CN109912511A - A kind of preparation method of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen - Google Patents
A kind of preparation method of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen Download PDFInfo
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- -1 amino acid esters Chemical class 0.000 title claims abstract description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 35
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 16
- 239000000543 intermediate Substances 0.000 claims abstract description 13
- 150000002148 esters Chemical class 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 12
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 claims description 11
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 235000007164 Oryza sativa Nutrition 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 235000009566 rice Nutrition 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000010828 elution Methods 0.000 claims 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001413 amino acids Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000004048 modification Effects 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 239000012043 crude product Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000012512 characterization method Methods 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 241000209094 Oryza Species 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- MNEIJGDSFRHGMS-UHFFFAOYSA-N 1-(phenylmethyl)benzimidazole Chemical compound C1=NC2=CC=CC=C2N1CC1=CC=CC=C1 MNEIJGDSFRHGMS-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
- 238000001914 filtration Methods 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- SZJUWKPNWWCOPG-UHFFFAOYSA-N methyl 2-anilinoacetate Chemical compound COC(=O)CNC1=CC=CC=C1 SZJUWKPNWWCOPG-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000002028 Biomass Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 2
- BHFLUDRTVIDDOR-MRVPVSSYSA-N methyl (2r)-2-amino-2-phenylacetate Chemical compound COC(=O)[C@H](N)C1=CC=CC=C1 BHFLUDRTVIDDOR-MRVPVSSYSA-N 0.000 description 2
- BHFLUDRTVIDDOR-QMMMGPOBSA-N methyl (2s)-2-amino-2-phenylacetate Chemical compound COC(=O)[C@@H](N)C1=CC=CC=C1 BHFLUDRTVIDDOR-QMMMGPOBSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YTLYLLTVENPWFT-UPHRSURJSA-N (Z)-3-aminoacrylic acid Chemical group N\C=C/C(O)=O YTLYLLTVENPWFT-UPHRSURJSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses the preparation methods of a kind of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen; using amino-acid ester or its hydrochloric acid salt compounds as raw material; α-chloro acetylamino amino acid ester intermediates are prepared with alpha-chloro acetyl chlorine acylation, then intermediate is further reacted with benzimidazoles compound to the azepine Cabbeen salt compounds that amino acid chiral modification structure is prepared.
Description
Technical field
The invention belongs to chemical fields, and in particular to the system of a kind of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen
Preparation Method.
Background technique
N-heterocyclic carbine mainly includes imidazole type, pyrazoles type, triazole and thiazole type Cabbeen because of contained heteroatomic difference
Deng (Fig. 1).Wherein imidazole type Cabbeen is the most stable in dry air.The stability of N-heterocyclic carbine mainly with taking on ring
Dai Ji is related, if ring system exists grips structure altogether, be conducive to being stabilized of heterocycle carbine [J.Am.Chem.Soc., 1995,
117 (44): 11027-11028.], and it is generally connected to 1, big steric hindrance substituent group (such as adamantyl, tertiary fourth on 3 nitrogen-atoms
Base etc.) it can both prevent dimerization from [Chem.Commun., 2004, (19): 2172-2173] occurs, again to lone electron on Cabbeen carbon
With shielding action, to effectively facilitate stability [Angew.Chem.Int.Ed., 1997,36 (23): 2607- of Cabbeen
2609].Therefore, in terms of the structural modification of azepine Cabbeen ring, the knot of azepine Cabbeen ring can effectively be enhanced around features described above
Structure stability.Based on the continuous development of various nitrogenous Cabbeens, the azepine carbone catalyst that finding can be stabilized is always to change
The direction that scholars constantly study.1991, Arduengo is successfully synthesized for the first time and the isolated imidazoles that can be stabilized
Carbone catalyst, and [J.Am.Chem.Soc., 1991,113 (1): 361-363] are characterized to its structure, relative to having
Machine phosphorus ligand, it is not easy to break since metal-carbon key opposing metallic-phosphorus key is stronger, it is not necessary that excess ligand is added, in metal catalytic
Reaction in gradually substitute organophosphor ligand.
Summary of the invention
The object of the present invention is to provide the preparation methods of a kind of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen, borrow
Help the azepine Cabbeen salt compounds that natural chiral amino acrylate structure building unit contains Chirality, further enriches
The structure of chiral azepine Cabbeen salt.
To achieve the above object, The technical solution adopted by the invention is as follows:
The preparation method of a kind of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen, it includes the following steps:
(1) chiral amino acid esters or its hydrochloride shown in formula I and alpha-chloro excess acetyl chloride preparation formula shown in formula II
α shown in III-chloro acetylamino amino acid ester intermediates；
(2) resulting α-chloro acetylamino amino acid ester intermediates will be prepared and react preparation with benzimidazole shown in formula IV
Azepine Cabbeen shown in formula V,
Wherein, the R' in I~formula of formula V is any one in alkyl and aromatic radical, and R " is methyl, ethyl, butyl, different
Any one in propyl and benzyl, wherein R' is preferably any one in methyl, isopropyl and phenyl, and R " is preferably first
Any one in base, ethyl, butyl and benzyl.
Wherein, in step (1), used amino-acid ester or its hydrochloride are the amino-acid ester or its hydrochloric acid of natural chiral
Salt.
In step (1), chiral amino acid esters or its hydrochloride shown in formula I are mixed with alkali, after solvent is added, magneton stirring
It is uniformly mixed, then under nitrogen atmosphere, alpha-chloro chloroacetic chloride shown in formula II is slowly added dropwise into system for constant pressure funnel,
React α-chloro acetylamino amino acid ester intermediates shown in preparation formula III.
In step (1), the molar ratio for controlling chiral amino acid esters or its hydrochloride and alpha-chloro chloroacetic chloride is 1:0.9~1:
1.5；The alkali is sodium bicarbonate, sodium carbonate, potassium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide and triethylamine and pyridine
In any one or more, base amount is the 1~5 of chiral amino acid esters or its hydrochloride and alpha-chloro chloroacetic chloride moles total number
Times；The solvent be tetrahydrofuran, chloroform, methylene chloride, 1,2- dichloroethanes, ethyl acetate, toluene, dimethylbenzene, ether,
Any one or more in dimethyl sulfoxide and n,N-Dimethylformamide, solvent usage and chiral amino acid esters or its hydrochloric acid
The volume mM of salt and alpha-chloro chloroacetic chloride is than being 2:1~20:1；The dropwise addition is the completion of dropwise addition in 10~30min.
In step (1), reaction stirring rate is 800~1500r/min, and reaction temperature is 0 DEG C~70 DEG C, and the reaction time is
1~5h.
Wherein, step (1) preferred embodiment is to control mole of chiral amino acid esters or its hydrochloride and alpha-chloro chloroacetic chloride
Than for 1:0.95~1:1.05；The alkali is any one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, and base amount is
1~2 times of chiral amino acid esters or its hydrochloride and alpha-chloro chloroacetic chloride moles total number；The solvent is low boiling point solvent:
Any one or more of tetrahydrofuran, chloroform, methylene chloride, solvent usage and chiral amino acid esters or its hydrochloride and α-chlorine
Volume mM ratio for chloroacetic chloride is 5:1~10:1；Time for adding is 15min, and reaction stirring rate is 800~1000r/
Min, reaction temperature are 5 DEG C~25 DEG C, and the reaction time is 2~4h.
Wherein, the molar ratio of chiral amino acid esters or its hydrochloride and alpha-chloro chloroacetic chloride is more preferably 1:1.
Step (1) after reaction material through reduced pressure, ethyl acetate or methylene chloride extraction, washing after obtain it is organic
Phase obtains α-chloro acetylamino amino acid ester intermediates after organic phase concentration.
In step (2), benzimidazole shown in resulting α-chloro acetylamino amino acid ester intermediates and formula IV will be prepared
Azepine Cabbeen shown in preparation formula V is stirred to react under heating pressurization, solvent existence condition.
It in step (2), disperses benzimidazoles compound in solvent, adds α-chloro acetylamino amino-acid ester.
In step (2), the molar ratio for controlling α-chloro acetylamino amino-acid ester and benzimidazole is 1.5:1~1:1；Reaction
Solvent be tetrahydrofuran, 1,4- dioxane, methyl tertiary butyl ether(MTBE), ethyl acetate, toluene and dimethylbenzene in any one or
A variety of, solvent usage is with the volume mM of α-chloro acetylamino amino-acid ester and benzimidazole than being 0.5:1~10:1.
In step (2), reaction stirring rate is 800~1500r/min, and heating temperature is 30~120 DEG C, and pressure range is
Under 1~5 atmospheric pressure, the reaction time is 1~10h.
Wherein, the preferred embodiment of step (2) is that the molar ratio for controlling α-chloro acetylamino amino-acid ester and benzimidazole is
0.95:1~1.05:1；Reaction dissolvent is any one or more of tetrahydrofuran, Isosorbide-5-Nitrae-dioxane and toluene, solvent usage
With the volume mM of α-chloro acetylamino amino-acid ester and benzimidazole than be 1:1~3:1, reaction stirring rate be 800~
1000r/min, heating temperature are 80~100 DEG C, and pressure range is 1~2 atmospheric pressure, and the reaction time is 3~5h.
After the reaction was completed, reaction system is spin-dried for for step (2), and methylene chloride is added and dissolves just to mixture, second is added dropwise
Ether is until there is white opacity just, and by -10~20 DEG C of system immigration, cooling crystallization is filtered, and ether elutes filter cake, obtains rice
White or faint yellow solid are azepine Cabbeen.
Above-mentioned preparation reaction is such as formula VI:
The utility model has the advantages that
The present invention has the advantage that
(1) use biomass chiral amino acid for raw material in the present invention, by the chiral structure feature construction of natural amino acid
Chiral azepine Cabbeen salt, raw material is convenient, green degree is high；
(2) from a wealth of sources since chiral amino acid structure species are more in the present invention, it is conducted into azepine carbone catalyst
Preparation can effectively promote the added value of natural amino acid；
(3) the azepine Cabbeen salt with Biomass Characteristics is prepared by simple building mode in the present invention, it is intermediate
Process is not necessarily to complex separations process, and combined coefficient is high, biological safety is high.
Detailed description of the invention
The different types of N-heterocyclic carbine of Fig. 1.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
Embodiment 1:
Step (1): raw material (R)-phenyl glycine methyl ester hydrochloride (10mmol) pretreatment: into 100mL reaction flask, benzene
Base glycine methyl ester hydrochloride (10mmol) is dissolved in methanol (20mL), is stirring evenly and then adding into Anhydrous potassium carbonate (15mmol),
After stirring 30min under room temperature, filtering is concentrated to get phenyl glycine methyl ester 1.60g, yield 97%.
Phenyl glycine methyl ester (2mmol) and sodium bicarbonate (5mmol) is added in 50mL there-necked flask, 10mL dichloro is added
Methane, the rear magneton that is added are uniformly mixed.Under nitrogen atmosphere, dripped through constant pressure funnel into system in 10min
Chloracetyl chloride (2mmol).30 DEG C, after reacting 4h in the case where being 1200rpm with stirring rate, material is through depressurizing after reaction
Organic phase is obtained after concentration, methylene chloride extraction, washing, obtains 2- (2- chloracetyl amido) -2- phenyl second after organic phase concentration
Sour methyl esters crude product 0.36g (1.49mmol), yield 74.5%, gained crude product are subsequent spare.
Nuclear magnetic data characterization:1H NMR(500MHz,d6- DMSO) δ 9.09 (d, J=7.0Hz, 1H), 7.59-7.28 (m,
5H), 5.47 (d, J=7.1Hz, 1H), 4.19 (s, 2H), 3.68 (s, 3H).
Step (2): 1- benzyl benzimidazole (1.5mmol) is added into 35mL pressure pipe, while tetrahydrofuran is added
After being uniformly dispersed, 2- (2- chloracetyl amido) -2- phenylacetate crude product prepared by step (1) is added in (3mL)
(1.49mmol), 80 DEG C, 1.5 atmospheric pressure under confined conditions, 7h is stirred to react with the revolving speed of 800r/min.Reaction terminates
Afterwards, reaction system is spin-dried for, methylene chloride is added and is dissolved just to mixture, ether is added dropwise until there is white opacity just,
System is moved into -10~20 DEG C, cooling crystallization filters, and ether elutes filter cake, obtains rice white or faint yellow solid is azepine
Cabbeen product 0.46g, yield 67%.
Nuclear magnetic data characterization:1H NMR(400MHz,d6- DMSO) δ 10.12 (s, 1H), 9.81 (s, 1H), 7.98 (d, J=
21.6Hz,2H),7.52(m,12H),5.88(s,2H),5.56(s,2H),5.49(s,1H),3.63(s,3H)。
HRMS-ESI+(m/z):C25H24ClN3O3[M+H]+, calcd for 449.1506, found 449.1525.
Embodiment 2:
Step (1): 50mL tri- is added in (R)-phenyl glycine methyl ester hydrochloride (2mmol) and sodium bicarbonate (6mmol)
In mouth bottle, 10mL methylene chloride is added, the rear magneton that is added is uniformly mixed.Under nitrogen atmosphere, through constant pressure addition in 10min
Funnel drips chloracetyl chloride (2mmol) into system.25 DEG C, after reacting 4h in the case where being 1000rpm with stirring rate, instead
Material is concentrated under reduced pressure after answering, ethyl acetate extracts, organic phase is obtained after washing, obtains 2- (2- chlorine after organic phase concentration
Acetamido) -2- phenylacetate crude product 0.33g (1.36mol), yield 68%.Gained crude product is subsequent spare.
Step (2): being added 1- benzyl benzimidazole (1.5mmol) into 35mL pressure pipe, while 3mL toluene be added, point
After dissipating uniformly, it is added above-mentioned 2- (2- chloracetyl amido) -2- phenylacetate crude product (1.36mol), 80 DEG C, in 1 atmosphere
Pressure under confined conditions, is stirred to react 7h with the revolving speed of 1000r/min.After reaction, reaction system is spin-dried for, dichloro is added
Methane dissolves just to mixture, and ether is added dropwise until there is white opacity just, system is moved into -10~20 DEG C, cooling analysis
Crystalline substance, filtering, ether elute filter cake, obtain rice white or faint yellow solid is azepine Cabbeen product 0.41g, yield 61%.
Nuclear magnetic data characterization:1H NMR(400MHz,d6- DMSO) δ 10.12 (s, 1H), 9.81 (s, 1H), 7.98 (d, J=
21.6Hz,2H),7.52(m,12H),5.88(s,2H),5.56(s,2H),5.49(s,1H),3.63(s,3H)。
HRMS-ESI+(m/z):C25H24ClN3O3[M+H]+, calcd for 449.1506, found 449.1525.
Embodiment 3:
Step (1): the pretreatment of (S)-phenyl glycine methyl ester hydrochloride Starting material: into 100mL reaction flask, by (S) benzene
Base glycine methyl ester hydrochloride (10mmol) is dissolved with methanol (20mL), is stirring evenly and then adding into Anhydrous potassium carbonate (15mmol),
After stirring 30min under room temperature, filtering is concentrated to get (S)-phenyl glycine methyl ester, 1.62g, yield 98%.
Above-mentioned gained phenyl glycine methyl ester (2mmol) and sodium bicarbonate (4mmol) are added in 50mL there-necked flask, are added
10mL tetrahydrofuran, the rear magneton that is added are uniformly mixed.Under nitrogen atmosphere, through constant pressure funnel to system in 10min
In drip chloracetyl chloride (2mmol).25 DEG C with stirring rate be 1000rpm in the case where react 5h after, object after reaction
Material is concentrated under reduced pressure, methylene chloride extracts, organic phase is obtained after washing, obtains 2- (2- chloracetyl amido)-after organic phase concentration
2- phenylacetate crude product 0.33g (1.36mol), products therefrom are subsequent spare.
Nuclear magnetic data characterization:1H NMR(500MHz,d6- DMSO) δ 9.09 (d, J=7.0Hz, 1H), 7.59-7.28 (m,
6H), 5.47 (d, J=7.1Hz, 1H), 4.19 (s, 2H), 3.68 (s, 3H).
Step (2): being added 1- benzyl benzimidazole (1.3mmol) into 35mL pressure pipe, while toluene (3mL) be added,
After being uniformly dispersed, above-mentioned 2- (2- chloracetyl amido) -2- phenylacetate crude product (1.36mol) is added, it is 100 DEG C, big at 1
Air pressure is stirred to react 5h under confined conditions, with the revolving speed of 1200r/min.After reaction, reaction system is spin-dried for, is added two
Chloromethanes dissolves just to mixture, and ether is added dropwise until there is white opacity just, system is moved into -10~20 DEG C, cooling
Crystallization, filtering, ether elute filter cake, obtain rice white or faint yellow solid is azepine Cabbeen product 0.48g, yield 82%.
Nuclear magnetic data characterization:1H NMR(400MHz,d6- DMSO) δ 10.12 (s, 1H), 9.81 (s, 1H), 7.98 (d, J=
21.6Hz,2H),7.52(m,12H),5.88(s,2H),5.56(s,2H),5.49(s,1H),3.63(s,3H)。
HRMS-ESI+(m/z):C25H24ClN3O3[M+H]+, calcd for 449.1506, found 449.1525.
Embodiment 4:
Step (1): Valine methyl ester hydrochloride (10mmol) and triethylamine (40mmol) are added in 100mL single port bottle,
The chloroform (50mL) of addition, the rear magneton that is added are uniformly mixed.Under nitrogen atmosphere, in 15min through constant pressure funnel to
Chloracetyl chloride (10mmol) is dripped in system.At 25 DEG C with stirring rate be 1000rpm in the case where react 3h after, instead
Material is concentrated under reduced pressure after answering, ethyl acetate extracts, organic phase is obtained after washing, obtains (S) -2- after organic phase concentration
(2- chloro acetylamino) -2,3- acid dimethyl methyl esters crude product (1.76g, yield 85.5%).
Nuclear magnetic data characterization:1H NMR(400MHz,CDCl3) δ 7.01 (d, J=6.4Hz, 1H), 4.48 (dd, J=8.8,
4.9Hz, 1H), 4.03 (s, 2H), 3.70 (s, 3H), 2.37-2.06 (m, 1H), 0.88 (dd, J=8.8,7.0Hz, 6H)
Step (2): being added 1- tolimidazole (2mmol) into 35mL pressure pipe, while toluene (4mL) be added, point
After dissipating uniformly, above-mentioned (S) -2- (2- chloro acetylamino) -2,3- acid dimethyl methyl esters crude product 0.414g (2.0mmol) is added,
100 DEG C, 1 atmospheric pressure under confined conditions, 3h is stirred to react with the revolving speed of 800r/min.After reaction, by reactant
System is spin-dried for, and methylene chloride is added and dissolves just to mixture, and ether is added dropwise until there is white opacity just, by system immigration-
10~20 DEG C, cooling crystallization filters, and ether elutes filter cake, obtains rice white or faint yellow solid is azepine Cabbeen product
0.584g, yield 86%.
Nuclear magnetic data characterization:1H NMR(CDCl3): 10.66 (s, 1H), 9.65 (d, J=7.3Hz, 1H), 8.05-8.02
(m, 1H), 7.68-7.60 (m, 3H), 5.94 (d, J=16.5Hz, 1H), 5.88 (d, J=16.5Hz, 1H), 4.29-4.26 (m,
1H), 4.22 (s, 3H), 3.61 (s, 3H), 2.32-2.24 (m, 1H), 1.07 (d, J=6.9Hz, 3H), 1.00 (d, J=
6.9Hz,3H)。
Embodiment 5:
Step (1): with (1) the step of embodiment 4；
Step (2): 1- benzyl benzimidazole (2mmol) is added into 35mL pressure pipe, while Isosorbide-5-Nitrae-dioxane is added
After being uniformly dispersed, above-mentioned (S) -2- (2- chloro acetylamino) -2,3- acid dimethyl methyl esters crude product (embodiment 4) is added in (4mL)
0.414g (2mmol), 80 DEG C, 1.5 atmospheric pressure under confined conditions, 7h is stirred to react with the revolving speed of 1000r/min.Reaction
After, reaction solution is transferred in 50mL single port bottle, is spin-dried for, a small amount of methylene chloride to mixture is added afterwards and dissolves, heats cold
Solidifying reflux, is completely dissolved to all solids, and a few drop ether are added afterwards to there is white opacity, moves into 0 DEG C of low temperature region, waits afterwards
Crystallization.It is complete to crystallization, it is filtered with sand mold funnel, obtained solid is product 0.639g, yield 77%.
Nuclear magnetic data characterization:1H NMR(400MHz,d6- DMSO) δ 10.12 (s, 1H), 9.36 (s, 1H), 7.98 (dd, J=
22.8,7.6Hz,2H),7.86–7.58(m,2H),7.65–7.49(m,2H),7.51–7.31(m,3H),5.88(s,2H),
5.77-5.39 (m, 2H), 4.22 (t, J=6.7Hz, 1H), 3.64 (s, 3H), 2.13 (dd, J=13.1,6.6Hz, 1H), 0.95
(dd, J=18.3,6.8Hz, 6H).
HRMS-ESI+(m/z):C22H27ClN3O3[M+H]+,calcd for 416.1735,found 416.1705。
Claims (10)
1. the preparation method of a kind of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen, which is characterized in that it includes as follows
Step:
(1) chiral amino acid esters or its hydrochloride shown in formula I and III institute of alpha-chloro excess acetyl chloride preparation formula shown in formula II
The α shown-chloro acetylamino amino acid ester intermediates；
(2) resulting α-chloro acetylamino amino acid ester intermediates will be prepared and react preparation formula V with benzimidazole shown in formula IV
Shown in azepine Cabbeen,
Wherein, the R' in I~formula of formula V is any one in alkyl and aromatic radical, and R " is methyl, ethyl, butyl, isopropyl
With any one in benzyl.
2. the preparation method of chiral amino acid esters according to claim 1 or its hydrochloride synthesis azepine Cabbeen, feature
It is, in step (1), chiral amino acid esters or its hydrochloride shown in formula I are mixed with alkali, and after solvent is added, magneton stirring is mixed
It closes uniformly, then under nitrogen atmosphere, alpha-chloro chloroacetic chloride shown in formula II is slowly added dropwise into system for constant pressure funnel, instead
Answer α shown in preparation formula III-chloro acetylamino amino acid ester intermediates.
3. the preparation method of chiral amino acid esters according to claim 2 or its hydrochloride synthesis azepine Cabbeen, feature
It is, in step (1), the molar ratio for controlling chiral amino acid esters or its hydrochloride and alpha-chloro chloroacetic chloride is 1:0.9~1:
1.5；The alkali is sodium bicarbonate, sodium carbonate, potassium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide and triethylamine and pyridine
In any one or more, base amount is the 1~5 of chiral amino acid esters or its hydrochloride and alpha-chloro chloroacetic chloride moles total number
Times；The solvent be tetrahydrofuran, chloroform, methylene chloride, 1,2- dichloroethanes, ethyl acetate, toluene, dimethylbenzene, ether,
Any one or more in dimethyl sulfoxide and n,N-Dimethylformamide, solvent usage and chiral amino acid esters or its hydrochloric acid
The volume mM of salt and alpha-chloro chloroacetic chloride is than being 2:1~20:1；The dropwise addition is the completion of dropwise addition in 10~30min.
4. the preparation method of chiral amino acid esters according to claim 2 or its hydrochloride synthesis azepine Cabbeen, feature
Be, in step (1), reaction stirring rate be 800~1500r/min, reaction temperature be 0 DEG C~70 DEG C, the reaction time be 1~
5h。
5. the system of the chiral amino acid esters according to any one of claim 2~4 or its hydrochloride synthesis azepine Cabbeen
Preparation Method, which is characterized in that material is extracted through reduced pressure, ethyl acetate or methylene chloride, washed step (1) after reaction
After obtain organic phase, obtain α-chloro acetylamino amino acid ester intermediates after organic phase concentration.
6. the preparation method of chiral amino acid esters according to claim 1 or its hydrochloride synthesis azepine Cabbeen, feature
It is, in step (2), resulting α-chloro acetylamino amino acid ester intermediates will be prepared with benzimidazole shown in formula IV through close
Closure ties up under 1~5 atmospheric pressure and is stirred to react azepine Cabbeen shown in preparation formula V under heating, solvent existence condition.
7. the preparation method of chiral amino acid esters according to claim 6 or its hydrochloride synthesis azepine Cabbeen, feature
It is, in step (2), disperses benzimidazoles compound in solvent, adds α-chloro acetylamino amino-acid ester.
8. the preparation method of chiral amino acid esters according to claim 6 or its hydrochloride synthesis azepine Cabbeen, feature
It is, in step (2), the molar ratio for controlling α-chloro acetylamino amino-acid ester and benzimidazole is 1.5: 1~1: 1；React molten
Agent be tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether(MTBE), ethyl acetate, toluene and dimethylbenzene in any one or it is more
Kind, solvent usage is with the volume mM of α-chloro acetylamino amino-acid ester and benzimidazole than being 0.5: 1~10: 1.
9. the preparation method of chiral amino acid esters according to claim 6 or its hydrochloride synthesis azepine Cabbeen, feature
It is, in step (2), reaction stirring rate is 800~1500r/min, and heating temperature is 30~120 DEG C, 1~5 atmospheric pressure
Under, the reaction time is 1~10h.
10. the system of the chiral amino acid esters according to any one of claim 6~9 or its hydrochloride synthesis azepine Cabbeen
Preparation Method, which is characterized in that after the reaction was completed, reaction system is spin-dried for for step (2), and it is just molten to mixture that methylene chloride is added
Solution is added dropwise ether until there is white opacity just, system is moved into -10~20 DEG C, and cooling crystallization filters, ether elution filter
Cake, obtains rice white or faint yellow solid is azepine Cabbeen.
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Citations (1)
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|---|---|---|---|---|
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-
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Non-Patent Citations (4)
| Title |
|---|
| MAKI SEKI，ET AL.: "A diastereoselective construction of pyrazinoisoquinoline skeletons via tandem cyclization of phenylalanine derivatives: a facile synthesis of optically active pyrazinoisoquinolines", 《TETRAHEDRON》 * |
| MISATO YOSHIMURA，ET AL.: "Ligand design for dual enantioselective control in Cu-catalyzed asymmetric conjugate addition of R2Zn to cyclic enone", 《TETRAHEDRON》 * |
| SHERIEF M.ABDEL-WAHAB，ET AL.: "Synthesis of 2-Aryl-and 2-Haloarylbenzimidazole-N1-acetamido Conjugates and a Preliminary Evaluation of Their Antifungal Properties", 《CHEMISTRYSELECT》 * |
| THORFINNUR GUNNLAUGSSON，ET AL.: "Synthesis, structural and biological evaluation of GlyAla based lanthanide macrocyclic conjugates as supramolecular ribonuclease mimics", 《POLYHEDRON》 * |
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|---|---|---|---|---|
| CN114195793A (en) * | 2021-12-09 | 2022-03-18 | 南京工业大学 | Nitrogen-aryl indole lactam compound, application thereof and preparation method of C-N axis-containing nitrogen-aryl indole axial chiral amino acid |
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