CN117069602A - Synthetic method of gamma-amino alcohol compound - Google Patents
Synthetic method of gamma-amino alcohol compound Download PDFInfo
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- CN117069602A CN117069602A CN202311043962.0A CN202311043962A CN117069602A CN 117069602 A CN117069602 A CN 117069602A CN 202311043962 A CN202311043962 A CN 202311043962A CN 117069602 A CN117069602 A CN 117069602A
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- 238000010189 synthetic method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- -1 alcohol compound Chemical class 0.000 claims abstract description 47
- 239000003054 catalyst Substances 0.000 claims abstract description 46
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 22
- 125000001424 substituent group Chemical group 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000001308 synthesis method Methods 0.000 claims abstract description 12
- 238000005913 hydroamination reaction Methods 0.000 claims abstract description 11
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- 238000005576 amination reaction Methods 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims abstract 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 14
- 229940126062 Compound A Drugs 0.000 claims description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 10
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- 238000011068 loading method Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002430 hydrocarbons Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 229910052761 rare earth metal Inorganic materials 0.000 abstract description 19
- 150000002910 rare earth metals Chemical class 0.000 abstract description 19
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003513 alkali Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000003213 activating effect Effects 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 29
- 238000012512 characterization method Methods 0.000 description 19
- 239000012043 crude product Substances 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 229910052723 transition metal Inorganic materials 0.000 description 9
- 150000003624 transition metals Chemical class 0.000 description 9
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- MKUWVMRNQOOSAT-UHFFFAOYSA-N methylvinylmethanol Natural products CC(O)C=C MKUWVMRNQOOSAT-UHFFFAOYSA-N 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000004808 allyl alcohols Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000009830 intercalation Methods 0.000 description 2
- 230000002687 intercalation Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000006479 redox reaction Methods 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- PRRFFTYUBPGHLE-UHFFFAOYSA-N 3-phenylpyrrolidine Chemical compound C1NCCC1C1=CC=CC=C1 PRRFFTYUBPGHLE-UHFFFAOYSA-N 0.000 description 1
- NBEFJLOFMCFDFK-UHFFFAOYSA-N 4-(n-methylanilino)butan-2-ol Chemical compound CC(O)CCN(C)C1=CC=CC=C1 NBEFJLOFMCFDFK-UHFFFAOYSA-N 0.000 description 1
- VLWRKVBQUANIGI-UHFFFAOYSA-N 4-fluoro-n-methylaniline Chemical compound CNC1=CC=C(F)C=C1 VLWRKVBQUANIGI-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- JFXDIXYFXDOZIT-UHFFFAOYSA-N 4-methoxy-n-methylaniline Chemical compound CNC1=CC=C(OC)C=C1 JFXDIXYFXDOZIT-UHFFFAOYSA-N 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a gamma-amino groupThe synthesis method of the alcohol compound comprises the steps of dissolving allyl primary alcohol or allyl secondary alcohol and primary amine or secondary amine of different types in an organic solvent, and carrying out anti-Mahalanobis hydrogen amination reaction under the catalysis of a catalyst to obtain a target product gamma-amino alcohol; wherein the reaction formula of the hydroamination reaction is shown in figure 1, R ', R' can represent a hydrogen atom, an electron-withdrawing substituent, an electron-donating substituent, an aryl group, a hydrocarbon group, the R 'and R' can be connected end to form a ring; the catalyst is YC 3 ，YC 3 Is Y (CH) 2 SiMe 3 ) 3 (THF) 2 . The application provides a new method for preparing the gamma-amino alcohol compound by using the rare earth catalyst, which improves the synthesis yield of the gamma-amino alcohol compound, and has the characteristics of easily available raw materials of the rare earth catalyst, few synthesis steps, simple preparation, high yield and no need of adding alkali and an activating agent, so that the synthesis method of the gamma-amino alcohol compound is cheaper and cleaner.
Description
Technical Field
The application relates to the field of preparation of gamma-amino alcohol compounds, in particular to a synthesis method of gamma-amino alcohol compounds.
Background
The gamma-amino alcohol compound has great potential, and may be used widely in agriculture, medicine, etc. and is intermediate for synthesizing various medicine and bioactive molecule. The gamma-amino alcohol compound can be used for synthesizing antipsychotics, antihypertensives, antidepressants and the like, and can also be used for researching anti-HIV viruses, so that the gamma-amino alcohol compound is more and more concerned, and the synthesis method is also valued by drug researchers. Therefore, how to develop a method for simply and rapidly synthesizing a gamma-amino alcohol compound with novel structure and biological activity is a hot subject for research in the field of organic synthesis.
The traditional synthesis process is to use gamma-amino ketone as a raw material and obtain the product through hydrogenation reduction. Therefore, a large amount of reducing agent is needed, and the excessive reducing agent not only needs a large amount of organic solvents, but also causes serious environmental pollution. Therefore, the gamma-amino alcohol compound is synthesized by introducing a catalyst, so that the use of reducing agents in a reaction system is reduced, but most of the catalysts contain noble metal ruthenium, and the price is high, so that the production cost of the gamma-amino alcohol compound is still high.
To further reduce production costs and reduce environmental impact, transition metals may now be used to catalyze the reaction, such as: (1) Can be effectively generated by series oxidation/1, 4-conjugate addition/1, 2-reduction series connectionForming gamma-amino alcohol. For example, nakamura group of subjects developed noble metal complexes as catalysts, when RuClH (CO) (PPh 3 ) Is supported by 2mol%, pyridine diamine 2.2mol% is ligand, KO t Bu 3mol% constitutes a catalyst system capable of effecting the inverse Markov Nikov hydroamination of allyl alcohol (cf. Chem. Commun, pages 2015,51,7459-7462). (2) The hydrogen-borrowing strategy of dehydrogenation, conjugate addition and asymmetric reaction synthesizes the gamma-secondary amino alcohol with high selectivity. As Wang Chao group, it was found that allyl alcohol can be incorporated into Fe-PNP complex, naHBEt 3 ，K 3 PO 4 Under the catalysis system, dehydrogenation, michael addition and reduction are carried out to obtain the gamma-amino alcohol of the anti-Markov Nikov product (refer to J.Am.chem.Soc, page 2019,141,13506-13515).
The two synthetic methods mainly adopt a transition metal catalysis mode to generate gamma-amino alcohol compounds, alkali is added to the transition metal catalyst to promote the oxidation of allyl alcohol into alpha, beta-unsaturated ketone, then the alpha, beta-unsaturated ketone is added with amine, and finally carbonyl is reduced. The defect of adopting transition metal catalysis is that 1, firstly, a ligand is synthesized through multi-step reaction, and then a transition metal complex is synthesized, so that the transition metal catalyst has more and complex synthesis steps and low production efficiency; 2. and secondly, a catalyst system is formed by adding alkali, so that the requirements of the reaction on equipment can be improved, and the reaction cost is increased.
Disclosure of Invention
The application aims to provide a synthesis method of a gamma-amino alcohol compound, which aims to solve the technical problems of higher synthesis cost and complicated steps in the prior art.
In order to solve the technical problems, the application specifically provides the following technical scheme:
the application provides a synthesis method of a gamma-amino alcohol compound, which comprises the following steps:
dissolving allyl primary alcohol or allyl secondary alcohol and primary amine or secondary amine of different types in an organic solvent, and carrying out anti-Mahalanobis hydrogen amination reaction under the catalysis of a catalyst to obtain a target product;
wherein, the reaction formula of the hydroamination reaction is shown in figure 1, and R ', R' can represent hydrogen atoms, electron-withdrawing substituents, electron-donating substituents, aryl groups and hydrocarbon groups;
the R 'and the R' can be connected end to form a ring;
YC 3 representing the catalyst, YC 3 Is Y (CH) 2 SiMe 3 ) 3 (THF) 2 。
As a preferred embodiment of the present application, the R ', the R ", the R '" and the R ' "are each independent.
As a preferable mode of the application, when R' "is a benzene ring, the priority of the substituent on the benzene ring is para, meta or ortho.
As a preferable scheme of the application, the synthesis of the target product comprises the following steps:
taking catalyst Y (CH) 2 SiMe 3 ) 3 (THF) 2 A compound A having a structure shown in formula (II) in FIG. 2, a compound B having a structure shown in formula (III) in FIG. 2, and an organic solvent;
sequentially adding the compound A, the compound B and the organic solvent into the catalyst, wherein the compound A and the compound B can be completely dissolved in the solvent, and nucleophilic addition reaction is carried out to obtain the target product with the structure shown as the formula (I) in figure 2;
wherein R in the formula (I), the formula (II) and the formula (III) 1 At least comprises-H, -CH 3 、-OCH 3 、-F、-Cl、-Br；
R 2 At least comprises-H, -Me;
R 3 at least comprising-H, -Ph, -Et;
R 4 at least comprises-H, -CH 3 、-Br；
R 5 At least comprises-H, -Me;
R 6 at least comprising-Me, -Et, -Ph, and substituted aryl;
R 7 at least comprises-H, -Ph.
As a preferable embodiment of the present application, the organic solvent is any one of n-hexane, toluene, tetrahydrofuran, and ethyl acetate.
As a preferred embodiment of the present application, the organic solvent is toluene.
As a preferred embodiment of the present application, the molar ratio of the compound A to the compound B is 1:2 to 1:3.
As a preferable mode of the application, the reaction conditions of the nucleophilic addition reaction are as follows:
the temperature is 70-90 ℃, the reaction time is 12-72h, and the catalyst loading is 10mol%.
As a preferable mode of the application, the reaction conditions of the nucleophilic addition reaction are as follows:
the temperature was 80℃and the reaction time was 48h.
As a preferred embodiment of the present application, the method further comprises the steps of:
before the reaction, the compound a, the compound B and the organic solvent are dried so that the water content of the compound a, the compound B and the organic solvent is lower than 0.1%.
As a preferred embodiment of the present application, the method further comprises the steps of:
taking the target product, and purifying the target product by silica gel column chromatography to obtain a high-purity product;
wherein, during the purification process, ethyl acetate: petroleum ether=1:2-1:8.
Compared with the prior art, the application has the following beneficial effects:
1. according to the application, nucleophilic addition of allylic primary alcohol or allylic secondary alcohol and primary amine or secondary amine of different types is carried out through hydroamination to effectively generate gamma-amino alcohol compounds, a rare earth metal catalyst is mainly used, 4f electrons of rare earth metal are shielded, and the rare earth metal exists in positive trivalent mode, and does not have double-electron redox reaction of transition metal, so that the reaction steps of the rare earth metal catalyst can be simplified when the rare earth metal catalyst participates in the reaction, and the production efficiency of the gamma-amino alcohol compounds is improved;
2. the application adopts rare earth metal catalyst and allyl alcohol to generate alkyl elimination and then generate beta-H elimination, and the target product is synthesized through intercalation reaction, the rare earth metal catalyst can independently catalyze the reaction, no alkali is needed to be added, and the pollution to the environment can be reduced.
3. The catalyst of the application adopts rare earth metal catalyst Y (CH) 2 SiMe 3 ) 3 (THF) 2 Rare earth metal catalyst Y (CH) 2 SiMe 3 ) 3 (THF) 2 Is a compound with low price and easy acquisition, has stable property, and can effectively reduce the cost of the gamma-amino alcohol compound in the preparation process.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It will be apparent to those of ordinary skill in the art that the drawings in the following description are exemplary only and that other implementations can be obtained from the extensions of the drawings provided without inventive effort.
FIG. 1 is a reaction scheme of a bond line structure of general formula 1 of the synthesis method of gamma-amino alcohol compounds provided by the application;
FIG. 2 is a reaction scheme of a bond line structure of general formula 2 providing a method for synthesizing a gamma-amino alcohol compound according to the present application;
FIG. 3 is a reaction scheme of example 1 provided in the present application;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of the product of example 1 provided by the present application;
FIG. 5 is a nuclear magnetic resonance spectrum of the product of example 1 provided by the present application;
FIG. 6 is a reaction scheme providing example 2 in accordance with the present application;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the product of example 2 provided by the present application;
FIG. 8 is a nuclear magnetic resonance spectrum of the product of example 2 provided by the present application;
FIG. 9 is a reaction scheme providing example 3 in accordance with the present application;
FIG. 10 is a nuclear magnetic resonance hydrogen spectrum of the product of example 3 provided by the present application;
FIG. 11 is a nuclear magnetic resonance spectrum of the product of example 3 provided by the present application;
FIG. 12 is a reaction scheme providing example 4 according to the present application;
FIG. 13 is a nuclear magnetic resonance hydrogen spectrum of the product of example 4 provided by the present application;
FIG. 14 is a nuclear magnetic resonance spectrum of the product of example 4 provided by the present application;
FIG. 15 is a reaction scheme providing example 5 according to the present application;
FIG. 16 is a reaction scheme providing example 6 in accordance with the present application;
FIG. 17 is a reaction scheme providing example 7 in accordance with the present application;
FIG. 18 is a reaction scheme providing example 8 according to the present application;
FIG. 19 is a reaction scheme providing example 9 according to the present application;
FIG. 20 is a reaction scheme providing example 10 according to the present application;
FIG. 21 is a reaction scheme providing example 11 according to the present application.
Detailed Description
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
The application provides a synthesis method of a gamma-amino alcohol compound, which comprises the following steps:
drying the allyl alcohol compound, the organic amine compound and the organic solvent to ensure that the water content of the allyl alcohol compound, the organic amine compound and the organic solvent is lower than 0.1 percent;
taking catalyst Y (CH) 2 SiMe 3 ) 3 (THF) 2 The above-mentioned dried allyl alcohol compound and the above-mentioned dried organic amineThe allyl alcohol compound, the organic amine compound and the organic solvent are added to the catalyst Y (CH 2 SiMe 3 ) 3 (THF) 2 In (a) and (b);
the temperature of the reaction system is regulated to 70-90 ℃, the mixture is stirred for 12-72 hours at 70-90 ℃, primary allylic alcohol or secondary allylic alcohol and primary amine or secondary amine are subjected to anti-Mahalanobis hydrogen amination reaction under the catalysis of a catalyst, and the reaction is tracked by thin layer chromatography, so that a target product is obtained.
Hydroamination, i.e., the addition of an olefinic bond to an amine compound, is a very atom-economical reaction. The reaction was two regioselective, markovnikov (Mahalanobis) and anti-Markovnikov (anti-Mahalanobis). Thus, there are two selectivities to hydroamination of allyl alcohol with amines, the products being either gamma-amino alcohols or beta-amino alcohols.
The application discloses a novel method for preparing gamma-amino alcohol compounds by adopting a reverse Mahalanobis hydrogen amination reaction to obtain a rare earth catalyst. The rare earth metal is shielded, the 4f electron exists mainly in positive trivalent, the oxidation-reduction reaction of double electrons without transition metal is carried out, the reaction steps are simple, the rare earth metal catalyst and allyl alcohol are subjected to alkyl elimination, beta-H elimination is carried out again, the target product is synthesized through intercalation reaction, and the rare earth metal catalyst can independently catalyze the reaction. Compared with ruthenium, manganese and iron complexes of a late transition metal catalyst for preparing gamma-amino alcohol by an allyl alcohol hydroamination method, the rare earth catalyst has the characteristics of easily available raw materials, few synthesis steps, simple preparation, high yield, no need of adding extra alkali and activator and the like.
The rare earth catalyst is commercially available YCl 3 With LiCH 2 SiMe 3 The one-step synthesis is simple to operate and high in yield.
Purifying the target product by silica gel column chromatography (ethyl acetate: petroleum ether=1:2-1:8) to obtain the target product with higher purity.
Wherein the catalyst loading is 10mol%, and the molar ratio of the compound A to the compound B is 1:2-1:3;
the allyl alcohol compound is allyl primary alcohol or allyl secondary alcohol;
the organic amine compound is primary amine or secondary amine.
FIG. 1 shows a general formula 1 of a synthesis method of a gamma-amino alcohol compound, wherein the general formula 1 is a bond line structure reaction formula of the reaction.
In the general formula shown in fig. 1, R ', R ", R'", R "" are each independently provided. R ', R ", R'", R "" can represent a hydrogen atom, an electron withdrawing substituent, an electron donating substituent, an aryl group, a hydrocarbon group. R' "and R" "can be joined end to end in a cyclic manner. YC (YC) 3 Representing the catalyst, YC 3 Is Y (CH) 2 SiMe 3 ) 3 (THF) 2 。
In the hydroamination reaction, when R' "is a benzene ring, the substituent on the benzene ring can be para, meta or ortho. From the point of view of electronic effect, the ortho-position steric hindrance is large and the reaction is difficult. Meta-position, para-position is most advantageous. Therefore, the para-position and meta-position are preferable.
The organic solvent can be selected from n-hexane, toluene, tetrahydrofuran, ethyl acetate, etc. Toluene is a nonpolar solvent and has a high boiling point (110 ℃ C.). The boiling point of other solvents is about 80 ℃. The reaction temperature is 80℃and high-boiling organic solvents are advantageous. The organic solvent is preferably toluene.
Preferably, after screening the reaction conditions, the optimal reaction conditions are: the catalyst loading is 10mol% at 80 ℃, toluene is used as solvent, and the reaction time is 48h.
When the temperature of the reaction is lower than 70 ℃, the reaction is difficult to proceed, and when the temperature is higher than 90 ℃, the energy consumption of the reaction is increased, and in order to increase the yield, the reaction temperature is suitably increased, so that the reaction temperature is preferably 80 ℃.
The hydroamination reaction time is 12-72h. However, in order to increase the yield, the reaction time is suitably prolonged, and the preferable reaction time of the gamma-amino alcohol is 48 hours. The conversion rate is incomplete after 24 hours, so that the reaction temperature can be increased by proper heating.
After the reaction is finished, purifying the crude product by silica gel column chromatography (ethyl acetate: petroleum ether=1:2-1:8), and obtaining the product with high purity.
The preferable molar ratio of the organic amine compound to the allyl alcohol compound is 1:2, the dosage of substituted allyl alcohol can be properly increased, the molar ratio is not more than 1:3, and the excessive reaction raw materials can increase the separation difficulty.
The organic solvent is used in an amount to completely dissolve the organic amine compound and the allyl alcohol compound.
For further explanation of the types of the organic amine compound and the allyl alcohol compound, the application preferably also provides a general formula shown in FIG. 2, wherein a compound A of the structure shown in the formula (II) in FIG. 2 and a compound B of the structure shown in the formula (III) in FIG. 2 are dissolved in the above organic solvent and can be reacted in the presence of a catalyst Y (CH 2 SiMe 3 ) 3 (THF) 2 The target product of the structure shown in the formula (I) in the figure 2, namely the gamma-amino alcohol compound is generated through the reaction under the catalysis of the catalyst.
In this process, a nucleophilic addition reaction, namely an anti-Markovnikov hydroamination reaction, takes place.
In the general formula shown in FIG. 2, R 1 is-H, -CH 3 、-OCH 3 -F, -Cl, -Br, etc.; r is R 2 Is substituent groups such as-H, -Me and the like; r is R 3 Is substituent groups such as-H, -Ph, -Et and the like; r is R 4 is-H, -CH 3 -Br and like substituents; r is R 5 Is substituent groups such as-H, -Me and the like; r is R 6 Is substituent groups such as-Me, -Et, -Ph, substituted aryl, and the like; r is R 7 Is substituent groups such as-H, -Ph and the like.
FIG. 2 is a general formula 2 of a synthesis method of a gamma-amino alcohol compound, wherein the general formula 2 is a bond line structure reaction formula of the reaction.
A number of embodiments are provided below.
Example 1
1. Taking raw materials
3-buten-2-ol 2.0mmol, N-methylaniline 1.0mmol, toluene 500. Mu.L and catalyst Y (CH) 2 SiMe 3 ) 3 (THF) 2 0.1mmol；
2. And (3) synthesis:
drying the raw materials to enable the water content of 3-butene-2-alcohol, N-methylaniline and toluene to be below 0.1%;
a clean 15mL reaction flask was taken, and Y (CH 2 SiMe 3 ) 3 (THF) 2 3-buten-2-ol, N-methylaniline and toluene;
stirring at 80deg.C for 48 hr, and tracking with thin layer chromatography to obtain crude product;
after the reaction, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:2) to give a pure yellow oily liquid in 94% yield.
The gamma-amino alcohols have better solvability and are easy to dissolve in polar solvents such as chloroform, ethyl acetate, diethyl ether and the like, so CDCl is used for nuclear magnetic characterization 3 Dissolving the compound.
The characterization results are as follows:
4-(methyl(phenyl)amino)butan-2-ol, 1 H NMR(400MHz,CDCl 3 ,ppm):δ7.23(t,J＝7.2Hz,2H,ArH),6.78(d,J＝8.0Hz,2H,ArH),6.73(t,J＝7.2Hz,1H,ArH),3.94-3.86(m,1H,CH),3.49-3.35(m,2H,CH 2 N),2.89(s,3H,NCH 3 ),2.27(br,1H,OH),1.72-1.65(m,2H,CH 2 ),1.21(d,J＝6.4Hz,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ149.8,129.3,117.1,113.4(ArC),66.9(OCH),50.8(NCH2),38.6(NCH 3 ),35.6,24.1.
the reaction scheme of example 1 is shown in FIG. 3.
The nuclear magnetic resonance hydrogen spectrum of the product of example 1 is shown in FIG. 4.
The nuclear magnetic resonance spectrum of the product of example 1 is shown in FIG. 5.
As can be seen from the analysis of FIG. 4 and FIG. 5, the structural formula of the obtained actual product is consistent with that of the target product in the reaction formula shown in FIG. 3, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 1.
Example 2
On the basis of the example 1, the organic amine compound is changed into 4-methoxy-N-methylaniline, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:4) to give a pure yellow oily liquid with a yield of 95%.
The characterization results are as follows:
4-((4-methoxyphenyl)(methyl)amino)butan-2-ol, 1 H NMR(400MHz,CDCl 3 ,ppm):δ6.89-6.82(m,4H,ArH),4.02-3.94(m,1H,CH),3.77(s,3H,OCH 3 ),3.37-3.23(m,2H,NCH 2 ),2.81(s,3H,NCH 3 ),1.70-1.63(m,2H,CH 2 ),1.21(d,J＝6.0Hz,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ153.1,145.1,117.5,114.6(ArC),67.9(OCH),55.7(OCH 3 ),53.7(NCH 2 ),40.1(NCH 3 ),35.1(CH 2 ),23.9(CH 3 ).HRMS(APCI):calcd for C 12 H 19 O 2 N[M + H] + :210.1489,found:210.1490.
the reaction scheme of example 2 is shown in FIG. 6.
The nuclear magnetic resonance hydrogen spectrum of the product of example 2 is shown in FIG. 7.
The nuclear magnetic resonance spectrum of the product of example 2 is shown in FIG. 8.
As can be seen from the analysis of FIG. 7 and FIG. 8, the structural formula of the obtained actual product is consistent with that of the target product in the reaction formula shown in FIG. 6, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 2.
Example 3
Based on the embodiment 1, the organic amine compound is changed into thiomorpholine, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:8) to give a pure yellow oily liquid with 97% yield.
The characterization results are as follows:
4-thiomorpholinobutan-2-ol, 1 H NMR(400MHz,CDCl3,ppm):δ5.84(br,1H,OH),3.97-3.89(m,1H,CH),2.90-2.86(m,2H,NCH 2 ),2.71-2.53(m,8H,CH 2 ),1.67-1.57(m,1H,CH 2 ),1.48-1.42(m,1H,CH 2 ),1.14(d,J＝6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 ,ppm):δ69.8(OCH),58.7(NCH 2 ),55.2(NCH 2 ),33.0(CH 2 ),28.1(SCH 2 ),23.4(CH 3 ).HRMS(APCI):calcd for C 8 H 17 ONS[M + H] + :176.1104,found:176.1097.
the reaction scheme of example 3 is shown in FIG. 9.
The nuclear magnetic resonance hydrogen spectrum of the product of example 3 is shown in FIG. 10.
The nuclear magnetic resonance spectrum of the product of example 3 is shown in FIG. 11.
As can be seen from the analysis of FIG. 10 and FIG. 11, the structural formula of the obtained actual product is identical to that of the target product in the reaction formula shown in FIG. 9, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 3.
Example 4
On the basis of the example 1, the organic amine compound is changed into 4-phenylpiperidine, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:8) to give a pure pale yellow solid with 94% yield.
The characterization results are as follows:
4-(4-phenylpiperidin-1-yl)butan-2-ol, 1 H NMR(400MHz,CDCl 3 ,ppm):δ7.29(t,J＝7.4Hz,2H,ArH),7.21-7.18(m,3H,ArH),6.48(br,1H,OH),4.02-3.94(m,1H,CH),3.30(d,J＝11.2Hz,1H,NCH 2 ),3.03(d,J＝11.2Hz,1H,NCH 2 ),2.72-2.65(dt,J＝3.2,12.0Hz,1H,NCH 2 ),2.62-2.57(m,1H,NCH 2 ),2.51-2.47(m,1H,CH),2.21(dt,J＝2.8,12.0Hz,1H,NCH 2 ),1.95-1.61(m,6H,NCH2 and CH 2 ),1.55-1.45(m,1H,CH 2 ),1.18(d,J＝6.4Hz,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ145.9,128.5,126.8,126.3(ArC),69.9(OCH),58.2,56.0,52.8,42.5,33.9,33.4,33.1,23.5(CH 3 ).HRMS(APCI):calcd for C 15 H 23 ON[M + H] + :234.1852,found:234.1857.
the reaction scheme of example 4 is shown in FIG. 12.
The nuclear magnetic resonance hydrogen spectrum of the product of example 4 is shown in FIG. 13.
The nuclear magnetic resonance spectrum of the product of example 4 is shown in FIG. 14.
As can be seen from the analysis of FIG. 13 and FIG. 14, the structural formula of the obtained actual product is identical to that of the target product in the reaction formula shown in FIG. 12, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 4.
Example 5
On the basis of the embodiment 1, the organic amine compound is changed into N-methyl-p-fluoroaniline, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:4) to give a pure yellow oily liquid in 91% yield.
The characterization results are as follows:
4-((4-methoxyphenyl)(methyl)amino)butan-2-ol, 1 H NMR(400MHz,CDCl 3 ,ppm):δ6.94(t,J＝8.4Hz,2H,ArH),6.75(d,J＝8.4Hz,1H,ArH),6.73(d,J＝8.4Hz,1H,ArH),3.95-3.87(m,1H,CH),3.42-3.28(m,2H,NCH 2 ),2.84(s,3H,NCH 3 ),2.76(s,1H,OH),1.69-1.63(m,2H,CH 2 ),1.21(d,J＝6.4Hz,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ156.0(d, 1 J C-F ＝235.0Hz),146.8,115.5(d, 2 J C-F ＝22.0Hz),115.3(d, 3 J C-F ＝9.0Hz),67.1(OCH),52.0(NCH 2 ),39.3(NCH 3 ),35.3(CH 2 ),23.9(CH 3 ). 19 F NMR(376MHz,CDCl 3 ,ppm):δ127.6.HRMS(APCI):calcd for C 11 H 16 ONF[M + H] + :198.1289,found:198.1282.
the reaction scheme of example 5 is shown in FIG. 15.
Analysis according to the characterization result shows that the structural formula of the obtained actual product is consistent with the structural formula of the target product in the reaction formula shown in fig. 15, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 5.
Example 6
Based on the embodiment 1, the organic amine compound is changed into 1,2,3, 4-tetrahydroisoquinoline, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:16) to give a pure yellow oily liquid with 93% yield.
The characterization results are as follows:
4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-2-ol, 1 H NMR(400MHz,CDCl 3 ,ppm):δ7.15-7.11(m,2H,ArH),7.10-7.08(m,1H,ArH),7.03-7.01(m,1H,ArH),4.04-3.96(m,1H,CH),3.76(d,J＝14.8Hz,1H,NCH 2 Ar),3.64(d,J＝14.8Hz,1H,NCH 2 Ar),3.01-2.95(m,1H,NCH 2 ),2.90(t,J＝6.0Hz,2H,NCH 2 ),2.85-2.79(m,1H,NCH 2 ),2.75-2.70(m,1H,CH 2 Ar),2.65-2.59(m,1H,CH 2 Ar),1.80-1.70(m,1H,CH 2 ),1.61-1.55(m,1H,CH 2 ),1.19(d,J＝6.4Hz,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ134.1,134.0,128.6,126.6,126.3,125.8(ArC),69.7(OCH),57.5,56.4,50.6(NCH 2 ),33.7,28.9,23.5.
the reaction scheme of example 6 is shown in FIG. 16.
Analysis according to the characterization result shows that the structural formula of the obtained actual product is consistent with the structural formula of the target product in the reaction formula shown in fig. 16, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 6.
Example 7
Based on the example 1, allyl alcohol compound is changed into 1- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-propylene-1-alcohol, and organic amine compound is changed into 3-phenylpyrrolidine, wherein other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:8) to give a pure yellow oily liquid with a yield of 85%.
The characterization results are as follows:
1-(2,3-dihydrobenzo[1,4]dioxin-6-piperidinyl)-3-(3-phenylpyrrolidin-1-piperi dinyl)-1-propanol, 1 H NMR(400MHz,CDCl 3 ,ppm):δ7.30-7.19(m,5H,ArH),6.91(s,1H,ArH),6.83-6.81(m,2H,ArH),4.85-4.82(m,1H,CH),4.21(s,4H,OCH 2 ),3.39-3.36(m,1H,NCH 2 ),3.21-3.10(m,1H,NCH 2 ),3.04-2.81(m,3H,NCH 2 ),2.76-2.56(m,2H,NCH 2 and CH 2 ),2.37-2.28(m,1H,CH 2 ),1.96-1.70(m,3H,CH 2 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ144.6,144.3,143.4,142.5,138.6,138.5,128.6,128.6,127.3,127.2,126.4,126.4,118.6,116.9,114.7,114.6(ArC),74.9,74.9(OCH),64.4,64.4(OCH 2 ),62.1,61.9,54.9,54.8,54.6,54.5(NCH 2 ),43.3,43.2,35.7(CH 2 ),33.2,33.1(CH 3 ).
the reaction scheme of example 7 is shown in FIG. 17.
Analysis according to the characterization result shows that the structural formula of the obtained actual product is consistent with the structural formula of the target product in the reaction formula shown in fig. 17, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 7.
Example 8
Based on the example 1, the organic amine compound is changed into 2, 3-indoline, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:8) to give a pure yellow oily liquid with a yield of 95%.
The characterization results are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.10(t,J＝7.6Hz,2H,ArH),6.72(t,J＝7.2Hz,1H,ArH),6.61(d,J＝7.6Hz,1H,ArH),4.05-4.01(m,1H,CH),3.48(dd,J＝15.6,8.4Hz,1H,NCH 2 ),3.35-3.29(m,1H,NCH 2 ),3.22(d,J＝8.4Hz,1H,NCH 2 ),3.19-3.12(m,1H,NCH 2 ),3.04(br,1H,OH),2.96(t,J＝8.0Hz,2H,CH 2 ),1.79-1.73(m,2H,CH 2 CH),1.25(d,J＝6.0Hz,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ152.5,130.5,127.4,124.6,118.7,108.2(ArC),67.9(OCH),54.0(NCH 2 ),48.5(NCH 2 ),35.8,28.6,23.7(CH 3 ).
the reaction scheme of example 8 is shown in FIG. 18.
Analysis according to the characterization result shows that the structural formula of the obtained actual product is consistent with the structural formula of the target product in the reaction formula shown in fig. 18, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 8.
Example 9
On the basis of the example 1, the organic amine compound is changed into 4-fluoroaniline, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:8) after the end of the reaction to give a pure pale yellow solid with a yield of 70%.
The characterization results are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm):δ6.89(t,J＝8.8Hz,2H,ArH),6.58(d,J＝8.8Hz,1H,ArH),6.57(d,J＝8.8Hz,1H,ArH),4.05-3.97(m,1H,CH),3.29-3.18(m,2H,NCH 2 ),1.83-1.67(m,2H,CH 2 ),1.25(d,J＝6.4Hz,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ156.1(d, 1 J C-F ＝234.0Hz),144.7,115.6(d, 2 J C-F ＝22.0Hz),114.2(d, 3 J C-F ＝7.0Hz),67.6(OCH),42.7(NCH 2 ),37.9(CH 2 ),23.9(CH 3 ). 19 F NMR(376MHz,CDCl 3 ,ppm):δ127.6.HRMS(APCI):calcd for C 10 H 14 ONF[M + H] + :184.1132,found:184.1135.
the reaction scheme of example 9 is shown in FIG. 19.
Analysis of the characterization results shows that the structural formula of the obtained actual product is consistent with that of the target product in the reaction formula shown in fig. 19, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 9.
Example 10
Based on the example 1, allyl alcohol compound is changed into 2-methyl-2-propylene-1-alcohol, organic amine compound is changed into 2, 3-indoline, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:4) to give a pure yellow oily liquid in 61% yield.
The characterization results are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.10(t,J＝7.6Hz,2H,ArH),6.72(t,J＝7.6Hz,1H,ArH),6.61(d,J＝8.0Hz,1H,ArH),3.66(d,J＝6.4Hz,2H,OCH 2 ),3.59-3.53(m,1H,NCH 2 ),3.25-3.14(m,2H,NCH 2 ),3.02(br,1H,OH),3.01-2.95(m,2H,CH 2 ),2.89(dd,J＝4.8,13.2Hz,1H,CH 2 ),2.24-2.10(m,1H,CH),0.96(d,J＝6.8Hz,3H). 13 C NMR(100MHz,CDCl 3 ,ppm):δ152.8,130.2,127.4,124.6,118.6,108.0(ArC),68.6(OCH 2 ),56.6,55.0(NCH 2 ),34.1(CH),28.7,15.2.HRMS(APCI):calcd for C 12 H 17 ON[M + H] + :192.1383,found:192.1387.
the reaction scheme of example 10 is shown in FIG. 20.
Analysis of the characterization results shows that the structural formula of the obtained actual product is consistent with that of the target product in the reaction formula shown in fig. 20, and the high-yield and high-purity gamma-amino alcohol compound is successfully obtained in example 10.
Example 11
Based on the example 1, allyl alcohol compound is changed into 1-phenyl-2-propylene-1-alcohol, organic amine compound is changed into N-methylaniline, and other steps, components and component ratios are consistent;
the crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:16) to give a pure yellow oily liquid in 86% yield.
The characterization results are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.36(d,J＝4.0Hz,4H,ArH),7.32-7.22(m,3H,ArH),6.78(d,J＝8.8Hz,2H,ArH),6.75-6.73(m,1H,ArH),4.80(dd,J＝5.2,7.2,Hz,1H,CH),3.52-3.41(m,2H,NCH2),2.92(s,3H,NCH3),2.60(br,1H,OH),2.04-1.95(m,2H,CH 2 ). 13 C NMR(100MHz,CDCl 3 ,ppm):δ149.8,144.6,129.3,128.6,127.7,125.8,117.1,113.4(ArC),73.0(OCH),50.5(NCH 2 ),38.6,35.7.HRMS(APCI):calcd for C 16 H 19 ON[M + H] + :242.1539,found:242.1538.
the reaction scheme of example 11 is shown in FIG. 21.
Analysis of the characterization results shows that the structural formula of the obtained actual product is consistent with that of the target product in the reaction formula shown in fig. 21, and example 11 successfully obtains the high-yield and high-purity gamma-amino alcohol compound.
The method for synthesizing the gamma-amino alcohol compound can realize the high-efficiency preparation of the gamma-amino alcohol compound, provides a novel method for preparing the gamma-amino alcohol compound by using the rare earth catalyst, improves the synthesis yield of the gamma-amino alcohol compound, has the characteristics of easily available raw materials of the rare earth catalyst, few synthesis steps, simple preparation, high yield and no need of adding alkali and an activating agent, and ensures that the synthesis method of the gamma-amino alcohol compound is cheaper and cleaner.
The above embodiments are only exemplary embodiments of the present application and are not intended to limit the present application, the scope of which is defined by the claims. Various modifications and equivalent arrangements of this application will occur to those skilled in the art, and are intended to be within the spirit and scope of the application.
Claims (10)
1. The synthesis method of the gamma-amino alcohol compound is characterized by comprising the following steps:
dissolving allyl primary alcohol or allyl secondary alcohol and primary amine or secondary amine of different types in an organic solvent, and carrying out anti-Mahalanobis hydrogen amination reaction under the catalysis of a catalyst to obtain a target product;
wherein, the reaction formula of the hydroamination reaction is shown in figure 1, and R ', R' can represent hydrogen atoms, electron-withdrawing substituents, electron-donating substituents, aryl groups and hydrocarbon groups;
the R 'and the R' can be connected end to form a ring;
the catalyst is YC 3 The YC 3 Is Y (CH) 2 SiMe 3 ) 3 (THF) 2 。
2. The method for synthesizing a gamma-amino alcohol compound according to claim 1, wherein,
the R ', the R ' and the R ' are each independent.
3. The method for synthesizing a gamma-amino alcohol compound according to claim 1, wherein,
when R' "is a benzene ring, the priority of the substituent groups on the benzene ring is para, meta and ortho.
4. A method for synthesizing a gamma-amino alcohol compound according to any one of claims 1 to 3, wherein the synthesis of the target product comprises the steps of:
taking proper amount of catalyst Y (CH) 2 SiMe 3 ) 3 (THF) 2 A compound A having a structure shown in formula (II) in FIG. 2, a compound B having a structure shown in formula (III) in FIG. 2, and an organic solvent;
sequentially adding the compound A, the compound B and the organic solvent into the catalyst, wherein the compound A and the compound B can be completely dissolved in the solvent, and nucleophilic addition reaction is carried out to obtain the target product with the structure shown as the formula (I) in figure 2;
wherein R in the formula (I), the formula (II) and the formula (III) 1 At least comprises-H, -CH 3 、-OCH 3 、-F、-Cl、-Br；
R 2 At least comprises-H, -Me;
R 3 at least comprising-H, -Ph, -Et;
R 4 at least comprises-H, -CH 3 、-Br；
R 5 At least comprises-H, -Me;
R 6 at least comprising-Me, -Et, -Ph, and substituted aryl;
R 7 at least comprises-H, -Ph.
5. The method for synthesizing a gamma-amino alcohol compound according to claim 4, wherein,
the organic solvent is any one of n-hexane, toluene, tetrahydrofuran and ethyl acetate.
6. The method for synthesizing a gamma-amino alcohol compound according to claim 4, wherein,
the molar ratio of the compound A to the compound B is 1:2-1:3.
7. The method for synthesizing a gamma-amino alcohol compound according to claim 4, wherein,
the reaction conditions of the nucleophilic addition reaction are as follows:
the temperature is 70-90 ℃, the reaction time is 12-72h, and the catalyst loading is 10mol%.
8. The method for synthesizing a gamma-amino alcohol compound according to claim 7, wherein,
the reaction conditions of the nucleophilic addition reaction are as follows:
the temperature was 80℃and the reaction time was 48h.
9. The method for synthesizing a gamma-amino alcohol compound according to claim 4, wherein,
the method also comprises the following steps:
before the reaction, the compound a, the compound B and the organic solvent are dried so that the water content of the compound a, the compound B and the organic solvent is lower than 0.1%.
10. The method for synthesizing a gamma-amino alcohol compound according to claim 4, wherein,
the method also comprises the following steps:
taking the target product, and purifying the target product by silica gel column chromatography to obtain a high-purity product;
wherein, during the purification process, ethyl acetate: petroleum ether=1:2-1:8.
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