CN115947697A - Synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester - Google Patents
Synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester Download PDFInfo
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- CN115947697A CN115947697A CN202211695797.2A CN202211695797A CN115947697A CN 115947697 A CN115947697 A CN 115947697A CN 202211695797 A CN202211695797 A CN 202211695797A CN 115947697 A CN115947697 A CN 115947697A
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- oxomorpholine
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- acetamide
- hydroxyethyl
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- HJYNLENYMULSAS-UHFFFAOYSA-N tert-butyl 3-oxomorpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOCC1=O HJYNLENYMULSAS-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims abstract description 66
- YMURLKIIDQPXRE-UHFFFAOYSA-N 2-chloro-n-(2-hydroxyethyl)acetamide Chemical compound OCCNC(=O)CCl YMURLKIIDQPXRE-UHFFFAOYSA-N 0.000 claims abstract description 50
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims abstract description 34
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000007112 amidation reaction Methods 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims description 73
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical group CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 238000003786 synthesis reaction Methods 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 16
- 150000007530 organic bases Chemical class 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 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
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 claims description 3
- -1 BOC acid anhydride Chemical class 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000002156 mixing Methods 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
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 25
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000013341 scale-up Methods 0.000 abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester, which comprises the steps of taking ethanolamine and p-chloroacetyl chloride as raw materials, and generating 2-chloro-N- (2-hydroxyethyl) acetamide through amidation reaction; 2-chloro-N- (2-hydroxyethyl) acetamide is used for ring closure under alkaline conditions to generate morpholine-3-ketone; morpholine-3-one is reacted with BOC anhydride to produce 3-oxomorpholine-4-carboxylic acid tert-butyl ester. The synthesis method of the 3-oxomorpholine-4-carboxylic acid tert-butyl ester has the advantages of mild reaction conditions, low cost, no high cost, high-risk raw materials and contribution to industrial scale-up production.
Description
Technical Field
The invention relates to a synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester, belonging to the technical field of preparation of medical intermediates.
Background
Patents published on 27/05/2021 and published on WO2021102204 A1, published on 04/2013 and published on WO2013049719 A1, published on 26/01/2017 and published on WO2017012576A1, and treatises journal of pharmaceutical chemistry (1992), 35 (16), 2928-38, report that: the 3-oxomorpholine-4-carboxylic acid tert-butyl ester is an active drug molecule capable of synthesizing drugs for treating various diseases, such as drugs for synthesizing specific opioid receptor antagonists, ATR kinase inhibitors for treating cancers, parkinson's syndrome, immune system related diseases and the like.
At present, the synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester adopts ethanolamine and chloroacetyl chloride as raw materials and carries out three-step reactions of lipase catalytic amidation, ring closing under sodium hydride condition and BOC on butyl lithium low-temperature hydrogen extraction to obtain the final product of 3-oxomorpholine-4-carboxylic acid tert-butyl ester. The method has harsh requirements on production conditions and low yield, and is not favorable for amplification production because high-activity biological enzyme and high-risk sodium hydride and butyl lithium are required.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a method for synthesizing 3-oxomorpholine-4-carboxylic acid tert-butyl ester, can synthesize the 3-oxomorpholine-4-carboxylic acid tert-butyl ester by a method of avoiding using high-activity biological enzyme and high-risk sodium hydride and butyl lithium, and is beneficial to industrial scale-up production.
In order to achieve the purpose, the invention is realized by adopting the following technical scheme:
the invention provides a synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester, which comprises the following steps:
ethanolamine and parachloroacetyl chloride are taken as raw materials, and are subjected to amidation reaction to generate 2-chloro-N- (2-hydroxyethyl) acetamide;
2-chloro-N- (2-hydroxyethyl) acetamide is used for ring closure under alkaline conditions to generate morpholine-3-ketone;
morpholine-3-one 3 and BOC anhydride are reacted to produce 3-oxomorpholine-4-carboxylic acid tert-butyl ester.
Further, the method for preparing the 2-chloro-N- (2-hydroxyethyl) acetamide by taking the ethanolamine and the p-chloroacetyl chloride as raw materials through amidation reaction comprises the following steps:
ethanolamine and p-chloroacetyl chloride are subjected to amidation reaction under the alkaline condition to generate 2-chloro-N- (2-hydroxyethyl) acetamide.
Further, the method for preparing 2-chloro-N- (2-hydroxyethyl) acetamide from ethanolamine and parachloroacetyl chloride through amidation reaction comprises the following steps:
adding ethanolamine into the first organic solvent, cooling the first mixed solution to-10 ℃, preferably, cooling the first mixed solution to-10-0 ℃, and further preferably, cooling the first mixed solution to-10 ℃;
after first organic alkali is dripped into the first mixed solution, the first mixed solution is cooled to minus 60 to minus 70 ℃;
and (3) dropwise adding p-chloroacetyl chloride into the first mixed solution, stirring for reacting for 1-3 h, and then carrying out post-treatment on the first mixed solution to obtain the 2-chloro-N- (2-hydroxyethyl) acetamide.
Further, the first organic base is triethylamine or N, N-diisopropylethylamine;
the first organic solvent is acetonitrile or a mixed solvent of acetonitrile and methanol.
Further, the molar ratio of the parachloroacetyl chloride to the ethanolamine is (1-1.5) to 1;
the molar ratio of the first organic base to the ethanolamine is (1-2) to 1;
the volume weight ratio of the first organic solvent to the ethanolamine is (3-30) ml:1g;
preferably, the volume weight ratio of the acetonitrile to the ethanolamine is (20-30) ml:1g;
preferably, the volume weight ratio of the methanol to the ethanolamine is (3-5) ml to 1g.
Further, the post-treating the first mixed solution to obtain 2-chloro-N- (2-hydroxyethyl) acetamide comprises: alkalizing, filtering, washing, drying and concentrating the first mixed solution;
preferably, the first mixed solution is alkalized with sodium carbonate, and then filtered, washed, dried and concentrated.
Further, the cyclization under alkaline conditions by utilizing 2-chloro-N- (2-hydroxyethyl) acetamide to generate the morpholine-3-ketone comprises the following steps:
mixing a second organic solvent and a second organic base, and cooling the second mixed solution to 15-20 ℃;
and (3) dropwise adding a second organic solvent solution of 2-chloro-N- (2-hydroxyethyl) acetamide into the second mixed solution, stirring and reacting for 1-5 h, preferably, stirring and reacting for 1-3 h at 15-20 ℃, and then post-treating the second mixed solution to obtain the morpholine-3-one.
Furthermore, the volume weight ratio of the second organic solvent to the 2-chloro-N- (2-hydroxyethyl) acetamide in the second organic solvent solution of the 2-chloro-N- (2-hydroxyethyl) acetamide is (5-10) ml:1g.
Further, the second organic base is selected from one of potassium tert-butoxide, sodium tert-butoxide, potassium tert-pentoxide and sodium tert-pentoxide;
the second organic solvent is tert-amyl alcohol or tert-butyl alcohol.
Further, the volume weight ratio of the second organic solvent to the 2-chloro-N- (2-hydroxyethyl) acetamide is (5-20) ml:1g;
preferably, the volume weight ratio of the second organic solvent to the 2-chloro-N- (2-hydroxyethyl) acetamide is (10-15) ml:1g;
the molar ratio of the second organic base to the 2-chloro-N- (2-hydroxyethyl) acetamide is (2-4): 1.
Further, the post-treating the second mixed solution to obtain the morpholin-3-one comprises: and quenching, extracting, alkali washing, drying, filtering and concentrating the second mixed solution.
Further, the generation of the 3-oxomorpholine-4-carboxylic acid tert-butyl ester by the reaction of morpholine-3-one and BOC anhydride comprises the following steps:
adding morpholine-3-ketone into the third organic solvent, and cooling the third mixed solution to 5-10 DEG O C, preferably, after replacing by liquid nitrogen gas, cooling the third mixed ice bath to 5-10 DEG O C；
And (3) dropwise adding a third organic base and BOC acid anhydride into the third mixed solution in sequence, stirring for reacting for 16-20h, preferably at 20-25 ℃, stirring for reacting for 16-20h, and then post-treating the third mixed solution to obtain the 3-oxomorpholine-4-carboxylic acid tert-butyl ester.
Further, the post-treating the third mixed solution to obtain the tert-butyl 3-oxomorpholine-4-carboxylate comprises: and carrying out acid washing, alkali washing, brine washing, drying, filtering and concentration treatment on the third mixed solution.
Preferably, the third mixed solution is subjected to acid washing with 10% citric acid, alkali washing with saturated sodium bicarbonate, and brine washing with saturated brine.
Further, the third organic base is triethylamine and 4-dimethylaminopyridine;
the third organic solvent is dichloromethane.
Further, the volume weight ratio of the third organic solvent to the morpholine-3-one 3 is (10-30) ml:1g;
the molar ratio of the third organic base to the morpholine-3-one 3 is (2-4) to 1;
the molar ratio of the BOC anhydride to the morpholine-3-one 3 is (1-2) to 1;
preferably, the molar ratio of triethylamine to morpholin-3-one 3 is (1-2): 1;
preferably, the molar ratio of 4-dimethylaminopyridine to morpholin-3-one 3 is (1-2): 1.
Compared with the prior art, the invention has the following beneficial effects:
the method has the advantages of mild reaction conditions, low raw material cost, no need of using high-activity biological enzyme and high-risk sodium hydride and butyl lithium, high yield of 95-99 percent, and contribution to industrial scale-up production.
Drawings
FIG. 1 is a schematic diagram showing a synthetic route of tert-butyl 3-oxomorpholine-4-carboxylate according to the present invention;
FIG. 2 shows an HPLC chromatogram of tert-butyl 3-oxomorpholine-4-carboxylate according to the present invention;
FIG. 3 shows the preparation of tert-butyl 3-oxomorpholine-4-carboxylate according to the invention 1 H NMR spectrum;
in the figure: 1. ethanolamine, 2-chloro-N- (2-hydroxyethyl) acetamide, 3, morpholin-3-one, 4, 3-oxomorpholine-4-carboxylic acid tert-butyl ester.
Detailed Description
The invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
In the description of the present invention, it is to be understood that the terms "center", "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", and the like, indicate orientations or positional relationships based on those shown in the drawings, and are used only for convenience in describing the present invention and for simplicity in description, and do not indicate or imply that the referenced devices or elements must have a particular orientation, be constructed and operated in a particular orientation, and thus, are not to be construed as limiting the present invention. Furthermore, the terms "first", "second", etc. are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first," "second," etc. may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless otherwise specified.
In the description of the present invention, it should be noted that, unless otherwise explicitly specified or limited, the terms "mounted," "connected," and "connected" are to be construed broadly, e.g., as meaning either a fixed connection, a removable connection, or an integral connection; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meaning of the above terms in the present invention can be understood by those of ordinary skill in the art through specific situations.
According to the invention, ethanolamine and chloroacetyl chloride are used as raw materials, and 3-oxomorpholine-4-carboxylic acid tert-butyl ester is obtained by a three-step method, referring to figure 1.
The synthesis of the 3-oxomorpholine-4-carboxylic acid tert-butyl ester specifically comprises the following steps:
synthesis of 2-chloro-N- (2-hydroxyethyl) acetamide: ethanolamine 1 and parachloroacetyl chloride are taken as raw materials, and are subjected to amidation reaction to generate 2-chloro-N- (2-hydroxyethyl) acetamide 2.
In application, the application does not need to use high-activity biological enzyme, but uses ethanolamine and p-chloroacetyl chloride to generate 2-chloro-N- (2-hydroxyethyl) acetamide through amidation reaction under alkaline condition.
In practical application, the synthesis reaction formula of the 2-chloro-N- (2-hydroxyethyl) acetamide is as follows:
synthesis of morpholin-3-one: 2-chloro-N- (2-hydroxyethyl) acetamide 2 is utilized to close the ring under the alkaline condition to generate the morpholine-3-ketone 3.
In practical application, the synthesis reaction formula of the morpholine-3-ketone is as follows:
synthesis of 3-oxomorpholine-4-carboxylic acid tert-butyl ester: morpholine-3-one 3 and BOC anhydride are reacted to produce 3-oxomorpholine-4-carboxylic acid tert-butyl ester 4.
In practical application, the synthesis reaction formula of the 3-oxomorpholine-4-carboxylic acid tert-butyl ester is as follows:
example 1
This example describes a method for synthesizing tert-butyl 3-oxomorpholine-4-carboxylate in detail, which specifically includes the following steps:
the synthesis of S1-2-chloro-N- (2-hydroxyethyl) acetamide specifically comprises the following steps:
firstly, adding a first organic solvent acetonitrile and methanol into a three-mouth reaction bottle with a stirrer, adding ethanolamine into the three-mouth reaction bottle, and then cooling a first mixed solution in the three-mouth reaction bottle to-10 ℃;
then, dripping the first organic base triethylamine into a three-port reaction bottle, and continuously cooling the first mixed solution to-60 to (-) 70 ℃ after dripping;
then slowly dripping p-chloroacetyl chloride into the first mixed solution, after dripping, stirring and reacting for 1-3 h, and post-treating the first mixed solution, namely: adding sodium carbonate solid into the first mixed solution and stirring for 16h to alkalize the first mixed solution, then filtering the alkalized first mixed solution, washing filter residue twice by using ethanol, combining the filtrate and the washing solution, and concentrating under reduced pressure to obtain the 2-chloro-N- (2-hydroxyethyl) acetamide, wherein the yield is as follows: 60 to 83 percent.
In application, the volume-to-weight ratio of acetonitrile to ethanolamine is (20-30) ml:1g; the volume-weight ratio of the methanol to the ethanolamine is (3-5) ml:1g; the molar ratio of triethylamine to ethanolamine is (1-2) to 1; the mol ratio of chloracetyl chloride to ethanolamine is (1-1.5) to 1; the weight ratio of the sodium carbonate to the ethanolamine is (2-5) to 1; the volume weight ratio of the ethanol to the ethanolamine is (1-5) ml to 1g.
The synthesis of S2 morpholine-3-one comprises the following steps:
firstly, adding a second organic solvent of tertiary amyl alcohol and a second organic alkali of potassium tertiary amyl alcohol into a three-port reaction bottle with a stirrer, and cooling a second mixed solution to 15-20 ℃;
then, dripping a tertiary amyl alcohol solution of 2-chloro-N- (2-hydroxyethyl) acetamide 2 into the second mixed solution, stirring and reacting for 1-5 h, and then post-treating the second mixed solution, namely: quenching the second mixed solution with water, extracting with dichloromethane, layering, washing with 1M sodium hydroxide, drying, filtering, and concentrating the organic phase to obtain morpholine-3-one with yield: 50 to 70 percent.
In the application, the volume-to-weight ratio of the tertiary amyl alcohol to the 2-chloro-N- (2-hydroxyethyl) acetamide is (5-10) ml to 1g; the molar ratio of the potassium tert-amylate to the 2-chloro-N- (2-hydroxyethyl) acetamide is (2-4) to 1; the volume weight ratio of the tertiary amyl alcohol to the 2-chloro-N- (2-hydroxyethyl) acetamide in the tertiary amyl alcohol solution of the 2-chloro-N- (2-hydroxyethyl) acetamide is (5-10) ml:1g.
The synthesis of S3-oxomorpholine-4-carboxylic acid tert-butyl ester specifically comprises the following steps:
firstly, adding a third organic solvent dichloromethane and morpholine-3-ketone into a three-mouth reaction bottle with a stirrer, and cooling a third mixed solution to 5-10% O C；
And then, sequentially dropwise adding a third organic base triethylamine and 4-dimethylaminopyridine into the third mixed solution, then slowly dropwise adding BOC anhydride, stirring and reacting for 16-20h after the dropwise adding is finished, and then post-treating the third mixed solution, namely: the third mixture was quenched with 10% citric acid, the layers were extracted with dichloromethane, and the combined organic phases were washed once with saturated sodium bicarbonate, brine, and the organic phase was then dried, filtered, washed, and concentrated to give 3-oxomorpholine-4-carboxylic acid tert-butyl ester in yield: 95 to 99 percent.
In the application, the volume-to-weight ratio of the dichloromethane to the morpholine-3-one is (10-30) ml:1g; the molar ratio of BOC anhydride to morpholine-3-one 3 is (1-2) to 1; the molar ratio of triethylamine to morpholine-3-one 3 is (1-2) to 1; the molar ratio of 4-dimethylamino pyridine to morpholine-3-one (3) is (1-2) to 1.
Example 2
This example describes a method for synthesizing tert-butyl 3-oxomorpholine-4-carboxylate in detail, which specifically includes the following steps:
the synthesis of S1-2-chloro-N- (2-hydroxyethyl) acetamide specifically comprises the following steps:
firstly, adding 2000ml of acetonitrile and 300ml of methanol into a three-mouth reaction bottle with a stirrer, then adding 100g of ethanolamine into the three-mouth reaction bottle, and cooling a first mixed solution in the three-mouth reaction bottle to-10 ℃;
then, 165.7g of triethylamine is added into the first mixed solution dropwise at room temperature; after finishing dropping, continuously cooling the first mixed solution to-60 to (-) 70 ℃;
then, slowly dropwise add 184.9g of p-chloroacetyl chloride into the first mixed solution, after the dropwise addition, stir and react for 1h until the reaction is complete, and then post-treat the first mixed solution, namely: to the first mixture was added 200g of sodium carbonate at room temperature and stirred overnight to alkalify the first mixture, followed by filtering the alkalified first mixture, washing the cake twice with 100mL of ethanol, combining the filtrate and the washings, and concentrating under reduced pressure to obtain 135.3g of 2-chloro-N- (2-hydroxyethyl) acetamide with purity of 90% LC, yield: 60 percent.
The synthesis of S2 morpholine-3-one comprises the following steps:
first, 500ml of t-amyl alcohol and 163.1g of potassium t-amyl alcohol were added to a three-necked reaction flask with a stirrer, and the second mixture was cooled to 15 ℃;
then, dripping a tertiary amyl alcohol solution of 2-chloro-N- (2-hydroxyethyl) acetamide into the second mixed solution, stirring and reacting for 1 hour after finishing dripping, and performing post-treatment on the second mixed solution, namely: adding 300ml of water and 500ml of dichloromethane into the second mixed solution, and demixing the second mixed solution; then, the organic phase was washed with a 1M aqueous solution of sodium hydroxide, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 36.8g of morpholin-3-one, which had an LC purity of 98% and a yield: 50 percent.
Wherein, the volume weight ratio of the tert-amyl alcohol to the 2-chloro-N- (2-hydroxyethyl) acetamide in the tert-amyl alcohol solution of the 2-chloro-N- (2-hydroxyethyl) acetamide is 15 ml.
The synthesis of the S3-oxomorpholine-4-carboxylic acid tert-butyl ester specifically comprises the following steps:
first, 300ml of methylene chloride and 30g of morpholin-3-one were added to a three-necked reaction flask equipped with a stirrer, and the third mixture was cooled to 10% O C。
And then, sequentially dropwise adding 30g of triethylamine and 36.2g of 4-dimethylamino pyridine into the third mixed solution, after dropwise adding, slowly dropwise adding 64.8g of BOC anhydride, after dropwise adding, stirring and reacting at room temperature for 16 hours until the reaction is complete, and then post-treating the third mixed solution, namely: adding 200ml of 10% citric acid aqueous solution into the third mixed solution, standing, layering, extracting the aqueous phase twice with 150ml dichloromethane, washing the combined organic phase once with 150ml saturated sodium bicarbonate and once with 150ml saturated brine, drying the organic phase with sodium sulfate, filtering, and concentrating under reduced pressure to obtain 56.7g of tert-butyl 3-oxomorpholine-4-carboxylate with purity of >99%, yield: 95 percent.
When in use, the HPLC1260 is used for detecting the 3-oxomorpholine-4-carboxylic acid tert-butyl ester by the high performance liquid chromatography. The sample amount of the HPLC is 5.000. Mu.l, and the HPLC detection results are shown in Table 1 and FIG. 2, which are shown in Table 1 and FIG. 2.
TABLE 1 detection results of high performance liquid chromatography of tert-butyl 3-oxomorpholine-4-carboxylate
In practical application, the 3-oxomorpholine-4-carboxylic acid tert-butyl ester is subjected to nuclear magnetic resonance detection and analysis, the test frequency is 400MHz, and the used solvent is deuterated CDCl 3 . As can be seen from the results of NMR measurement in FIG. 3, the synthesis of t-butyl 3-oxomorpholine-4-carboxylate in this example was successful。
Example 3
This example describes a method for synthesizing tert-butyl 3-oxomorpholine-4-carboxylate in detail, which specifically includes the following steps:
the synthesis of S1-2-chloro-N- (2-hydroxyethyl) acetamide specifically comprises the following steps:
firstly, 3000ml of acetonitrile and 500ml of methanol are added into a three-mouth reaction bottle with a stirrer; then 100g of ethanolamine is added into the three-mouth reaction bottle, and the first mixed solution in the three-mouth reaction bottle is cooled to-10 ℃;
then, 331.3g of triethylamine is added into the first mixed solution dropwise at room temperature; after finishing dripping, continuously cooling the first mixed solution to-60 to (-) 70 ℃;
then, 277.3g of parachloroacetyl chloride is slowly dripped into the first mixed solution, and after dripping, the first mixed solution is stirred and reacted for 1h until the reaction is completed, and then the first mixed solution is post-treated, namely: to the first mixture was added 500g of sodium carbonate at room temperature, stirred overnight and stirred overnight to basify the first mixture, followed by filtering the basified first mixture, washing the filter cake twice with 500mL of ethanol, combining the filtrate and washings, and concentrating under reduced pressure to give 186.9g of 2-chloro-N- (2-hydroxyethyl) acetamide in 92% lc purity, yield: 83 percent.
The synthesis of S2 morpholine-3-one comprises the following steps:
firstly, 1000ml of tertiary amyl alcohol and 326.3g of potassium tertiary amyl alcohol are added into a three-mouth reaction bottle with a stirrer, and the second mixed solution is cooled to 15 ℃;
then, dripping a tertiary amyl alcohol solution of 2-chloro-N- (2-hydroxyethyl) acetamide into the second mixed solution, stirring and reacting for 1h after finishing dripping, and then post-treating the second mixed solution, namely: adding 500ml of water and 500ml of dichloromethane into the second mixed solution, and demixing the second mixed solution; subsequently, the organic phase was washed with a 1M aqueous solution of sodium hydroxide, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 51.5g of morpholin-3-one having an LC purity of 98%, yield: 70 percent.
Wherein the volume weight ratio of the tertiary amyl alcohol to the 2-chloro-N- (2-hydroxyethyl) acetamide in the tertiary amyl alcohol solution of the 2-chloro-N- (2-hydroxyethyl) acetamide is 10ml.
The synthesis of S3-oxomorpholine-4-carboxylic acid tert-butyl ester specifically comprises the following steps:
first, 1500ml of methylene chloride and 50g of morpholin-3-one were added to a three-necked reaction flask equipped with a stirrer, and the third mixture was cooled to 5 ℃.
And then, sequentially dropwise adding 100g of triethylamine and 120.8g of 4-dimethylaminopyridine into the third mixed solution, after dropwise adding, slowly dropwise adding 215.9g of BOC anhydride, after dropwise adding, stirring and reacting at room temperature for 16 hours until the reaction is completed, and then post-treating the third mixed solution, namely: adding 500ml of 10% citric acid aqueous solution into the third mixed solution, standing for layering, extracting the aqueous phase twice by using 300ml of dichloromethane, washing the combined organic phase once by using 500ml of saturated sodium bicarbonate, then washing the combined organic phase once by using 300ml of saturated brine, drying the organic phase by using sodium sulfate, filtering and concentrating under reduced pressure to obtain 98.5g of 3-oxomorpholine-4-carboxylic acid tert-butyl ester, wherein the LC purity is more than 99%, and the yield is as follows: 99 percent.
In conclusion, the embodiment shows that the method has the advantages of mild reaction conditions, low raw material cost, no need of using high-activity biological enzyme and high-risk sodium hydride and butyl lithium, high yield up to 95-99 percent and contribution to industrial scale-up production.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A synthetic method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
ethanolamine (1) and parachloroacetyl chloride are used as raw materials, and 2-chloro-N- (2-hydroxyethyl) acetamide (2) is generated through amidation reaction;
2-chloro-N- (2-hydroxyethyl) acetamide (2) is used for ring closure under alkaline conditions to generate morpholine-3-ketone (3);
morpholine-3-one (3) and BOC anhydride are reacted to produce 3-oxomorpholine-4-carboxylic acid tert-butyl ester (4).
2. The method for synthesizing tert-butyl 3-oxomorpholine-4-carboxylate as claimed in claim 1, wherein the amidation reaction of ethanolamine 1 and p-chloroacetyl chloride as raw materials to produce 2-chloro-N- (2-hydroxyethyl) acetamide 2 comprises the following steps:
ethanolamine and p-chloroacetyl chloride are subjected to amidation reaction under the alkaline condition to generate 2-chloro-N- (2-hydroxyethyl) acetamide.
3. The method for synthesizing tert-butyl 3-oxomorpholine-4-carboxylate as claimed in claim 1, wherein the amidation reaction of ethanolamine (1) and p-chloroacetyl chloride as raw materials to produce 2-chloro-N- (2-hydroxyethyl) acetamide (2) comprises the following steps:
adding ethanolamine into a first organic solvent, and cooling the first mixed solution to-10 ℃;
after first organic alkali is dripped into the first mixed solution, the first mixed solution is cooled to minus 60 to minus 70 ℃;
and (3) dropwise adding parachloroacetyl chloride into the first mixed solution, stirring and reacting for 1-3 h, and then post-treating the first mixed solution to obtain the 2-chloro-N- (2-hydroxyethyl) acetamide (2).
4. A process for the synthesis of tert-butyl 3-oxomorpholine-4-carboxylate according to claim 3, characterized in that the first organic base is triethylamine or N, N-diisopropylethylamine;
the first organic solvent is acetonitrile or a mixed solvent of acetonitrile and methanol.
5. The process for the synthesis of tert-butyl 3-oxomorpholine-4-carboxylate according to claim 4,
the molar ratio of the parachloroacetyl chloride to the ethanolamine is (1-1.5) to 1;
the molar ratio of the first organic alkali to the ethanolamine is (1-2) to 1;
the volume weight ratio of the first organic solvent to the ethanolamine is (3-30) ml:1g.
6. The method of claim 3, wherein the post-treating the first mixture to obtain 2-chloro-N- (2-hydroxyethyl) acetamide (2) comprises: and alkalifying, filtering, washing, drying and concentrating the first mixed solution.
7. The method for synthesizing 3-oxomorpholine-4-carboxylic acid tert-butyl ester according to claim 1, characterized in that the ring closure under basic condition by 2-chloro-N- (2-hydroxyethyl) acetamide (2) to form morpholine-3-one (3) comprises the following steps:
mixing a second organic solvent and a second organic base, and cooling the second mixed solution to 15-20 ℃;
and (3) dropwise adding a second organic solvent solution of 2-chloro-N- (2-hydroxyethyl) acetamide (2) into the second mixed solution, stirring for reacting for 1-5 h, and then carrying out post-treatment on the second mixed solution to obtain morpholine-3-one (3).
8. The method for synthesizing tert-butyl 3-oxomorpholine-4-carboxylate according to claim 7, wherein the second organic base is selected from one of potassium tert-butoxide, sodium tert-butoxide, potassium tert-pentoxide and sodium tert-pentoxide;
the second organic solvent is tert-amyl alcohol or tert-butyl alcohol.
9. The method for synthesizing tert-butyl 3-oxomorpholine-4-carboxylate according to claim 1, wherein the step of reacting morpholine-3-one (3) with BOC anhydride to produce tert-butyl 3-oxomorpholine-4-carboxylate (4) comprises the steps of:
adding morpholine-3-ketone (3) into the third organic solvent, and cooling the third mixed solution to 5-10% O C；
And (3) sequentially dropwise adding a third organic base and BOC acid anhydride into the third mixed solution, stirring for reacting for 16-20h, and then carrying out post-treatment on the third mixed solution to obtain the 3-oxomorpholine-4-carboxylic acid tert-butyl ester (4).
10. The process for the synthesis of tert-butyl 3-oxomorpholine-4-carboxylate according to claim 9,
the third organic base is triethylamine and 4-dimethylaminopyridine;
the third organic solvent is dichloromethane.
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