CN116283635A - Method for synthesizing N, 3-trimethyl-2-oxo butyramide - Google Patents
Method for synthesizing N, 3-trimethyl-2-oxo butyramide Download PDFInfo
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- CN116283635A CN116283635A CN202211732114.6A CN202211732114A CN116283635A CN 116283635 A CN116283635 A CN 116283635A CN 202211732114 A CN202211732114 A CN 202211732114A CN 116283635 A CN116283635 A CN 116283635A
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- trimethyl
- oxobutanamide
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- dimethyl
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims abstract description 10
- IAWVHZJZHDSEOC-UHFFFAOYSA-N 3,3-dimethyl-2-oxobutanoic acid Chemical compound CC(C)(C)C(=O)C(O)=O IAWVHZJZHDSEOC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 150000007530 organic bases Chemical class 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical group F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 231100000086 high toxicity Toxicity 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- -1 diphenylphosphino Chemical group 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing N, 3-trimethyl-2-oxo-butyramide. Taking 3, 3-dimethyl-2-oxo-butyric acid as a raw material, and performing condensation reaction with methylamine hydrochloride under the action of organic base and condensing agent to generate N, 3-trimethyl-2-oxo-butyramide. The N, 3-trimethyl-2-oxo-butyramide generated by the synthesis method has high yield which reaches 82%, mild reaction conditions, suitability for large-scale production, no adoption of high-toxicity raw materials, safety and environmental protection.
Description
Technical Field
The invention relates to the technical field of amides, in particular to a method for synthesizing N, 3-trimethyl-2-oxo-butyramide.
Background
N, 3-trimethyl-2-oxobutanamide (3), the English name N, 3-trimethyl-2-oxobutanamide, is a key intermediate for synthesizing tlANOP ligand (N- (diphenylphosphino) -2- [ (diphenylphosphino) oxy ] -3, N-trimethylbutanamide) phosphine ligand used in efficient asymmetric hydrogenation reaction. Document High yield acyl anion trapping reactions: direct nucleophilic acylation of isocyanates and isothiocyanates (Tetrahedron: asymmetry 1998,9,4043-4054) discloses a method of synthesis of the following figure:
there are few documents and patents on the synthesis of N, 3-trimethyl-2-oxobutanamide (Tetrahedron Letters (1984), 25 (46), 5251-4.; EP0798289A 1). The specific synthesis method is as follows:
in this method, N, 3-trimethyl-2-oxobutanamide is synthesized in 84% yield from lithium tert-butoxide, highly toxic carbon monoxide and active isocyanate as raw materials at a low temperature of-110 ℃. The application of high activity, high toxicity raw materials and ultralow temperature conditions obviously limits the wide application of the method. Although the means for synthesizing amides are various at present, there is no gentle and efficient method for synthesizing N, 3-trimethyl-2-oxobutanamide, an important compound.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a method for synthesizing N, 3-trimethyl-2-oxo-butyramide, which solves the problem that the method is limited in application due to high-toxicity raw materials and ultralow-temperature conditions existing in the prior art.
In one aspect of the invention, a method for synthesizing N, 3-trimethyl-2-oxobutanamide is provided, wherein 3, 3-dimethyl-2-oxobutanoic acid is used as a raw material, and the raw material is subjected to condensation reaction with methylamine hydrochloride under the action of organic base and a condensing agent to generate N, 3-trimethyl-2-oxobutanamide.
Further, the method comprises the steps of:
s1: dissolving 3, 3-dimethyl-2-oxobutanoic acid in an organic solvent;
s2: adding methylamine hydrochloride, organic base and condensing agent to perform condensation reaction.
Further, the molar volume ratio of the 3, 3-dimethyl-2-oxo-butyric acid to the organic solvent is 1:10-30.
Further, the molar ratio of the 3, 3-dimethyl-2-oxo-butyric acid, the methylamine hydrochloride, the condensing agent and the organic base is 1:2:2:1.21.
Further, the organic base is N-methyl morpholine.
Further, the condensing agent is COMU.
Further, the organic solvent used was methylene chloride.
Further, the temperature of the condensation reaction is 20-35 ℃ and the reaction time is 9-12 hours.
The term "eq" or "equiv" is herein defined as molar equivalent, "V" is solvent volume, e.g. 10V represents a solvent volume that is 10 times the molar equivalent of solute per mole per liter. Specifically, the molar equivalent of 3, 3-dimethyl-2-carbonylbutyric acid was 1eq., the amount of methylene chloride was 10V, and the concentration was 0.1mol/L.
Compared with the prior art, the invention has the following beneficial effects:
1) The yield of the N, 3-trimethyl-2-oxo-butyramide generated by the synthesis method is high and reaches 82 percent.
2) The invention has mild reaction condition and is suitable for large-scale production.
3) The invention is safe and environment-friendly, and does not adopt high-toxicity raw materials.
Drawings
FIG. 1 is a schematic diagram of N, 3-trimethyl-2-oxobutanamide in example 1 of the present invention 1 H-NMR spectrum.
FIG. 2 is a schematic diagram of N, 3-trimethyl-2-oxobutanamide in example 1 of the invention 31 P-NMR spectrum.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings and examples.
Example 1 preparation of N, 3-trimethyl-2-oxobutanamide
N-methyl morpholine (2 eq), methylamine hydrochloride (2 eq) and (2-oximino-cyanoethyl acetate) -N, N-dimethyl-morpholino urea hexafluorophosphate (COMU) (1.21 eq) were slowly added in sequence to a reaction solution of 3, 3-dimethyl-2-carbonyl butyric acid (1 eq) in methylene chloride (15V) at room temperature, and the reaction solution was stirred at room temperature for 10 hours. Can be separated to obtain 82 percentThe final product N, 3-trimethyl-2-oxybutylamine (3). The end product 1 H-NMR 31 The P-NMR spectra are shown in FIGS. 1 and 2. The reaction formula is as follows:
example 2 preparation of N, 3-trimethyl-2-oxobutanamide
N-methyl morpholine (2 eq), methylamine hydrochloride (2 eq) and (2-oximino-cyanoethyl acetate) -N, N-dimethyl-morpholino urea hexafluorophosphate (COMU) (1.21 eq) were slowly added in sequence to a reaction solution of 3, 3-dimethyl-2-carbonyl butyric acid (1 eq) in methylene chloride (10V) at room temperature, and the reaction solution was stirred at 20℃for 12 hours. 80% of the final product N, 3-trimethyl-2-oxybutylamine (3) is obtained by separation.
Example preparation of 3N, 3-trimethyl-2-oxobutanamide
N-methyl morpholine (2 eq), methylamine hydrochloride (2 eq) and (2-oximino-cyanoethyl acetate) -N, N-dimethyl-morpholino urea hexafluorophosphate (COMU) (1.21 eq) were slowly added in sequence to a reaction solution of 3, 3-dimethyl-2-carbonyl butyric acid (1 eq) in methylene chloride (30V) at room temperature, and the reaction solution was stirred at 35℃for 9 hours. 77% of the final product N, 3-trimethyl-2-oxybutylamine (3) was isolated.
Comparative example preparation of 1N, 3-trimethyl-2-oxobutanamide
Similar to example 1, the difference is that: the COMU is replaced by EDCI and HOBt, the N-methyl morpholine is replaced by DIPEA, and the optimal proportion and reaction temperature are adjusted, wherein the reaction formula is as follows:
the yield of N, 3-trimethyl-2-oxobutanamide is less than 15% through detection.
Comparative example preparation of 2N, 3-trimethyl-2-oxobutanamide
Similar to example 1, the difference is that: COMU was replaced with DCC and HOBt, N-methylmorpholine was replaced with DIPEA, DCM was replaced with THF, and the optimum ratio and reaction temperature were adjusted, the reaction formula was as follows:
the yield of N, 3-trimethyl-2-oxobutanamide is less than 13% through detection.
Comparative example preparation of 3N, 3-trimethyl-2-oxobutanamide
Similar to example 1, the difference is that: COMU was replaced with HATU and HOAT, N-methylmorpholine was replaced with DIPEA, DCM was replaced with DMF, and the optimum ratio and reaction temperature were adjusted, the reaction formula was as follows:
the yield of N, 3-trimethyl-2-oxobutanamide is less than 10% through detection.
Comparative example preparation of 4N, 3-trimethyl-2-oxobutanamide
The reaction formula is as follows:
the yield of N, 3-trimethyl-2-oxobutanamide is less than 5% through detection.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (8)
1. A method for synthesizing N, 3-trimethyl-2-oxobutanamide, which is characterized by comprising the following steps: taking 3, 3-dimethyl-2-oxo-butyric acid as a raw material, and performing condensation reaction with methylamine hydrochloride under the action of organic base and condensing agent to generate N, 3-trimethyl-2-oxo-butyramide.
2. A method of synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1, wherein: the method comprises the following steps:
s1: dissolving 3, 3-dimethyl-2-oxobutanoic acid in an organic solvent;
s2: adding methylamine hydrochloride, organic base and condensing agent to perform condensation reaction.
3. A method of synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 2, wherein: the volume of the organic solvent is 10-30V based on the molar equivalent of 3, 3-dimethyl-2-oxobutanoic acid.
4. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the molar equivalent ratio of the 3, 3-dimethyl-2-oxo-butyric acid to the methylamine hydrochloride to the condensing agent to the organic base is 1:2:2:1.21.
5. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the organic base is N-methyl morpholine.
6. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the condensing agent is COMU.
7. A method of synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 2, wherein: the organic solvent used was methylene chloride.
8. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the condensation reaction temperature is 20-35 ℃ and the reaction time is 9-12 hours.
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