CN117088830A - Synthesis method of 2-amino-2- (furan-3-yl) acetic acid compound - Google Patents
Synthesis method of 2-amino-2- (furan-3-yl) acetic acid compound Download PDFInfo
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- -1 2-amino-2- (furan-3-yl) acetic acid compound Chemical class 0.000 title claims abstract description 40
- 238000001308 synthesis method Methods 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- PGRLXLPRSSHTCN-UHFFFAOYSA-N 2-azaniumyl-2-(furan-3-yl)acetate Chemical class OC(=O)C(N)C=1C=COC=1 PGRLXLPRSSHTCN-UHFFFAOYSA-N 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 4
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 4
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000009987 spinning Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 2
- 239000011259 mixed solution Substances 0.000 claims 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 22
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 abstract description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- 238000005265 energy consumption Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- JLPJFSCQKHRSQR-UHFFFAOYSA-N oxolan-3-one Chemical compound O=C1CCOC1 JLPJFSCQKHRSQR-UHFFFAOYSA-N 0.000 description 10
- HAKFKLNJIKJGET-UHFFFAOYSA-N 2-azaniumyl-2-(oxolan-3-yl)acetate Chemical compound OC(=O)C(N)C1CCOC1 HAKFKLNJIKJGET-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-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
- 230000000052 comparative effect Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention relates to a synthesis method of 2-amino-2- (furan-3-yl) acetic acid compounds, which comprises the following steps: allowing a compound represented by the formula (I)With 2- (dimethoxyphosphono) -2- [ [ (phenylmethoxy) carbonyl group]Amino group]Methyl acetate or 2- (dimethoxyphosphono) -2- [ [ (phenylmethoxy) carbonyl]Amino group]Ethyl acetate in the presence of a base to produce a compound of formula (II)Subjecting a compound represented by the formula (II) to hydrolysis reaction to produce a compound represented by the formula (III)Hydrogenation reaction of a compound shown in a formula (III) in the presence of a catalyst to generate 2-amino-2- (furan-3-yl) acetic acid compoundsArticle (B)Compared with the existing synthesis method, the synthesis method has the advantages of three-step reaction, simple operation steps, mild reaction temperature of each step, low energy consumption and more than 49 percent of total yield of the three-step reaction.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of a 2-amino-2- (furan-3-yl) acetic acid compound.
Background
The 2-amino-2- (furan-3-yl) acetic acid compound is an important intermediate as a protease inhibitor and has very wide application in the field of medicinal chemistry.
The synthesis method of the compound disclosed at present has complicated steps, such as reference documents: potent HIV protease inhibitors the development oftetrahydrofuranylglycines as novel P-ligands and pyrazine amidesas P3-linkages, arun K.Ghosh, wayne J.Thompson, M.Katharine Holloway JournalofMedicinal Chemistry, 1993. Published synthetic routes are as follows:
the method takes 3-hydroxytetrahydrofuran as a raw material, and the 2-amino-2- (tetrahydrofuran-3-yl) acetic acid product is prepared through 6 steps of reaction, so that the steps are complicated, the reaction time is long, the operation difficulty is high, for example, the steps (e) and (f) are operated at the temperature of minus 78 ℃, more raw materials and solvents are adopted in each step of reaction, the whole synthesis process is finished, the required raw materials and solvents are excessive, and the cost is high; and various toxic substances and corrosive raw materials such as MsCl, naH and the like are also required to be adopted in the reaction.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of 2-amino-2- (furan-3-yl) acetic acid compounds, which has the advantages of simple and efficient steps, mild reaction and high yield.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing a 2-amino-2- (furan-3-yl) acetic acid compound, the method comprising the steps of:
s1, reacting a compound shown in a formula (I) with methyl 2- (dimethoxy phosphonous) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate or ethyl 2- (dimethoxy phosphonous) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate in the presence of a base to generate the compound shown in the formula (II);
s2, carrying out hydrolysis reaction on the compound shown in the formula (II) to generate a compound shown in the formula (III);
s3, carrying out hydrogenation reaction on a compound shown in a formula (III) in the presence of a catalyst to generate a 2-amino-2- (furan-3-yl) acetic acid compound;
the structural formula of the compound shown in the formula (I) is as follows:
the structural formula of the compound shown in the formula (II) is as follows:
the structural formula of the compound shown in the formula (III) is as follows:
the structural formula of the 2-amino-2- (furan-3-yl) acetic acid compound is as follows:
wherein R is 1 、R 2 、R 3 、R 4 Each independently is one selected from a H, C C1-C8 straight-chain or branched-chain alkyl group and a C1-C4 alkoxy group; r is R 5 Is methyl or ethyl.
According to some embodiments of the invention, the R 1 、R 2 、R 3 、R 4 Each independently is one selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy and propoxy.
Further, the R 1 、R 3 Respectively H, R is 2 、R 4 Each independently is one selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy and propoxy.
Further, the feeding mole ratio of the compound shown in the formula (I) to the methyl 2- (dimethoxy phosphonite) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate or the ethyl 2- (dimethoxy phosphonite) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate is 1:1-1.5.
In step S1, the feeding molar ratio of the compound shown in the formula (I) to the alkali is 1:1-2.
In the invention, the structural formula of the 2- (dimethoxy phosphono) -2- [ [ (phenylmethoxy) carbonyl ] amino ] methyl acetate is as follows:
the structural formula of the 2- (dimethoxy phosphonite) -2- [ [ (phenylmethoxy) carbonyl ] amino ] ethyl acetate is as follows:
according to some embodiments of the invention, in step S1, the base is an organic base. Further, the base is one or a combination of several selected from triethylamine, N-methyl morpholine, pyridine, 1, 8-diazabicyclo undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN) and Tetramethylguanidine (TMG).
Further, the base is one or a combination of a plurality of 1, 8-diazabicyclo undec-7-ene and 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN).
Preferably, the base is added in the form of a drop. Further, the dropping speed is 1 to 5 drops/second. Further, the dropping speed is 1 to 3 drops/second
According to some embodiments of the invention, in step S1, the reaction is carried out at-5 to 5℃for a period of 1 to 3 hours.
According to some embodiments of the invention, in step S1, after the reaction is finished, the reaction solution is washed with water, extracted, and purified to obtain the compound shown in the formula (II).
According to some embodiments of the invention, in step S1, the reaction is performed in the presence of an organic solvent. Further, the organic solvent is one or a combination of a plurality of Dichloromethane (DCM) and dichloroethane.
According to some embodiments of the invention, in step S2, the hydrolysis reaction is performed in a mixture of methanol and water and in the presence of a base, wherein the base is one or a combination of several of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
Further, in the step S2, the volume ratio of the methanol to the water is 1.5-2.5:1.
According to some embodiments of the invention, in step S2, the hydrolysis reaction is carried out at 15-45 ℃.
According to some embodiments of the invention, in step S2, after the hydrolysis reaction is finished, the methanol is spin-dried, the impurities are extracted, the pH is adjusted to 1-3, and the compound shown in the formula (III) is obtained by recrystallization.
Further, the extraction impurities adopt a mixture of Petroleum Ether (PE) and Ethyl Acetate (EA), wherein the volume ratio of petroleum ether to ethyl acetate is 1:1 to 3. The pH is adjusted by hydrochloric acid.
According to some embodiments of the invention, in step S3, the catalyst is one or a combination of several of Pd/C, palladium alumina, palladium barium sulfate.
According to some embodiments of the invention, in step S3, the compound of formula (III) is dissolved in methanol, and then the hydrogenation reaction is performed.
According to some embodiments of the invention, in step S3, the hydrogenation reaction is carried out at 15-45 ℃.
According to some embodiments of the present invention, in step S3, after the hydrogenation reaction is completed, the reaction solution is filtered to obtain an organic phase and a catalyst phase; the catalyst phase is washed and filtered to obtain a water phase and a catalyst; and combining the aqueous phase and the organic phase, spin-drying, washing with ethanol, filtering and drying to obtain the 2-amino-2- (furan-3-yl) acetic acid compound. The catalyst is recovered and can be reused.
Further, in the step S3, the mass ratio of the catalyst to the compound shown in the formula (III) is 1:5-10.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the synthesis method of the invention takes 3-tetrahydrofuranone as a starting material, and the reactant obtained by the reaction of the 3-tetrahydrofuranone and 2- (dimethoxy phosphonite) -2- [ [ (phenylmethoxy) carbonyl ] amino ] methyl acetate or 2- (dimethoxy phosphonite) -2- [ [ (phenylmethoxy) carbonyl ] amino ] ethyl acetate in the presence of alkali is hydrolyzed and hydrogenated in sequence to prepare the 2-amino-2- (furan-3-yl) acetic acid compound.
The synthetic method of the invention does not need to use extremely toxic and corrosive substances (such as MsCl and NaH) in the whole synthetic route, has high safety coefficient, is easy to operate and control, and is suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 2-amino-2- (tetrahydrofuran-3-yl) acetic acid of example 1.
Detailed Description
The following detailed description of the present invention is provided in connection with specific embodiments so that those skilled in the art may better understand and practice the present invention, but is not intended to limit the scope of the present invention.
The starting materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.
The structure of the compound was obtained by nuclear magnetic resonance (1H-NMR). The NMR measurement was performed using an ACF-400BRUKER type nuclear magnetic resonance apparatus, and the solvent was deuterated chloroform (CDCl) 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) Or heavy water (D) 2 O), TMS is an internal standard. Column chromatography adopts 200-300 mesh silica gel (produced by Qingdao ocean chemical plant).
Example 1
Synthesis of 2-amino-2- (tetrahydrofuran-3-yl) acetic acid provided in this example
Step S1, under ice bath conditions, 3-tetrahydrofuranone (5 g,0.06 mol), methyl 2- (dimethoxy phosphono) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate (23.1 g,0.07 mol) and 5mL of DCM solution are respectively added into a 100mL three-neck flask, the rotating speed is adjusted to 1500rpm, DBN (9.3 g,0.075 mol) is slowly added dropwise through a dropping funnel, 2 drops/sec are kept, stirring reaction is carried out for 2H, the reaction is finished, water washing is carried out twice, ethyl acetate extraction is carried out, column chromatography purification is carried out, 17.5g of (Z) -2- (((benzyloxy) carbonyl) amino) -2- (dihydrofuran-3 (2H) -subunit) methyl acetate is obtained, the yield: 99.5%.
1 H NMR(400MHz,CDCl 3 )δ8.15(s,1H),7.34(m,5H),5.14(d,2H),4.12(d,2H),3.95(t,2H),3.76(s,3H),2.86(t,2H).
Step S2, adding 50mLMeOH/25mL H into a flask under ice bath condition 2 O, methyl (Z) -2- (((benzyloxy) carbonyl) amino) -2- (dihydrofuran-3 (2H) -subunit) acetate (10 g,0.035 mol) is added, 50mL of 1N sodium hydroxide solution is then added dropwise, the reaction is carried out overnight at room temperature, after the reaction is finished, meOH is dried by spinning, PE: EA (volume ratio of 1:1) is extracted for 2 times, hydrochloric acid is used for adjusting pH to 2, and the product (Z) -2- (((benzyloxy) carbonyl) amino) -2- (dihydrofuran-3 (2H) -subunit) acetic acid is obtained after recrystallization, 9.3g of the product is obtained, the yield: 96%.
1 H NMR(400MHz,CDCl 3 )δ7.99(s,1H),7.34(m,5H),5.14(d,2H),4.09(d,2H),3.95(t,2H),2.82(t,2H).
S3, dissolving (Z) -2- (((benzyloxy) carbonyl) amino) -2- (dihydrofuran-3 (2H) -subunit) acetic acid (8.2 g,0.03 mol) in 50mL of MeOH, introducing hydrogen, adding 1g of Pd/C, reacting at room temperature overnight, filtering the reaction solution after the reaction is finished to obtain a methanol phase and Pd/C, washing the Pd/C with pure water for multiple times, and filtering and recovering the Pd/C; the methanol phase and the water phase are combined, spin-dried, washed by a small amount of ethanol, filtered and dried to obtain 4.3g of the final product 2-amino-2- (tetrahydrofuran-3-yl) acetic acid, and the yield is 98%.
The nuclear magnetic spectrum of the product of this example is shown in FIG. 1.
1 H NMR(400MHz,D 2 O)δ3.88(m,2H),3.67(ddt,3H),2.66(hept,1H),2.09(ttd,1H),1.76(m,1H).
Example 2
Synthesis of 2-amino-2- (4-methyltetrahydrofuran-3-yl) acetic acid provided in this example
In this example, the specific preparation method is basically the same as in example 1, except that: in step S1, 0.06molInstead of 3-tetrahydrofuranone, the drop rate of DBN is 1 drop/sec; and step S2, adding corresponding materials in the step S3. Total yield of the final product: 93.6%.
1 H NMR(400MHz,D 2 O)4.14(td,1H),3.88(dd,3H),3.69(dd,1H),2.47(pq,1H),2.25(hept,1H),0.90(dd,3H).
Example 3
This example provides the synthesis of 2-amino-2- (4-ethyltetrahydrofuran-3-yl) acetic acid
In this example, the specific preparation method is basically the same as in example 1, except that: in step S1, 0.05molReplacing 3-tetrahydrofuranone; step S2, adding corresponding materials in the step S3; in step S3, 1.5g Pd/C was added.Total yield of the final product: 93.1%.
1 H NMR(400MHz,D 2 O)δ4.22(td,1H),3.88(m,4H),2.52(p,1H),2.26(dqdd,1H),1.42(m,2H),0.92(td,3H).
Example 4
This example provides the synthesis of 2-amino-2- (5-methyltetrahydrofuran-3-yl) acetic acid
In this example, the specific preparation method is basically the same as in example 1, except that: in step S1, 0.06molReplacing 3-tetrahydrofuranone; step S2, adding corresponding materials in the step S3; in step S2, 55mL MeOH/25mL H was added to the flask 2 O. Total yield of the final product: 94%.
1 H NMR(400MHz,D 2 O)δ4.06(m,2H),3.81(ddd,2H),2.63(h,1H),2.09(t,2H),1.24(d,3H).
Example 5
This example provides the synthesis of 2-amino-2- (5-isopropyltetrahydrofuran-3-yl) acetic acid
In this example, the specific preparation method is basically the same as in example 1, except that: in step S1, 0.06molAnd (3) replacing 3-tetrahydrofuranone, and adding corresponding materials in the step S2 and the step S3. Total yield of the final product: 93.3%.
1 H NMR(400MHz,D 2 O)δ4.11(m,2H),3.91(m,2H),2.60(h,1H),1.89(m,3H),0.98(ddd,6H).
Example 6
The synthesis method of 2-amino-2- (tetrahydrofuran-3-yl) acetic acid provided in this example is basically the same as that of example 1, except that: in step S1, DBU is used instead of DBN.
3-tetrahydrofuranone (5 g,0.06 mol), methyl 2- (dimethoxyphosphono) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate (23.1 g,0.07 mol), 5mL of DCM solution, were added to a 100mL three-necked flask under ice bath conditions, the rotation speed was adjusted to 1500rpm, DBU (11.5 g,0.075 mol) was slowly added dropwise through a dropping funnel, 2 drops/sec was maintained, the reaction was stirred for 2 hours, the reaction was completed, water washing was performed twice, ethyl acetate extraction was performed, and column chromatography purification was performed to obtain a product yield of 92%.
Example 7
The synthesis method of 2-amino-2- (tetrahydrofuran-3-yl) acetic acid provided in this example is basically the same as that of example 1, except that: in step S1, TMG is used instead of DBN.
3-tetrahydrofuranone (5 g,0.06 mol), methyl 2- (dimethoxy phosphono) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate (23.1 g,0.07 mol), 5mL of DCM solution, were added to a 100mL three-neck flask under ice bath conditions, the rotation speed was adjusted to 1500rpm, TMG (8.7 g,0.075 mol) was slowly added dropwise through a dropping funnel, 2 drops/sec was maintained, the reaction was stirred for 2 hours, the reaction was completed, water washing was performed twice, ethyl acetate extraction was performed, and column chromatography purification was performed, to obtain a product yield of 52%.
Example 8
The synthesis method of 2-amino-2- (tetrahydrofuran-3-yl) acetic acid provided in this example is basically the same as that of example 1, except that: in step S1, DBN is not added dropwise, but is added to the flask all at once. The product yield of step S1 was 83%.
Comparative example 1
The synthesis method of 2-amino-2- (tetrahydrofuran-3-yl) acetic acid provided in this comparative example is substantially the same as in example 1, except that: in step S1, an inorganic base sodium hydride is used instead of DBN. 3-tetrahydrofuranone (5 g,0.06 mol), methyl 2- (dimethoxyphosphono) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate (23.1 g,0.07 mol), 5mL of DCM solution, adjusting the rotation speed to 1500rpm, adding NaH (1.8 g,0.075 mmol), stirring for 2h, reacting, washing twice with water, extracting with ethyl acetate, and purifying by column chromatography to obtain the product with 18% yield.
The above embodiments are only for illustrating the technical concept and features of the present invention, and it is intended to cover all the equivalent changes and modifications made by those skilled in the art within the scope of the present invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
Claims (10)
1. A method for synthesizing a 2-amino-2- (furan-3-yl) acetic acid compound, which is characterized by comprising the following steps:
s1, reacting a compound shown in a formula (I) with methyl 2- (dimethoxy phosphonous) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate or ethyl 2- (dimethoxy phosphonous) -2- [ [ (phenylmethoxy) carbonyl ] amino ] acetate in the presence of a base to generate the compound shown in the formula (II);
s2, carrying out hydrolysis reaction on the compound shown in the formula (II) to generate a compound shown in the formula (III);
s3, carrying out hydrogenation reaction on a compound shown in a formula (III) in the presence of a catalyst to generate a 2-amino-2- (furan-3-yl) acetic acid compound;
the structural formula of the compound shown in the formula (I) is as follows:
the structural formula of the compound shown in the formula (II) is as follows:
the structural formula of the compound shown in the formula (III) is as follows:
the structural formula of the 2-amino-2- (furan-3-yl) acetic acid compound is as follows:
wherein R is 1 、R 2 、R 3 、R 4 Each independently is one selected from a H, C C1-C8 straight-chain or branched-chain alkyl group and a C1-C4 alkoxy group; r is R 5 Is methyl or ethyl.
2. The method for synthesizing 2-amino-2- (furan-3-yl) acetic acid compounds according to claim 1, wherein: the R is 1 、R 2 、R 3 、R 4 Each independently is one selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy and propoxy.
3. The method for synthesizing 2-amino-2- (furan-3-yl) acetic acid compounds according to claim 2, wherein: the R is 1 、R 3 Respectively H, R is 2 、R 4 Each independently is one selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy and propoxy.
4. A method for synthesizing a 2-amino-2- (furan-3-yl) acetic acid compound according to any one of claims 1 to 3, characterized in that: in the step S1, the alkali is one or a combination of a plurality of triethylamine, N-methyl morpholine, pyridine, 1, 8-diazabicyclo undec-7-ene and 1, 5-diazabicyclo [4.3.0] -5-nonene and tetramethyl guanidine; and/or, in step S1, the reaction is performed in the presence of an organic solvent.
5. The method for synthesizing 2-amino-2- (furan-3-yl) acetic acid compounds according to claim 4, wherein: the alkali is one or a combination of a plurality of 1, 8-diazabicyclo undec-7-ene and 1, 5-diazabicyclo [4.3.0] -5-nonene; and/or the organic solvent is one or a combination of a plurality of dichloromethane and dichloroethane.
6. The method for synthesizing 2-amino-2- (furan-3-yl) acetic acid compounds according to claim 4, wherein: the base is added in the form of a drop.
7. A method for synthesizing a 2-amino-2- (furan-3-yl) acetic acid compound according to any one of claims 1 to 3, characterized in that: in the step S1, the reaction is carried out at the temperature of-5 to 5 ℃ for 1 to 3 hours; and/or, in the step S1, after the reaction is finished, washing the reaction liquid with water, extracting and purifying to obtain the compound shown in the formula (II).
8. A method for synthesizing a 2-amino-2- (furan-3-yl) acetic acid compound according to any one of claims 1 to 3, characterized in that: in the step S2, the hydrolysis reaction is carried out in a mixed solution of methanol and water and in the presence of alkali, wherein the alkali is one or a combination of more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; and/or, in the step S2, the hydrolysis reaction is carried out at 15-45 ℃.
9. The method for synthesizing 2-amino-2- (furan-3-yl) acetic acid compounds according to claim 8, wherein: in the step S2, after the hydrolysis reaction is finished, the methanol is dried in a spinning way, the impurities are extracted, the pH value is regulated to be 1-3, and the compound shown in the formula (III) is obtained through recrystallization.
10. A method for synthesizing a 2-amino-2- (furan-3-yl) acetic acid compound according to any one of claims 1 to 3, characterized in that: in the step S3, the catalyst is one or a combination of a plurality of Pd/C, palladium aluminum oxide and palladium barium sulfate; and/or, in step S3, the compound represented by the formula (III) is dissolved in methanol, and then the hydrogenation reaction is performed; and/or, in the step S3, the hydrogenation reaction is carried out at 15-45 ℃; and/or, in the step S3, after the hydrogenation reaction is finished, filtering the reaction liquid to obtain an organic phase and a catalyst phase; the catalyst phase is washed and filtered to obtain a water phase and a catalyst; and combining the aqueous phase and the organic phase, spin-drying, washing with ethanol, filtering and drying to obtain the 2-amino-2- (furan-3-yl) acetic acid compound.
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