CN111518036A - Preparation method of Dasabovir key intermediate - Google Patents
Preparation method of Dasabovir key intermediate Download PDFInfo
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- CN111518036A CN111518036A CN202010358080.3A CN202010358080A CN111518036A CN 111518036 A CN111518036 A CN 111518036A CN 202010358080 A CN202010358080 A CN 202010358080A CN 111518036 A CN111518036 A CN 111518036A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000758 substrate Substances 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 229940126062 Compound A Drugs 0.000 claims abstract description 18
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- SKMUVBQJIOZVNK-UHFFFAOYSA-N 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)-1,3-diazinane-2,4-dione Chemical compound C1=C(C(C)(C)C)C(OC)=C(I)C=C1N1C(=O)NC(=O)CC1 SKMUVBQJIOZVNK-UHFFFAOYSA-N 0.000 claims abstract description 10
- PBISNKVQOXSGFO-UHFFFAOYSA-N 1-tert-butyl-3,5-diiodo-2-methoxybenzene Chemical compound COC1=C(I)C=C(I)C=C1C(C)(C)C PBISNKVQOXSGFO-UHFFFAOYSA-N 0.000 claims abstract description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 7
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- CMOBXBANKIGTSJ-UHFFFAOYSA-N n-(2-cyanophenyl)pyridine-2-carboxamide Chemical compound C=1C=CC=NC=1C(=O)NC1=CC=CC=C1C#N CMOBXBANKIGTSJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005489 Bromoxynil Substances 0.000 claims abstract description 5
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical group NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 14
- 238000007872 degassing Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 239000012044 organic layer Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 3
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 3
- 239000011574 phosphorus Substances 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000010791 quenching Methods 0.000 abstract description 2
- 230000000171 quenching effect Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- NBRBXGKOEOGLOI-UHFFFAOYSA-N dasabuvir Chemical compound C1=C(C(C)(C)C)C(OC)=C(C=2C=C3C=CC(NS(C)(=O)=O)=CC3=CC=2)C=C1N1C=CC(=O)NC1=O NBRBXGKOEOGLOI-UHFFFAOYSA-N 0.000 description 3
- -1 2,4-Dioxo-3,4-dihydro-1(2H) -pyrimidinyl Chemical group 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- RFAABRLZVLYULW-UHFFFAOYSA-N 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4-dione Chemical compound C1=C(C(C)(C)C)C(OC)=C(I)C=C1N1C(=O)NC(=O)C=C1 RFAABRLZVLYULW-UHFFFAOYSA-N 0.000 description 1
- LMKVCNVFEZSRKN-UHFFFAOYSA-N 2-(2h-pyridin-1-yl)benzonitrile Chemical compound N#CC1=CC=CC=C1N1C=CC=CC1 LMKVCNVFEZSRKN-UHFFFAOYSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 229940123066 Polymerase inhibitor Drugs 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 229960001418 dasabuvir Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- PZNVTOFDKURNCF-UHFFFAOYSA-N n-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl]methanesulfonamide Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(C=C(NS(C)(=O)=O)C=C2)C2=C1 PZNVTOFDKURNCF-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a Dasassafvir key intermediate, which comprises the following steps: 2-bromoxynil and compound B: 2-pyridine carboxamide substitution reaction to prepare a substrate C: n- (2-cyanophenyl) picolinamide; substrate C in turn with substrate D: 1-tert-butyl-3, 5-diiodo-2-methoxybenzene reacts to obtain the Dasabovir key intermediate 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione. A substrate C is prepared by reacting a compound A with a compound B, the reaction is catalyzed by TEA (triethylamine), DMDAA (N, N' -dimethylethylenediamine) and cuprous iodide, the reaction is carried out for 10 to 20 hours at the temperature of between 80 and 100 ℃, and the reaction is stopped when the temperature is reduced to between 25 and 35 ℃, so that the use of toxic catalysts and expensive phosphorus ligands is avoided, the process is simple, the reaction conditions are mild, the quenching is easy, the yield is high, and the large-scale production is facilitated.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, and particularly relates to a preparation method of a Daxabuvir key intermediate.
Background
N- (6- (3-tert-butyl-5- (2,4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide, IUPAC name: n- {6- [5- (2,4-Dioxo-3,4-dihydro-1(2H) -pyrimidinyl) -2-methoxy-3- (2-methyl-2-propyl) phenyl]-2-naphthyl } methanesulfoamide, formula: c26H27N3O5S, CAS: 1132935-63-7, is a non-nucleoside polymerase inhibitor, is sold under the trade name Dasabovir (Dasabrevir), is one of the main components of ABT triple anti-hepatitis C medicine, and has the structural formula:
1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione is a key intermediate for the synthesis of dasabuvir. Dasabrevir was synthesized from 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione by the following pathway (CN 102746239A): an ethanol-toluene solution of a solution of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione, N- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-yl) methanesulfonamide and sodium carbonate was degassed by nitrogen sparging in a microwave tube. 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex was added, and degassing was continued. Sealing the tube, and heating with microwave at 100 deg.C for 1 h. Dilute with dichloromethane, wash with citric acid solution and brine. The organic layer was then stirred with (3-mercaptopropyl) silica gel. Filter through Celite and concentrate in vacuo. Grinding to obtain the target product Dasapivir.
1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione can be prepared by reacting N- (2-cyanophenyl) picolinamide with 1-tert-butyl-3, 5-diiodo-2-methoxybenzene. In the prior art, the research is mostly focused on the synthesis route of 1-tert-butyl-3, 5-diiodo-2-methoxybenzene (CN 102746239A; homoshibo. synthesis of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidine-2, 4(1H,3H) -dione [ J]The proceedings of the institute of science and technology, Hebei, 2017,31(1): 39-43.). The synthetic route of N- (2-cyanophenyl) picolinamide is not much studied, and is generally prepared from aminobenzonitrile and 2-bromopyridine in Mo (CO)6、CataCXium A、Pd(OAC)2And DBU participates in catalytic synthesis, wherein molybdenum has high toxicity and large dosage, a phosphorus ligand CatACRHIUM A is expensive, and the reaction yield is low and is only about 37%.
Disclosure of Invention
The invention aims to provide a preparation method of a Dasassafvir key intermediate, which aims to overcome the defects in the prior art.
The invention adopts the following technical scheme:
a preparation method of a Dasabovir key intermediate comprises the following steps: 2-bromoxynil and compound B: 2-pyridine carboxamide substitution reaction to prepare a substrate C: n- (2-cyanophenyl) picolinamide; substrate C in turn with substrate D: 1-tert-butyl-3, 5-diiodo-2-methoxybenzene to obtain 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione.
Further, the method for preparing the substrate C by carrying out substitution reaction on the compound A and the compound B specifically comprises the following steps:
1) adding the compound B into a toluene solution of the compound A at a temperature of between 25 and 35 ℃ and under the stirring condition, adding triethylamine and N, N' -dimethylethylenediamine, degassing for 10 to 30min, adding cuprous iodide, and degassing for 10 to 30 min; wherein the molar ratio of the compound A to the compound B to the triethylamine to the N, N' -dimethylethylenediamine to cuprous iodide is 1-3: 1-3: 2-4: 2-4: 0.5 to 2;
2) heating to 80-100 ℃, stirring for reaction for 10-20h, and cooling to 25-35 ℃ to terminate the reaction;
3) and carrying out post-treatment to obtain a substrate C.
Further, the post-treatment process of step 3) is as follows: after the reaction was terminated, the obtained reaction mixture was added with ethyl acetate, filtered with celite, and the celite was washed with ethyl acetate; mixing the washed ethyl acetate and the filtrate, washing with water, and evaporating and drying the washed organic layer at 45-55 ℃ under reduced pressure to obtain a crude product; and refining the crude product once or twice to obtain a substrate C.
The synthetic route is as follows:
the invention has the beneficial effects that:
the invention adopts a compound A (2-bromoxynil) and a compound B (2-pyridine carboxamide) to react to prepare a key substrate C (N- (2-cyanophenyl) pyridine amide), and the substrate C reacts with a substrate D (1-tert-butyl-3, 5-diiodo-2-methoxybenzene) to prepare a Dasabovir key intermediate 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione.
The invention adopts the reaction of the compound A and the compound B to prepare the substrate C, the reaction is catalyzed by TEA (triethylamine), DMDAA (N, N' -dimethylethylenediamine) and cuprous iodide, the reaction is carried out for 10 to 20 hours at the temperature of between 80 and 100 ℃, and the reaction is stopped when the temperature is reduced to between 25 and 35 ℃, thereby avoiding the use of toxic catalysts and expensive phosphorus ligands, having simple process, mild reaction conditions, easy quenching and high yield (up to 85.0 percent), and being beneficial to large-scale production.
Detailed Description
The present invention will be further explained with reference to examples. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of N- (2-cyanophenyl) picolinamide (substrate C)
1. 40g of 2-bromoxynil (Compound A) was dissolved in 400ml of toluene at 25 ℃ with stirring, 26.8g of 2-pyridinecarboxamide (Compound B) was added to the toluene solution of Compound A, 44.42g of Triethylamine (TEA) and 38.66g of N, N' -dimethylethylenediamine (DMDAA) were added, and degassing was carried out for 20min, 20.92g of copper iodide (CuI) was added, and degassing was carried out for 10 min.
2. Heating to 80 ℃, stirring and reacting for 10h, and cooling to 25 ℃ to terminate the reaction.
3. The reaction mixture obtained in step 2 was brought to a volume of 200ml with ethyl acetate, filtered through 4g of celite, and the celite was washed 2 times with 100ml each time with ethyl acetate. The washed ethyl acetate and the filtrate were combined, the total organic layer was washed with 200ml of water, and the washed organic layer was evaporated at 50 ℃ under reduced pressure and dried to obtain a crude product.
4. And (3) dissolving the crude product obtained in the step (3) by using 160ml of ethyl acetate, crystallizing at normal temperature, filtering, evaporating and drying crystals at 50 ℃ under reduced pressure, and detecting the purity of a product (substrate C) by using HPLC (high performance liquid chromatography) to be 51.2%.
5. Dissolving the product obtained in the step 4 by using 100ml of ethyl acetate, adding 4g of activated carbon, filtering, recrystallizing the filtrate at normal temperature, filtering, evaporating and drying crystals at 50 ℃ under reduced pressure, and detecting the purity of the product (substrate C) by HPLC (high performance liquid chromatography) to be 95.3%. The yield thereof was found to be 42.2%.
Example 2
Preparation of substrate C
1. 40g of Compound A was dissolved in 400ml of toluene at 25 ℃ with stirring, 26.8g of Compound B was added to the toluene solution of Compound A, 44.42g of TEA and 38.66g of DMDAA were added, and degassing was carried out for 20min, 20.92g of CuI was added, and degassing was carried out for 10 min.
2. Heating to 90 ℃, stirring and reacting for 15h, and cooling to 25 ℃ to terminate the reaction.
3. The reaction mixture obtained in step 2 was brought to a volume of 200ml with ethyl acetate, filtered through 4g of celite, and the celite was washed 2 times with 100ml each time with ethyl acetate. The washed ethyl acetate and the filtrate were combined, the total organic layer was washed with 200ml of water, and the washed organic layer was evaporated at 50 ℃ under reduced pressure and dried to obtain a crude product.
4. And (3) dissolving the crude product obtained in the step (3) by using 160ml of ethyl acetate, crystallizing at normal temperature, filtering, evaporating and drying crystals at 50 ℃ under reduced pressure, and detecting the purity of a product (substrate C) by using HPLC (high performance liquid chromatography) to be 83.1%.
5. Dissolving the product obtained in the step 4 by using 100ml of ethyl acetate, adding 4g of activated carbon, filtering, recrystallizing the filtrate at normal temperature, filtering, evaporating and drying the crystals at 50 ℃ under reduced pressure, and detecting the purity of the product (substrate C) by HPLC (high performance liquid chromatography) to be 98.2%. The yield thereof was found to be 63.5%.
Example 3
Preparation of substrate C
1. 40g of Compound A was dissolved in 400ml of toluene at 30 ℃ with stirring, 26.8g of Compound B was added to the toluene solution of Compound A, 44.42g of TEA and 38.66g of DMDAA were added, and degassing was carried out for 20min, 20.92g of CuI was added, and degassing was carried out for 10 min.
2. Heating to 100 ℃, stirring and reacting for 18h, and cooling to 30 ℃ to terminate the reaction.
3. The reaction mixture obtained in step 2 was brought to a volume of 200ml with ethyl acetate, filtered through 4g of celite, and the celite was washed 2 times with 100ml each time with ethyl acetate. The washed ethyl acetate and the filtrate were combined, the total organic layer was washed with 200ml of water, and the washed organic layer was evaporated at 50 ℃ under reduced pressure and dried to obtain a crude product.
4. And (3) dissolving the crude product obtained in the step (3) by using 160ml of ethyl acetate, crystallizing at normal temperature, filtering, evaporating and drying crystals at 50 ℃ under reduced pressure, and detecting the purity of a product (substrate C) by using HPLC (high performance liquid chromatography) to be 96.4%. The yield thereof was found to be 79.1%.
Example 4
Preparation of substrate C
1. 40g of Compound A was dissolved in 400ml of toluene at 35 ℃ with stirring, 26.8g of Compound B was added to the toluene solution of Compound A, 44.42g of TEA and 38.66g of DMDAA were added, degassing was carried out for 20min, 20.92g of CuI was added, and degassing was carried out for 10 min.
2. Heating to 100 ℃, stirring and reacting for 20h, and cooling to 35 ℃ to terminate the reaction.
3. The reaction mixture obtained in step 2 was brought to a volume of 200ml with ethyl acetate, filtered through 4g of celite, and the celite was washed 2 times with 100ml each time with ethyl acetate. The washed ethyl acetate and the filtrate were combined, the total organic layer was washed with 200ml of water, and the washed organic layer was evaporated at 50 ℃ under reduced pressure and dried to obtain a crude product.
4. And (3) dissolving the crude product obtained in the step (3) by using 160ml of ethyl acetate, crystallizing at normal temperature, filtering, evaporating and drying crystals at 50 ℃ under reduced pressure, wherein the purity of a product (substrate C) is 99.1% by HPLC detection, and the yield is 85.0%.
Example 5
Preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione
300g of 1-tert-butyl-3, 5-diiodo-2-methoxybenzene (substrate D) was dissolved in 3000ml of dimethyl sulfoxide (DMSO) at 30 ℃ with stirring, and 8g of substrate C (prepared in example 4) and 329g K were added3PO497g uracil, degassed for 20min, added once with 13.73g CuI, degassed again for 15 min. The reaction was stirred for 20h while heating to 80 ℃. After the reaction was completed, it was cooled to room temperature, quenched with 2000ml of water, and stirred for 20 min.
Then, acidifying the mixture by using a 4N hydrochloric acid solution until the pH is 4-5. Then extracted with 2L ethyl acetate and 1L ethyl acetate and the total organic layers were extracted with 1500ml20 wt% Na2S2O3The solution was washed with 600ml of 20 wt% saline solution. Evaporated to dryness at 50 ℃ under reduced pressure to give the crude product.
The crude product is dispersed by 1200ml of petroleum ether, stirred for 30min, filtered by a funnel, washed by 300ml of petroleum ether, filtered to be dry and dried in an oven at 50 ℃ for 1H to obtain the product, and the purity of the product (1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione) is 99.2 percent and the yield is 85.4 percent by HPLC.
Claims (3)
1. A preparation method of a Dasabovir key intermediate is characterized in that a compound A: 2-bromoxynil and compound B: 2-pyridine carboxamide substitution reaction to prepare a substrate C: n- (2-cyanophenyl) picolinamide; substrate C in turn with substrate D: 1-tert-butyl-3, 5-diiodo-2-methoxybenzene reacts to obtain the Dasabovir key intermediate 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidine-2, 4(1H,3H) -dione.
2. The preparation method of the Dasabovir key intermediate, according to claim 1, wherein the substrate C is prepared by the substitution reaction of the compound A and the compound B, and the method specifically comprises the following steps:
1) adding the compound B into a toluene solution of the compound A at a temperature of between 25 and 35 ℃ and under the stirring condition, adding triethylamine and N, N' -dimethylethylenediamine, degassing for 10 to 30min, adding cuprous iodide, and degassing for 10 to 30 min; wherein the molar ratio of the compound A to the compound B to the triethylamine to the N, N' -dimethylethylenediamine to cuprous iodide is 1-3: 1-3: 2-4: 2-4: 0.5 to 2;
2) heating to 80-100 ℃, stirring for reaction for 10-20h, and cooling to 25-35 ℃ to terminate the reaction;
3) and carrying out post-treatment to obtain a substrate C.
3. The preparation method of the Dasabovir key intermediate, according to claim 2, is characterized in that the post-treatment process in step 3) is as follows: after the reaction was terminated, the obtained reaction mixture was added with ethyl acetate, filtered with celite, and the celite was washed with ethyl acetate; mixing the washed ethyl acetate and the filtrate, washing with water, and evaporating and drying the washed organic layer at 45-55 ℃ under reduced pressure to obtain a crude product; and refining the crude product once or twice to obtain a substrate C.
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