary alkylamine compound and its synthesis method and application - Google Patents
Tertiary alkylamine compound and its synthesis method and application Download PDFInfo
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- CN116621761A CN116621761A CN202310680921.6A CN202310680921A CN116621761A CN 116621761 A CN116621761 A CN 116621761A CN 202310680921 A CN202310680921 A CN 202310680921A CN 116621761 A CN116621761 A CN 116621761A
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- -1 alkylamine compound Chemical group 0.000 title claims abstract description 61
- 238000001308 synthesis method Methods 0.000 title abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 44
- 238000003756 stirring Methods 0.000 claims description 17
- 239000000654 additive Substances 0.000 claims description 15
- 230000000996 additive effect Effects 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 15
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 230000001430 anti-depressive effect Effects 0.000 claims description 3
- 239000000935 antidepressant agent Substances 0.000 claims description 3
- 229940005513 antidepressants Drugs 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical group [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- 239000001095 magnesium carbonate Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002008 alkyl bromide group Chemical group 0.000 claims 3
- 230000000561 anti-psychotic effect Effects 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 6
- 239000002184 metal Substances 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- KTHADMDGDNYQRX-UHFFFAOYSA-N methyl (indol-3-yl)acetate Chemical compound C1=CC=C2C(CC(=O)OC)=CNC2=C1 KTHADMDGDNYQRX-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 150000001347 alkyl bromides Chemical class 0.000 description 9
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 8
- 238000012512 characterization method Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000003973 alkyl amines Chemical group 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- RVRKIDBKYOGRAT-UHFFFAOYSA-N (2-bromo-2-methylpropyl)benzene Chemical compound CC(C)(Br)CC1=CC=CC=C1 RVRKIDBKYOGRAT-UHFFFAOYSA-N 0.000 description 2
- VSGXTQWTJYAQHO-UHFFFAOYSA-N 1-bromo-1-methylcyclohexane Chemical compound CC1(Br)CCCCC1 VSGXTQWTJYAQHO-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 150000002475 indoles Chemical group 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical compound O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
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- 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
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Abstract
The invention relates to a tertiary alkylamine compound and a synthesis method and application thereof. The method has the advantages of using cheap metal catalyst, simple and easily obtained raw materials, mild reaction, simple steps, safe operation, higher yield and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a tertiary alkylamine compound and a synthesis method and application thereof.
Background
Amine compounds are one of important components in the fields of biology and medicine, and have irreplaceable effects on human life. Tertiary alkylamine compounds have potential biological activity and medical value.
The existing synthesis method utilizes metal palladium to catalyze the reaction of aryl halide or halogen-like compound and tert-butylamine, but the metal palladium is too expensive and is not suitable for mass production, and the existing synthesis method utilizes the reaction of aniline and 2, 2-trichloroiminocarboxylic acid tert-butyl ester, but the preparation process of raw materials of the method is complex, and the reaction is limited.
In summary, the existing methods have great defects, and the raw materials in the method for synthesizing tertiary alkylamine are difficult to prepare, expensive and limited in application range. Thus, there is a need to find a more convenient and cheaper way to solve these problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a tertiary alkylamine compound, a synthesis method and application thereof, wherein tertiary alkylamine is prepared by taking tertiary alkyl bromide and 3-substituted indole derivatives as substrates, and reacting for 8-12 hours under the action of a catalyst, a ligand, a reducing agent and an additive at the temperature of 40 ℃. The method has the advantages of using cheap metal catalyst, simple and easily obtained raw materials, mild reaction, simple steps, safe operation, higher yield and the like.
The aim of the invention can be achieved by the following technical scheme:
a tertiary alkylamine compound has a structural general formula I:
wherein R is selected from any one of alkyl groups with ester groups or amide groups;
R 1 ，R 2 ，R 3 and is selected from any one of alkyl or aryl groups.
Further, R is selected from 2-methoxy-2-oxoethyl;
R 1 ，R 2 ，R 3 and each is independently selected from any one of methyl, ethyl or phenyl.
The above further, the tertiary alkylamine compound includes:
the invention also provides a synthesis method of the tertiary alkylamine compound, which comprises the following specific steps:
taking 3-substituted indole or derivative thereof with a structure shown in a formula II and tertiary alkyl bromide with a structure shown in a formula III as raw materials, sequentially adding a catalyst, a ligand, a reducing agent and an additive, stirring to obtain a tertiary alkylamine compound with a structure shown in a formula I,
the structural general formulas I to III are shown as follows:
wherein R is selected from any one of alkyl groups with ester groups or amide groups;
R 1 ，R 2 ，R 3 and is selected from any one of alkyl or aryl groups.
Further, R is selected from 2-methoxy-2-oxoethyl;
R 1 ，R 2 ，R 3 respectively selected from methyl, ethyl or phenyl.
Further, 3-substituted indole or derivative thereof having a structure represented by formula II: tertiary alkyl bromides of the structure shown in formula III: catalyst: ligand: reducing agent: additive = 1: (1.9-2.1): (0.08-0.12): (0.10-0.15): (0.5-1.0): (1.0-2.0).
Further, the catalyst is cuprous bromide (CuBr), the ligand is 4-di-tert-butyl bipyridine, the reducing agent is zinc powder, and the additive is magnesium carbonate.
Further, in an air atmosphere, taking 3-substituted indole or a derivative thereof with a structure shown in a formula II and tertiary alkyl bromide with a structure shown in a formula III as raw materials, sequentially adding a catalyst, a ligand, a reducing agent and an additive, adding a solvent to obtain a reactant solution, uniformly stirring the reactant solution, and reacting to obtain the tertiary alkylamine compound with the structure shown in the formula I.
The stirring temperature is 38-42 ℃ and the stirring time is 8-12 hours.
The above further, the solvent is dichloromethane and benzotrifluoride.
The above further comprises, in terms of volume ratio, methylene chloride: benzotrifluoride=1: 1.
further, 3-substituted indoles or derivatives thereof having the structure of formula II: dichloromethane = 1:1 to 2.
In addition, the invention also provides application of the tertiary alkylamine compound in preparation of antidepressant or antipsychotic drugs.
Compared with the prior art, the invention has the following beneficial effects:
1. the tertiary alkyl bromide and indole derivative are used as substrates, and react for 8-12 hours at 40 ℃ under the action of a catalyst, a ligand, a reducing agent and an additive to obtain tertiary alkylamine.
2. The invention has the advantages of cheap metal catalyst, simple and easily obtained raw materials, mild reaction, simple steps, safe operation and higher yield.
3. The method is simple and feasible, has low cost and is suitable for popularization and application.
Drawings
FIG. 1 is a reaction scheme of the present invention.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples.
The principle of the invention is shown in figure 1, and a tertiary alkylamine compound has a structural general formula I:
wherein R is selected from any one of alkyl groups with ester groups or amide groups;
R 1 ，R 2 ，R 3 and is selected from any one of alkyl or aryl groups.
Further, R is selected from 2-methoxy-2-oxoethyl;
R 1 ，R 2 ，R 3 respectively selected from methyl, ethyl or phenyl.
The above further, the tertiary alkylamine compound includes:
the invention also provides a synthesis method of the tertiary alkylamine compound, which comprises the following specific steps:
taking 3-substituted indole or derivative thereof with a structure shown in a formula II and tertiary alkyl bromide with a structure shown in a formula III as raw materials, sequentially adding a catalyst, a ligand, a reducing agent and an additive, stirring to obtain a tertiary alkylamine compound with a structure shown in a formula I,
the structural general formulas I to III are shown as follows:
wherein R is selected from any one of alkyl groups with ester groups or amide groups;
R 1 ，R 2 ，R 3 any one of the groups independently selected from alkyl or arylA bolus.
Further, R is selected from 2-methoxy-2-oxoethyl;
R 1 ，R 2 ，R 3 respectively selected from methyl, ethyl or phenyl.
Further, 3-substituted indole or derivative thereof having a structure represented by formula II: tertiary alkyl bromides of the structure shown in formula III: catalyst: ligand: reducing agent: additive = 1: (1.9-2.1): (0.08-0.12): (0.10-0.15): (0.5-1.0): (1.0-2.0).
Further, the catalyst is cuprous bromide (CuBr), the ligand is 4-di-tert-butyl bipyridine, the reducing agent is zinc powder, and the additive is magnesium carbonate.
Further, in an air atmosphere, taking 3-substituted indole or a derivative thereof with a structure shown in a formula II and tertiary alkyl bromide with a structure shown in a formula III as raw materials, sequentially adding a catalyst, a ligand, a reducing agent and an additive, adding a solvent to obtain a reactant solution, uniformly stirring the reactant solution, and reacting to obtain the tertiary alkylamine compound with the structure shown in the formula I.
The stirring temperature is 38-42 ℃ and the stirring time is 8-12 hours.
The above further, the solvent is dichloromethane and benzotrifluoride.
The above further comprises, in terms of volume ratio, methylene chloride: benzotrifluoride=1: 1.
further, 3-substituted indoles or derivatives thereof having the structure of formula II: dichloromethane = 1:1 to 2.
In addition, the invention also provides application of the tertiary alkylamine compound in preparation of antidepressant or antipsychotic drugs.
The above embodiments are described in more detail below with reference to specific examples.
Example 1
A synthetic method of tertiary alkylamine compound takes indole-3-methyl acetate and tertiary butyl bromide as raw materials to synthesize a product 1, which comprises the following specific steps:
to a dried Schlenk tube was added successively methyl indole-3-acetate (0.30 mmol,56.8mg,100 mol%), zn (0.15 mmol,9.8mg,50 mol%), 4-di-tert-butylbipyridine (0.03 mmol,8.0mg,10 mol%), cuBr (0.03 mmol,4.3mg,10 mol%), mgCO 3 (0.60 mmol,50.6mg,200 mol%). The Schlenk tube was then sealed with a sealing film. Tert-butyl bromide (0.60 mmol,82.2mg,200 mmol%) and solvent benzotrifluoride 0.5mL and dichloromethane 0.5mL were added via syringe. Stirring in an oil bath at 40deg.C for 8-12 hr. After the reaction is finished, directly separating by column chromatography (ethyl acetate: petroleum ether=3:97) without post-treatment to obtain pale yellow oily liquid 1, wherein the structure is shown in formula 1, and the yield is 89-91%;
characterization of the product synthesized by the method of this example:
1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝8.5Hz,2H),7.26(s,1H),7.20–7.17(m,1H),7.12(m,1H),3.77(s,2H),3.71(s,3H),1.73(s,9H).
13 C NMR(101MHz,CDCl 3 )δ172.8,135.2,129.4,124.4,120.9,119.2,118.8,113.4,105.7,55.8,52.0,31.2,29.9.
example 2
A synthetic method of tertiary alkylamine compound takes indole-3-methyl propionate and tertiary butyl bromide as raw materials to synthesize a product 2, and the specific steps are as follows:
to a dried Schlenk tube was added successively methyl indole-3-acetate (0.30 mmol,61.0mg,100 mol%), zn (0.15 mmol,9.8mg,50 mol%), 4-di-tert-butylbipyridine (0.03 mmol,8.0mg,10 mol%), cuBr (0.03 mmol,4.3mg,10 mol%), mgCO 3 (0.60 mmol,50.6mg,200 mol%). The Schlenk tube was then sealed with a sealing film. Tert-butyl bromide (0.60 mmol,82.2mg,200 mmol%) and solvent benzotrifluoride 0.5mL and dichloromethane 0.5mL were added via syringe. Stirring in an oil bath at 40deg.C for 8-12 hr. After the reaction is finished, the post-treatment is not needed, and the column is directly usedChromatographic separation (ethyl acetate: petroleum ether=3:97) gives pale yellow oily liquid 2 with a structure shown in formula 2 and a yield of 87-91%;
characterization of the product synthesized by the method of this example:
1 H NMR(400MHz,CDCl 3 )δ7.64–7.58(m,2H),7.20–7.15(m,1H),7.12–7.07(m,2H),3.69(s,3H),3.09(m,2H),2.75–2.69(m,2H),1.71(s,9H).
13 C NMR(101MHz,CDCl 3 )δ174.1,135.3,129.3,122.9,120.9,119.0,118.5,113.4,112.2,55.7,51.7,35.1,29.9,20.8.
example 3
A synthesis method of tertiary alkylamine compound takes phthalimide protected tryptamine and tertiary butyl bromide as raw materials to synthesize a product 3, and specifically comprises the following steps:
to a dried Schlenk tube was added in order phthalimide protected tryptamine (0.30 mmol,87.1mg,100 mol%), zn (0.15 mmol,9.8mg,50 mol%), 4-di-tert-butylbipyridine (0.03 mmol,8.0mg,10 mol%), cuBr (0.03 mmol,4.3mg,10 mol%), mgCO 3 (0.60 mmol,50.6mg,200 mol%). The Schlenk tube was then sealed with a sealing film. Tert-butyl bromide (0.60 mmol,82.2mg,200 mmol%) and solvent benzotrifluoride 0.5mL and dichloromethane 0.5mL were added via syringe. Stirring in an oil bath at 40deg.C for 8-12 hr. After the reaction is finished, directly separating by column chromatography (ethyl acetate: petroleum ether=3:97) without post-treatment to obtain pale yellow oily liquid 3, wherein the structure is shown in formula 3, and the yield is 71-73%;
characterization of the product synthesized by the method of this example:
1 H NMR(400MHz,CDCl 3 )δ7.85(m,2H),7.78(m,1H),7.71(m,2H),7.61(m,J＝8.3Hz,1H),7.21–7.16(m,2H),7.13(m,1H),4.03–3.97(m,2H),3.16–3.09(m,2H),1.71(s,9H).
13 C NMR(101MHz,CDCl 3 )δ168.5,135.3,134.0,132.4,129.6,123.6,123.3,120.9,119.3,118.7,113.4,109.6,55.7,53.6,38.7,29.9,24.6.
example 4
A synthesis method of tertiary alkylamine compound takes Obz protected color alcohol and tertiary butyl bromide as raw materials to synthesize a product 4, which comprises the following specific steps:
to a dried Schlenk tube was added Obz protected chromanol (0.30 mmol,80.0mg,100 mol%), zn (0.15 mmol,9.8mg,50 mol%), 4-di-tert-butylbipyridine (0.03 mmol,8.0mg,10 mol%), cuBr (0.03 mmol,4.3mg,10 mol%), mgCO in this order 3 (0.60 mmol,50.6mg,200 mol%). The Schlenk tube was then sealed with a sealing film. Tert-butyl bromide (0.60 mmol,82.2mg,200 mmol%) and solvent benzotrifluoride 0.5mL and dichloromethane 0.5mL were added via syringe. Stirring in an oil bath at 40deg.C for 8-12 hr. After the reaction is finished, directly separating by column chromatography (ethyl acetate: petroleum ether=3:97) without post-treatment to obtain pale yellow oily liquid 4, wherein the structure is shown in formula 4, and the yield is 51-54%;
characterization of the product synthesized by the method of this example:
1 H NMR(400MHz,CDCl 3 )δ8.07(d,J＝8.3Hz,2H),7.69(m,1H),7.63(m,1H),7.57(m,1H),7.45(m,2H),7.21–7.17(m,2H),7.15–7.10(m,1H),4.59(t,J＝7.4Hz,2H),3.23(t,J＝7.4Hz,2H),1.72(s,9H).
13 C NMR(101MHz,CDCl 3 )δ166.8,135.3,133.0,130.6,129.7,128.5,123.7,121.0,119.2,118.7,113.5,109.2,65.3,55.8,53.6,30.0,25.0.
example 5
A synthetic method of tertiary alkylamine compound takes indole-3-methyl acetate and 1-bromo-1-methylcyclohexane as raw materials to synthesize a product 5, and specifically comprises the following steps:
to a dried Schlenk tube was added successively methyl indole-3-acetate (0.30 mmol,56.8mg,100 mol%), zn (0.15 mmol,9.8mg,50 mol%), 4-di-tert-butylbipyridine (0.03 mmol,8.0mg,10 mol%), cuBr (0.03 mmol,4.3mg,10 mol%), mgCO 3 (0.60 mmol,50.6mg,200 mol%). The Schlenk tube was then sealed with a sealing film. 1-bromo-1-methylcyclohexane (0.60 mmol,106.3mg,200 mmol%) and solvent benzotrifluoride 0.5mL and dichloromethane 0.5mL were added via syringe. Stirring in an oil bath at 40deg.C for 8-12 hr. After the reaction is finished, directly separating by column chromatography (ethyl acetate: petroleum ether=3:97) without post-treatment to obtain pale yellow oily liquid 5, wherein the structure is shown in formula 5, and the yield is 67-69%;
characterization of the product synthesized by the method of this example:
1H NMR(400MHz,CDCl3)δ7.68–7.60(m,2H),7.35(s,1H),7.14(m,2H),3.78(s,2H),3.72(s,3H),2.35(m,2H),2.08–2.01(m,2H),1.68-1.58(m,5H)1.64(s,3H),1.43-1.19(m,1H).
13C NMR(101MHz,CDCl3)δ172.9,135.1,129.5,124.7,120.8,119.2,118.8,113.8,105.9,58.8,52.0,37.7,31.3,25.8,22.8.
HRMS(ESI)m/z:[M+H]+Calced for C18H24NO2 286.1802；Found:282.1790.
example 6
A synthetic method of tertiary alkylamine compound takes indole-3-methyl acetate and 2-bromo-2-benzyl propane as raw materials to synthesize a product 6, which comprises the following specific steps:
to a dried Schlenk tube was added successively methyl indole-3-acetate (0.30 mmol,56.8mg,100 mol%), zn (0.15 mmol,9.8mg,50 mol%), 4-di-tert-butylbipyridine (0.03 mmol,8.0mg,10 mol%), cuBr (0.03 mmol,4.3mg,10 mol%), mgCO 3 (0.60 mmol,50.6mg,200 mol%). The Schlenk tube was then sealed with a sealing film. 2-bromo-2-benzyl propane (0.60 mmol) was added via syringe127.9mg,200 mmol%) and 0.5mL of benzotrifluoride as a solvent and 0.5mL of methylene chloride. Stirring in an oil bath at 40deg.C for 8-12 hr. After the reaction is finished, directly separating by column chromatography (ethyl acetate: petroleum ether=3:97) without post-treatment to obtain pale yellow oily liquid 6, wherein the structure is shown in formula 6, and the yield is 61-63%;
characterization of the product synthesized by the method of this example:
1 H NMR(400MHz,CDCl 3 )δ7.70–7.63(m,2H),7.29(s,1H),7.24–7.13(m,5H),7.00(d,J＝7.1Hz,2H),3.80(s,2H),3.72(s,3H),2.42–2.37(m,2H),2.29–2.23(m,2H),1.78(s,6H).
13 C NMR(101MHz,CDCl 3 )δ172.8,141.9,135.3,129.6,128.5,128.4,125.9,125.3,121.3,119.3,119.1,113.3,106.0,58.6,52.1,43.2,31.3,30.5,28.5.
as can be seen from the above examples, the synthesis method of tertiary alkylamine of the present invention is carried out by using tertiary alkyl bromide and indole derivatives as substrates, and reacting for 8-12 hours at 40 ℃ under the action of catalyst, ligand, reducing agent and additive. The method has the advantages of cheap metal catalyst, simple and easily obtained raw materials, mild reaction, simple steps, safe operation and higher yield.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. A tertiary alkylamine compound is characterized in that the structural general formula I of the compound is as follows:
wherein R is selected from any one of alkyl groups with ester groups or amide groups;
R 1 ，R 2 ，R 3 and is selected from any one of alkyl or aryl groups.
2. A tertiary alkylamine compound as claimed in claim 1, wherein R is selected from 2-methoxy-2-oxoethyl;
R 1 ，R 2 ，R 3 and each is independently selected from any one of methyl, ethyl or phenyl.
3. A tertiary alkylamine compound as claimed in claim 2, wherein the tertiary alkylamine compound comprises:
4. a method for synthesizing a tertiary alkylamine compound as described in any one of claims 1 to 3, comprising the steps of:
taking 3-substituted indole or derivative thereof with a structure shown in a formula II and tertiary alkyl bromide with a structure shown in a formula III as raw materials, sequentially adding a catalyst, a ligand, a reducing agent and an additive, stirring to obtain a tertiary alkylamine compound with a structure shown in a formula I,
the structural general formulas I to III are shown as follows:
wherein R is selected from any one of alkyl groups with ester groups or amide groups;
R 1 ，R 2 ，R 3 and is selected from any one of alkyl or aryl groups.
5. The method for synthesizing a tertiary alkylamine compound according to claim 4, wherein R is selected from 2-methoxy-2-oxoethyl;
R 1 ，R 2 ，R 3 respectively selected from methyl, ethyl or phenyl.
6. The method for synthesizing tertiary alkylamine compound according to claim 4, wherein the 3-substituted indole or derivative thereof has a structure represented by formula II: tertiary alkyl bromides of the structure shown in formula III: catalyst: ligand: reducing agent: additive = 1: (1.9-2.1): (0.08-0.12): (0.10-0.15): (0.5-1.0): (1.0-2.0).
7. The method for synthesizing tertiary alkylamine compound according to claim 4, wherein the catalyst is cuprous bromide, the ligand is 4-di-tert-butyl bipyridine, the reducing agent is zinc powder, and the additive is magnesium carbonate.
8. The method for synthesizing tertiary alkylamine compound according to claim 4, wherein 3-substituted indole or derivative thereof having a structure represented by formula II and tertiary alkyl bromide having a structure represented by formula III are used as raw materials in an air atmosphere, a catalyst, a ligand, a reducing agent and an additive are sequentially added, a solvent is added to obtain a reaction object solution, and the reaction object solution is uniformly stirred to perform a reaction to obtain the tertiary alkylamine compound having a structure represented by formula I.
9. The method for synthesizing tertiary alkylamine compound according to claim 8, wherein the stirring temperature is 38-42 ℃ and the stirring time is 8-12 hours,
the solvent is dichloromethane and benzotrifluoride,
according to the volume ratio, methylene dichloride: benzotrifluoride=1: 1,
3-substituted indole or derivative thereof having a structure represented by formula II: dichloromethane = 1:1 to 2.
10. Use of a tertiary alkylamine compound as claimed in any one of claims 1 to 3, in the potential use of the tertiary alkylamine compound in the manufacture of an antidepressant or antipsychotic.
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