CN102285884A - Method for synthesizing 7-chloro-2-oxoheptanoate - Google Patents
Method for synthesizing 7-chloro-2-oxoheptanoate Download PDFInfo
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- CN102285884A CN102285884A CN2011101871241A CN201110187124A CN102285884A CN 102285884 A CN102285884 A CN 102285884A CN 2011101871241 A CN2011101871241 A CN 2011101871241A CN 201110187124 A CN201110187124 A CN 201110187124A CN 102285884 A CN102285884 A CN 102285884A
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- bromo
- chlorobutane
- oxoheptanoate
- chloro
- ethyl ester
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- ZJUYOWJXXHLBOO-UHFFFAOYSA-N 7-chloro-2-oxoheptanoic acid Chemical compound OC(=O)C(=O)CCCCCCl ZJUYOWJXXHLBOO-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 claims abstract description 53
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 238000004821 distillation Methods 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 10
- 238000006482 condensation reaction Methods 0.000 claims abstract description 9
- 239000012046 mixed solvent Substances 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000010189 synthetic method Methods 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 239000007795 chemical reaction product Substances 0.000 claims description 10
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- 230000006837 decompression Effects 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 239000000047 product Substances 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 229940117360 ethyl pyruvate Drugs 0.000 abstract 2
- 238000001914 filtration Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229960004912 cilastatin Drugs 0.000 description 6
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 6
- 238000012423 maintenance Methods 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 210000005239 tubule Anatomy 0.000 description 4
- IDDYNNYMUPHFMO-UHFFFAOYSA-N 2-Keto-n-heptylic acid Chemical compound CCCCCC(=O)C(O)=O IDDYNNYMUPHFMO-UHFFFAOYSA-N 0.000 description 3
- 102000003850 Dipeptidase 1 Human genes 0.000 description 3
- 108090000204 Dipeptidase 1 Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- JSAKRLDIZOGQTN-UHFFFAOYSA-M 4-[(2-hydroxynaphthalen-1-yl)diazenyl]naphthalene-1-sulfonate Chemical compound OC1=C(C2=CC=CC=C2C=C1)N=NC1=CC=C(C2=CC=CC=C12)S(=O)(=O)[O-] JSAKRLDIZOGQTN-UHFFFAOYSA-M 0.000 description 1
- RXQNKKRGJJRMKD-UHFFFAOYSA-N 5-bromo-2-methylaniline Chemical compound CC1=CC=C(Br)C=C1N RXQNKKRGJJRMKD-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229960003716 cilastatin sodium Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-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
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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Abstract
The invention discloses a method for synthesizing 7-chloro-2-oxoheptanoate, which comprises: dissolving ethyl pyruvate in an organic solvent, adding alkali and 1-bromo-4-chlorobutane in turn, and performing a condensation reaction; filtering the product of the reaction, removing solvent from filtrate by reduced-pressure distillation; purifying by distillation; and thus, obtaining 7-chloro-2-oxoheptanoate. In the invention, nontoxic and cheap ethyl pyruvate is used as a main raw material and subjected to one-step condensation reaction with 1-bromo-4-chlorobutane under the action of alkali to form the 7-chloro-2-oxoheptanoate, and the yield of the product reaches 88 to 98 percent. The synthesis method disclosed by the invention has the advantages of high product yield, simple steps, wide reaction conditions, low cost, environment friendliness and the like and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of cilastatin intermediate, relate in particular to the cilastatin intermediate--the synthetic method of 7-chloro-2-oxoheptanoate belongs to the synthetic field of 7-chloro-2-oxoheptanoate.
Background technology
Cilastatin (another name: be a kind of dehydropeptidase I inhibitor cilastatin sodium), be synthetic.The dehydropeptidase I is present in the brush edge of uriniferous tubules, when imipenum enters uriniferous tubules, is promptly lost antimicrobial activity by this enzymes metabolism.Cilastatin not only can suppress the metabolism of this enzyme, also has the generation that stops possible renal toxicity product.The destruction that cilastatin can protect imipenum not suffer the dehydropeptidase I in uriniferous tubules makes the imipenum of being saved reclaim 70% from uriniferous tubules again, strengthens the anti-microbial effect of imipenum, forms compound formulation with imipenum, and the treatment Related Bacteria infects.
7-chloro-2-oxoheptanoate is the key intermediate of cilastatin.The synthetic method of 7-chloro-2-oxoheptanoate in the world mainly contains schematized version and two kinds of main synthetic methods of oxime hydrolysis method at present.Wherein, the synthesis route figure of schematized version sees Fig. 1.The existing major defect of method of the synthetic 7-chloro-2-oxoheptanoate of schematized version is that synthesis condition is comparatively harsh, production cost is high.(patent: synthesis route figure EP0441371B1) sees Fig. 2 to the synthetic 7-chloro-2-oxoheptanoate of oxime hydrolysis method, though the oxime hydrolysis method has advantage with low cost, but this synthetic method need be used very big nitrosyl-sulfuric acid of pollution and formaldehyde, produce a large amount of acid waste water, there are comparatively serious problems such as contaminate environment in this method.
Summary of the invention
Technical problem to be solved by this invention is to overcome defective such as existing severe reaction conditions, cost height, contaminate environment in the synthetic method of existing 7-chloro-2-oxoheptanoate, a kind of synthetic method of new 7-chloro-2-oxoheptanoate is provided, and this synthetic method has that step is simple and direct, reaction conditions is wide in range, with low cost, advantages of environment protection.
Technical problem to be solved by this invention is achieved through the following technical solutions:
A kind of synthetic method of 7-chloro-2-oxoheptanoate comprises:
Pyruvic Acid Ethyl ester is dissolved in the organic solvent, successively to wherein adding alkali and 1-bromo-4-chlorobutane, carries out condensation reaction again; Reaction product is filtered, and solvent is removed in the filtrate decompression distillation, rectification and purification, promptly.
In order to reach better synthetic effect, by mass ratio, the proportion optimization of Pyruvic Acid Ethyl ester and organic solvent is 1:2-15; Wherein, described organic solvent is preferably from toluene, tetrahydrofuran (THF), sherwood oil, normal hexane, methylene dichloride, dimethyl sulfoxide (DMSO), N, any one or more than one mixed solvent formed by arbitrary proportion in dinethylformamide or the alcohol organic solvent; Wherein said alcohol organic solvent can be organic solvents such as ethanol, propyl alcohol.
Described alkali is any one in butyllithium, diisopropylamine lithium, sodium hydride, sodium ethylate, potassium tert.-butoxide or salt of wormwood or multiple preferably.
In order to guarantee synthetic effect preferably, be under-78 ℃ to 80 ℃ the condition keeping temperature, in reaction solvent, add alkali and 1-bromo-4-chlorobutane, be to carry out condensation reaction under-78 ℃ to 80 ℃ the condition in temperature; Wherein, preferable, the time that adds alkali or 1-bromo-4-chlorobutane is controlled within 0.5-3 hour the scope.
Preferably, the time of described condensation reaction is controlled to be 3-15 hour.
The present invention is by further test discovery, consumption proportion by control Pyruvic Acid Ethyl ester, 1-bromo-4-chlorobutane and alkali, can effectively improve the yield and the purity of product, the present invention finally finds by a large amount of optimization Test, the mole proportioning of Pyruvic Acid Ethyl ester, 1-bromo-4-chlorobutane and alkali is controlled in the following category, helps improving the yield and the purity of product most: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: alkali=0.5-1:0.5-1:0.5-2.
The present invention is that main raw material effect and 1-bromo-4-chlorobutane by alkali in organic solvent goes on foot the synthetic 7-chloro-2-oxoheptanoate that obtains of condensation reaction by one with nontoxic cheap Pyruvic Acid Ethyl ester; product yield can reach 88%-98%; this synthetic method has the product yield height, step is simple and direct, reaction conditions is wide in range, with low cost, advantages of environment protection, is suitable for large-scale industrial production.
Description of drawings
Synthetic method-schematized version road technology the line chart of the existing 7-chloro-of Fig. 1 2-oxoheptanoate.
Synthetic method-oxime hydrolysis method the process route chart of the existing 7-chloro-of Fig. 2 2-oxoheptanoate.
The synthetic method craft route map of Fig. 3 7-chloro-of the present invention 2-oxoheptanoate.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage of the present invention and characteristics will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not constituted any restriction.It will be understood by those skilled in the art that and down can make amendment or replace without departing from the spirit and scope of the present invention, but these modifications and replacing all fall within the scope of protection of the present invention the details of technical solution of the present invention and form.
Embodiment 1
Pyruvic Acid Ethyl ester is dissolved in the tetrahydrofuran (THF), and the mass ratio of Pyruvic Acid Ethyl ester and tetrahydrofuran (THF) is 1:2, obtains mixed solvent 1; Controlled temperature is 60 ℃, drips diisopropylamine lithium (is solvent with the tetrahydrofuran (THF)) in mixed solvent 1, add diisopropylamine lithium time be controlled to be 0.5 hour, obtain mixed solvent 2; Keeping temperature is 60 ℃, adds 1-bromo-4-chlorobutane again in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 0.5 hour; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and diisopropylamine lithium is: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: diisopropylamine lithium=0.5:0.5:2.The temperature that 1-bromo-4-chlorobutane adds back maintenance mixed solvent is 60 ℃, reacts 6 hours; Reaction finishes, reaction product filtered, and filtrate decompression distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 98%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.28 (2H, q, J=5.6 Hz), (3.51 2H, t, J=5.2 Hz), (2.84 2H, t, J=5.6 Hz), 1.74-1.81 (2H, m), 1.61-1.69 (2H, m), and 1.40-1.50 (2H, m), (1.34 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?194.3,?161.2,?62.4,?44.6,?39.0,?32.2,?26.2,?22.2,?14.0.
Embodiment 2
Pyruvic Acid Ethyl ester is dissolved in the mixed organic solvents of being made up of by arbitrary proportion tetrahydrofuran (THF) and normal hexane, and the mass ratio of Pyruvic Acid Ethyl ester and mixed organic solvents is 1:15, obtains mixed solvent 1; Controlled temperature-78 ℃ drips butyllithium (is solvent with tetrahydrofuran (THF)/normal hexane) in mixed solvent 1, add butyllithium time be controlled to be 3 hours, obtain mixed solvent 2; Keeping temperature is-78 ℃, adds 1-bromo-4-chlorobutane in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 3 hours; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and butyllithium is controlled to be: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: butyllithium=0.5:1:2.1-bromo-4-chlorobutane adds the back and keeps the temperature of mixed solvent to be-78 ℃, reacts 15 hours; Reaction finishes, reaction product filtered, and filtrate decompression distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 97%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.27 (2H, q, J=5.6 Hz), (3.52 2H, t, J=5.2 Hz), (2.86 2H, t, J=5.6 Hz), 1.74-1.83 (2H, m), 1.62-1.69 (2H, m), and 1.40-1.51 (2H, m), (1.35 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?195.2,?161.4,?62.5,?45.2,?39.1,?32.2,?26.2,?22.2,?14.0.
Embodiment 3
Pyruvic Acid Ethyl ester is dissolved in the dimethyl sulfoxide (DMSO), and the mass ratio of Pyruvic Acid Ethyl ester and dimethyl sulfoxide (DMSO) is 1:5, obtains mixed solvent 1; Controlled temperature-4 ℃ adds sodium hydride in mixed solvent, add sodium hydride time be controlled to be 2 hours and (please examine the joining day that needs to control sodium hydride?), obtain mixed solvent 2; Keeping temperature is-4 ℃, adds 1-bromo-4-chlorobutane in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 2 hours; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and sodium hydride is controlled to be: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: sodium hydride=1:1:2.1-bromo-4-chlorobutane adds the back and keeps the temperature of mixed solvent to be-4 ℃, reacts 12 hours; Reaction finishes, reaction product filtered, and filtrate decompression distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 98%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.26 (2H, q, J=5.6 Hz), (3.49 2H, t, J=5.2 Hz), (2.87 2H, t, J=5.6 Hz), 1.74-1.81 (2H, m), 1.62-1.68 (2H, m), and 1.41-1.52 (2H, m), (1.34 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?194.6,?161.2,?62.8,?44.6,?39.1,?32.4,?26.2,?22.5,?14.1.
Embodiment 4
Pyruvic Acid Ethyl ester is dissolved in N, in the dinethylformamide, Pyruvic Acid Ethyl ester and N, the mass ratio of dinethylformamide is 1:3, obtains mixed solvent 1; Controlled temperature is 80 ℃, adds salt of wormwood in mixed solvent 1, add salt of wormwood time be controlled to be 0.5 hour, obtain mixed solvent 2; Keeping temperature is 80 ℃, adds 1-bromo-4-chlorobutane in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 0.5 hour; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and dimethyl sulfoxide (DMSO) is controlled to be: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: dimethyl sulfoxide (DMSO)=1:0.5:2.The temperature that 1-bromo-4-chlorobutane adds back maintenance mixed solvent is 80 ℃, reacts 3 hours; Reaction finishes, reaction product filtered, and filtrate decompression distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 96%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.29 (2H, q, J=5.6 Hz), (3.54 2H, t, J=5.2 Hz), (2.86 2H, t, J=5.6 Hz), 1.75-1.87 (2H, m), 1.60-1.68 (2H, m), and 1.40-1.51 (2H, m), (1.35 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?195.1,?162.1,?62.4,?44.6,?39.0,?32.2,?26.3,?22.7,?14.5.
Embodiment 5
Pyruvic Acid Ethyl ester is dissolved in the ethanol, and Pyruvic Acid Ethyl ester and alcoholic acid mass ratio are 1:10, obtain mixed solvent 1; Controlled temperature-12 ℃ drips sodium ethylate in mixed solvent, add sodium ethylate time be controlled to be 2.5 hours, obtain mixed solvent 2; Keeping temperature is-12 ℃, adds 1-bromo-4-chlorobutane in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 2.5 hours; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and sodium ethylate is controlled to be: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: sodium ethylate=0.8:0.6:1.5.1-bromo-4-chlorobutane adds the back and keeps the temperature of mixed solvent to be-12 ℃, reacts 8 hours; Reaction finishes, reaction product filtered, and filtrate decompression distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 97.5%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.29 (2H, q, J=5.6 Hz), (3.53 2H, t, J=5.2 Hz), (2.87 2H, t, J=5.6 Hz), 1.77-1.84 (2H, m), 1.62-1.67 (2H, m), and 1.41-1.52 (2H, m), (1.34 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?195.1,?162.1,?62.7,?44.8,?39.2,?32.6,?26.1,?22.3,?14.1.
Embodiment 6
Pyruvic Acid Ethyl ester is dissolved in the propyl alcohol, and the mass ratio of Pyruvic Acid Ethyl ester and propyl alcohol is 1:10, obtains mixed solvent 1; 10 ℃ of controlled temperature drip potassium tert.-butoxide in mixed solvent 1, add potassium tert.-butoxide time be controlled to be 1 hour, obtain mixed solvent 2; Keeping temperature is 10 ℃, adds 1-bromo-4-chlorobutane in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 1.5 hours; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and potassium tert.-butoxide is controlled to be: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: potassium tert.-butoxide=1:0.8:0.5.The temperature that 1-bromo-4-chlorobutane adds back maintenance mixed solvent is 10 ℃, reacts 8 hours; Reaction finishes, reaction product filtered, and filtrate decompression distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 96.8%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.29 (2H, q, J=5.6 Hz), (3.57 2H, t, J=5.2 Hz), (2.86 2H, t, J=5.6 Hz), 1.74-1.81 (2H, m), 1.61-1.69 (2H, m), and 1.44-1.50 (2H, m), (1.34 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?194.4,?161.2,?62.4,?44.6,?39.1,?32.2,?26.3,?22.6,?14.0.
Embodiment 7
Pyruvic Acid Ethyl ester is dissolved in the toluene, and the mass ratio of Pyruvic Acid Ethyl ester and toluene is 1:3, obtains mixed solvent 1; Controlled temperature is 30 ℃, drips diisopropylamine lithium (is solvent with the tetrahydrofuran (THF)) in mixed solvent 1, add diisopropylamine lithium time be controlled to be 1 hour, obtain mixed solvent 2; Keeping temperature is 30 ℃, adds 1-bromo-4-chlorobutane in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 1.5 hours; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and diisopropylamine lithium is controlled to be: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: diisopropylamine lithium=0.5:1.5:2.The temperature that 1-bromo-4-chlorobutane adds back maintenance mixed solvent is 30 ℃, reacts 6 hours; Reaction finishes, reaction product filtered, and filtrate decompression distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 97%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.26 (2H, q, J=5.6 Hz), (3.54 2H, t, J=5.2 Hz), (2.85 2H, t, J=5.6 Hz), 1.72-1.81 (2H, m), 1.63-1.69 (2H, m), and 1.40-1.52 (2H, m), (1.34 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?195.1,?162.1,?62.5,?44.9,?39.1,?32.8,?26.4,?22.2,?14.0.
Embodiment 8
Pyruvic Acid Ethyl ester is dissolved in the sherwood oil, and the mass ratio of Pyruvic Acid Ethyl ester and sherwood oil is 1:10, obtains mixed solvent 1; 70 ℃ of controlled temperature add salt of wormwood in mixed solvent 1, add salt of wormwood time be controlled to be 1 hour, obtain mixed solvent 2; Keeping temperature is 70 ℃, adds 1-bromo-4-chlorobutane in mixed solvent 2, and the time that adds 1-bromo-4-chlorobutane is controlled to be 0.6 hour; Wherein, in molar ratio, the consumption of the Pyruvic Acid Ethyl ester that is added, 1-bromo-4-chlorobutane and salt of wormwood is controlled to be: Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: alkali salt of wormwood=0.8:0.6:1.8.The temperature that 1-bromo-4-chlorobutane adds back maintenance mixed solvent is 70 ℃, reacts 9 hours; Reaction finishes, reaction product filtered, and underpressure distillation (removal solvent), rectification and purification promptly gets 7-chloro-2-oxoheptanoate.Yield 98%.
7-chloro-2-oxoheptanoate: 1HNMR (CDCl3,400 MHz): δ 4.26 (2H, q, J=5.6 Hz), (3.54 2H, t, J=5.2 Hz), (2.85 2H, t, J=5.6 Hz), 1.72-1.83 (2H, m), 1.62-1.68 (2H, m), and 1.40-1.53 (2H, m), (1.34 3H, t, J=5.6 Hz).
13CNMR?(CDCl3,?400?MHz):?δ?194.8,?161.5,?62.9,?44.9,?39.0,?32.2,?26.3,?22.4,?14.1.。
Claims (10)
1. the synthetic method of a 7-chloro-2-oxoheptanoate comprises:
Pyruvic Acid Ethyl ester is dissolved in the organic solvent, adds alkali and 1-bromo-4-chlorobutane more successively, carry out condensation reaction; Reaction product is filtered, the filtrate decompression distillation, rectification and purification, promptly.
2. according to the described synthetic method of claim 1, it is characterized in that: by mass ratio, the proportioning of Pyruvic Acid Ethyl ester and organic solvent is 1:2-15.
3. according to claim 1 or 2 described synthetic methods, it is characterized in that: described organic solvent is selected from toluene, tetrahydrofuran (THF), sherwood oil, normal hexane, methylene dichloride, dimethyl sulfoxide (DMSO), N, any one or more than one mixed solvent formed by arbitrary proportion in dinethylformamide or the alcoholic solvent.
4. according to the described synthetic method of claim 3, it is characterized in that: described alcoholic solvent comprises ethanol or propyl alcohol.
5. according to the described synthetic method of claim 1, it is characterized in that: described alkali be selected from butyllithium, diisopropylamine lithium, sodium hydride, sodium ethylate, potassium tert.-butoxide or the salt of wormwood any one or multiple.
6. according to the described synthetic method of claim 1, it is characterized in that: keeping temperature is under-78 ℃ to 80 ℃ the condition, adds alkali and 1-bromo-4-chlorobutane successively.
7. according to claim 1 or 6 described synthetic methods, it is characterized in that: the time that adds alkali or 1-bromo-4-chlorobutane was controlled at 0.5-3 hour.
8. according to the described synthetic method of claim 1, it is characterized in that: the temperature of described condensation reaction is-78 ℃ to 80 ℃.
9. according to claim 1 or 8 described synthetic methods, it is characterized in that: the time of described condensation reaction is 3-15 hour.
10. according to the described synthetic method of claim 1, it is characterized in that: by the mole proportioning, Pyruvic Acid Ethyl ester: 1-bromo-4-chlorobutane: alkali=0.5-1:0.5-1:0.5-2.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103724200A (en) * | 2013-12-12 | 2014-04-16 | 太仓浦源医药原料有限公司 | Preparation method of 7-chloro-2-oxoheptanoic acid ethyl ester |
| CN106083581A (en) * | 2016-06-21 | 2016-11-09 | 深圳市海滨制药有限公司 | A kind of preparation method of 7 chlorine (1 oxoethyl) cognac oil |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103724200A (en) * | 2013-12-12 | 2014-04-16 | 太仓浦源医药原料有限公司 | Preparation method of 7-chloro-2-oxoheptanoic acid ethyl ester |
| CN106083581A (en) * | 2016-06-21 | 2016-11-09 | 深圳市海滨制药有限公司 | A kind of preparation method of 7 chlorine (1 oxoethyl) cognac oil |
| CN106083581B (en) * | 2016-06-21 | 2019-04-09 | 深圳市海滨制药有限公司 | A kind of preparation method of the chloro- 2- of 7- (1- oxoethyl) cognac oil |
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