Preparation method of niraparib intermediate
Through a new process route, including amino protection, esterification reaction and other steps, the nirapani intermediate was successfully prepared, solving the problem of using high-risk chemicals and high-cost enzyme catalysis in the existing methods, and achieving High purity and low cost preparation effect.
Patent Information
- Application Number
- CN202411545918.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-31
- Publication Date
- 2025-02-11
AI Technical Summary
The existing preparation methods for nirapani intermediates have high risk of chemicals such as methyl lithium and low-temperature reactions, and the enzyme catalytic process is relatively costly and complex in operation.
A new process route is adopted to prepare nirapani intermediate through amino protection, esterification, C-alkylation, deprotecting group Boc, ring-off reaction, reduction reaction and chiral resolution. Avoid special hazardous reactions and high-cost enzyme catalysis.
It realizes the ease of operation and safety of the process, reduces costs, and improves the purity and yield of the product.
Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing a niraparib intermediate, and belongs to the technical field of organic synthesis. Background Art
[0002] PARP is a type of DNA damage detection enzyme that plays a key role in DNA damage repair and cell apoptosis. Many studies have shown that PARP is a good target for tumor treatment. In addition to participating in DNA repair, PARP can also be used as a mediator of cell death.
[0003] This paper studies the piperidine intermediate of niraparib, 3-(4-bromo-phenyl)-piperidine, whose molecular formula is C11H14BrN and molecular weight is 240.14. 3-(4-bromo-phenyl)-piperidine is a widely used chemical raw material. Since there are 8 replaceable hydrogens and 1 nucleophilic nitrogen on the piperidine ring in the phenylpiperidine molecule, it can synthesize a large number of 3-phenylpiperidine derivatives. It is an important intermediate in medicinal chemistry and organic synthesis, and is also the core intermediate of the latest PARP inhibitor Niraparib. Due to the huge clinical application prospects of niraparib, researchers have carried out certain research on its synthesis pathway, especially the synthesis of its core piperidine intermediate. With the rapid development of organic synthesis technology, its further synthesis, preparation, pharmaceutical research and toxicological research have a very important impact and significance. Summary of the invention
[0004] The present invention provides a method for preparing a niraparib intermediate.
[0005] The process currently reported in the literature uses methyl lithium (which is highly dangerous and expensive) and a low-temperature reaction, requiring a temperature of -78 degrees, which is a special reaction.
[0006] There is another reported process that uses enzyme catalysis, but the cost is relatively high.
[0007] The process route of the present invention is easy to operate and has no special hazardous reactions.
[0008] The reaction materials are cheap and readily available, and the obtained products are of high purity.
[0009] The specific steps are as follows:
[0010] The first step is the protection of the amino group:
[0011] The raw material 3-bromopropylamine hydrobromide (SM-1) was dissolved in water and added dropwise to a solution of potassium carbonate, Boc anhydride in tetrahydrofuran and water to obtain the Boc-protected intermediate 1.
[0012] Second step esterification reaction
[0013] The raw material p-bromophenylacetic acid (SM-2) was dissolved in ethanol and heated under reflux in the presence of a catalytic amount of sulfuric acid to complete the esterification reaction to obtain intermediate 2.
[0014] Step 3: C-alkylation
[0015] Intermediate 1 and intermediate 2 were dissolved in solvent DMSO, and sodium hydride was used to extract hydrogen to form a carbon anion, which was then docked to generate intermediate 3.
[0016] Step 4: Deprotection of Boc
[0017] Boc removal was performed with ethyl acetate and hydrochloric acid to obtain intermediate 4.
[0018] Step 5: Ring Closure Reaction
[0019] Intermediate 4 is dissolved in ethanol, potassium carbonate is added as a base, and the mixture is heated under reflux to form lactam through intramolecular amine ester exchange, thereby completing the ring-closing reaction to obtain intermediate 5.
[0020] Step 6 Reduction reaction
[0021] Intermediate 5 was dissolved in ethanol and reduced with sodium borohydride / boron trifluoride etherate to reduce the lactam to amine to give intermediate 6.
[0022] Step 7: Chiral separation
[0023] The racemate was chirally resolved using methanol as solvent and tartaric acid as a resolving agent, and then recrystallized using methanol / water as solvent to increase the EE value.
[0024] Advantageous Effects of the Invention
[0025] The process route is easy to operate.
[0026] The reaction materials are cheap and readily available, and the obtained products are of high purity. Specific embodiments
[0027] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.
[0028] Example 1
[0029] First step synthesis of intermediate 1
[0030] Add 19L of water to a 100L reactor, add 15.13kg of K2CO3 while stirring, cool down after it is completely dissolved, and add 8.38kg of Boc anhydride dissolved in 27L of tetrahydrofuran (THF) solution at 10℃.
[0031] Continue to cool down to 5℃, add 8kg SM-1 dissolved in 8L aqueous solution, stop cooling when the solution has 1 / 3 volume remaining, and heat naturally. After adding, heat to 35℃ and react overnight.
[0032] After the reaction was detected to be complete, the mixture was allowed to stand for stratification, and the lower aqueous phase was extracted with ethyl acetate (10 L*2), and the ethyl acetate phase was collected.
[0033] The upper tetrahydrofuran phase was separated, concentrated under reduced pressure, and then combined with the ethyl acetate phase to form an organic phase.
[0034] The organic phase was washed with saturated brine (5 L*2), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a light yellow oil (9.19 kg, yield>100%, HNMR: qualified with residual ethyl acetate).
[0035] Note: A total of 5 batches of materials were added (total: 40.89 kg).
[0036] Example 2
[0037] The second step is to synthesize intermediate 2
[0038] Add 48L of anhydrous ethanol to a 100L reactor, add 12kg of SM-2 while stirring, and dissolve completely.
[0039] Concentrated sulfuric acid was added dropwise at room temperature, which produced a slight heat release. After the addition was complete, the mixture was heated to 80°C and refluxed for 16 hours.
[0040] HPLC control: SM-2 remaining 4%, treatment (because the raw material reaction was not complete, TLC detection with ethyl acetate / petroleum ether
[0041] =1:3(uv)).
[0042] The mixture was cooled, concentrated under reduced pressure, and then 11 L of ethyl acetate was added. After stirring to dissolve, 24 L of (1 M / L) NaOH was slowly added dropwise to adjust the pH value to 7, and the mixture was allowed to stand and separate into layers.
[0043] The lower layer of ethyl acetate was collected, and the upper aqueous phase was extracted with ethyl acetate (5L*2). The ethyl acetate was combined, washed with saturated brine (5L*2), dried over anhydrous sodium sulfate, filtered, and spin-dried. After hydrating with toluene, a light yellow oil was obtained (15.25kg, yield>100%, solvent residue, HNMR: qualified, HPLC: 97%).
[0044] Note: 2 batches of materials were added (total: 26.88kg).
[0045] Example 3
[0046] Step 3 Synthesis of Intermediate 3
[0047] 20 L of anhydrous DMSO and 10 kg of intermediate 1 were added to a 100 L reactor, stirred until completely dissolved, cooled, and N2 (regulated by a bubbler) was introduced at the same time.
[0048] Add NaH in batches at 0-10℃, about 250g per batch, bubbles are generated, exotherm is intense, temperature is controlled ≤15℃, it takes 3hrs. After addition, stir at 5-10℃ for 0.5hr, turn off N2.
[0049] A solution of 12.68 kg of intermediate 2 dissolved in 10 L of DMSO was slowly dripped at 0-10°C. Exothermic heat was generated. The dripping speed was controlled and the temperature was controlled to ≤15°C. After the dripping was completed, the mixture was heated to 45-50°C and reacted for 1 hour.
[0050] After the reaction was complete, the temperature was lowered and 10 L of saturated NH4Cl solution was quickly added dropwise at 15°C. After the addition was completed, 20 L of water and 10 L of ethyl acetate were added, stirred, and allowed to stand for stratification. The upper ethyl acetate was collected, and the lower aqueous phase was extracted with 10 L of ethyl acetate. The ethyl acetate was combined, washed with water (8 L*1) and saturated brine (8 L*2), respectively, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a brown viscous oil (16.45 kg, yield: 99.9%, HPLC: 84.6%).
[0051] Remark:
[0052] The second batch of intermediate 1 was charged with 10 kg, and the product was 13.77 kg, with a yield of 83.7%, and HPLC: 51%.
[0053] The third batch of intermediate 1 was 10.275 kg, and the product was 15.75 kg, with a yield of 95.7%, and HPLC: 64%.
[0054] Example 4
[0055] Step 4 Synthesis of intermediate 4
[0056] Add 36 L (4 M / L) HCl / ethyl acetate solution into a 100 L reactor and cool down.
[0057] Add 22.985 kg of intermediate 3 diluted in 5 L of ethyl acetate solution at 5-10 ° C. After the addition is completed, stop cooling, stir (speed = 150), and react at room temperature overnight (a large amount of solid precipitates at 9.8 ° C, and the stirring state is not good. Add 7 L / ethyl acetate overnight).
[0058] After the reaction was complete, the mixture was filtered, and the filter cake was rinsed with ethyl acetate and dried to obtain 11.39 kg of a white solid with a yield of 58.9% and an HPLC value of 87%.
[0059] Remark:
[0060] The second batch of intermediate 3 was charged with 22.985 kg, and the product was 12.76 kg, with a yield of 66% and HPLC: 89%.
[0061] Example 5
[0062] Step 5 Synthesis of Intermediate 5
[0063] 34 L of anhydrous ethanol was added to a 100 L reactor, and 11.39 kg of intermediate 4 and 14 kg of K2CO3 were added under stirring. After the addition was completed, the mixture was refluxed at 80°C and reacted for six days (15 hrs).
[0064] After the reaction is complete, the temperature is lowered to 25°C and filtered. The filtrate is concentrated under reduced pressure to remove ethanol and set aside as A. All filter cakes are collected. After filtering, 20L of water and 20L of dichloromethane are added to the reactor, and the filter cake is added under stirring. There is an exothermic phenomenon. Stirring and stratification are allowed to stand, and the upper layer of dichloromethane is collected. The lower aqueous phase is extracted with 5L of dichloromethane, and the two dichloromethane phases are combined and concentrated under reduced pressure to a paste. Then 8L of methyl tert-butyl ether is used for pulping, stirring, filtering, and the filter cake is washed with methyl tert-butyl ether to obtain a white solid. Drying is 3-(4-bromophenyl)piperidin-2-one (6.065kg, yield: 70.6%, HNMR: qualified, HPLC: 99%).
[0065] Remark:
[0066] The second batch of intermediate 4 (12.765 kg) was added to obtain 6.515 kg of white solid product; yield: 67.7%, HNMR: qualified, HPLC: 99%.
[0067] The mother liquor was collected and combined with the above A, concentrated under reduced pressure, and then slurried twice to obtain 2.5 kg of white solid product, HNMR: qualified, HPLC: 95%.
[0068] Example 6 Step 6 Synthesis of Intermediate 6
[0069] 40 L of anhydrous tetrahydrofuran and 5.43 kg of anhydrous ethanol were added to a 100 L reactor, and 5 kg of intermediate 5 was added under stirring. After the addition, stirring was continued for 0.5 hr.
[0070] The temperature was lowered to 0-10°C and NaBH4 was added in portions. After the addition, the mixture was stirred at 5-10°C for 1 hr.
[0071] 16.75 kg of boron trifluoride-ether was slowly added dropwise at 0-10°C. Exotherm was generated. After the addition was completed, the mixture was stirred at 5-10°C for 1 hour and reacted at room temperature for 15 hours.
[0072] After the reaction is complete, the temperature is lowered to 5-10°C and 8.5 L of anhydrous methanol is slowly dripped in, which releases heat violently. After the dripping is completed, 4.5 L of concentrated hydrochloric acid is slowly dripped in at 5-10°C, which releases heat violently. After the dripping is completed, the mixture is heated to 50°C and reacted for 2 hrs. The temperature is lowered to 15°C and (6 M / L) NaOH solution is dripped in to adjust the pH to 6-7, and the solvent is concentrated under reduced pressure.
[0073] The residue was evaporated and adjusted to pH = 12 with (6M / L) NaOH, extracted with ethyl acetate (10L*3), combined, washed with saturated brine (5L*4), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a viscous oil (partially solidified) (4.97kg, yield>100%, HNMR: qualified, HPLC: 95%).
[0074] Remark:
[0075] The second batch of intermediate 5 was charged with 5.0 kg of material, and 5.18 kg of viscous oily product (partially solidified) was obtained, with a yield of >100%, HNMR: qualified, HPLC: 93.6%.
[0076] The third batch of intermediate 5 (4.985 kg) was added to obtain 5.3 kg of viscous oily product (partially solidified), with a yield of >100%, HNMR: qualified, HPLC: 96.3%.
[0077] The product obtained by combining three times was a viscous oil (partially solidified) of 14.17 kg.
[0078] Example 7 Seventh step synthesis product
[0079] 70L methanol and 14.17kg intermediate 6 were added to a 100L reactor. After stirring and dissolving, 6.195kg tartaric acid was added. After the addition was completed, the mixture was heated under reflux and reacted overnight. The next day, the temperature was lowered, and crystallization was carried out naturally. A white solid was obtained by filtration, and the ee value was measured: 95.6%. The obtained white solid was heated under reflux with 5vol methanol and reacted overnight. The above operation was repeated to obtain 7.7kg of white solid, which is (S)-3-(4-bromo-phenyl)-piperidine L-tartrate, and the ee value was measured: 97.7%. Recrystallization was carried out once to obtain 5.7kg of white solid, and the ee value was measured: 99.7%.
[0080] 5.7 kg of white solid was added with (6M / L) NaOH solution to adjust pH=12, extracted with ethyl acetate (8L*3), combined with ethyl acetate, and directly reacted in the next step (or the ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a white solid (4.225 kg, yield: 85.3%, HNMR: qualified, HPLC: 99.2%, ee: 99.7%). The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field within the technical scope disclosed in the present invention, according to the technical solution and the inventive concept of the present invention, is equivalently replaced or changed, which should be covered within the protection scope of the present invention.
Claims
1. A method for preparing a niraparib intermediate, characterized in that: The steps include: The first step is the protection of the amino group: The raw material 3-bromopropylamine hydrobromide was dissolved in water and added dropwise to a solution of potassium carbonate, Boc anhydride in tetrahydrofuran and water to obtain the Boc-protected intermediate 1. Second step esterification reaction The raw material p-bromophenylacetic acid was dissolved in ethanol and heated under reflux in the presence of a catalytic amount of sulfuric acid to complete the esterification reaction to obtain intermediate 2. Step 3: C-alkylation Intermediate 1 was dissolved in solvent DMSO, and sodium hydride was used to extract hydrogen to form a carbon anion, which was docked with intermediate 2 to generate intermediate 3. Step 4: Deprotection of Boc Boc removal was performed with hydrochloric acid and ethyl acetate to obtain intermediate 4. Step 5: Ring Closure Reaction Intermediate 4 is dissolved in ethanol, potassium carbonate is added as a base, and the mixture is heated under reflux to form lactam through intramolecular amine ester exchange, thereby completing the ring-closing reaction to obtain intermediate 5. Step 6 Reduction reaction Intermediate 5 was dissolved in ethanol and reduced with sodium borohydride / boron trifluoride etherate to reduce the lactam to amine to give intermediate 6. Step 7: Chiral separation The racemate was chirally resolved using methanol as solvent and tartaric acid as a resolving agent, and then recrystallized using methanol / water as solvent to increase the EE value.
2. The method for preparing a niraparib intermediate according to claim 1, characterized in that : The solvent used in the first step, as well as the method of adding materials, and the last thing added is the material (changing the order of adding materials will result in an increase in by-products).
3. The method for preparing a niraparib intermediate according to claim 1, characterized in that :The second step of esterification is catalyzed by a trace amount of sulfuric acid.
4. The method for preparing a niraparib intermediate according to claim 1, characterized in that : The sixth step reduction reaction is carried out using sodium borohydride / boron trifluoride etherate.
5. The method for preparing a niraparib intermediate according to claim 1, characterized in that The solvent used for the seventh step of separation is methanol, the resolving agent is tartaric acid, and the solvent used for recrystallization is methanol / water.