CN117624189A - Preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride - Google Patents
Preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride Download PDFInfo
- Publication number
- CN117624189A CN117624189A CN202311579745.3A CN202311579745A CN117624189A CN 117624189 A CN117624189 A CN 117624189A CN 202311579745 A CN202311579745 A CN 202311579745A CN 117624189 A CN117624189 A CN 117624189A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- preparation
- azodicarbonate
- oxa
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- AEUJPECOKQPLTC-UHFFFAOYSA-N 6-oxa-3-azabicyclo[3.1.1]heptane;hydrochloride Chemical compound Cl.C1NCC2CC1O2 AEUJPECOKQPLTC-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 12
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 239000011574 phosphorus Substances 0.000 claims abstract description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 6
- 229940125782 compound 2 Drugs 0.000 claims abstract description 6
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 5
- 239000002585 base Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 238000010306 acid treatment Methods 0.000 claims abstract description 3
- CNIBHMMDDXGDNR-UHFFFAOYSA-N ethyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate Chemical compound CCOC(=O)CNC(=O)OC(C)(C)C CNIBHMMDDXGDNR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 14
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000000967 suction filtration Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- QIEBRPAPXOIWES-UHFFFAOYSA-N 2-propan-2-yloxypropane;hydrochloride Chemical compound Cl.CC(C)OC(C)C QIEBRPAPXOIWES-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 241000221785 Erysiphales Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- -1 chloracetyl Chemical group 0.000 description 2
- 239000001257 hydrogen Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, which comprises the following steps: (1) Mixing chloroacetone with N-tert-butyloxycarbonyl glycine ethyl ester, a catalyst and alkali for reaction to obtain a compound 1; (2) mixing the compound 1 with a base to react to obtain a compound 2; (3) Mixing and reacting the compound 2 with a reducing agent to obtain a compound 3; (4) And mixing the compound 3 with a phosphorus ligand and azodicarbonate for reaction to obtain a compound 4, and then carrying out hydrochloric acid treatment to obtain the 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride. The preparation method provided by the invention can realize the preparation of the 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride by only five steps of reactions, and has the advantages of few synthesis steps, low raw material cost and high total reaction yield.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, in particular to a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride with few preparation steps and high yield.
Background
The 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride is a key fragment of a medicine containing oxa-bridged rings, and is prepared by the conventional method that 4-methoxybenzaldehyde reacts with ammonia water to generate imine, then epoxy chloropropane is subjected to ring opening, amino is subjected to chloracetyl, the ring is closed twice continuously, borane is reduced, hydrogenation is carried out, and hydrochloride is formed.
However, the steps are complex and are unfavorable for large-scale production, and the total yield is low, so that the unit cost is high. Therefore, how to provide an alternative method for synthesizing 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride with high yield, low cost and few reaction steps is a problem to be solved.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, in particular to a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride with less preparation steps and high yield. The preparation method provided by the invention can realize the preparation of the 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride by only five steps of reactions, and has the advantages of few synthesis steps, low raw material cost and high total reaction yield.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
the invention provides a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, which comprises the following steps:
(1) Mixing chloroacetone with N-tert-butyloxycarbonyl glycine ethyl ester, a catalyst and alkali for reaction to obtain a compound 1;
(2) Mixing the compound 1 with alkali for reaction to obtain a compound 2;
(3) Mixing and reacting the compound 2 with a reducing agent to obtain a compound 3;
(4) And mixing the compound 3 with a phosphorus ligand and azodicarbonate for reaction to obtain a compound 4, and then carrying out hydrochloric acid treatment to obtain the 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride.
The reaction route is as follows:
the reaction starts from chloroacetone, reacts with N-tert-butoxycarbonyl glycine ethyl ester under the action of alkali, then a ring-closed product is obtained by a one-pot method under the action of alkali, then a bridged ring compound is obtained by reduction and photo-extension reaction, boc is removed and salt is formed at the same time, the preparation of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride can be realized by only carrying out five steps of reactions, the whole process is simple, the process required by the preparation can be effectively reduced by adopting the one-pot method for synthesis, the total yield is improved, the raw materials are low and easy to obtain, and the production cost is reduced.
Preferably, the molar ratio of the chloroacetone to the ethyl N-t-butoxycarbonyl glycine ester, the catalyst and the alkali in the step (1) is (1-1.5): 1 (0.08-0.12): 1-1.5, wherein the part of the chloroacetone can be 1, 1.1, 1.2, 1.3, 1.4 or 1.5, and the like, the part of the catalyst can be 0.08, 0.09, 0.1, 0.11 or 0.12, and the like, and the part can be 1, 1.1, 1.2, 1.3, 1.4 or 1.5, and the like, but the method is not limited to the values listed above, and other non-listed values in the numerical range are applicable.
Preferably, the catalyst of step (1) comprises any one or a combination of at least two of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium bisulfate (TBAB), trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride, preferably tetrabutylammonium bromide.
Preferably, the reaction in step (1) is carried out at a temperature of 10 to 20℃for 1 to 5 hours, wherein the temperature may be 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃,16 ℃, 17 ℃,18 ℃, 19 ℃,20 ℃ or the like, and the time may be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or the like, but not limited to the above-listed values, and other non-listed values within the above-listed ranges are equally applicable.
Preferably, the temperature of the reaction in the step (2) is 0-10 ℃ for 1-5 hours, wherein the temperature may be 0 ℃,1 ℃,2 ℃,3 ℃,4 ℃,5 ℃,6 ℃,7 ℃, 8 ℃, 9 ℃ or 10 ℃, and the time may be 1 hour, 2 hours, 3 hours, 4 hours or 5 hours, etc., but not limited to the above-listed values, and other non-listed values within the above-listed value range are equally applicable.
Preferably, the base comprises any one or a combination of at least two of sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
Preferably, the reducing agent of step (3) comprises sodium borohydride or potassium borohydride.
Preferably, the molar ratio of the compound 3 to the phosphorus ligand and azodicarbonate in the step (4) is 1 (1-1.2): (1-1.2), wherein the part of the phosphorus ligand can be 1, 1.05, 1.1, 1.15 or 1.2, and the like, and the part of the azodicarbonate can be 1, 1.05, 1.1, 1.15 or 1.2, and the like, but is not limited to the above-listed values, and other non-listed values in the above-listed value range are equally applicable.
Preferably, the phosphorus ligand of step (4) comprises triphenylphosphine.
Preferably, the azodicarbonate in step (4) comprises any one or a combination of at least two of diisopropyl azodicarbonate, dimethyl azodicarbonate or diethyl azodicarbonate, preferably diisopropyl azodicarbonate.
Preferably, the temperature of the reaction in the step (4) is 10-30 ℃ for 8-16 hours, wherein the temperature may be 10 ℃, 15 ℃,20 ℃, 25 ℃,30 ℃ or the like, the time may be 8 hours, 9 ℃,10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃,16 ℃ or the like, but not limited to the above-listed values, and other non-listed values within the above-listed value range are equally applicable.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, which can realize the preparation of the 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride by carrying out five steps of reactions, has simple integral process, can effectively reduce the procedures required by the preparation by adopting a one-pot synthesis method, improves the total yield, has low and easily obtained raw materials, and reduces the production cost.
Detailed Description
In order to further describe the technical means adopted by the present invention and the effects thereof, the following describes the technical scheme of the present invention in combination with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.
Example 1
The embodiment provides a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, which comprises the following specific steps:
(1) 2.2L of tetrahydrofuran, ethyl N-t-butoxycarbonyl glycinate (298 g,1.46 mol) and tetrabutylammonium bromide (47 g,0.146 mol) were added to a 5L reaction vessel, and then sodium hydride (65 g,1.62mol,60% in mineral oil) was added in portions in an ice bath, followed by stirring for 30 minutes, and then chloroacetone (150 g,16.2 mol) was added dropwise at a temperature of 15 to 20℃and the mixture was kept at the end of the dropwise addition for 3 hours. Then cooling to 0 ℃, adding sodium tert-butoxide (156 g,1.62 mol) in one part under nitrogen, controlling the temperature between 5 and 10 ℃, and preserving the heat for 3 hours after the addition. Thereafter, methyl t-butyl ether (1.5L) was introduced thereinto, and 100mL of water was added dropwise thereto, followed by stirring overnight. Suction filtration, washing the filter cake with a small amount of cold methyl tertiary butyl ether, and drying to obtain a yellow crude sodium salt product. Dissolving the crude product in 1L water, filtering to remove insoluble substances, adjusting pH of the filtrate to 4-5 with 0.5M hydrochloric acid, cooling to 0-5deg.C, and stirring overnight. Suction filtration, washing filter cake with a small amount of water, and drying solid to obtain 288.7g of yellow powder with 93% yield;
(2) 180g (0.844 mol) of the product from the previous step is dissolved in 2.5L of methanol and the mixture is cooled in an ice bath, and sodium borohydride (35.2 g,0.92 mol) is added in portions at a temperature of between 5 and 10 ℃. Naturally heating to 25 ℃ and stirring for 4 hours. Then, the temperature was lowered to 0℃and a saturated ammonium chloride solution (200 mL) was added dropwise thereto, followed by stirring for 30 minutes. Concentrating to dryness, adding 1L of water, extracting three times with DCM, combining organic phases, drying and concentrating to obtain 165g of the product with the yield of 90%.
(3) The product of the above step (65 g,300 mmol) was dissolved in 2L of methylene chloride, triphenylphosphine (80 g,305 mmol) was added, followed by dropwise addition of diisopropyl azodicarboxylate (61.7 g,305 mmol). After the completion of the dropping, stirring was carried out at 20℃for 12 hours. Anhydrous zinc chloride (42 g,310 mol) was added, the temperature was raised to 30 ℃, stirred for 2 hours, suction filtered, and the filtrate was concentrated to dryness. Then, the insoluble matter was filtered off by dissolving in 500mL of isopropyl ether, and the filtrate was ice-cooled and added dropwise to a 4M solution of isopropyl ether hydrogen chloride. Controlling the intermediate temperature between 5 and 10 ℃. Suction filtration and washing of the filter cake with isopropyl ether. And (3) putting 300mL of acetone into the filter cake for pulping, carrying out suction filtration and vacuum pumping to obtain 30.5g of powdery mildew powder, wherein the yield is 75%. Characterization data are as follows:
1H NMR(500MHz,DMSO-d6):δ10.1(s,2H),4.57(d,2H),3.29-3.41(m,4H),3.14-3.20(q,1H),2.25-2.28(d,1H)。
example 2
This example provides a process for the preparation of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, the specific steps are the same as in example 1 except for step (1) as follows:
(1) 2.2L of tetrahydrofuran, ethyl N-t-butoxycarbonyl glycinate (292 g,1.46 mol) and tetrabutylammonium bisulfate (49.5 g,0.146 mol) are added into a 5L reaction kettle, and then sodium hydride (65 g,1.62mol,60% of mineral oil) is added into the reaction kettle in portions by portions, stirred for 30 minutes, and then chloroacetone (150 g,16.2 mol) is added dropwise, the temperature is controlled to be between 15 and 20 ℃, and the dropwise is kept for 3 hours. Then cooling to 0 ℃, adding sodium tert-butoxide (156 g,1.62 mol) in one part under nitrogen, controlling the temperature between 5 and 10 ℃, and preserving the heat for 3 hours after the addition. Thereafter, methyl t-butyl ether (1.5L) was introduced thereinto, and 100mL of water was added dropwise thereto, followed by stirring overnight. Suction filtration, washing the filter cake with a small amount of cold methyl tertiary butyl ether, and drying to obtain a yellow crude sodium salt product. Dissolving the crude product in 1L water, filtering to remove insoluble substances, adjusting pH of the filtrate to 4-5 with 0.5M hydrochloric acid, cooling to 0-5deg.C, and stirring overnight. Suction filtration, washing the filter cake with a small amount of water, and drying the solid to obtain 273g of yellow powder with a yield of 88%.
Example 3
This example provides a process for the preparation of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, the specific steps are the same as in example 1 except for step (1) as follows:
(1) 2.2L of tetrahydrofuran, ethyl N-t-butoxycarbonyl glycinate (292 g,1.46 mol) and dodecyltrimethylammonium chloride (83.4 g,0.146 mol) are added into a 5L reaction kettle, and then sodium hydride (65 g,1.62mol,60% of mineral oil) is added into the reaction kettle in portions by portions, and after stirring for 30 minutes, chloroacetone (150 g,16.2 mol) is added dropwise, the temperature is controlled to be between 15 and 20 ℃, and the dropwise is kept for 3 hours. Then cooling to 0 ℃, adding sodium tert-butoxide (156 g,1.62 mol) in one part under nitrogen, controlling the temperature between 5 and 10 ℃, and preserving the heat for 3 hours after the addition. Thereafter, methyl t-butyl ether (1.5L) was introduced thereinto, and 100mL of water was added dropwise thereto, followed by stirring overnight. Suction filtration, washing the filter cake with a small amount of cold methyl tertiary butyl ether, and drying to obtain a yellow crude sodium salt product. Dissolving the crude product in 1L water, filtering to remove insoluble substances, adjusting pH of the filtrate to 4-5 with 0.5M hydrochloric acid, cooling to 0-5deg.C, and stirring overnight. Suction filtration, washing the filter cake with a small amount of water, and drying the solid to obtain 254.6g of yellow powder with the yield of 82%.
Example 4
This example provides a process for the preparation of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, the specific steps are the same as in example 1 except for step (3) as follows:
(3) The product of the above step (65 g,300 mmol) was dissolved in dichloromethane 2L, triphenylphosphine (80 g,305 mmol) was added, followed by dropwise dimethyl azodicarboxylate (305 mmol). After the completion of the dropping, stirring was carried out at 20℃for 12 hours. Anhydrous zinc chloride (42 g,310 mol) was added, the temperature was raised to 30 ℃, stirred for 2 hours, suction filtered, and the filtrate was concentrated to dryness. Then, the insoluble matter was filtered off by dissolving in 500mL of isopropyl ether, and the filtrate was ice-cooled and added dropwise to a 4M solution of isopropyl ether hydrogen chloride. Controlling the intermediate temperature between 5 and 10 ℃. Suction filtration and washing of the filter cake with isopropyl ether. And (3) putting 300mL of acetone into the filter cake for pulping, carrying out suction filtration and vacuum pumping to obtain 28g of powdery mildew powder, wherein the yield is 69%.
Example 5
This example provides a process for the preparation of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, the specific steps are the same as in example 1 except for step (3) as follows:
(3) The product of the above step (65 g,300 mmol) was dissolved in dichloromethane 2L, triphenylphosphine (80 g,305 mmol) was added, followed by dropwise diethyl azodicarboxylate (305 mmol). After the completion of the dropping, stirring was carried out at 20℃for 12 hours. Anhydrous zinc chloride (42 g,310 mol) was added, the temperature was raised to 30 ℃, stirred for 2 hours, suction filtered, and the filtrate was concentrated to dryness. Then, the insoluble matter was filtered off by dissolving in 500mL of isopropyl ether, and the filtrate was ice-cooled and added dropwise to a 4M solution of isopropyl ether hydrogen chloride. Controlling the intermediate temperature between 5 and 10 ℃. Suction filtration and washing of the filter cake with isopropyl ether. And (3) putting 300mL of acetone into the filter cake for pulping, carrying out suction filtration and vacuum pumping to obtain 26.8g of powdery mildew powder, wherein the yield is 66%.
Comparative example 1
The comparative example provides a preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, which comprises the following specific steps:
(1) To 500mL of MTBE (methyl tert-butyl ether) was added 4-methoxybenzaldehyde (56.3 g,413.5 mol), 30% aqueous ammonia (47 mL) was added, epichlorohydrin (36.5 mL) was added, and the mixture was reacted at 20℃for 18 hours. 30% aqueous ammonia (28 mL) was further added, epichlorohydrin (23 mL) was added, and the reaction was completed for 4 hours. After the reaction, standing for layering, drying and concentrating an organic layer to obtain an oily product, adding 300ml of normal hexane for crystallization to obtain 80g of white solid with the yield of 85%.
(2) To 800mL of methanol was added (80 g,351.4 mmol) of the product of step (1), cooled to 0deg.C, sodium borohydride (20 g, 227 mmol) was added in portions, the reaction was completed for one hour, the pH was adjusted to 8 after quenching with 1M hydrochloric acid, the mixture was concentrated to 200mL volume, the pH was adjusted to 14 with 6M sodium hydroxide, extracted 2 times with 200mL of dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give 62g of a white solid in 77% yield.
(3) To 600mL of methylene chloride was added (60 g,261.2 mmol) of the product of step (2) and 1M sodium hydroxide solution (300 mL), cooled to 0℃and chloroacetyl chloride (30.4 g, 268 mmol) was added dropwise. After completion of the dropwise addition of 0℃for 1 hour, the temperature was raised to 20℃and 10M sodium hydroxide solution (195 mL) was added for 4 hours at 20℃and 300mL of water was added, the layers were separated, the aqueous layer was extracted once with 150mL of methylene chloride, the organic layers were combined, and 200mL of saturated brine was washed once, dried over anhydrous magnesium sulfate and concentrated to give 57g of a product in 81% yield.
(4) To 500mL of tetrahydrofuran was added (50 g,185.37 mmol) of the product of step (3), cooled to 0℃and a solution of LDA (lithium diisopropylamide) in tetrahydrofuran (2.1 eq) was added dropwise. After completion of the dropwise addition, the reaction was allowed to stand at 0℃for 2 hours, quenched in 300mL of a saturated ammonium chloride solution, the solid was removed by suction filtration, the aqueous layer was extracted 2 times with 200mL of ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 18g of a product, and the yield was 42%.
(5) To 200mL of tetrahydrofuran solution was added (18 g,77.2 mmol) of the product of step (4), the temperature was lowered to 0℃under nitrogen protection, 1M borane tetrahydrofuran solution (11 mL) was added dropwise, and the mixture was naturally warmed to 20℃overnight. 50mL of methanol is added dropwise into the system for quenching, stirring is carried out for 30min at 20 ℃, and 15.2g of oily product is obtained by decompression and concentration, and the yield is 90%.
(6) To 150mL of methanol was added (15 g,68.4 mmol) of the product of step (5), 2g of 10% palladium on charcoal, hydrogen was replaced 3 times, heated to 50℃and hydrogen balloon was hydrogenated overnight until the starting material was reacted, suction filtered, concentrated under pressure, 50mL of tetrahydrofuran was added, 30mL of 4M HCl isopropyl ether solution was added dropwise, stirred for half an hour, suction filtered, and the isopropyl ether was rinsed to give 7.2g of a white solid with a yield of 78%.
Test case
The overall yields of the preparation methods provided in examples 1-5 and comparative example 1 were calculated as follows:
| group of | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Comparative example 1 |
| Total yield (%) | 62.7％ | 59.4％ | 55.3％ | 57.7％ | 55.2％ | 15.6％ |
As can be found from the data in the table, compared with the prior art (comparative example 1), the preparation method provided by the invention has the advantages that the reaction steps and working procedures are obviously reduced, the whole process is simpler, and the total yield is higher; as can be seen from comparative examples 1 to 5, the present invention can further improve the overall yield of the reaction by selecting a specific catalyst and azodicarbonate.
The applicant states that the present invention illustrates the preparation of the 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride of the present invention by the above examples, but the present invention is not limited to, i.e. it is not meant that the present invention must be practiced in dependence upon the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. A process for the preparation of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride, said process comprising the steps of:
(1) Mixing chloroacetone with N-tert-butyloxycarbonyl glycine ethyl ester, a catalyst and alkali for reaction to obtain a compound 1;
(2) Mixing the compound 1 with alkali for reaction to obtain a compound 2;
(3) Mixing and reacting the compound 2 with a reducing agent to obtain a compound 3;
(4) Mixing the compound 3 with a phosphorus ligand and azodicarbonate for reaction to obtain a compound 4, and then carrying out hydrochloric acid treatment to obtain the 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride;
the reaction route is as follows:
2. the preparation method according to claim 1, wherein the molar ratio of the chloroacetone to the ethyl N-t-butoxycarbonyl glycinate, the catalyst and the base in the step (1) is (1-1.5): 1 (0.08-0.12): 1-1.5).
3. The preparation method according to claim 1 or 2, wherein the catalyst of step (1) comprises any one or a combination of at least two of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium bisulfate, trioctylmethyl ammonium chloride, dodecyltrimethyl ammonium chloride or tetradecyltrimethylammonium chloride, preferably tetrabutylammonium bromide.
4. A process according to any one of claims 1 to 3, wherein the reaction in step (1) is carried out at a temperature of 10 to 20 ℃ for a period of 1 to 5 hours.
5. The process according to any one of claims 1 to 4, wherein the reaction in step (2) is carried out at a temperature of 0 to 10 ℃ for a time of 1 to 5 hours.
6. The method of any one of claims 1-5, wherein the base comprises any one or a combination of at least two of sodium hydride, sodium tert-butoxide, or potassium tert-butoxide.
7. The method of any one of claims 1-6, wherein the reducing agent of step (3) comprises sodium borohydride or potassium borohydride.
8. The process according to any one of claims 1 to 7, wherein the molar ratio of compound 3 to phosphorus ligand, azodicarbonate in step (4) is 1 (1-1.2): 1-1.2.
9. The method of any one of claims 1-8, wherein the phosphorus ligand of step (4) comprises triphenylphosphine;
preferably, the azodicarbonate in step (4) comprises any one or a combination of at least two of diisopropyl azodicarbonate, dimethyl azodicarbonate or diethyl azodicarbonate, preferably diisopropyl azodicarbonate.
10. The process according to any one of claims 1 to 9, wherein the reaction in step (4) is carried out at a temperature of 10 to 30 ℃ for a period of 8 to 16 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311579745.3A CN117624189A (en) | 2023-11-24 | 2023-11-24 | Preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311579745.3A CN117624189A (en) | 2023-11-24 | 2023-11-24 | Preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117624189A true CN117624189A (en) | 2024-03-01 |
Family
ID=90029721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311579745.3A Pending CN117624189A (en) | 2023-11-24 | 2023-11-24 | Preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117624189A (en) |
-
2023
- 2023-11-24 CN CN202311579745.3A patent/CN117624189A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108430999A (en) | The preparation method of Yi Zhong oxazolidone intermediates | |
| CN110615744A (en) | Buvalracetam intermediate and preparation method thereof | |
| CN108084130A (en) | A kind of preparation method of antidiabetic drug Dapagliflozin | |
| CN117624189A (en) | Preparation method of 6-oxa-3-azabicyclo [3.1.1] heptane hydrochloride | |
| CN109942446B (en) | Preparation method of pregabalin | |
| CN112457318A (en) | Synthesis process of Reidesciclovir intermediate | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN109456253A (en) | A kind of method of chiral induction synthesis (S) -3- (4- bromophenyl)-piperidines or its salt | |
| CN110818619B (en) | Synthetic method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide | |
| CN110590601B (en) | Synthesis method of malononitrile | |
| CN110003083B (en) | Process method for preparing S-indoline-2-carboxylic acid by using Ir catalyst | |
| CN110698381A (en) | Method for synthesizing N- (benzyloxycarbonyl) succinimide by one-pot two-phase method | |
| CN113651751B (en) | Preparation method of N-methoxycarbonyl-3-trifluoromethylpyridine-2-sulfonamide | |
| CN110483402B (en) | Synthetic method of 3-bromo-5-phenyl-1H-pyrazole | |
| CN112300059B (en) | Preparation method of PF-06651600 intermediate | |
| CN114292297B (en) | Method for preparing antiviral drug tenofovir alafenamide fumarate | |
| CN113527250B (en) | Octabolmod intermediate and preparation method thereof | |
| CN115141183B (en) | Preparation method and application of myocardial perfusion developer precursor | |
| CN110452139B (en) | Preparation method of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile | |
| CN114907415B (en) | Preparation method of bis (di-tert-butyl-4-dimethylaminophenylphosphine) palladium chloride | |
| CN116354870A (en) | Method for synthesizing 3-benzyl-1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid | |
| CN114539073A (en) | Synthesis method of 3-bromo-2-chloro-4, 6-difluoroaniline | |
| CN117843584A (en) | Method for improving cyclic oxazinone yield through continuous reaction | |
| CN114907283A (en) | Preparation method of 2- (3, 5-dichlorophenyl) -benzoxazole-6-carboxylic acid | |
| CN114292297A (en) | Method for preparing antiviral drug tenofovir alafenamide fumarate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |