CN111072550A - Nilapari important intermediate and enzyme catalytic synthesis method thereof - Google Patents
Nilapari important intermediate and enzyme catalytic synthesis method thereof Download PDFInfo
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- CN111072550A CN111072550A CN201911214909.6A CN201911214909A CN111072550A CN 111072550 A CN111072550 A CN 111072550A CN 201911214909 A CN201911214909 A CN 201911214909A CN 111072550 A CN111072550 A CN 111072550A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
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- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/008—Preparation of nitrogen-containing organic compounds containing a N-O bond, e.g. nitro (-NO2), nitroso (-NO)
Abstract
The invention discloses an important intermediate of nilapali and an enzymatic synthesis method thereof, wherein the important intermediate of nilapali is prepared by dissolving 2- (4-nitrophenyl) dimethyl malonate in methanol, adding sodium borohydride to obtain an intermediate I, dissolving the intermediate I in acetonitrile, adding esterifying enzyme and vinyl acetate to obtain an intermediate II, dissolving the intermediate II in dichloromethane, adding triphenylphosphine and bromine to obtain an intermediate III, dissolving the intermediate III in tetrahydrofuran, sodium tert-butoxide and ethyl glyoxylate to obtain an intermediate IV, dissolving the intermediate IV in methanol, reducing palladium on carbon to obtain an intermediate V, dissolving the intermediate V in methanol, reducing the sodium borohydride to obtain an intermediate VI, dissolving the intermediate VI in dichloromethane, adding triethylamine, p-toluenesulfonate and p-methylbenzylamine to obtain a final product. The invention has the advantages of low cost of the synthetic method, simple operation process, high catalytic efficiency of the enzyme by adopting an enzyme catalysis method and high specificity.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to an important intermediate of nilapali and an enzyme catalytic synthesis method thereof.
Background
Nilaparib (Niraparib) is a poly adenosine diphosphate ribose polymerase 1/2(PARP-1 and PARP-2) inhibitor drug commonly developed by Moshadong and Tesaro. The chemical name is 2-r-4- [ (3S) -3-piperidyl) phenyl ] -2H-indazole-7-formamide, and the effective component is p-toluenesulfonate thereof. The product is approved by the Food and Drug Administration (FDA) to be marketed in 2017, 3 and 27 months, and has the trade name of Zejua. Is mainly used for treating recurrent epithelial ovarian cancer, salpingemphraxis and primary peritoneal cancer.
Jones et al completed the total synthesis of Niraparib earlier at 2009. Wallace et al improved the protocol reported by Jones and the yield of the Niraparib synthesis was significantly increased. In 2014, Chung et al reported a novel synthetic scheme for Niraparib, which separates Niraparib into chiral 3-arylpiperidine and indole derivative 2 parts for synthesis, and then completes the synthesis of Niraparib through regioselective C-N coupling. Compared with the previously reported synthetic scheme of the Niraparib, the scheme avoids using NaN when the indazole ring is formed, converts the synthesis of the Niraparib into the synthesis of 2 intermediates, and reduces the risk of industrial production. However, in the prior art, the cost of the nilapanib is high, and the synthesis difficulty is high.
Disclosure of Invention
The invention aims to solve the problems and designs an important intermediate of nilapali and an enzyme catalytic synthesis method thereof.
The technical scheme of the invention is that an important intermediate of nilapali and an enzyme catalytic synthesis method thereof are provided, raw materials required by the synthesis step comprise 2- (4-nitrophenyl) dimethyl malonate, and the synthesis step comprises:
s1, dissolving the raw materials in methanol, adding sodium borohydride in the dissolving process, slightly refluxing after the reaction, reacting at the same temperature, and carrying out post-treatment to obtain an intermediate I.
And S2, dissolving the intermediate I in acetonitrile, adding esterifying enzyme and vinyl acetate into the solution A, reacting at a certain temperature, and carrying out post-treatment to obtain an intermediate II.
And S3, dissolving the intermediate II in dichloromethane to obtain a solution B for later use, dissolving triphenylphosphine in dichloromethane in a clean container to obtain a solution C, dropwise adding bromine into the solution C at a certain temperature, stirring the solution C after the dropwise adding of the bromine is finished, dropwise adding the prepared solution B into the solution C after the stirring is finished, stirring at room temperature after the dropwise adding of the solution B is finished, obtaining a reaction system A after the stirring is finished, precipitating a large amount of solids in the reaction system A, filtering the reaction system A, and drying to obtain an intermediate III.
And S4, dissolving the intermediate III in anhydrous tetrahydrofuran, adding sodium tert-butoxide into the obtained solution D, stirring at room temperature, dropwise adding ethyl glyoxylate when the temperature is reduced to a certain condition, heating and refluxing after the dropwise addition is finished, and carrying out post-treatment to obtain an intermediate IV.
And S5, dissolving the intermediate IV in methanol, adding palladium carbon into the obtained solution E, adding hydrogen under a certain pressure, reacting, and after the reaction is finished, carrying out post-treatment to obtain an intermediate V.
And S6, dissolving the intermediate V in methanol, adding sodium borohydride into the obtained solution F for reaction, and after the reaction is finished, carrying out post-treatment to obtain an intermediate VI.
S7: dissolving the intermediate VI in dichloromethane, adding triethylamine, adding p-methylbenzenesulfonyl chloride under a certain temperature condition, stirring at room temperature, adding p-methoxybenzylamine after stirring is finished, carrying out antipyretic reflux, and carrying out post-treatment to obtain a final product.
Wherein, the reaction time at the same temperature in the S1 in the synthesis step is preferably 3 hours, and the method for adding the sodium borohydride is preferably added in batches; in the synthesis step, the reaction temperature in S2 is preferably 45 ℃, and the reaction time is preferably 48 hours; in the step S3, the temperature condition of adding bromine is preferably 0-5 ℃, the time of adding bromine is preferably 2 hours, the stirring time is preferably 3 hours after adding bromine, the time of adding solution B is preferably 2 hours, and the stirring time is preferably 24 hours after adding solution B; in the synthesis step S4, the room temperature stirring time is preferably 2 hours, and the temperature is preferably reduced to 0 ℃; in the synthesis step S5, the palladium carbon is preferably 10% palladium carbon, the pressure condition is preferably 5kg, and the hydrogen is added for reaction for preferably 12 hours; in the synthesis step S6, the sodium borohydride is preferably added in portions, and the reaction time is preferably 6 hours; in S7 in the synthesis step, the temperature for adding the p-methyl benzene sulfonyl chloride is preferably 0 ℃, the stirring time at room temperature is preferably 24 hours, and the antipyretic reflux time is preferably 48 hours.
The invention has the beneficial effects that the invention provides an important intermediate for synthesizing nilapali and a synthesis step thereof by adopting an enzyme catalysis method, wherein 2- (4-nitrophenyl) dimethyl malonate is adopted as a raw material to be dissolved in methanol, and sodium borohydride is added to obtain an intermediate I:
dissolving the intermediate I in acetonitrile, adding esterifying enzyme and vinyl acetate, and reacting at 45 ℃ for 48 hours to obtain an intermediate II:
dissolving the intermediate II in dichloromethane, and adding triphenylphosphine and bromine to obtain an intermediate III:
the intermediate III is subjected to the action of tetrahydrofuran, sodium tert-butoxide and ethyl glyoxylate to obtain an intermediate IV:
dissolving the intermediate IV in methanol, and reducing by palladium carbon to obtain an intermediate V:
dissolving the intermediate V in methanol, and reducing by sodium borohydride to obtain an intermediate VI:
dissolving the intermediate VI in dichloromethane, and adding triethylamine, p-toluenesulfonic acid chloride and p-methylbenzylamine to obtain a final product:
the synthesis method has the advantages of low cost, simple operation process, low synthesis difficulty, high catalytic efficiency of the enzyme by adopting an enzyme catalysis method, and high specificity of the enzyme during catalysis.
Drawings
FIG. 1 is a schematic of the synthetic route of the present invention;
FIG. 2 is a schematic diagram of the synthetic route of the synthetic step S1 according to the present invention;
FIG. 3 is a schematic diagram of the synthetic route of the synthetic step S2 according to the present invention;
FIG. 4 is a schematic diagram of the synthetic route of the synthetic step S3 according to the present invention;
FIG. 5 is a schematic diagram of the synthetic route of the synthetic step S4 according to the present invention;
FIG. 6 is a schematic diagram of the synthetic route of the synthetic step S5 according to the present invention;
FIG. 7 is a schematic diagram of the synthetic route of the synthetic step S6 according to the present invention;
FIG. 8 is a schematic diagram of the synthesis route of the synthesis step S7 according to the present invention.
Detailed Description
In order to make the present invention more clear to those skilled in the art, the following will specifically describe the synthetic steps of the present invention:
s1: 2.53kg of the starting material dimethyl 2- (4-nitrophenyl) malonate (1 equivalent) having the formula:
dissolving in 25.3L (10 times volume) of methanol, adding 0.57kg of sodium borohydride (1.5 equivalents) in batches in the reaction process, slightly refluxing after the reaction, reacting for 3 hours at the same temperature, and carrying out aftertreatment to obtain 1.98kg of an intermediate I, wherein the intermediate I is diol and has the structural formula:
in the step, the glycol is obtained by dissolving 2- (4-nitrophenyl) malonic acid dimethyl ester in methanol and adding sodium borohydride, and the reaction yield is 100%.
S2, dissolving 1.98kg of intermediate I (1 equivalent) in 20L of acetonitrile (10 times volume), adding 0.099kg of esterifying enzyme (0.05 equivalent) and 0.86kg of vinyl acetate (1 equivalent) into the solution A, reacting at 45 ℃ for 48 hours, and post-treating to obtain 2.15kg of intermediate II which is R chiral monoester and has the structural formula:
in the step, glycol is dissolved in acetonitrile, and esterifying enzyme and vinyl acetate are added for reaction to obtain R chiral monoester, wherein the reaction yield is 90%.
S3, dissolving 2.15kg of intermediate II (1 equivalent) in 5L of dichloromethane (2.5 times volume) to obtain solution B for later use, dissolving 7kg of triphenylphosphine (3 equivalents) in 35L of dichloromethane (5 times volume) in a clean container to obtain solution C, dropwise adding 1.6kg of bromine (1.1 equivalents) into the solution C at the temperature of 0-5 ℃, dropwise adding for 2 hours, stirring the solution C for 3 hours after the dropwise adding of the bromine is completed, dropwise adding the prepared solution B into the solution C after stirring, dropwise adding for 2 hours, stirring for 24 hours at room temperature after the dropwise adding of the solution B is completed, obtaining a reaction system A after the stirring is completed, precipitating a large amount of solids in the reaction system A, filtering and drying the reaction system A to obtain 3.1kg of intermediate III, wherein the structural formula is as follows:
in the step, R chiral monoester is dissolved in dichloromethane, triphenylphosphine and bromine are added to obtain an intermediate III, and the reaction yield is 70%.
S4, dissolving 3.1kg of intermediate III (1 equivalent) in 24L of anhydrous tetrahydrofuran (8 times volume), adding 0.93kg of sodium tert-butoxide (1.5 equivalents) into the obtained solution D, stirring at room temperature for 2 hours, dropwise adding 0.71kg of ethyl glyoxylate (1.1 equivalents) when the temperature is reduced to 0 ℃, heating and refluxing for 12 hours after the dropwise adding is completed, and post-treating to obtain 1.5kg of intermediate IV, wherein the intermediate IV is vinyl ester and has the structural formula:
in the step, vinyl ester is obtained from the intermediate III under the action of tetrahydrofuran, sodium tert-butoxide and ethyl glyoxylate, and the reaction yield is 75%.
S5.1.5 kg of intermediate IV (1 eq) are dissolved in 15L of methanol (10 times the volume), 150g of 10% palladium on carbon (0.1 eq) are added to the solution E, and the mixture is pressed under 5kgAdding hydrogen under the condition of force, reacting for 12 hours, and carrying out post-treatment to obtain 1.23kg of an intermediate V, wherein the structural formula is as follows:
in the step, the vinyl ester is dissolved in methanol, and the intermediate V is obtained by palladium-carbon reduction, wherein the reaction yield is 90%.
S6, dissolving 1.23kg of intermediate V (1 equivalent) in 12.3L of methanol (10 times of volume), adding 0.25kg of sodium borohydride (1.5 equivalents) into the obtained solution F in a plurality of times, reacting for 6 hours, and after the reaction is finished, carrying out post-treatment to obtain 0.69kg of intermediate VI, wherein the structural formula is as follows:
in the step, the intermediate IV is dissolved in methanol, and sodium borohydride is reduced to obtain an intermediate VI, wherein the reaction yield is 80%.
S7: dissolving 0.69kg of intermediate VI (1 equivalent) in 14L of dichloromethane (20 times volume), adding 1.1kg of triethylamine (3 equivalents), adding 1.98kg of p-toluenesulfonyl chloride (3 equivalents) at 0 ℃, stirring at room temperature for 24 hours, adding 0.62kg of p-methoxybenzylamine (1.3 equivalents) after stirring is finished, cooling and refluxing for 48 hours, and performing post-treatment to obtain 0.94kg of a final product, wherein the structural formula is as follows:
in the step, the intermediate VI 7 is dissolved in dichloromethane, triethylamine, p-toluenesulfonic acid chloride and p-methylbenzylamine are added to obtain a final product, and the reaction yield is 91%.
The technical solutions described above only represent the preferred technical solutions of the present invention, and some possible modifications to some parts of the technical solutions by those skilled in the art all represent the principles of the present invention, and fall within the protection scope of the present invention.
Claims (10)
1. An important intermediate of nilapali and an enzyme catalysis synthesis method thereof are characterized in that the enzyme catalysis synthesis steps are as follows:
s1, dissolving the raw materials in methanol, adding sodium borohydride in the reaction process, reacting at the same temperature after refluxing, and carrying out post-treatment to obtain an intermediate I.
And S2, dissolving the intermediate I in acetonitrile, adding esterifying enzyme and vinyl acetate into the obtained solution A, reacting at a certain temperature, and carrying out post-treatment to obtain an intermediate II.
And S3, dissolving the intermediate II in dichloromethane to obtain a solution B for later use, dissolving triphenylphosphine in dichloromethane in a clean container to obtain a solution C, dropwise adding bromine into the solution C at a certain temperature, stirring the solution C after the dropwise adding of the bromine is finished, dropwise adding the prepared solution B into the solution C after the stirring is finished, stirring at room temperature after the dropwise adding of the solution B is finished, obtaining a reaction system A after the stirring is finished, precipitating a large amount of solids in the reaction system A, filtering the reaction system A, and drying to obtain an intermediate III.
And S4, dissolving the intermediate III in anhydrous tetrahydrofuran, adding sodium tert-butoxide into the obtained solution D, stirring at room temperature, dropwise adding ethyl glyoxylate when the temperature is reduced to a certain condition, heating and refluxing after the dropwise addition is finished, and carrying out post-treatment to obtain an intermediate IV.
And S5, dissolving the intermediate IV in methanol, adding palladium carbon into the obtained solution E, adding hydrogen under a certain pressure, reacting, and after the reaction is finished, carrying out post-treatment to obtain an intermediate V.
And S6, dissolving the intermediate V in methanol, adding sodium borohydride into the obtained solution F for reaction, and after the reaction is finished, carrying out post-treatment to obtain an intermediate VI.
S7: dissolving the intermediate VI in dichloromethane, adding triethylamine, adding p-methylbenzenesulfonyl chloride under a certain temperature condition, stirring at room temperature, adding p-methoxybenzylamine after stirring is finished, carrying out antipyretic reflux, and carrying out post-treatment to obtain a final product.
2. The method of claim 1, wherein the final product has the following structural formula:
3. the method of claim 1, wherein the raw material comprises dimethyl 2- (4-nitrophenyl) malonate of formula:
4. the method for the catalytic synthesis of important intermediates of nilapali and the enzyme thereof according to claim 1, wherein the reaction time at the same temperature in the step S1 is preferably 3 hours, and the method for adding the sodium borohydride is preferably added in portions.
5. The method for the catalytic synthesis of an important intermediate of nilapali and the enzyme thereof according to claim 1, wherein the reaction temperature in the synthesis step S2 is preferably 45 ℃ and the reaction time is preferably 48 hours.
6. The method for the catalytic synthesis of an important intermediate of nilapali and an enzyme thereof according to claim 1, wherein in the synthesis step S3, the temperature condition of adding bromine is preferably 0-5 ℃, the time of adding bromine is preferably 2 hours, the stirring time after adding bromine is preferably 3 hours, the time of adding solution B is preferably 2 hours, and the stirring time after adding solution B is preferably 24 hours.
7. The method for the catalytic synthesis of important intermediates of nilapali and the enzyme thereof according to claim 1, wherein in the synthesis step S4, the stirring time at room temperature is preferably 2 hours, and the temperature is preferably reduced to 0 ℃.
8. The method for the catalytic synthesis of important intermediates of nilapali and the enzyme thereof according to claim 1, wherein in the step of synthesis, in S5, the palladium carbon is preferably 10% palladium carbon, the pressure condition is preferably 5kg, and the hydrogen gas is added for reaction for preferably 12 hours.
9. The method for the catalytic synthesis of important intermediates of nilapali and the enzyme thereof according to claim 1, wherein the sodium borohydride is added in S6, preferably in portions, and the reaction time is preferably 6 hours.
10. The method for the catalytic synthesis of important nilapali intermediates and enzymes thereof according to claim 1, wherein in the synthesis step S7, the temperature of the p-toluenesulfonyl chloride is preferably 0 ℃, the stirring time at room temperature is preferably 24 hours, and the antipyretic reflux time is preferably 48 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115626891A (en) * | 2022-10-20 | 2023-01-20 | 四川轻化工大学 | Synthesis method of nilapanib key intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115626891A (en) * | 2022-10-20 | 2023-01-20 | 四川轻化工大学 | Synthesis method of nilapanib key intermediate |
| CN115626891B (en) * | 2022-10-20 | 2024-01-26 | 四川轻化工大学 | Synthesis method of nilaparib key intermediate |
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