CN111362853A - Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester - Google Patents
Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester Download PDFInfo
- Publication number
- CN111362853A CN111362853A CN202010343166.9A CN202010343166A CN111362853A CN 111362853 A CN111362853 A CN 111362853A CN 202010343166 A CN202010343166 A CN 202010343166A CN 111362853 A CN111362853 A CN 111362853A
- Authority
- CN
- China
- Prior art keywords
- reaction
- tert
- bromomethyl
- bis
- dioxolane
- 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 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 35
- MOPJSMIEGALASX-UHFFFAOYSA-N 2,2-bis(bromomethyl)-1,3-dioxolane Chemical compound BrCC1(CBr)OCCO1 MOPJSMIEGALASX-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical compound BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 14
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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
- 238000010992 reflux Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 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
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- -1 benzaldehyde compound Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 150000002443 hydroxylamines Chemical class 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 1
- 229950000971 baricitinib Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 150000002466 imines Chemical group 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- SNUDIPVBUUXCDG-QHSBEEBCSA-N tebipenem pivoxil Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(=O)OCOC(=O)C(C)(C)C)=O)[C@H](O)C)SC(C1)CN1C1=NCCS1 SNUDIPVBUUXCDG-QHSBEEBCSA-N 0.000 description 1
- 229950007537 tebipenem pivoxil Drugs 0.000 description 1
- XRRXRQJQQKMFBC-UHFFFAOYSA-N tert-butyl 3-hydroxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O)C1 XRRXRQJQQKMFBC-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester, which comprises the steps of firstly utilizing 1, 3-dibromoacetone and ethylene glycol as raw materials to synthesize 2, 2-bis (bromomethyl) -1, 3-dioxolane under the action of acid, and then cyclizing the 2, 2-bis (bromomethyl) -1, 3-dioxolane and carbamic acid tert-butyl ester under the action of alkali to generate the 3-oxazetidine-1-carboxylic acid tert-butyl ester. The method has the advantages of cheap and easily obtained raw materials, simple operation of the synthetic method, mild reaction conditions, low requirement on equipment and suitability for the requirement of industrial mass production.
Description
Technical Field
The invention belongs to the technical field of chemical drug intermediate preparation methods, and particularly relates to a preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester.
Background
The 3-oxazetidine-1-carboxylic acid tert-butyl ester is an important organic synthesis intermediate, is widely applied to the field of drug synthesis, and can be used for synthesizing rheumatoid arthritis drugs of Baricitinib, broad-spectrum antibacterial drugs of Tebipenem pivoxil, antitumor drugs of Cobimtinib and the like. Therefore, the development of an efficient synthetic method for preparing the 3-oxazetidine-1-carboxylic acid tert-butyl ester is of great significance. The literature research finds that the synthesis of 3-oxazetidine-1-carboxylic acid tert-butyl ester mainly adopts the following two methods:
the method comprises the following steps: the method comprises the steps of carrying out a ring-opening reaction on epoxy chloropropane and benzylamine (CN108752254) or benzhydrylamine (WO2009114512) serving as raw materials to obtain a hydroxylamine intermediate, closing the ring of the hydroxylamine intermediate under the action of alkali to obtain an azetidine skeleton, carrying out hydrogenolysis deprotection and oxidation reaction to finally obtain the 3-oxaazetidine-1-carboxylic acid tert-butyl ester, wherein palladium/carbon catalytic hydrogenation is used for removing a protecting group (benzyl or benzhydryl) in the hydrogenolysis process of the method, the requirement on equipment for the reaction is high, and the raw material palladium/carbon catalyst is expensive and is not suitable for industrial production.
The second method comprises the following steps: chinese patent CN106831523 reports that 3-substituent-1, 2-epoxypropane, benzaldehyde compound and ammonia water are used as starting materials, a first intermediate with an imine structure is obtained through a ring opening/condensation reaction, the first intermediate is hydrolyzed to obtain a hydroxylamine salt (a second intermediate), then the hydroxylamine salt can efficiently synthesize N-Boc-3-hydroxyazetidine by adopting a strategy of firstly closing the ring and then introducing a Boc group or firstly introducing a Boc group and then closing the ring, and finally, the target product, namely 3-oxazetidine-1-tert-butyl carboxylate, is obtained through an oxidation reaction. Although the method can avoid using palladium/carbon catalyst and hydrogen, the synthesis steps are long, and the intermediate I and the intermediate II are difficult to purify in the actual synthesis, so the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester, which has the advantages of cheap and easily obtained raw materials, simple operation of the synthesis method, mild reaction conditions, lower equipment requirement, feasibility in technology, reasonableness in economy and higher cost performance and is suitable for industrial production.
The preparation method of the 3-oxazetidine-1-carboxylic acid tert-butyl ester comprises the following steps:
step 1:1, 3-dibromoacetone and ethylene glycol are used as raw materials to synthesize 2, 2-bis (bromomethyl) -1, 3-dioxolane under the action of acid;
step 2: and (2) cyclizing the 2, 2-bis (bromomethyl) -1, 3-dioxolane obtained in the step (1) and tert-butyl carbamate under the action of alkali to generate 3-oxazetidine-1-carboxylic acid tert-butyl ester.
The reaction equation is as follows:
in the step 1, the acid is any one or a combination of several of sulfuric acid, phosphoric acid, nitric acid and p-toluenesulfonic acid, and p-toluenesulfonic acid is further preferable.
In step 1, the molar ratio of 1, 3-dibromoacetone to ethylene glycol and acid is 1:1.0-5.0:0.1-0.5, such as 1:1.0:0.1, 1:2.0:0.2, 1:3.0:0.3, 1:4.0:0.4 or 1:5.0: 0.5.
In the step 1, the reaction is carried out in the presence of a solvent, wherein the solvent is one or a combination of more of common aromatic hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene and the like.
In step 1, the reaction is carried out at an appropriate temperature, which may range from room temperature to the boiling point of the solvent used, e.g., 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or at the boiling point of the solvent, i.e., under reflux.
In the step 2, the base is any one or a combination of more of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, and sodium carbonate is further preferred.
In step 2, the molar ratio of 2, 2-bis (bromomethyl) -1, 3-dioxolane to t-butyl carbamate and base is 1:1.0-1.5:1.0-5.0, for example 1:1.0:1.0, 1:1.1:2.0, 1:1.2:3.0, 1:1.3:4.0, 1:1.4:5.0 or 1:1.5: 5.0.
In the step 2, the reaction is carried out in the presence of a solvent, wherein the solvent is any one or a combination of several of toluene, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or hexamethylphosphoric triamide.
In step 2, the reaction is carried out at an appropriate temperature, which may range from room temperature to the boiling point of the solvent used, e.g., 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or at the boiling point of the solvent, i.e., under reflux.
Further, in the step 1, the reaction process of synthesizing 2, 2-bis (bromomethyl) -1, 3-dioxolane from 1, 3-dibromoacetone and ethylene glycol as raw materials under the action of acid comprises the following steps:
dissolving 1, 3-dibromoacetone in toluene, sequentially adding ethylene glycol and p-toluenesulfonic acid at room temperature, heating the raw material system to reflux (110 ℃), separating generated water by a water separator in the reflux process, and finishing the reaction by TLC (thin layer chromatography) monitoring until the reaction is not carried out any more; and cooling the reaction liquid to room temperature, adding water into the reaction liquid to quench the reaction, extracting with ethyl acetate, washing an organic layer with saturated saline solution, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain colorless oily liquid, namely a crude product 2, 2-bis (bromomethyl) -1, 3-dioxolane, wherein the crude product is not purified and is directly subjected to the next reaction.
Further, the reaction process of cyclizing 2, 2-bis (bromomethyl) -1, 3-dioxolane and tert-butyl carbamate to generate 3-oxazetidine-1-carboxylic acid tert-butyl ester under the action of alkali in the step 2 comprises the following steps:
dissolving 2, 2-bis (bromomethyl) -1, 3-dioxolane by using 1, 4-dioxane, adding sodium carbonate and tert-butyl carbamate at room temperature, adding the raw materials, heating the system to 50 ℃ for reaction for 16h, cooling the system to room temperature after the reaction is finished, removing insoluble substances by suction filtration, decompressing and concentrating mother liquor, recrystallizing by using petroleum ether, and obtaining white solid by suction filtration, namely the product of the tert-butyl 3-oxaazetidine-1-carboxylate.
Compared with the prior art, the invention has the beneficial effects that:
the method for preparing the 3-oxazetidine-1-carboxylic acid tert-butyl ester has the advantages of simple reaction operation, mild reaction conditions, cheap and easily obtained raw materials and low equipment requirement, and can meet the requirement of industrial mass production.
Drawings
FIG. 1 shows the nuclear magnetic spectrum of tert-butyl 3-oxazetidine-1-carboxylate.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1:
(1) the preparation method of the 2, 2-bis (bromomethyl) -1, 3-dioxolane comprises the following steps:
1, 3-dibromoacetone (50.00g,231.62mmol,1.0eq) is dissolved in toluene (100mL), ethylene glycol (28.75g,463.24mmol,2.0eq) and p-toluenesulfonic acid (3.99g,23.16mmol,0.1eq) are added sequentially at room temperature, the raw material system is heated and refluxed (110 ℃) after the addition is finished, water generated in the reaction process is separated out by a water separator, and the reaction is finished when the reaction is monitored by TLC (thin layer chromatography). The reaction solution was cooled to room temperature, water was added to the reaction solution to quench the reaction, ethyl acetate was used for extraction (50mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily liquid, i.e., a crude product of 2, 2-bis (bromomethyl) -1, 3-dioxolane (54.18g, yield: about 90%), which was directly fed to the next step without purification.
(2) The preparation method of the 3-oxaazetidine-1-carboxylic acid tert-butyl ester comprises the following steps:
dissolving 2, 2-bis (bromomethyl) -1, 3-dioxolane (54.18g,208.45mmol,1.0eq) with 1, 4-dioxane (100mL), adding sodium carbonate (44.19g,416.89mmol,2.0eq) and tert-butyl carbamate (25.64g,218.87mmol,1.05eq) at room temperature, adding the raw materials, heating the system to 50 ℃ for reaction for 16h, cooling the system to room temperature after the reaction is finished, performing suction filtration to remove insoluble substances, performing vacuum concentration on mother liquor, recrystallizing with petroleum ether, and performing suction filtration to obtain a white solid, namely the product tert-butyl 3-oxaazetidine-1-carboxylate (32.83g, yield: 92%).1H NMR(400MHz,DMSO-d6)δ4.67(s,4H),1.42(s,9H).
Example 2:
(1) the preparation method of the 2, 2-bis (bromomethyl) -1, 3-dioxolane comprises the following steps:
1, 3-dibromoacetone (50.00g,231.62mmol,1.0eq) is dissolved in toluene (100mL), ethylene glycol (28.75g,463.24mmol,2.0eq) and concentrated sulfuric acid (2.27g,23.16mmol,0.1eq) are added sequentially at room temperature, the temperature of the raw material system is raised and the mixture is refluxed (110 ℃) after the addition, water generated during the reaction is separated out by a water separator, and the reaction is ended when the reaction is not carried out any more by TLC monitoring. The reaction solution was cooled to room temperature, water was added to the reaction solution to quench the reaction, ethyl acetate was used for extraction (50mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily liquid, i.e., a crude product of 2, 2-bis (bromomethyl) -1, 3-dioxolane (30.10g, yield: about 50%), which was directly fed to the next step without purification.
(2) The preparation method of the 3-oxaazetidine-1-carboxylic acid tert-butyl ester comprises the following steps:
dissolving 2, 2-bis (bromomethyl) -1, 3-dioxolane (30.10g,115.80mmol,1.0eq) with 1, 4-dioxane (100mL), adding sodium hydroxide (9.26g,231.61mmol,2.0eq) and tert-butyl carbamate (14.24g,121.59mmol,1.05eq) at room temperature, adding the raw materials, heating the system to 50 ℃ for reaction for 16h, cooling the system to room temperature after the reaction is finished, removing insoluble substances by suction filtration, concentrating the mother liquor under reduced pressure, recrystallizing with petroleum ether, and obtaining white solid by suction filtration, namely the product of tert-butyl 3-oxaazetidine-1-carboxylate (14.87g, yield: 75%).1H NMR(400MHz,DMSO-d6)δ4.67(s,4H),1.42(s,9H).
Example 3:
(1) the preparation method of the 2, 2-bis (bromomethyl) -1, 3-dioxolane comprises the following steps:
1, 3-dibromoacetone (50.00g,231.62mmol,1.0eq) is dissolved in xylene (100mL), ethylene glycol (28.75g,463.24mmol,2.0eq) and p-toluenesulfonic acid (3.99g,23.16mmol,0.1eq) are added sequentially at room temperature, the raw material system is heated and refluxed (140 ℃) after the addition is finished, water generated in the reaction process is separated out by a water separator, and the reaction is finished when the reaction is monitored by TLC (thin layer chromatography) to be not carried out any more. The reaction solution was cooled to room temperature, water was added to the reaction solution to quench the reaction, ethyl acetate was used for extraction (50mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily liquid, which was a crude product of 2, 2-bis (bromomethyl) -1, 3-dioxolane (42.14g, yield: about 70%), and the crude product was directly fed to the next step without purification.
(2) The preparation method of the 3-oxaazetidine-1-carboxylic acid tert-butyl ester comprises the following steps:
dissolving 2, 2-bis (bromomethyl) -1, 3-dioxolane (42.14g,162.12mmol,1.0eq) in toluene (100mL), adding sodium carbonate (34.37g,324.25mmol,2.0eq) and tert-butyl carbamate (19.94g,170.23mmol,1.05eq) at room temperature, adding the raw materials, heating the system to 70 ℃ for reaction for 16h, cooling the system to room temperature after the reaction is finished, removing insoluble substances by suction filtration, concentrating the mother liquor under reduced pressure, recrystallizing with petroleum ether, and obtaining white solid by suction filtration, namely the product of tert-butyl 3-oxaazetidine-1-carboxylate (22.20g, yield: 80%).1H NMR(400MHz,DMSO-d6)δ4.67(s,4H),1.42(s,9H).
The present invention is illustrated by the above examples of the preparation of t-butyl 3-oxazetidine-1-carboxylate according to the invention, but the invention is not limited to the above examples, i.e. it is not intended that the invention must be practiced by means of the above examples. It should be understood by those skilled in the art that any modifications to the present invention, equivalent substitutions of the raw materials for the product of the present invention, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
step 1:1, 3-dibromoacetone and ethylene glycol are used as raw materials to synthesize 2, 2-bis (bromomethyl) -1, 3-dioxolane under the action of acid;
step 2: cyclizing the 2, 2-bis (bromomethyl) -1, 3-dioxolane obtained in the step 1 and tert-butyl carbamate under the action of alkali to generate 3-oxazetidine-1-carboxylic acid tert-butyl ester;
the reaction equation is as follows:
2. the method of claim 1, wherein:
in the step 1, the acid is any one or a combination of several of sulfuric acid, phosphoric acid, nitric acid and p-toluenesulfonic acid.
3. The method of claim 1, wherein:
in the step 1, the molar ratio of the 1, 3-dibromoacetone to the glycol and the acid is 1:1.0-5.0: 0.1-0.5.
4. The method of claim 1, wherein:
in the step 1, the reaction is carried out in the presence of a solvent, wherein the solvent is one or a combination of more of benzene, toluene, xylene and chlorobenzene.
5. The method of claim 1, wherein:
in the step 2, the base is any one or a combination of more of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride.
6. The method of claim 1, wherein:
in the step 2, the molar ratio of the 2, 2-bis (bromomethyl) -1, 3-dioxolane to the tert-butyl carbamate to the base is 1:1.0-1.5: 1.0-5.0.
7. The method of claim 1, wherein:
in the step 2, the reaction is carried out in the presence of a solvent, wherein the solvent is any one or a combination of several of toluene, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and hexamethylphosphoric triamide.
8. The production method according to claim 1,2, 3 or 4, characterized in that:
in the step 1, the reaction process of synthesizing 2, 2-bis (bromomethyl) -1, 3-dioxolane by using 1, 3-dibromoacetone and ethylene glycol as raw materials under the action of acid comprises the following steps:
dissolving 1, 3-dibromoacetone in toluene, sequentially adding ethylene glycol and p-toluenesulfonic acid at room temperature, heating the raw material system to reflux after the addition, separating generated water by using a water separator in the reflux process, and finishing the reaction when the TLC monitoring is carried out until the reaction is not carried out any more; cooling the reaction liquid to room temperature, adding water into the reaction liquid to quench the reaction, extracting with ethyl acetate, washing an organic layer with saturated saline solution, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain colorless oily liquid, namely the crude product 2, 2-bis (bromomethyl) -1, 3-dioxolane.
9. The production method according to claim 1, 5, 6 or 7, characterized in that:
in the step 2, the reaction process of cyclizing 2, 2-bis (bromomethyl) -1, 3-dioxolane and tert-butyl carbamate to generate 3-oxazetidine-1-carboxylic acid tert-butyl ester under the action of alkali comprises the following steps:
dissolving 2, 2-bis (bromomethyl) -1, 3-dioxolane by using 1, 4-dioxane, adding sodium carbonate and tert-butyl carbamate at room temperature, adding the raw materials, heating the system to 50 ℃ for reaction for 16h, cooling the system to room temperature after the reaction is finished, removing insoluble substances by suction filtration, carrying out recrystallization after mother liquor is decompressed and concentrated, and carrying out suction filtration to obtain a white solid, namely the product of the tert-butyl 3-oxaazetidine-1-carboxylate.
10. The method of claim 9, wherein:
the solvent used for recrystallization is petroleum ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010343166.9A CN111362853A (en) | 2020-04-27 | 2020-04-27 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010343166.9A CN111362853A (en) | 2020-04-27 | 2020-04-27 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111362853A true CN111362853A (en) | 2020-07-03 |
Family
ID=71205683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010343166.9A Pending CN111362853A (en) | 2020-04-27 | 2020-04-27 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111362853A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999153A (en) * | 2021-11-18 | 2022-02-01 | 安徽益多康尔医药科技有限公司 | Preparation method of 3-oxetane-1-carboxylic acid tert-butyl ester |
| CN115417766A (en) * | 2022-08-31 | 2022-12-02 | 天津药明康德新药开发有限公司 | Synthesis method of 3-hydroxy-4, 5-dimethoxy benzoic acid tert-butyl ester |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090233903A1 (en) * | 2008-03-11 | 2009-09-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as jak inhibitors |
| CN101555205A (en) * | 2009-04-10 | 2009-10-14 | 浙江金伯士药业有限公司 | Preparing method of 3-oxo-1-cyclobutane-carboxylic acid |
| CN101638378A (en) * | 2009-06-25 | 2010-02-03 | 浙江汇能动物药品有限公司 | Synthetic method of N-alkyl substituted-3-piperidones |
| CN101891693A (en) * | 2010-08-05 | 2010-11-24 | 浙江金伯士药业有限公司 | New method for preparing fluconazole |
| CN108129482A (en) * | 2017-12-13 | 2018-06-08 | 江苏中邦制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
-
2020
- 2020-04-27 CN CN202010343166.9A patent/CN111362853A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090233903A1 (en) * | 2008-03-11 | 2009-09-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as jak inhibitors |
| CN101555205A (en) * | 2009-04-10 | 2009-10-14 | 浙江金伯士药业有限公司 | Preparing method of 3-oxo-1-cyclobutane-carboxylic acid |
| CN101638378A (en) * | 2009-06-25 | 2010-02-03 | 浙江汇能动物药品有限公司 | Synthetic method of N-alkyl substituted-3-piperidones |
| CN101891693A (en) * | 2010-08-05 | 2010-11-24 | 浙江金伯士药业有限公司 | New method for preparing fluconazole |
| CN108129482A (en) * | 2017-12-13 | 2018-06-08 | 江苏中邦制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
Non-Patent Citations (1)
| Title |
|---|
| ADAM J. M. BURRELL等: "Stereoselective Formation of Fused Tricyclic Amines from Acyclic Aldehydes by a Cascade Process Involving Condensation,Cyclization, and Dipolar Cycloaddition", 《J. ORG. CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999153A (en) * | 2021-11-18 | 2022-02-01 | 安徽益多康尔医药科技有限公司 | Preparation method of 3-oxetane-1-carboxylic acid tert-butyl ester |
| CN115417766A (en) * | 2022-08-31 | 2022-12-02 | 天津药明康德新药开发有限公司 | Synthesis method of 3-hydroxy-4, 5-dimethoxy benzoic acid tert-butyl ester |
| CN115417766B (en) * | 2022-08-31 | 2024-05-17 | 天津药明康德新药开发有限公司 | Synthesis method of 3-hydroxy-4, 5-dimethoxy benzoic acid tert-butyl ester |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109320436B (en) | Method for preparing perfluoronitrile by gas phase catalysis | |
| CN111362853A (en) | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester | |
| KR101125853B1 (en) | Process for preparing of n-methyl pyrrolidone | |
| EA200400015A1 (en) | IMPROVED METHOD FOR HIGH-CLEAN MELAMINE WITH HIGH-OUTPUT | |
| CN112321589A (en) | Synthesis method of antiviral drug Reidesciclovir and intermediate thereof | |
| CN100357266C (en) | Process for producing methyl carbamate | |
| KR20060071887A (en) | Process for producing cyclohexanone oxime | |
| Elinson et al. | Multicomponent assembling of salicylaldehydes, malononitrile and cyanoacetamides: A simple and efficient approach to medicinally relevant 2-amino-4H-chromene scaffold | |
| CN102718768A (en) | Chiral five-membered bicyclic guanidine compound, preparation method and application thereof | |
| CN111285782B (en) | Preparation method of 1-cyano-cyclohexyl acetonitrile | |
| CN112457175B (en) | Method for preparing 1, 3-dibenzyloxy-2-acetone | |
| CN109232430A (en) | A kind of preparation method of carbonyl dimidazoles | |
| CN111943928B (en) | Synthesis method and application of stiripentol intermediate impurity and stiripentol impurity | |
| OA11660A (en) | New derivatives of 6-(4-phenylbutoxy)hexylamine and process for producing salmeterol. | |
| CN113105363B (en) | Method for synthesizing 6-aminocapronitrile from cyclohexanone oxime in one step | |
| KR20010005573A (en) | Method for debenzylation of dibenzyl biotin | |
| CN110734354B (en) | Method for preparing biaryl compound from alcohol compound | |
| CN111393402B (en) | N & lt/EN & gt acid/quaternary ammonium salt composite catalytic CO 2 Method for preparing cyclic carbonate by cycloaddition with epoxide | |
| KR20110101691A (en) | Improved method for producing catechol and hydroquinone from phenol and hydrogen peroxide | |
| CN110343056A (en) | A kind of preparation method of N- tertbutyloxycarbonyl-N- methyl-2-amino -4,4- dimethyl valeric acid | |
| Rozwadowska | Rearrangements Involving alkoxycarbonyl group migration between nitrogen and oxygen. III. Reactions of modified isoquinoline Reissert compounds with aldehydes | |
| US9056868B1 (en) | Three-step synthesis of CL-20 | |
| KR20070056105A (en) | Process for production of 2-chloro-4-nitroimidazole | |
| CN1054375C (en) | Preparation of 3-methylpyrazole | |
| CN114105961B (en) | Preparation method of IDO1 inhibitor (LY-3381916) |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200703 |