A kind of synthetic method of duvilisse
Through the aldol condensation of compound 2 and acetone, the ammonialysis of oxalyl chloride and aniline, the ring-catalyzed by palladium and copper, and the asymmetric reduction amination of chiral metal iridium catalyzed by the existing Duveliser synthesis process, the existing Duveliser synthesis process was solved The problems of low rate and harsh reaction conditions have achieved efficient, safe and environmentally friendly synthesis, suitable for industrial production.
Patent Information
- Application Number
- CN202410590918.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-13
- Publication Date
- 2024-12-20
- Estimated Expiration
- 2044-05-13
AI Technical Summary
The existing Duweiliser synthesis process has problems such as low process yield, rare raw materials, harsh reaction conditions, unsafe and unenvironmental protection, and is difficult to be suitable for industrial production.
Compound 2 is used to condensate the aldol with acetone, followed by ammonialysis of oxalyl chloride and aniline, followed by a ring-closed reaction in the presence of palladium and copper catalysts, and then asymmetric reduction amine catalyzed by chiral metal iridium complex The chemical reaction is made of Duveliser.
It improves the total yield of the process, is easy to obtain raw materials, is easy to operate, is safe and environmentally friendly, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of compound synthesis, in particular to a method for synthesizing duvelice. Background Art
[0002] Duvelisib, with the generic name duvelisib, the chemical name 8-chloro-2-phenyl-3-[(1S)-1-(3H-purin-6-ylamino)ethyl]-1-(2H)-isoquinoline, and the trade name Copiktra, was developed by Verastem Pharmaceuticals in the United States and approved by the FDA in September 2018. The drug is an oral drug that acts on the phosphoinositide-3-kinase (PI3K) target and is also the first approved dual inhibitor of PI3Kδ and PI3Kγ. It is mainly used clinically to treat a variety of relapsed or difficult-to-cure blood cancers, including adult patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. In addition, the FDA also authorized the accelerated approval of duvelisib for adult patients with relapsed or refractory follicular lymphoma. In March 2022, the China National Medical Products Administration (NMPA) also approved the listing of Shijiazhuang Pharmaceutical Group's duvelisib capsules for the treatment of relapsed or refractory follicular lymphoma that has undergone at least two previous systemic treatments.
[0003] Regarding the preparation of duvilisel, documents WO2011146882, US202202665637A1 and CN102711767A all report similar preparation methods, and the specific routes are:
[0004]
[0005] The method uses L-alanine as a raw material, undergoes amino protection, peptide formation reaction, condensation reaction, and then ring closure and hydrolysis reactions to prepare an 8-chloro-1-oxo-3-aminoethyl-2-phenylisoquinoline intermediate, then the intermediate undergoes a nucleophilic substitution reaction with 6-chloro-9-(2-tetrahydropyran)-purine, and finally removes the tetrahydropyran protecting group to obtain duvelice.
[0006] The second step of the peptide formation reaction in this method requires the use of expensive 1-hydroxybenzotriazole (HOBt) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) as condensing agents. The 6-chloro-9-(2-tetrahydropyran)-purine used in the fifth step is also difficult to purchase. It needs to be prepared by chlorinating hypoxanthine with more than 10 times the amount of phosphorus oxychloride and then reacting it with dihydropyran for ammonia protection. The chlorination reaction has a low yield, and the post-processing of the large excess of phosphorus oxychloride is troublesome and environmentally unfriendly. Friendly; a greater drawback is that the condensation reaction in the third step must be carried out at a low temperature of -78 to -50°C and under the action of highly flammable n-butyl lithium and Grignard reagent. The reaction conditions are very harsh, difficult to control, and the process is unsafe. In addition, the yield of this condensation reaction is low; the stereoselectivity of the fourth step ring-closing hydrolysis reaction is also low, and the optical purity of the obtained chiral amine is low (S:R=7:1), and further resolution with D-tartaric acid is required. The literature reports that the total yield of the condensation and ring-closing hydrolysis two-step reaction is only 9.1%. Therefore, the process for preparing dovirice reported in the literature has the disadvantages of low total process yield, difficult to obtain raw materials, very harsh reaction conditions, difficult to control, unsafe process, and environmental pollution, which is not conducive to industrial production. For this purpose, a synthesis method of dovirice is provided. Summary of the Invention
[0007] The purpose of the present invention is to provide a method for synthesizing duvelice in view of the defects of the prior art, so as to solve the problems raised by the above background technology.
[0008] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing duvelice,
[0009] The specific preparation route is as follows:
[0010]
[0011] The specific steps are as follows:
[0012] S1: Compound 2 reacts with acetone to produce compound 3;
[0013] S2: Compound 3 reacts with oxalyl chloride to prepare acyl chloride, which is then directly reacted with aniline for aminolysis to obtain compound 4 without purification;
[0014] S3: Compound 4 undergoes a ring-closing reaction in the presence of catalyst 1, a base, and oxygen to obtain compound 5; the catalyst 1 is a mixture of a palladium compound and a copper compound, and the base is an organic amine;
[0015] S4: Compound 5 undergoes an asymmetric reductive amination reaction with 9H-purine-6-amine and hydrogen in the presence of catalyst 2 to obtain dovilice. The catalyst 2 is a chiral metal iridium complex and an auxiliary agent.
[0016] Preferably, in step S3, the palladium compound is selected from palladium acetate, palladium trifluoroacetate or acetonitrile palladium chloride; and the copper compound is selected from CuCl2, CuBr2, CuI2, CuCl, CuBr or CuI.
[0017] Preferably, the organic amine in step S3 is selected from triethylamine, tributylamine, diethylmethylamine or diethylisopropylamine.
[0018] Preferably, in step S3, the molar ratio of compound 4 to catalyst 1 and base is: compound 4: palladium compound: copper compound: base = 1.0: 0.05-0.2: 0.05-0.2: 0.1-0.4.
[0019] Preferably, the reaction temperature in step S3 is 40-100° C., and the oxygen pressure is 1-3 atmospheres.
[0020] Preferably, the reaction solvent in step S3 is one or a mixture of methanol, ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, and 1,4-dioxane.
[0021] Preferably, in step S4, the chiral metal iridium complex has the structural formula Ir-L* and is generated in situ in the experiment from (1,5-cyclooctadiene)iridium(I) chloride dimer [Ir(COD)Cl]2 and ligand L*;
[0022] In the Ir-L* structural formula, L* is a chiral phosphine-phosphinamide ligand with the structure:
[0023]
[0024] Wherein, R1 is H, C1-C4 alkyl, and R2 is H, methyl, ethyl, chlorine or bromine.
[0025] Preferably, the amount of the chiral metal iridium complex is 1 to 5% of the amount of compound 5.
[0026] Preferably, in step S4, the reaction temperature is 40-80° C., and the hydrogen pressure is 10-50 atmospheres.
[0027] Preferably, the auxiliary agent is a titanate selected from isopropyl titanate, ethyl titanate, methyl titanate or isobutyl titanate.
[0028] Compared with the prior art, the present invention has the following beneficial effects: the raw materials are cheap and readily available, the steps are few, the operation is simple, the total yield is high, the process is safe and environmentally friendly, and it is more suitable for industrial production. DETAILED DESCRIPTION
[0029] The preferred embodiments of the present invention are described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more precise definition of the protection scope of the present invention.
[0030] Example 1: Preparation of Compound 3
[0031] 50 mmol of compound 2, 30 mL of 10% sodium hydroxide solution, and 20 mL of ethanol were added sequentially to a reaction flask and stirred to mix thoroughly. The temperature of the reaction system was raised to 50°C, and 55 mmol of acetone was added dropwise with stirring. After the addition was complete, the reaction was stirred and maintained at this temperature for 2 hours. The reaction was stopped, the ethanol was evaporated under reduced pressure, and 1 M hydrochloric acid was added dropwise to the residue to adjust the pH to 7. 50 mL of ethyl acetate was then added to the mixture, and the organic layer was separated. The aqueous layer was extracted twice with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure to obtain compound 3, which was directly used in the next experiment without purification.
[0032] Example 2: Preparation of Compound 4
[0033] Compound 3 prepared in Example 1, 150 mL of dichloroethane, and 3 drops of DMF were added sequentially to a reaction flask and stirred to mix thoroughly. 50 mmol of oxalyl chloride was then added dropwise. After complete addition, the reaction system was heated to 30-40°C and stirred for 1 hour. The reaction was terminated, the solvent and hydrogen chloride were evaporated under reduced pressure, and 40 mL of dichloroethane was added to the residue. The resulting dichloroethane mixture was set aside.
[0034] 50mmol of aniline, 150mmol of triethylamine and 150mL of dichloroethane were added to the reaction flask in sequence, and the dichloroethane mixture obtained above was added dropwise at room temperature. After the addition was complete, the temperature of the reaction system was raised to 30-40°C, and the mixture was stirred and reacted for 2 hours. The reaction was stopped, 100mL of water was added, the organic layer was separated, and the aqueous layer was extracted twice with 100mL of dichloroethane. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. 150mL of petroleum ether was added to the residue and stirred. The precipitated solid was filtered and dried to obtain compound 4 with a yield of 61% (based on 2). The structure is shown in FIG. 1 H NMR characterization, 1 HNMR (500MHz, CDCl3) δ: 8.97 (s, 1H), 7.97 (d, J = 30.2Hz, 1H), 7.85-7.75 (m, 1H), 7.73-7.64 (m, 2H ),7.62-7.51(m,2H),7.37-7.26(m,2H),7.12-7.01(m,1H),6.52(d,J=30.2Hz,1H),2.37(s,3H).
[0035] Example 3: Preparation of Compound 5
[0036] 2.5mmol acetonitrile palladium chloride, 2.5mmol CuCl, 5mmol diethylisopropylamine and 300mL methanol and 50mmol compound 4 were added to the reaction flask in sequence, stirred and mixed evenly, oxygen was introduced, the temperature of the reaction system was raised to 60°C, and the reaction was stirred and reacted for 8h under an oxygen atmosphere of 1 atmosphere. Stop the reaction, concentrate to dryness under reduced pressure, add 200mL dichloroethane to the residue, stir and dissolve, and then add 200mL water. Separate the organic layer, extract the aqueous layer with 100mL dichloroethane twice, combine the organic layers, dry with anhydrous Na2SO4, and concentrate to dryness under reduced pressure. Add 50mL ethyl acetate and 200mL petroleum ether to the residue for pulping, filter the precipitated solid, and obtain compound 5 after drying with a yield of 80%. The structure is known by 1 H NMR characterization, 1 H NMR (500MHz, CDCl3) δ: 7.82 (t, J = 7.5Hz, 1H), 7.71-7.52 (m, 5H), 7.50-7.33 (m, 2H), 6.94 (s, 1H), 2.20 (s, 3H).
[0037] Example 4: Preparation of Compound 5
[0038] 5 mmol of acetonitrile palladium chloride, 5 mmol of CuCl, 10 mmol of diethylisopropylamine, 300 mL of methanol and 50 mmol of compound 4 were added to the reaction flask in sequence. Other operations were the same as those in Example 3 to obtain compound 5 with a yield of 89%.
[0039] Example 5: Preparation of Compound 5
[0040] 10 mmol of acetonitrile palladium chloride, 10 mmol of CuCl, 20 mmol of diethylisopropylamine, 300 mL of methanol and 50 mmol of compound 4 were added to the reaction flask in sequence. Other operations were the same as those in Example 3 to obtain compound 5 with a yield of 94%.
[0041] Example 6: Preparation of Compound 5
[0042] 10 mmol of acetonitrile palladium chloride, 10 mmol of CuCl, 20 mmol of diethylisopropylamine, 300 mL of methanol, and 50 mmol of compound 4 were added sequentially to a reaction kettle and stirred until uniformly mixed. Oxygen was then introduced, and the reaction temperature was raised to 60°C. The reaction was stirred and maintained under an oxygen atmosphere of 3 atmospheres for 6 hours. Post-processing was performed as in Example 3 to obtain compound 5 in a yield of 95%.
[0043] On the basis of the reaction conditions of Example 5 (i.e., the molar ratio of compound 4, palladium compound, copper compound and base is 1:0.2:0.2:0.4), the acetonitrile palladium chloride in the reaction can be replaced by palladium acetate or palladium trifluoroacetate; the CuCl in the reaction can be replaced by CuCl2, CuBr2, CuI2, CuBr, or CuI; the diethylisopropylamine in the reaction can be replaced by triethylamine, tributylamine, or diethylmethylamine; the temperature of the reaction system can be adjusted between 40°C and 100°C; the solvent methanol can be replaced by ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, 1,4-dioxane, etc., and the other reaction conditions remain unchanged. Some experimental results are shown in Table 1.
[0044] Table 1: Conditions and results for preparing compound 5 in Examples 7 to 23
[0045]
[0046]
[0047] Example 24: Preparation of Duvelice
[0048] Under N2 protection, 0.25mmol [Ir (COD) Cl]2, 0.55mmol chiral phosphine-phosphinamide ligand L* (R1 = CH3, R2 = H) and 200mL toluene were added to the reactor and stirred at room temperature for 15min. Then, 50mmol compound 5 and 55mmol 9H-purine-6-amine and 20mL isopropyl titanate were added. After hydrogen replacement 3 times, hydrogen was introduced to 30 atmospheres. The temperature was raised to 60°C with stirring, and the temperature and pressure were kept stirring for 10h. The hydrogen was released, cooled to room temperature and filtered. The filtrate was washed once with 100mL saturated ammonium chloride and 200mL brine, dried, and the solvent was evaporated under reduced pressure. 200mL MTBE and 200mL 1NHCl were added to the residue, stirred, and separated. The organic phase was washed with 100mL 1NHCl was washed once more, the aqueous phases were combined, and the pH was adjusted to 8 with saturated Na2CO3, extracted with 100mL MTBE, the organic phases were combined, dried, and the solvent was evaporated under reduced pressure to obtain a crude solid. 200mL ethyl acetate was added to the crude solid, stirred for 0.5h, and the precipitated solid was filtered and dried to obtain develise with a yield of 54% and a purity of 95.6%. The structure was determined by MS and 1 HNMR characterization, ESI-LRMS m / z: 417.1 [M+H] +,1H NMR(500MHz, CDCl3)δ:9.32(s,1H),8.21(s,1H),7.86(s,1H),7.66-7.52(m,4H),7.48-7.36(m,2H ),7.35-7.25(m,2H),6.43(s,1H),5.68-5.58(q,J=3.9Hz,1H),3.82(s,1H),1.35(d,J=3.9Hz,3H).
[0049] Example 25: Preparation of Duvelice
[0050] Under N2 protection, 0.75mmol [Ir(COD)Cl]2, 1.65mmol chiral phosphine-phosphinamide ligand L* (R1=CH3, R2=H) and 100mL toluene were added to the reactor and stirred at room temperature for 15min. Then, 50mmol compound 5, 55mmol 9H-purine-6-amine and 20mL isopropyl titanate were added. The subsequent operation was the same as that in Example 24. The yield was 65% and the purity was 97.8%.
[0051] Example 26: Preparation of Duvelice
[0052] Under N2 protection, 1.25mmol [Ir(COD)Cl]2, 2.75mmol chiral phosphine-phosphinamide ligand L* (R1=CH3, R2=H) and 100mL toluene were added to the reactor and stirred at room temperature for 15min. Then, 50mmol compound 5, 55mmol 9H-purine-6-amine and 20mL isopropyl titanate were added. The subsequent operation was the same as in Example 24, with a yield of 76% and a purity of 99%.
[0053] Based on the reaction conditions of Example 26 (i.e., the molar ratio of compound 5, 9H-purine-6-amine and catalyst 2 is 1:1.1:0.05), R1 in the chiral phosphine-phosphinamide ligand L* can be adjusted to H, C1-C4 alkyl, and R2 can be adjusted to H, methyl, ethyl, chlorine, or bromine; the isopropyl titanate in the reaction can be replaced by ethyl titanate, methyl titanate, or isobutyl titanate; the reaction temperature can be adjusted between 40 and 80°C, and the hydrogen pressure can be adjusted between 10 and 50 atmospheres. Other reaction conditions remain unchanged. Some experimental results are shown in Table 2.
[0054] Table 2: Conditions and results for preparing Develise in Examples 27 to 42
[0055]
[0056]
[0057] The above embodiments merely illustrate the implementation methods of the present invention. Although the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that a person skilled in the art may make various modifications and improvements without departing from the scope of the present invention, and these modifications and improvements fall within the scope of protection of the present invention.
Claims
1. A method for synthesizing duvilisse, characterized in that: The specific preparation route is as follows: The specific steps are as follows: S1: Compound 2 undergoes aldol condensation reaction with acetone to obtain compound 3; S2: Compound 3 reacts with oxalyl chloride to prepare acyl chloride, which is then directly reacted with aniline for aminolysis to obtain compound 4 without purification; S3: Compound 4 undergoes a ring-closing reaction in the presence of catalyst 1, a base and oxygen to obtain compound 5; the catalyst 1 is a mixture of a palladium compound and a copper compound, and the base is an organic amine; The palladium compound is selected from palladium acetate, palladium trifluoroacetate or acetonitrile palladium chloride; the copper compound is selected from CuCl2, CuBr2, CuI2, CuCl, CuBr or CuI; S4: Compound 5 reacts with 9H-purine-6-amine and hydrogen in the presence of catalyst 2 to undergo an asymmetric reductive amination reaction to obtain dovilicel, wherein the catalyst 2 is a chiral metal iridium complex and an auxiliary agent; The chiral metal iridium complex, with the structural formula Ir-L*, is generated in situ in the experiment by (1,5-cyclooctadiene) iridium (I) chloride dimer [Ir(COD)Cl]2 and ligand L*; In the Ir-L* structural formula, L* is a chiral phosphine-phosphinamide ligand with the structure: Wherein, R1 is H, C1-C4 alkyl, R2 is H, methyl, ethyl, chlorine or bromine; The auxiliary agent is a titanate ester selected from isopropyl titanate, ethyl titanate, methyl titanate or isobutyl titanate.
2. A method for synthesizing duvilisse according to claim 1, characterized in that: The organic amine in step S3 is selected from triethylamine, tributylamine, diethylmethylamine or diethylisopropylamine.
3. A method for synthesizing duvilisse according to claim 1, characterized in that: The reaction temperature in step S3 is 40-100° C., and the pressure of oxygen is 1-3 atmospheres.
4. A method for synthesizing duvilisse according to claim 1, characterized in that: The reaction solvent in step S3 is one or a mixture of methanol, ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, and 1,4-dioxane.
5. A method for synthesizing duvilisse according to claim 1, characterized in that: In step S3, the ratio of the amount of compound 4 to the catalyst 1 and the base is: compound 4: palladium compound: copper compound: base = 1.0: 0.05-0.2: 0.05-0.2: 0.1-0.
4.
6. A method for synthesizing duvilisse according to claim 1, characterized in that: The amount of the chiral metal iridium complex used is 1-5% of the amount of compound 5.
7. A method for synthesizing duvilisse according to claim 1, characterized in that: The reaction temperature in step S4 is 40 to 80° C., and the hydrogen pressure is 10 to 50 atmospheres.