CN115677639B - Preparation method of tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate - Google Patents
Preparation method of tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- MWMWCWFQGDBSIR-UHFFFAOYSA-N methyl 3-oxooxane-4-carboxylate Chemical compound COC(=O)C1CCOCC1=O MWMWCWFQGDBSIR-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 239000003054 catalyst Substances 0.000 claims abstract description 34
- JUYVXCGKMCYNBN-UHFFFAOYSA-N methyl 4-hydroxybutanoate Chemical compound COC(=O)CCCO JUYVXCGKMCYNBN-UHFFFAOYSA-N 0.000 claims abstract description 17
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 claims abstract description 16
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 claims abstract description 7
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- CVEDICQELWZMLV-UHFFFAOYSA-N C(C)OC(COCCCC(=O)OC)=O Chemical compound C(C)OC(COCCCC(=O)OC)=O CVEDICQELWZMLV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- 150000007530 organic bases Chemical class 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- -1 triphenyllithium Chemical compound 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 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 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000011701 zinc Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- APAWJCZGOJKZPB-UHFFFAOYSA-N ethyl 3-oxooxane-4-carboxylate Chemical compound CCOC(=O)C1CCOCC1=O APAWJCZGOJKZPB-UHFFFAOYSA-N 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- 239000010948 rhodium Substances 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- 229940006015 4-hydroxybutyric acid Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- ITDJKCJYYAQMRO-UHFFFAOYSA-L rhodium(2+);diacetate Chemical compound [Rh+2].CC([O-])=O.CC([O-])=O ITDJKCJYYAQMRO-UHFFFAOYSA-L 0.000 description 1
- SYBXSZMNKDOUCA-UHFFFAOYSA-J rhodium(2+);tetraacetate Chemical compound [Rh+2].[Rh+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O SYBXSZMNKDOUCA-UHFFFAOYSA-J 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical group [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 description 1
Abstract
The invention relates to a preparation method of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate, which comprises the following steps: s1, carrying out substitution reaction on 4-hydroxybutyric acid methyl ester in the presence of diazoacetic acid ethyl ester and a catalyst to obtain 4- (2-ethoxy-2-oxo ethoxy) butyric acid methyl ester; s2, 4- (2-ethoxy-2-oxo ethoxy) methyl butyrate undergoes intramolecular nucleophilic substitution reaction in the presence of alkali to obtain tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester; wherein the catalyst is selected from Zn (OTf) 2 、ZnCl 2 、Mg(OTf) 2 、Cu(OTf) 2 、Pd(OTf) 2 、Cu(OAc) 2 、Ag 2 CO 3 Any one of them. The preparation method has the advantages of simple preparation process, mild reaction conditions and no need of strict inert gas environment; the catalyst has low cost and can be recycled, which is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate.
Background
The tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester is an important organic synthesis intermediate and a medical intermediate, and is widely used in laboratory research and development processes and chemical production processes.
In the preparation of methyl tetrahydro-3-oxo-2H-pyran-4-carboxylate, it is generally prepared by intramolecular nucleophilic substitution reaction of methyl 4- (2-ethoxy-2-oxoethoxy) butyrate in the presence of a base, and has the following reaction formula:
methyl 4- (2-ethoxy-2-oxoethoxy) butyrate is also particularly important as an intermediate in the preparation of methyl tetrahydro-3-oxo-2H-pyran-4-carboxylate. In the existing synthesis of 4- (2-ethoxy-2-oxoethoxy) methyl butyrate, gamma-butyrolactone is mainly used as a raw material, and the gamma-butyrolactone is hydrolyzed and substituted to obtain the 4- (2-ethoxy-2-oxoethoxy) methyl butyrate. In the synthesis process, rhodium diacetate dimer is used as a catalyst, the price is very high, and the rhodium diacetate can not be recycled, so that the reaction cost is greatly increased.
Disclosure of Invention
Based on the defects in the prior art, the invention aims to provide a preparation method of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate, which has simple preparation procedures, mild reaction conditions and no need of strict inert gas environment; the catalyst has low cost and can be recycled, which is beneficial to industrial production.
Therefore, the invention provides the following technical scheme.
The invention provides a preparation method of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate, which comprises the following steps:
s1, carrying out substitution reaction on 4-hydroxybutyric acid methyl ester in the presence of diazoacetic acid ethyl ester and a catalyst to obtain 4- (2-ethoxy-2-oxo ethoxy) butyric acid methyl ester;
s2, 4- (2-ethoxy-2-oxo ethoxy) methyl butyrate undergoes intramolecular nucleophilic substitution reaction in the presence of alkali to obtain tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester;
wherein the catalyst is selected from Zn (OTf) 2 、ZnCl 2 、Mg(OTf) 2 、Cu(OTf) 2 、Pd(OTf) 2 、Cu(OAc) 2 、Ag 2 CO 3 Any one of them.
Preferably, the catalyst is Zn (OTf) 2 。
Preferably, the catalyst is used in an amount of 5mol% to 12mol%, preferably 10mol%.
Preferably, the base is at least one selected from the group consisting of organic bases and inorganic bases; the organic base is at least one selected from potassium tert-butoxide, tert-butyllithium, triphenyllithium, sodium tert-butoxide and triphenylsodium, and preferably potassium tert-butoxide; the inorganic base is at least one selected from sodium hydroxide, potassium hydroxide and sodium carbonate.
Preferably, the molar ratio of the methyl 4-hydroxybutyrate to the ethyl diazoacetate is 1:1.1-1:1.5, preferably 1:1.2.
Preferably, in the step S2, the reaction temperature is 100 ℃ or less.
Preferably, the reaction temperature is 81 ℃.
Preferably, the methyl 4-hydroxybutyrate is prepared from gamma-butyrolactone by hydrolysis in an organic base reagent.
Preferably, the organic base reagent is at least one selected from triethylamine, ethylenediamine, isopropylamine, pyridine, 4-dimethylaminopyridine, morpholine and N-methylmorpholine.
Preferably, the molar ratio of the gamma-butyrolactone to the organic base reagent is 1:5 to 1:10.
The invention has the following technical effects:
the invention aims to provide a preparation method of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate, which is characterized in that 4-hydroxybutyric acid methyl ester is subjected to substitution reaction in the presence of diazoacetic acid ethyl ester and a catalyst to prepare an intermediate I, wherein the intermediate I is 4- (2-ethoxy-2-oxo-ethoxy) butyric acid methyl ester; the intermediate I is subjected to intramolecular nucleophilic substitution reaction to finally prepare the tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester, the preparation process is simple, the reaction condition is mild, and a strict inert gas environment is not needed. In addition, by defining the catalyst to be selected from Zn (OTf) 2 、ZnCl 2 、Mg(OTf) 2 、Cu(OTf) 2 、Pd(OTf) 2 、Cu(OAc) 2 、Ag 2 CO 3 Any one of the catalyst systems avoids using expensive rhodium reagents, ensures good reaction efficiency and yield, reduces the cost of the catalyst, can be recycled, is more environment-friendly, and is beneficial to industrial production.
Detailed Description
In order to make the technical scheme and the beneficial effects of the invention more obvious and understandable, the following detailed description is given by way of example. The present invention will be further understood by the following description of embodiments, but the specific embodiments given by the applicant should not be considered as limiting the technical solution of the present invention, and any modification of the definition of components or technical features and/or the form of the whole structure without substantial change should be considered as the protection scope defined by the technical solution of the present invention. Unless defined otherwise, technical and scientific terms used herein have the same meaning as technical and scientific terms in the technical field to which this application belongs.
The present invention will be further described with reference to the following specific embodiments, and it should be noted that, on the premise of no conflict, new embodiments may be formed by any combination of the embodiments or technical features described below.
The invention provides a preparation method of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate, which comprises the following steps:
s1, carrying out substitution reaction on 4-hydroxybutyric acid methyl ester in the presence of diazoacetic acid ethyl ester and a catalyst to obtain 4- (2-ethoxy-2-oxo ethoxy) butyric acid methyl ester;
s2, 4- (2-ethoxy-2-oxo ethoxy) methyl butyrate undergoes intramolecular nucleophilic substitution reaction in the presence of alkali to obtain tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester;
wherein the catalyst is selected from Zn (OTf) 2 、ZnCl 2 、Mg(OTf) 2 、Cu(OTf) 2 、Pd(OTf) 2 、Cu(OAc) 2 、Ag 2 CO 3 Any one of them.
In this example, 4-hydroxybutyric acid was usedMethyl ester is subjected to substitution reaction in the presence of ethyl diazoacetate and a catalyst to prepare an intermediate I, wherein the intermediate I is 4- (2-ethoxy-2-oxo-ethoxy) methyl butyrate; the intermediate I is subjected to intramolecular nucleophilic substitution reaction to finally prepare the tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester, the preparation process is simple, the reaction condition is mild, and a strict inert gas environment is not needed. In addition, by defining the catalyst to be selected from Zn (OTf) 2 、ZnCl 2 、Mg(OTf) 2 、Cu(OTf) 2 、Pd(OTf) 2 、Cu(OAc) 2 、Ag 2 CO 3 Any one of the catalyst systems avoids using expensive rhodium reagents, ensures good reaction efficiency and yield, reduces the cost of the catalyst, and is capable of being recycled and environment-friendly.
In this example, the structural formula of methyl 4-hydroxybutyrate is shown in the following formula (I):
the structural formula of the ethyl diazoacetate is shown in the following formula (II):
the structural formula of the intermediate I is shown in the following formula (III):
the structural formula of the tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester is shown in the following formula (IV):
the reaction formula of the S1 step is as follows:
the reaction formula of the S2 step is as follows:
further, the catalyst is zinc trifluoromethane sulfonate Zn (OTf) 2 The catalytic efficiency is high.
In one embodiment, the catalyst is used in an amount of 5mol% to 12mol% to ensure a high catalytic efficiency. Wherein mol% means a mole percentage, and means a ratio of the amount of the substance of the catalyst to the amount of the substance of methyl 4-hydroxybutyrate.
Further, the catalyst was used in an amount of 10mol%.
In an embodiment, in the step S2, the base is at least one selected from an organic base and an inorganic base; the organic base is at least one selected from potassium tert-butoxide, tert-butyllithium, triphenyllithium, sodium tert-butoxide and triphenylsodium, and preferably potassium tert-butoxide; the inorganic base is at least one selected from sodium hydroxide, potassium hydroxide and sodium carbonate.
In one embodiment, the molar ratio of the methyl 4-hydroxybutyrate to the ethyl diazoacetate is 1:1.1 to 1:1.5. Further, the molar ratio of the methyl 4-hydroxybutyrate to the ethyl diazoacetate was 1:1.2.
In one embodiment, in the step S2, the reaction temperature is 100 ℃ or less, and the reaction temperature is a reflux temperature of the system. The reaction temperature condition of the step S2 is mild, and the safety of a reaction system is high.
Further, the reaction temperature is 81 ℃, which is favorable for improving the reaction efficiency.
In one embodiment, the methyl 4-hydroxybutyrate is prepared from gamma-butyrolactone by hydrolysis in an organic base reagent, methyl 4-hydroxybutyrate as intermediate II, having the following reaction scheme:
further, the organic base reagent is at least one selected from triethylamine, ethylenediamine, isopropylamine, pyridine, 4-dimethylaminopyridine, morpholine and N-methylmorpholine. Specifically, the preparation process of the methyl 4-hydroxybutyrate is simple, and the reaction condition is mild. Preferably, the organic base reagent is triethylamine.
Further, the molar ratio of the gamma-butyrolactone to the organic base reagent is 1:5-1:10. Preferably, the molar ratio of the gamma-butyrolactone to the organic base reagent is 1:6.
The process of the present invention is illustrated by the following specific examples, it being understood that these examples are illustrative of the basic principles, main features and advantages of the present invention, and the present invention is not limited by the scope of the following examples; the implementation conditions employed in the examples may be further adjusted according to specific requirements, and the implementation conditions not specified are generally those in routine experiments.
In the following examples 1 H NMR representation method: s=singlet, t=triplet, m=multiplet.
Example 1
Preparation of intermediate II
250mL of methanol, 4.3g of gamma-butyrolactone (50 mmol) and 30.4g of triethylamine (300 mmol) were successively added to a 500mL reaction flask, the temperature of the reaction mixture was raised to 60℃and stirring was continued for 16 hours, and the reaction was completed.
Cooling to room temperature, distilling the reaction liquid under reduced pressure, and concentrating in vacuum to obtain 5.6g of intermediate II, wherein the yield of the intermediate II is 96%.
1 H NMR(DMSO-d 4 ，400MHz)δ3.65-3.60(m，5H)；2.40(t，J＝7.2Hz，2H)；1.87-1.80(m，2H)。
Example 2
Preparation of intermediate II
To a 500mL reaction flask was successively added 250mL of methanol, 4.3g of gamma-butyrolactone (50 mmol), and 23.7g of pyridine (300 mmol). The reaction solution was warmed to 60℃and stirred for 16h, and the reaction was completed.
Cooling to room temperature, distilling the reaction solution under reduced pressure, and concentrating in vacuum to obtain 5.1g of intermediate II, wherein the yield of the intermediate II is 87%.
Example 3
Preparation of intermediate I
Into a 250mL reaction flask were successively charged 5.6g of intermediate II (47.4 mmol), 250mL of cyclohexane, 6.5g of ethyl diazoacetate (56.9 mmol), and 1.7g of Zn (OTf) 2 (4.7 mmol) the reaction was warmed to reflux (81 ℃ C.) and stirring was continued for 12h. TLC monitoring reaction, filtering the reaction system to recover Zn (OTf) after the reaction is complete 2 The filtrate was distilled in vacuo to give crude yellow oil which was purified by column chromatography (petroleum ether/ethyl acetate=12/1) to give 9.3g of intermediate i in 92% yield.
1 H NMR(400MHz，CDCl 3 )δ4.21-4.14(q，J＝7.2Hz，2H)；4.03(s，2H)；3.65(s，3H)；3.55(t，J＝6.2Hz，2H)；2.43(t，J＝7.4Hz，2H)；1.96-1.86(m，2H)；1.28-1.23(t，J＝7.2Hz，3H)。
In this example, zn (OTf) was used 2 As intermediate II and
example 4
Zn (OTf) recovered by example 3 2 Catalyst for use in preparation of intermediate I
Into a 250mL reaction flask were successively charged 5.6g of intermediate II (47.4 mmol), 250mL of cyclohexane, 6.5g of ethyl diazoacetate (56.9 mmol) and 1.7g of Zn (OTf) recovered in example 3 2 (4.7 mmol). The reaction was warmed to reflux (81 ℃) and stirring was continued for 12h. TLC monitoring reaction, filtering the reaction system to recover Zn (OTf) after the reaction is complete 2 The filtrate was distilled in vacuo to give a crude yellow oil which was purified by column chromatography (petroleum ether/ethyl acetate=12/1) to give 6.0g of intermediate i in 59% yield.
This example uses Zn (OTf) recovered in example 3 2 As a catalyst in the preparation of intermediate I, the yield of intermediate I in this example was slightly lower than in example 3 using the original Zn (OTf) 2 Yield of intermediate I as catalyst, but Zn (OTf) recovered in this example 2 The amount of Zn (OTf) in example 3 2 The amount of (C) was the same, and the yield of intermediate I in this example was also higher than 50%. Comparison of the yields of intermediate I from example 3 and example 4 shows that the catalyst defined in the present invention can be recovered and that the catalytic performance of the recovered catalyst is kept good.
Example 5
Preparation of intermediate I
Into a 250mL reaction flask were successively added 5.6g of intermediate II (47.4 mmol), 250mL of cyclohexane, 6.5g of ethyl diazoacetate (56.9 mmol), and 0.64g of ZnCl 2 (4.7 mmol). The reaction was warmed to reflux (81 ℃) and stirring was continued for 12h. TLC monitoring reaction, filtering the reaction system to recover ZnCl after the reaction is completed 2 The filtrate was distilled in vacuo to give crude yellow oil which was purified by column chromatography (petroleum ether/ethyl acetate=12/1) to give 5.6g of intermediate i in 55% yield.
Example 6:
preparation of intermediate I
Into a 250mL reaction flask were successively added 5.6g of intermediate II (47.4 mmol), 250mL of cyclohexane, 6.5g of ethyl diazoacetate (56.9 mmol), and 1.5.2 g of Mg (OTf) 2 (4.7 mmol). The reaction was warmed to reflux (81 ℃) and stirring was continued for 12h. TLC monitoring the reaction, after the reaction is completed, filtering the reaction system to recover Mg (OTf) 2 The filtrate was distilled in vacuo to give crude yellow oil which was purified by column chromatography (petroleum ether/ethyl acetate=12/1) to give 7.3g of intermediate i (72%).
Example 7:
preparation of methyl tetrahydro-3-oxo-2H-pyran-4-carboxylate
To a 250mL reaction flask, 9.3g of intermediate I (45.5 mmol) and 150mL of toluene were successively added, and 55mL of a tetrahydrofuran solution (1.0M, 54.6 mmol) of potassium tert-butoxide was added dropwise to the reaction system at room temperature. After the completion of the dropwise addition, the mixture was stirred at room temperature for 18 hours. 1M HCl (200 mL) was added dropwise to the reaction system. The organic phase was separated and the aqueous phase was extracted with methyl tert-butyl ether. The organic phases were combined and washed with 200mL of water and 200mL of Brine, and dried over anhydrous sodium sulfate. Crude brown oil is obtained after vacuum distillation, and the crude product is purified by column chromatography (petroleum ether/ethyl acetate=15/1) to give tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester and tetrahydro-3-oxo-2H-pyran-4-carboxylic acid ethyl ester, the total mass of the products being 4.0g, the weight ratio of tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester to tetrahydro-3-oxo-2H-pyran-4-carboxylic acid ethyl ester being about 1: the yield of the mixture of methyl tetrahydro-3-oxo-2H-pyran-4-carboxylate and ethyl tetrahydro-3-oxo-2H-pyran-4-carboxylate was 56%.
1 H NMR(400MHz，CDCl 3 )δ11.75(s，1H)；4.12(s，H)；3.79-3.76(m，5H)；2.34-2.37(m，2H)。
The invention provides a preparation method of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate, which has mild reaction conditions and does not need strict inert gas environment; in the step S1, a catalytic system using an expensive rhodium reagent is avoided, the cost of the catalyst is reduced while good reaction efficiency and yield are ensured, and the catalyst can be recycled and reused, so that the method is more environment-friendly and suitable for industrial production.
It should be understood that the above examples are illustrative and are not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes may be made in the above embodiments without departing from the scope of the disclosure. Likewise, the individual features of the above embodiments can also be combined arbitrarily to form further embodiments of the invention which may not be explicitly described. Therefore, the above examples merely represent several embodiments of the present invention and do not limit the scope of protection of the patent of the present invention.
Claims (12)
1. A process for the preparation of a tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester intermediate, said process comprising the steps of:
s1, carrying out substitution reaction on 4-hydroxybutyric acid methyl ester in the presence of diazoacetic acid ethyl ester and a catalyst to obtain 4- (2-ethoxy-2-oxo ethoxy) butyric acid methyl ester;
s2, 4- (2-ethoxy-2-oxo ethoxy) methyl butyrate undergoes intramolecular nucleophilic substitution reaction in the presence of alkali to obtain tetrahydro-3-oxo-2H-pyran-4-carboxylic acid methyl ester;
wherein the catalyst is selected from Zn (OTf) 2 。
2. The method according to claim 1, wherein the catalyst is used in an amount of 5mol% to 12 mol%.
3. The method according to claim 2, wherein the catalyst is used in an amount of 10mol%.
4. The method according to claim 1, wherein the base is at least one selected from the group consisting of an organic base and an inorganic base; the organic base is at least one selected from potassium tert-butoxide, tert-butyllithium, triphenyllithium, sodium tert-butoxide and triphenylsodium; the inorganic base is at least one selected from sodium hydroxide, potassium hydroxide and sodium carbonate.
5. The method of claim 4, wherein the organic base is potassium t-butoxide.
6. The method of claim 1, wherein the molar ratio of the methyl 4-hydroxybutyrate to the ethyl diazoacetate is 1:1.1 to 1:1.5.
7. The method of claim 6, wherein the molar ratio of methyl 4-hydroxybutyrate to ethyl diazoacetate is 1:1.2.
8. The method according to claim 1, wherein in the step S2, the reaction temperature is 100 ℃ or less.
9. The method of claim 8, wherein the reaction temperature is 81 ℃.
10. The process according to any one of claims 1 to 9, wherein the methyl 4-hydroxybutyrate is prepared by hydrolysis of gamma-butyrolactone in an organic base reagent.
11. The method according to claim 10, wherein the organic base reagent is selected from at least one of triethylamine, ethylenediamine, isopropylamine, pyridine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine.
12. The method of claim 10, wherein the molar ratio of the gamma-butyrolactone to the organic base reagent is from 1:5 to 1:10.
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| WO2016045125A1 (en) * | 2014-09-28 | 2016-03-31 | Merck Sharp & Dohme Corp. | Inhibitors of hif prolyl hydroxylase |
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| Diastereoselectiv ity Switch in Cooperatively Catalyzed Three-Component Reactions of an Aryldiazoacet ate, an Alcohol, and a β, γ -Unsaturated r-Keto Ester;Jingjing Ji et al;The Journal of Organic Chemistry;第76卷;5821–5824 * |
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