CN117327008A - Green synthesis process of dortefovir intermediate - Google Patents
Green synthesis process of dortefovir intermediate Download PDFInfo
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- CN117327008A CN117327008A CN202210731951.0A CN202210731951A CN117327008A CN 117327008 A CN117327008 A CN 117327008A CN 202210731951 A CN202210731951 A CN 202210731951A CN 117327008 A CN117327008 A CN 117327008A
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- 238000000034 method Methods 0.000 title claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 title abstract description 7
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 39
- 239000012074 organic phase Substances 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 24
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- XAXGEECGULRZGN-UHFFFAOYSA-N 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxopyridine-3-carboxylic acid Chemical compound COC(OC)CN1C=C(C(O)=O)C(=O)C(OC)=C1C(=O)OC XAXGEECGULRZGN-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 claims description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000001276 controlling effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 claims description 3
- -1 2-methyl 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid Chemical compound 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000003809 water extraction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000002699 waste material Substances 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 description 11
- 238000011084 recovery Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229960000980 entecavir Drugs 0.000 description 3
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 3
- QGBPKJFJAVDUNC-UHFFFAOYSA-N methyl 4-methoxy-3-oxobutanoate Chemical compound COCC(=O)CC(=O)OC QGBPKJFJAVDUNC-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- YNQRWVCLAIUHHI-UHFFFAOYSA-L dilithium;oxalate Chemical compound [Li+].[Li+].[O-]C(=O)C([O-])=O YNQRWVCLAIUHHI-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 2
- 229940039790 sodium oxalate Drugs 0.000 description 2
- 239000002910 solid waste Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 241000208152 Geranium Species 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000010812 mixed waste Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940014075 tivicay Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a green synthesis process of a doravir intermediate (compound I), which has mild reaction conditions, simple operation and environment-friendly property, and can be used in the reaction by using a solvent in a circulating way; meanwhile, the conversion rate is greatly improved, the total reaction yield can reach more than 80 percent, and the production cost is greatly reduced while the three-waste treatment investment is reduced.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry synthesis, and particularly relates to a green synthesis process of a entecavir intermediate 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-dipicolinate-2-methyl ester.
Background
Duolite (DTG), trade name TIVICAY, a new anti-AIDS drug developed by the Cooperation of the salt wild-type pharmaceutical companies, geranium, and Japan, jupiter, UK, is an integrase chain transfer inhibitor (INSTI), approved by the U.S. food and drug administration at 8 in 2012, and used in combination with other antiretroviral drugs for the treatment of HIV-1 infections in children older than 12 years and weighing at least 40 kg.
1- (2, 2-Dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester (compound of formula I below) is an important intermediate for entecavir, and the most commonly used production method in the industry at present is the synthetic route published in WO2011119566 by VIIV health-care company, which is shown in detail below, has the advantages of readily available raw materials, simple operation, mild reaction conditions and ideal industrialized route.
The synthesis method of the route is researched and repeated, and the report method in the patent is found that the synthesis of the compound in the formula I from the condensation of 4-Methoxy Methyl Acetoacetate (MMA) and DMF-DMA is completed in one step, and the intermediate does not have any separation and purification process, so that the reaction procedures are reduced, the reaction time is saved, the production efficiency is improved, but the conversion rate of the intermediate in each step is not high, and the total productivity is not large; and a large amount of salt is added in each reaction step, and when the last step is processed, a plurality of salts such as sodium oxalate, sodium methoxide and the like exist in the system, so that the lithium hydroxide reagent added in the last step needs to be consumed, the usage amount of lithium hydroxide is greatly excessive (4.0 eq) and a large amount of residual salt is not separated, and the lithium hydroxide is partially converted into lithium oxalate and lithium methoxide after being added, so that at least a plurality of salts such as sodium methoxide, sodium oxalate, lithium methoxide, lithium oxalate, lithium hydroxide and the like exist in the system, on one hand, the recovery of the salts is influenced, on the other hand, the separation efficiency is low in the product wrapping salt, so that the total reaction yield is lower, and only about 36%.
In view of the defects existing in the prior art, the synthesis process of the intermediate formula I of the entecavir is researched and developed, the solid waste generated by the reaction is reduced, the reaction conversion rate is improved, the green production can be realized while the product yield is improved, the solid waste is reduced, and the solvent use is reduced. The research is the direction of the current state advocating green chemical industry and the future chemical process improvement.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a method for preparing 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridine dicarboxylic acid-2-methyl ester (a compound shown in a formula I), which is environment-friendly, mild in reaction condition, high in conversion rate, capable of obviously reducing the generation of waste salt and greatly reducing the investment of three waste treatment.
In one aspect of the present invention, there is provided a process for preparing 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester (a compound of formula I) comprising the steps of:
(1) Adding 4-Methoxy Methyl Acetoacetate (MMA) and N, N-dimethylformamide dimethyl acetal (DMF-DMA) into an organic system, and reacting to obtain a compound I-1-containing mixed system A;
(2) Adding aminoacetaldehyde dimethyl acetal (DMEA) into the mixed system A, continuing to react, and concentrating to obtain a mixed system B containing a compound I-2;
(3) Adding a methanol solvent into the mixed system B, then adding dimethyl oxalate and sodium methoxide, stirring for reaction, and then adjusting the pH value of the system, concentrating, extracting and separating the solution to obtain a mixed system C containing a compound I-3;
(4) Adding lithium hydroxide into the mixed system C, reacting, concentrating, adding a mixture of a solvent and water, crystallizing, filtering and drying to obtain the compound of the formula I.
Wherein the organic phase collected after concentration in the step (2) is washed with water, and the recovered solvent obtained by distillation can be optionally used in the step (1); concentrating the collected organic solvent in the step (4), washing with water, distilling, and optionally applying to the extraction solvent in the step (3).
In another preferred embodiment, in the step (1), the molar ratio of MMA to DMF-DMA is 1.0:0.8-4.0, preferably 1.0:0.9-1.5.
In another preferred embodiment, in step (1), the organic solvent is selected from toluene, tetrahydrofuran or a mixture thereof, preferably toluene.
In another preferred embodiment, in the step (1), the reaction temperature is 30 to 70 ℃, preferably 40 to 50 ℃; the reaction time is 1 to 7 hours, preferably 1 to 3 hours.
In another preferred embodiment, in the step (2), the molar ratio of DMEA to MMA is 1.0 to 2.0:1.0, preferably 1.0 to 1.5:1.0.
In another preferred embodiment, in the step (2), the reaction temperature is 10 to 40 ℃, preferably 20 to 30 ℃.
In another preferred embodiment, in the step (2), the concentration is performed under reduced pressure, and the concentration temperature is 30 to 60 ℃, preferably 40 to 45 ℃.
In another preferred embodiment, in the step (2), the collected organic phase is concentrated, washed with water, separated, and then the organic layer is distilled, and the collected organic phase can be optionally used in the step (1).
In another preferred example, in the step (3), the molar ratio of dimethyl oxalate to sodium methoxide to MMA is 1.5-7.5: 1.0 to 5.0:1.0, preferably 2.0 to 4.0:1.5 to 2.5:1.0.
In another preferred embodiment, in the step (3), the reaction temperature is 10 to 50 ℃, preferably 20 to 40 ℃; the reaction time is 1 to 5 hours, preferably 2 to 3 hours.
In another preferred embodiment, in the step (3), after the reaction is completed, the pH of the reaction system is adjusted by an acid, wherein the acid may be hydrochloric acid, sulfuric acid, acetic acid or a combination thereof, preferably hydrochloric acid; the pH of the system is adjusted to between 5 and 8, preferably ph=6 to 7.
In another preferred example, in the step (3), the specific operation steps are that dimethyl oxalate and sodium methoxide are added into the mixed system B to react, acid is added into the reacted system to adjust pH, the mixture is concentrated under reduced pressure, an organic solvent and water are added into the concentrate to extract, and the organic solution containing the compound I-3 is obtained after liquid separation, namely the mixed system C, wherein the organic solvent is selected from toluene, dichloromethane, ethyl acetate, methyl tertiary butyl ether or a combination thereof; toluene and methylene chloride are preferred.
In another preferred embodiment, in the step (4), the molar ratio of lithium hydroxide to MMA is 1.0-3.0:1.0, preferably 1.0-1.5:1.0.
In another preferred embodiment, the process for the preparation of 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester (compound of formula I) comprises, in particular, the steps of:
(I) Adding toluene, acetic acid and MMA into a reactor, stirring at room temperature, dropwise adding DMF-DMA, heating to 40-50 ℃ for reaction after the dropwise adding is finished, and carrying out heat preservation and stirring for 1-3 hours to obtain a mixed system A-1;
(II) dropwise adding DMEA into the mixed system A-1, controlling the temperature to be 20-30 ℃, carrying out heat preservation reaction for 1 hour, concentrating under reduced pressure, collecting an organic phase S1 containing toluene, and then adding methanol into the concentrate to obtain a mixed system B-1;
(III) adding dimethyl oxalate and sodium methoxide into the mixed system B-1, controlling the temperature to be 20-40 ℃, reacting for 2 hours, cooling the system to be below 20 ℃, dripping hydrochloric acid to adjust the pH value to be 6-7, concentrating under reduced pressure, adding dichloromethane and water into the concentrate, extracting, and separating to obtain a dichloromethane solution containing the compound I-3, namely the mixed system C-1;
and (IV) adding lithium hydroxide into the C-1 system, reacting for 2 hours at 20 ℃, regulating the pH value to be about 2-3 by using hydrochloric acid, concentrating, collecting an organic phase S2 containing methylene dichloride, adding methanol into the concentrated system, concentrating, adding water, stirring for crystallization, filtering at room temperature, washing a filter cake with water, and vacuum drying at 45 ℃ to obtain the compound I.
Wherein the toluene-containing organic phase S1 concentrated and collected in the step (II) is washed by water, and the recovered toluene obtained by distillation can be optionally used in the step (I); the methylene dichloride-containing organic phase S2 collected in the step (IV) is concentrated, washed by water and distilled to obtain recovered methylene dichloride, and the recovered methylene dichloride can be optionally used in the step (III) as an extraction solvent.
In another preferred embodiment, the toluene solvent recovery specifically comprises the steps of: adding water into the toluene solution concentrated in the step (II), washing twice, regulating the pH value of the water phase to 2-3 by using hydrochloric acid, separating liquid, washing the separated organic phase with water again, and distilling the organic phase at normal pressure to separate water to obtain recovered toluene, wherein the volume ratio of the water extraction amount to the toluene is 0.2-0.3:1.0 each time.
In another preferred embodiment, the recovery of the dichloromethane solvent specifically comprises the following steps: washing the methylene dichloride phase concentrated and collected in the step (IV) twice by water, collecting an organic phase, and drying to obtain the recovered methylene dichloride.
In another preferred embodiment, the recovered toluene and methylene chloride solvents may be optionally used in the step of preparing 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester (compound of formula I).
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Is limited to a space and will not be described in detail herein.
Detailed Description
Through long-term extensive and intensive researches, the invention discovers a green process for preparing 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-dipicolinic acid-2-methyl ester (a compound shown as a formula I) for the first time, realizes recycling and application of a solvent, reduces the generation of waste salt and reduces the treatment cost of three wastes.
The term "jacket" refers to recycling.
The code of the reagent used in the invention and the corresponding chemical name are as follows:
MMA: 4-Methoxyacetoacetic acid methyl ester
DMF-DMA: n, N-dimethylformamide dimethyl acetal
DMEA: aminoacetaldehyde dimethyl acetal
A process for preparing 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester (a compound of formula I) comprising the steps of:
(1) Adding 4-Methoxy Methyl Acetoacetate (MMA) and N, N-dimethylformamide dimethyl acetal (DMF-DMA) into an organic system, and reacting to obtain a compound I-1-containing mixed system A;
(2) Adding DMEA into the mixed system A, continuing to react, and concentrating to obtain a mixed system B containing the compound I-2;
(3) Adding a methanol solvent into the mixed system B, then adding dimethyl oxalate and sodium methoxide, stirring for reaction, and then adjusting the pH value of the system, concentrating, extracting and separating the solution to obtain a mixed system C containing a compound I-3;
(4) Adding lithium hydroxide into the mixed system C, reacting, concentrating, adding a mixture of a solvent and water, crystallizing, filtering and drying to obtain the compound of the formula I.
Wherein the organic phase collected after concentration in the step (2) is washed with water, and the recovered solvent obtained by distillation can be optionally used in the step (1); concentrating the collected organic solvent in the step (4), washing with water, distilling, and optionally applying to the extraction solvent in the step (3).
The invention has the advantages that:
(1) The conversion rate of the reaction is greatly improved by adjusting the reaction conditions, and the organic solvent applied to the reaction can be recycled through recovery;
(2) The use of inorganic salt is reduced by adding the purification operation of the intermediate, so that the generated mixed waste salt is greatly reduced, and the recovery rate of the salt is improved;
(3) The reaction condition is mild, the operation is simple, and the environment is protected;
(4) The conversion rate is greatly improved, the total reaction yield can reach more than 80 percent, and the production cost is greatly reduced while the three-waste treatment investment is reduced.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
EXAMPLE 1 preparation of Compounds of formula I
40g (0.27 mol) of methyl 4-methoxyacetoacetate (MMA), 160ml of toluene, and 34.6g (0.30 mol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA) were added dropwise thereto under stirring at room temperature, and the temperature was raised to 40℃for 3 hours. The system was cooled to room temperature, 30.2g (0.29 mol) of DMEA was added dropwise, the reaction was completed at 20℃for 1 hour, the reaction system was concentrated at 45℃under reduced pressure until no liquid was dropped out, organic phase 1 was collected, 200ml of methanol was added to the concentrate, 80.8g (0.68 mol) of dimethyl oxalate, and 26.6g (0.49 mol) of sodium methoxide were added, and the reaction was completed at room temperature for 2 hours until the substrate conversion was completed. Hydrochloric acid is added into the system, the pH value is regulated to be about 6, the solution is decompressed and concentrated, then 200ml of dichloromethane and 150ml of water are added into the concentrate, extraction and liquid separation are carried out, the aqueous phase is extracted by 100ml of dichloromethane, after the organic phases are combined, 7.6g (0.32 mol) of lithium hydroxide is added into the organic phase, and the reaction is carried out for about 2 hours at 20 ℃ until the substrate conversion is completed. After the reaction, hydrochloric acid is added into the system, the pH is regulated to about 3, the mixture is concentrated, an organic phase 2 is collected, 300ml of methanol and 300ml of water are added into the concentrate, the mixture is stirred for 1 hour at room temperature, the mixture is filtered by suction, a filter cake is washed by water, and the filter cake is dried to constant weight in a vacuum drying oven at 45 ℃ to obtain 72.8g of the compound of the formula I, wherein the molar yield is 84.3%, and the purity is 99.4%.
Example 2 recovery of organic phase
Toluene solvent recovery
And (3) adding 20ml of 4 water to wash the organic phase 1 concentrated and collected in the embodiment, wherein hydrochloric acid is added to adjust the pH value to 3 in the third water washing, collecting the organic phase after water washing, distilling at normal pressure, and collecting the fraction at 108-110 ℃ which is the recovered toluene solvent, and collecting 120ml, wherein the recovery rate is 75%.
Recovery of dichloromethane solvent
The organic phase 2 concentrated and collected in the examples is added with 40ml of 4 water for four times, the organic phase is added with 30g of anhydrous magnesium sulfate for drying, distilled under normal pressure, and the fraction at 38-40 ℃ is collected, namely the recovered dichloromethane solvent, and the total concentration of the dichloromethane is 210ml, and the recovery rate is 70%.
EXAMPLE 3 preparation of Compounds of formula I
40g (0.27 mol) of methyl 4-methoxyacetoacetate (MMA) was charged into the reaction flask, 160ml of toluene was recovered, and the reaction was stirred at room temperature, 40.5g (0.34 mol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA) was added dropwise, and the temperature was raised to 40℃for 3 hours. The system was cooled to room temperature, 42.5g (0.41 mol) of DMEA was added dropwise, the reaction was completed at room temperature for 1 hour, the reaction system was concentrated under reduced pressure at 45℃until no liquid was dropped out, organic phase 1 was collected, 200ml of methanol was added to the concentrate, 80.8g (0.68 mol) of dimethyl oxalate, and 26.6g (0.49 mol) of sodium methoxide were added, and the reaction was completed at room temperature for 2 hours until the substrate conversion was completed. Hydrochloric acid is added into the system, the pH value is regulated to 6, the solution is concentrated under reduced pressure, then 200ml of recovered dichloromethane and 150ml of water are added, extraction, liquid separation and extraction of the aqueous phase by using 100ml of recovered dichloromethane are carried out, 9.7g (0.4 mol) of lithium hydroxide is added into the organic phase after the organic phase is combined, and the reaction is carried out for about 2 hours at 20 ℃ until the substrate conversion is completed. After the reaction, hydrochloric acid is added into the system, the pH is regulated to about 3, the mixture is concentrated, an organic phase 2 is collected, 300ml of methanol and 300ml of water are added into the concentrate, the mixture is stirred for 1 hour at room temperature, the mixture is filtered by suction, a filter cake is washed by water, and the filter cake is dried to constant weight in a vacuum drying oven at 45 ℃ to obtain 71.2g of the compound of the formula I, wherein the molar yield is 82.5%, and the purity is 99.2%.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be understood that various changes and modifications may be made by those skilled in the art after reading the above list of the invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. A process for the preparation of 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester (compound of formula I), comprising the steps of:
(1) Adding 4-Methoxy Methyl Acetoacetate (MMA) and N, N-dimethylformamide dimethyl acetal (DMF-DMA) into an organic system, and reacting to obtain a compound I-1-containing mixed system A;
(2) Adding aminoacetaldehyde dimethyl acetal (DMEA) into the mixed system A, continuing to react, and concentrating to obtain a mixed system B containing a compound I-2;
(3) Adding a methanol solvent into the mixed system B, then adding dimethyl oxalate and sodium methoxide, stirring for reaction, and then adjusting the pH value of the system, concentrating, extracting and separating the solution to obtain a mixed system C containing a compound I-3;
(4) Adding lithium hydroxide into the mixed system C, reacting, concentrating, adding a mixture of a solvent and water, crystallizing, filtering and drying to obtain the compound of the formula I.
Wherein the organic phase collected after concentration in the step (2) is washed with water, and the recovered solvent obtained by distillation can be optionally used in the step (1); concentrating the collected organic solvent in the step (4), washing with water, distilling, and optionally applying to the extraction solvent in the step (3).
2. The process according to claim 1, wherein the organic solvent in step (1) is selected from toluene, tetrahydrofuran or mixtures thereof.
3. The process of claim 1, wherein the volume ratio of the organic solvent to MMA in step (1) is 3.0 to 10.0:1.0.
4. The process of claim 1, wherein the reaction temperature in step (1) is from 30 to 70 ℃.
5. The method of claim 1, wherein the molar ratio of DMEA to MMA in step (2) is 1.0 to 2.0:1.0.
6. The method of claim 1, wherein the molar ratio of dimethyl oxalate to sodium methoxide to MMA in step (3) is 1.5 to 7.5:1.0 to 5.0:1.0.
7. The process of claim 1 wherein the molar ratio of lithium hydroxide to MMA in step (4) is 1.0 to 3.0:1.0.
8. A process according to claim 1, characterized in that it comprises the following steps, in particular, of preparing 2-methyl 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid (compound of formula I):
(I) Adding toluene and MMA into a reactor, stirring at room temperature, dropwise adding DMF-DMA, heating to 40-50 ℃ for reaction after the dropwise adding, and carrying out heat preservation and stirring for 1-3 hours to obtain a mixed system A-1;
(II) dropwise adding DMEA into the mixed system A-1, controlling the temperature to be 20-30 ℃, carrying out heat preservation reaction for 1 hour, concentrating under reduced pressure, collecting an organic phase S1 containing toluene, and then adding methanol into the concentrate to obtain a mixed system B-1;
(III) adding dimethyl oxalate and sodium methoxide into the mixed system B-1, controlling the temperature to be 20-40 ℃, reacting for 2 hours, cooling the system to be below 20 ℃, dripping hydrochloric acid to adjust the pH value to be 6-7, concentrating under reduced pressure, adding dichloromethane and water into the concentrate, extracting, and separating to obtain a dichloromethane solution containing the compound I-3, namely the mixed system C-1;
and (IV) adding lithium hydroxide into the C-1 system, reacting for 2 hours at 20 ℃, regulating the pH value to be about 2-3 by using hydrochloric acid, concentrating, collecting an organic phase S2 containing methylene dichloride, adding methanol into the concentrated system, concentrating, adding water, stirring for crystallization, filtering at room temperature, washing a filter cake with water, and vacuum drying at 45 ℃ to obtain the compound I.
Wherein the toluene-containing organic phase S1 concentrated and collected in the step (II) is washed by water, and the recovered toluene obtained by distillation can be optionally used in the step (I); the methylene dichloride-containing organic phase S2 collected in the step (IV) is concentrated, washed by water and distilled to obtain recovered methylene dichloride, and the recovered methylene dichloride can be optionally used in the step (III) as an extraction solvent.
9. The method according to claim 8, characterized in that toluene solvent is recovered, comprising in particular the following steps: adding water into the toluene organic phase S1 concentrated in the step (II), washing twice, regulating the pH value of the water phase to 2-3 by using hydrochloric acid, separating liquid, washing the separated organic phase again by using water, and distilling the organic phase at normal pressure to separate water to obtain recovered toluene, wherein the volume ratio of the water extraction amount to the toluene is 0.2-0.3:1.0 each time.
10. The method according to claim 8, wherein the methylene chloride solvent is recovered, comprising the steps of: and (3) washing the methylene dichloride organic phase S2 concentrated and collected in the step (IV) twice with water, collecting the organic phase, and drying to obtain the recovered methylene dichloride.
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