CN111518036A - Preparation method of Dasabovir key intermediate - Google Patents

Preparation method of Dasabovir key intermediate Download PDF

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Publication number
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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compound
substrate
reaction
key intermediate
dasabovir
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王喆明
谭昊
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Hangzhou Yongchengrui Biotechnology Co ltd
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Hangzhou Yongchengrui Biotechnology Co ltd
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    • 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

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

Preparation method of Dasabovir key intermediate
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:
Figure BDA0002474172240000011
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:
Figure BDA0002474172240000031
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.
CN202010358080.3A 2020-04-29 2020-04-29 Preparation method of Dasabovir key intermediate Pending CN111518036A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101801935A (en) * 2007-09-17 2010-08-11 雅培制药有限公司 uracil or thymine derivative for treating hepatitis c
CN101918369A (en) * 2007-09-17 2010-12-15 雅培制药有限公司 N-phenyl-dioxo-hydropyrimidines useful as hepatitis c virus (HCV) inhibitors
CN104628655A (en) * 2007-09-17 2015-05-20 艾伯维巴哈马有限公司 Anti-infective pyrimidines and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101801935A (en) * 2007-09-17 2010-08-11 雅培制药有限公司 uracil or thymine derivative for treating hepatitis c
CN101918369A (en) * 2007-09-17 2010-12-15 雅培制药有限公司 N-phenyl-dioxo-hydropyrimidines useful as hepatitis c virus (HCV) inhibitors
CN104628655A (en) * 2007-09-17 2015-05-20 艾伯维巴哈马有限公司 Anti-infective pyrimidines and uses thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CARRIE P. JONES ET AL.: "Sequential Cu-Catalyzed Amidation-Base-Mediated Camps Cyclization: A Two-Step Synthesis of 2-Aryl-4-quinolones from o-Halophenones", 《J. ORG. CHEM.》 *
DAVID M. BARNES ET AL.: "Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor", 《J. ORG. CHEM.》 *
LIQIN JIANG: "Copper/N,N-Dimethylglycine Catalyzed Goldberg Reactions Between Aryl Bromides and Amides, Aryl Iodides and Secondary Acyclic Amides", 《MOLECULES》 *
XIAO-FENG WU ET AL.: "Palladium-catalyzed carbonylative synthesis of N-(2-cyanoaryl) benzamides and sequential synthesis of quinazolinones", 《TETRAHEDRON》 *
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