CN108752353B - Preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib - Google Patents
Preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib Download PDFInfo
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Abstract
A preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib relates to the preparation of medical intermediate. Reacting the compound 1 with potassium nitrate to obtain a compound 2; reacting the compound 2 with trimethylsilyl acetylene to obtain a compound 3; reacting the compound 3 with hydrogen to obtain a compound 4; compound 4 itself is cyclized to obtain compound 5; reacting the compound 5 with nitroethylene to obtain a compound 6; the compound 6 reacts with hydrogen to obtain key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib. The nitration reaction of the nitric-sulfuric mixed acid is avoided, the discharge of waste water and waste gas is avoided, the safety production is ensured, and the safety and the environmental protection are realized; the raw materials are easy to obtain and low in price, the cost is low, and the industrial production is convenient; greatly improves the reaction yield, optimizes the reaction route, simplifies the product purification steps and is beneficial to industrial production.
Description
Technical Field
The invention relates to preparation of a medical intermediate, in particular to a preparation method of key intermediate 1408282-26-7 (CAS No. 1408282-26-7) of anti-ovarian cancer drug Rucaparib (trade name Rubraca)
Background
Rucaparib qualifies as "breakthrough therapy" in us 2015 as the first polyadenylic diphosphate ribose polymerase (PARP) inhibitor to obtain this qualification as a monotherapy for advanced ovarian cancer with BRCA (Breast cancer susceptibility gene mutation).
Poly (adenosine diphosphate ribose) polymerase (PARP) is a class of DNA damage detection enzymes that play a key role in DNA damage repair and apoptosis. Several studies have shown that PARP is a good target for tumor treatment.
The Rucaparib can synthesize a final product by four steps starting from a key intermediate CAS No. 1408282-26-7, 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one (8-fluoro-4, 5-dihydro-1H-azepino [5,4, 3-cd ] indole-6 (3H) -one), as shown in the following:
the key intermediate CAS No. 1408282-26-7, 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one has a total of two synthetic routes:
route one: adam t. gillmore, Matthew Badland, Clare l. crook et al (org. process res. dev.2012,16,1897-
And a second route: gunn Yuan Shuo, Hu clap, Wangxin, Liu super, Li Shi Yu, (intermediate of fine chemical engineering, 2012,42 (5): 48-52)
The two routes are both nitrified by using sulfuric acid and nitric acid mixed acid, so that a large amount of acidic waste water and waste gas pollution are caused; the nitration reaction is an exothermic reaction, the reaction rate is high, the reaction is easy to be out of control, and great potential safety hazards are caused; sulfuric acid is used as a catalyst for esterification, so that the using amount of the sulfuric acid is large, and the waste water amount is large; the raw and auxiliary materials are high in price and high in cost; the column chromatography is used for purification, so that the efficiency is low, and the large-scale production is not facilitated; the total yield of the reaction is low, and the product cost is high.
Disclosure of Invention
The invention aims to provide a synthesis method of key intermediate CAS No. 1408282-26-7, 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one (8-fluoro-4, 5-dihydro-1H-azepino [5,4, 3-cd ] ind-ol-6 (3H) -one) of Rucaparib (trade name Rubraca) with simple and easily obtained raw materials, concise synthetic route, convenient production and operation, less three wastes, high reaction yield and greatly reduced cost,
the preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib comprises the following steps:
1) reacting the compound 1 with potassium nitrate by using acetic acid and acetic anhydride as solvents to obtain a compound 2; the structural formula of the compound 1 is as follows:
the structural formula of the compound 2 is as follows:
in the step 1), the potassium nitrate can adopt powdery potassium nitrate; the molar ratio of the compound 1 to potassium nitrate can be 1: 1.0-1.5; the reaction temperature can be-10-20 ℃, the reaction time can be 2-10 h, the reaction temperature is preferably 0-20 ℃, and the reaction time is preferably 2-6 h.
2) Adding a catalyst into N, N-dimethylformamide serving as a solvent, and reacting the compound 2 with trimethylsilyl acetylene to obtain a compound 3; the structural formula of the compound 3 is as follows:
in the step 2), the catalyst may be one selected from bis triphenylphosphine palladium dichloride, trifluoromethanesulfonic anhydride, triethylamine, trimethylsilylacetylene, etc.; the molar ratio of the compound 2 to the catalyst can be 1: 1.2-2.0; the reaction temperature can be 20-80 ℃, and the reaction time can be 0.5-4 h.
3) Reacting the compound 3 with hydrogen by using methanol as a solvent and 10% palladium-carbon as a catalyst to obtain a compound 4; the structural formula of the compound 4 is as follows:
in the step 3), the mass ratio of the compound 3 to 10% palladium carbon can be 1: 0.01-0.1; the reaction temperature can be 20-80 ℃, and the reaction time can be 2-12 h.
4) Reacting the compound 4 by using N, N-dimethylformamide as a solvent and cuprous iodide as a catalyst to obtain a compound 5; the structural formula of the compound 5 is as follows:
in the step 4), the molar ratio of the compound 4 to cuprous iodide can be 1: 0.05-0.2; the reaction temperature can be 40-140 ℃, and the reaction time can be 4-24 h.
5) Reacting a compound 5 with nitroethylene by using acetic acid as a solvent to obtain a compound 6; the structural formula of the compound 6 is as follows:
in the step 5), the molar ratio of the compound 5 to nitroethylene can be 1: 1.2-2.0; the reaction temperature can be 20-80 ℃, and the reaction time can be 6-24 h.
6) Using methanol as a solvent and Raney nickel as a catalyst, and reacting a compound 6 with hydrogen to obtain a compound 7, namely a key intermediate 1408282-26-7 of the anti-ovarian cancer drug Rucaparib, wherein the key intermediate 1408282-26-7 of the anti-ovarian cancer drug Rucaparib is a white solid, namely a key intermediate 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one of the anti-ovarian cancer drug Rucaparib; the structural formula of the compound 7 is as follows:
in the step 6), the reaction temperature can be 20-80 ℃, and the reaction time from normal pressure to 20 atmospheric pressures can be 6-24 h.
The reaction formula of the preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib is as follows:
the invention has the following beneficial effects:
1) the invention avoids nitration reaction of nitric-sulfuric mixed acid, avoids discharge of waste water and waste gas, and ensures safe production and environmental protection.
2) The raw materials are easy to obtain, the cost is low, and the industrial production is convenient;
3) greatly improves the reaction yield, optimizes the reaction route, simplifies the purification steps of the product and is beneficial to industrial production.
Detailed Description
Example 1:
the method comprises the following steps: compound 1(17.0g, 0.1mol) was dissolved in 80mL of acetic acid and 40mL of acetic anhydride, the temperature was reduced to 0 ℃, powdered potassium nitrate (10.1g, 0.1mol) was added in portions, reaction was carried out for 2 hours after completion of the addition, insoluble matter was removed by filtration, the reaction solution was poured into 400mL of ice water, and filtration and drying were carried out to give 18.6g of Compound 2.
Step two: compound 2(18.6g, 0.086mol) was dissolved in 150mL of N, N-dimethylformamide, bis-triphenylphosphine palladium dichloride (0.9g, 5% by mass), trifluoromethanesulfonic anhydride (12.2g, 0.043mol), triethylamine (17.4g, 0.172mol), trimethylsilylacetylene (9.8g, 0.10mol) were added and reacted at 20 ℃ for 0.5h, the insoluble matter was removed by filtration, and the reaction solution was poured into 400mL of water, filtered, and dried to give 17.6g of Compound 3.
Step three: adding the compound 3(17.6g, 0.063mol) into 150mL of methanol, adding 10% palladium carbon (0.18g, 1% by mass), introducing hydrogen, reacting at 20 ℃ for 2h, filtering to remove the catalyst, and concentrating under reduced pressure to obtain 15.8g of a crude compound 4, which is directly used for the next reaction without purification.
Step four: compound 4(15.8g, 0.060mol) was dissolved in 150mLN, N-dimethylformamide, cuprous iodide (0.57g, 0.0030mol) was added and reacted at 40 ℃ for 4 hours, insoluble matter was removed by filtration, and the reaction solution was added to 500mL of water, filtered and dried to give 14.4g of Compound 5, which was reacted without purification in the next step.
Step five: compound 5(14.4g, 0.054mol) was dissolved in 150mL of acetic acid, nitroethylene (4.8g, 0.065mol) was added, and the reaction was reacted at 20 ℃ for 6 hours, and the reaction solution was poured into 600mL of water, filtered, and dried to obtain 11.4g of Compound 6.
Step six: compound 6(11.4g, 0.043mol) was dissolved in 110mL of methanol, raney nickel (1.1g, 10% by mass) was added, and reacted with hydrogen at 20 ℃ under normal pressure for 6 hours, the catalyst was removed by filtration, and the solvent was removed under reduced pressure to give a yellow solid, which was recrystallized to give 6.8g of off-white solid 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one.
Example 2:
the method comprises the following steps: compound 1(17.0g, 0.1mol) was dissolved in 80mL of acetic acid and 40mL of acetic anhydride, the temperature was reduced to 20 ℃, powdered potassium nitrate (15.2g, 0.15mol) was added in portions, reaction was carried out for 6 hours after completion of the addition, insoluble matter was removed by filtration, and the reaction solution was poured into 400mL of ice water, filtered and dried to give 19.7g of Compound 2.
Step two: compound 2(19.7g, 0.092mol) was dissolved in 170mL N, N-dimethylformamide, bis triphenylphosphine palladium dichloride (0.99g, 5% by mass), trifluoromethanesulfonic anhydride (13.1g, 0.046mol), triethylamine (18.6g, 0.184mol), trimethylsilylacetylene (18.0g, 0.184mol) were added and reacted at 80 ℃ for 4h, the insoluble matter was removed by filtration, and the reaction solution was poured into 450mL water, filtered, and dried to give 20.9g of Compound 3.
Step three: compound 3(20.9g, 0.075mol) was added to 170mL of methanol, 10% palladium on carbon (2.09g, 10% by mass) was added, hydrogen was introduced, the reaction was carried out at 80 ℃ for 12 hours, the catalyst was removed by filtration, and the reaction mixture was concentrated under reduced pressure to give 19.1g of crude compound 4, which was used in the next reaction without purification.
Step four: compound 4(19.1g, 0.072mol) was dissolved in 180mL of N, N-dimethylformamide, cuprous iodide (2.7g, 0.0144mol) was added and the reaction was carried out at 140 ℃ for 24 hours, insoluble matter was removed by filtration, and the reaction mixture was added to 700mL of water, filtered and dried to give 18.1g of Compound 5, which was directly subjected to the next reaction without purification.
Step five: compound 5(18.1g, 0.068mol) was dissolved in 180mL of acetic acid, nitroethylene (10g, 0.136mol) was added, the reaction was carried out at 80 ℃ for 24 hours, the reaction solution was poured into 720mL of water, filtered, and dried to give 15.3g of Compound 6.
Step six: compound 6(15.3g, 0.058mol) was dissolved in 150mL of methanol, raney nickel (1.5g, 10% by mass) was added, and reacted with hydrogen at 80 ℃ under 20 atm for 24 hours, the catalyst was removed by filtration, and the solvent was removed under reduced pressure to give a yellow solid, which was recrystallized to give 9.8g of off-white solid 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one.
Example 3:
the method comprises the following steps: compound 1(17.0g, 0.1mol) was dissolved in 80mL of acetic acid and 40mL of acetic anhydride, the temperature was reduced to 10 ℃, powdered potassium nitrate (12.1g, 0.12mol) was added in portions, reaction was carried out for 2 hours after the addition, insoluble matter was removed by filtration, the reaction solution was poured into 400mL of ice water, and filtration and drying were carried out to give 20g of Compound 2.
Step two: compound 2(20g, 0.093mol) was dissolved in 170mL N, N-dimethylformamide, bis-triphenylphosphine palladium dichloride (1g, 5% by mass), trifluoromethanesulfonic anhydride (13.3g, 0.047mol), triethylamine (18.8g, 0.186mol), trimethylsilylacetylene (14.6g, 0.149mol) were added and reacted at 50 ℃ for 2 hours, the insoluble matter was removed by filtration, and the reaction solution was poured into 450mL water, filtered and dried to give 21.6g of Compound 3.
Step three: compound 3(21.6g, 0.077mol) was added to 170mL of methanol, 10% palladium on carbon (1.08g, 5% by mass) was added, hydrogen was introduced, reaction was carried out at 50 ℃ for 6 hours, the catalyst was removed by filtration, and the reaction mixture was concentrated under reduced pressure to give 19.4g of crude compound 4, which was used in the next reaction without purification.
Step four: compound 4(19.4g, 0.073mol) was dissolved in 180mL of N, N-dimethylformamide, cuprous iodide (1.39g, 0.0073mol) was added thereto, the reaction was carried out at 90 ℃ for 12 hours, insoluble matter was removed by filtration, and the reaction solution was added to 700mL of water, filtered and dried to obtain 18.3g of Compound 5, which was directly subjected to the next reaction without purification.
Step five: compound 5(18.3g, 0.069mol) was dissolved in 180mL of acetic acid, nitroethylene (8.1g, 0.11mol) was added, and the reaction mixture was reacted at 50 ℃ for 12 hours, poured into 720mL of water, filtered, and dried to give 15.5g of Compound 6.
Step six: compound 6(15.5g, 0.059mol) was dissolved in 150mL of methanol, raney nickel (1.5g, 10% by mass) was added, and the mixture was reacted with hydrogen at 50 ℃ under 10 atm for 12 hours, followed by filtration to remove the catalyst and removal of the solvent under reduced pressure to give a yellow solid, followed by recrystallization to give 10.1g of an off-white solid, 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one.
Claims (11)
1. The preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib is characterized by comprising the following steps:
1) reacting the compound 1 with potassium nitrate by using acetic acid and acetic anhydride as solvents to obtain a compound 2; the structural formula of the compound 1 is as follows:
the structural formula of the compound 2 is as follows:
2) adding a catalyst into N, N-dimethylformamide serving as a solvent, and reacting the compound 2 with trimethylsilyl acetylene to obtain a compound 3; the structural formula of the compound 3 is as follows:
3) reacting the compound 3 with hydrogen by using methanol as a solvent and 10% palladium-carbon as a catalyst to obtain a compound 4; the structural formula of the compound 4 is as follows:
4) reacting the compound 4 by using N, N-dimethylformamide as a solvent and cuprous iodide as a catalyst to obtain a compound 5; the structural formula of the compound 5 is as follows:
5) reacting a compound 5 with nitroethylene by using acetic acid as a solvent to obtain a compound 6; the structural formula of the compound 6 is as follows:
6) using methanol as a solvent and Raney nickel as a catalyst, and reacting a compound 6 with hydrogen to obtain a compound 7, namely a key intermediate 1408282-26-7 of the anti-ovarian cancer drug Rucaparib, wherein the key intermediate 1408282-26-7 of the anti-ovarian cancer drug Rucaparib is a white solid, namely a key intermediate 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one of the anti-ovarian cancer drug Rucaparib; the structural formula of the compound 7 is as follows:
2. the method for preparing key intermediate 1408282-26-7 of Rucaparib as an anti-ovarian cancer drug in claim 1, wherein in step 1), the potassium nitrate is powdered potassium nitrate; the molar ratio of the compound 1 to potassium nitrate is 1: 1.0-1.5.
3. The preparation method of key intermediate 1408282-26-7 of Rucaparib as an anti-ovarian cancer drug in claim 1, wherein in step 1), the reaction temperature is-10 to 20 ℃ and the reaction time is 2 to 10 hours.
4. The preparation method of key intermediate 1408282-26-7 of Rucaparib as an anti-ovarian cancer drug in claim 3, wherein the reaction temperature is 0-20 ℃ and the reaction time is 2-6 h.
5. The method for preparing key intermediate 1408282-26-7 of Rucaparib as an anti-ovarian cancer drug in claim 1, wherein in step 2), the catalyst is selected from one of bis (triphenylphosphine) palladium dichloride, trifluoromethanesulfonic anhydride, triethylamine and trimethylsilyl acetylene; the mol ratio of the compound 2 to the catalyst is 1: 1.2-2.0.
6. The method for preparing Rucaparib key intermediate 1408282-26-7 as an anti-ovarian cancer drug in claim 1, wherein in the step 2), the reaction temperature is 20-80 ℃ and the reaction time is 0.5-4 h.
7. The preparation method of key intermediate 1408282-26-7 of Rucaparib as an anti-ovarian cancer drug in claim 1, wherein in the step 3), the mass ratio of the compound 3 to 10% palladium carbon is 1: 0.01-0.1; the reaction temperature is 20-80 ℃, and the reaction time is 2-12 h.
8. The method for preparing Rucaparib key intermediate 1408282-26-7 as an anti-ovarian cancer drug in claim 1, wherein in the step 4), the molar ratio of the compound 4 to cuprous iodide is 1: 0.05-0.2; the reaction temperature is 40-140 ℃, and the reaction time is 4-24 h.
9. The method for preparing Rucaparib key intermediate 1408282-26-7 as an anti-ovarian cancer drug in claim 1, wherein in the step 5), the molar ratio of the compound 5 to nitroethylene is 1: 1.2-2.0; the reaction temperature is 20-80 ℃, and the reaction time is 6-24 h.
10. The preparation method of key intermediate 1408282-26-7 of Rucaparib as an anti-ovarian cancer drug in claim 1, wherein in step 6), the reaction temperature is 20-80 ℃, and the reaction time is 6-24 hours from normal pressure to 20 atmospheres.
11. The preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib as claimed in claim 1, which is characterized by the following reaction formula:
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