CN118388485B - Du Weili Sibub synthesis method - Google Patents

Du Weili Sibub synthesis method Download PDF

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CN118388485B
CN118388485B CN202410608374.5A CN202410608374A CN118388485B CN 118388485 B CN118388485 B CN 118388485B CN 202410608374 A CN202410608374 A CN 202410608374A CN 118388485 B CN118388485 B CN 118388485B
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weili
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CN118388485A (en
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程青芳
王炫懿
王启发
王志轩
纪子文
方慧珍
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Blue Bay Marine Resources Development Technology Innovation Center
Jiangsu Ocean University
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Jiangsu Ocean University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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Abstract

The invention relates to the technical field of compound synthesis, and particularly discloses a Du Weili Sibub synthesis method, which comprises the following steps: the compound 2 and dimethyl oxalate firstly undergo condensation reaction and then undergo ring closure reaction to obtain a compound 3; step (2): carrying out ester hydrolysis reaction on the compound 3 to obtain a compound 4; step (3): the compound 4 and acetic anhydride undergo condensation reaction to obtain a compound 5; step (4): the compound 5 and (S) -tert-butyl sulfonamide undergo an addition dehydration reaction under the action of B (OCH 2CF3)3) and then undergo a reduction reaction to obtain a compound 6, the compound 6 undergoes a hydrolysis reaction to obtain a compound 7, and the compound 7 and hypoxanthine undergo an amine alkylation reaction under the action of a catalyst, an oxidant and DMF to obtain Du Weili sibutre.

Description

Du Weili Sibub synthesis method
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a method for synthesizing Du Weili sibutra.
Background
Du Weili Sibuh is an oral kinase inhibitor of phosphoinositide-3-kinase (PI 3K) target, commonly known as duvelisib, developed by the pharmaceutical company of America Verastem, approved by FDA at month 9 of 2018, and used for treating various recurrent or refractory cancers including chronic lymphocytic leukemia, small lymphocytic lymphoma and follicular lymphoma, and has the trade name Copiktra. The drug is the first PI3K delta and PI3K gamma dual inhibitor to be approved, and in addition, the FDA is authorized to accelerate approval of the drug for adult patients with recurrent or refractory follicular lymphoma.
For Du Weili sibutra synthesis, few literature reports have reported similar synthetic methods, only US202202665637A1, WO2011146882 and CN 102711767a, etc., with specific routes:
The method takes L-alanine as a raw material, and obtains Weinreb amide intermediate after amino protection and ammonolysis reaction, the amide intermediate and 2-chloro-6-methylphenyl benzamide undergo condensation, ring closure and deprotection reaction to prepare 8-chloro-1-oxo-3-aminoethyl-2-phenylisoquinoline intermediate, then the intermediate and 6-chloro-9- (2-tetrahydro-2H pyran-2 yl) -9H-purine undergo nucleophilic substitution, and finally the Du Weili western cloth is obtained after deprotection.
In the second step of the method, expensive HOBt and EDCl are used as condensing agents, the third step of condensation reaction is carried out at the temperature below-50 ℃ under the catalysis of n-butyllithium and Grignard reagent, the reaction conditions are very harsh, the control is difficult, the n-butyllithium is inflammable, the process is unsafe, the yield of the condensation reaction is lower, and the literature reports that the yield of the condensation reaction is only 17.5%; the stereoselectivity of the ring closing reaction in the fourth step is not high, and the S isomer and the R isomer of the chiral amine obtained after deprotection are 7:1 and are further resolved by D-tartaric acid; in addition, the 6-chloro-9- (2-tetrahydropyran) -purine used in the fifth step is not easy to purchase, and is prepared by carrying out chlorination reaction on hypoxanthine and more than 10 times of phosphorus oxychloride and then carrying out nitrogen protection reaction on the hypoxanthine and the dihydropyran, wherein the chlorination reaction yield is low, and the post-treatment of a large amount of phosphorus oxychloride is troublesome and is not friendly to the environment; therefore, the total yield of the process for preparing Du Weili Sibutu reported in the literature is very low, partial raw materials are not easy to obtain, the reaction conditions are very harsh, the control is not easy, the safety is not high, the environment is not friendly, and the industrial production is not facilitated.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and provides a Du Weili Sibub synthesis method which aims at solving the problems existing in the prior art.
In order to achieve the above purpose, the invention provides the following technical scheme, and the specific preparation route is as follows:
The method comprises the following specific steps:
Step (1): the compound 2 and dimethyl oxalate firstly undergo condensation reaction and then undergo ring closure reaction to obtain a compound 3;
Step (2): carrying out ester hydrolysis reaction on the compound 3 to obtain a compound 4;
Step (3): the compound 4 and acetic anhydride undergo condensation reaction under the action of pyridine to obtain a compound 5;
step (4): the compound 5 and (S) -tert-butyl sulfonamide undergo an addition dehydration reaction under the action of B (OCH 2CF3)3) and then undergo a reduction reaction with a reducing agent to obtain a compound 6;
step (5): carrying out hydrolysis reaction on the compound 6 to obtain a compound 7;
step (6): and (3) carrying out an amine hydrocarbylation reaction on the compound 7 and hypoxanthine under the action of a catalyst, an oxidant and DMF to obtain Du Weili sibutre.
Preferably, the reaction temperature in step (4) is 40 to 80 ℃.
Preferably, in step (4), the ratio of the amount of compound 5 to the amount of (S) -tert-butylsulfonamide and the amount of B (OCH 2CF3)3) is 1.0:1.0 to 1.5:1.5 to 3.0.
Preferably, in step (4), the reducing agent for the reduction reaction is selected from LiBH 4、NaBH4、KBH4、Me4NBH4、BH3, THF or LiAlH 4.
Preferably, in step (6), the catalyst is a copper compound.
Preferably, the copper compound is selected from CuCl 2、CuBr2、CuI2、Cu(OAc)2 or Cu (acac) 2.
Preferably, in step (6), the oxidizing agent is a peroxide.
Preferably, the peroxide is selected from TBHP (t-butyl peroxide), DTBP (bis-t-butyl peroxide), CHP (cumyl hydroperoxide), m-CPBA (m-chloroperoxybenzoic acid) or BPO (benzoyl peroxide).
Preferably, the reaction temperature in step (6) is 60 to 120 ℃.
Preferably, in step (6), the ratio of the amount of hypoxanthine to the amount of compound 7, the amount of the oxidizing agent, and the amount of the catalyst substance is: 1.0:1.2:1.5-3:0.03-0.08.
Compared with the prior art, the invention has the beneficial effects that:
(1) The raw materials used in the method are low in cost and easy to obtain, the compound 1 is prepared through six steps, and the yield of each step is high;
(2) The whole reaction process has mild conditions, simple operation, safety and environmental protection;
(3) The purity of the compound 1 prepared by the method can reach more than 99 percent.
Detailed Description
The following detailed description of the preferred embodiments of the invention will provide those skilled in the art with a better understanding of the invention with its advantages and features, and thus define the scope of the invention more clearly and clearly.
Example 1: synthesis of Compound 3
120Mmol of sodium ethoxide and 100mL of ethanol are added into a reaction bottle and stirred and mixed uniformly. The temperature of the reaction system is reduced to 10-15 ℃, 100mmol of compound 2 is added, the reaction is carried out for 0.5h by heat preservation and stirring, then 110mmol of dimethyl oxalate is dripped, the temperature of the reaction system is increased to reflux after dripping, the reaction is carried out for 4h by heat preservation and stirring, the reaction is stopped, the solvent is distilled off under reduced pressure, 100mL of distilled water and 100mL of ethyl acetate are added, stirring is carried out, the water layer is separated, the water layer is washed by 60mL of ethyl acetate twice, the ethyl acetate layer is combined, the solvent is distilled off under reduced pressure after the drying by anhydrous Na 2SO4, and the crude product is obtained.
To the crude product obtained above, 100mL of 10M hydrochloric acid-methanol solution was added, and the mixture was dissolved with stirring, the reaction temperature was raised to reflux, and the reaction was continued with stirring for 3 hours. Stopping the reaction, evaporating the solvent and hydrogen chloride under reduced pressure, adding 100mL of ethyl acetate into the residue, stirring at room temperature for 0.5h, filtering the precipitated solid, washing the filter cake with 100mL of ethyl acetate for 2 times, and drying under reduced pressure to obtain the compound 3 with the yield of 87%. Characterization of the Structure by 1 HNMR ,1H NMR(500MHz,CDCl3)δ:7.81(dd,J＝15.5,14.6Hz,1H),7.69-7.52(m,5H),7.49-7.32(m,2H),6.87(s,1H),3.71(s,3H).
Example 2: synthesis of Compound 4
50Mmol of compound 3 and 150mL of 2M NaOH solution are added into a reaction bottle, after stirring and mixing uniformly, the temperature of a reaction system is raised to 40 ℃, the reaction system is kept at a temperature and stirred for reaction, after TLC (developing agent: DCM: meOH=6:1) monitors that the reaction is complete, 100mL of ethanol is added, stirring is carried out for 10min, after cooling to room temperature, 6M hydrochloric acid is used for regulating the pH to 3-4, stirring is carried out for 30min, the precipitated solid is filtered by suction, and compound 4 is obtained after drying, and the yield is 93%. The structure was characterized by 1 H NMR ,1H NMR(500MHz,CDCl3)δ:7.82(t,J＝7.5Hz,1H),7.58(d,J＝5.0Hz,5H),7.54-7.30(m,2H),6.93(s,1H).
Example 3: synthesis of Compound 5
50Mmol of Compound 4, 40mL of pyridine, and 25mL of acetic anhydride were added to the reaction flask, and stirred and mixed well. The temperature of the system is raised to 75-80 ℃, the reaction is stirred for 5 hours at the temperature, heating is stopped, the solvent is distilled off under reduced pressure, 60mL of dimethylbenzene is added three times, the distillation under reduced pressure is carried out until the mixture is dry, saturated sodium bicarbonate solution is added into the residue, the pH is regulated to 6-7, the mixture is extracted for 2 times by 150mL of ethyl acetate, the organic layers are combined, anhydrous Na 2SO4 is dried, the solvent is distilled off under reduced pressure, and the yield of the compound 5 is 79%. The structure was characterized by 1 H NMR ,1H NMR(500MHz,CDCl3)δ:7.84(t,J＝7.5Hz,1H),7.73-7.56(m,5H),7.49-7.32(m,2H),6.96(s,1H),2.23(s,3H).
Example 4: synthesis of Compound 6
Under the protection of N 2, sequentially adding 50mmol of compound 5, 50mmol of (S) -tert-butyl sulfonamide and 50mL of THF into a reaction bottle, stirring and mixing uniformly, then dripping 75mmol of B (OCH 2CF3)3), heating the reaction system to 60 ℃ after dripping, keeping the temperature and stirring for reacting for 12 hours, stopping the reaction, adding 100mL of ethyl acetate, respectively washing with 30mL of saturated sodium bicarbonate solution and 30mL of water, separating an organic layer, extracting a water layer with 100mL of ethyl acetate for 2 times, combining the organic layers, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain a crude solid, adding 50mL of methyl tert-butyl ether into the crude solid, stirring uniformly, then adding 200mL of petroleum ether for pulping, adding 50mL of mixed solution of THF/H 2 O (98:2) to the obtained solid, cooling to-10-0 ℃, adding 150mmol of NaBH 4 three times under stirring, slowly heating to room temperature after the addition, and stirring for 3H under heat preservation, distilling off the solvent under reduced pressure, adding 100mL of dichloromethane to the residue, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, adding 50mL of petroleum ether to the residue, heating to reflux, stopping heating, cooling to room temperature, filtering the precipitated solid, and drying to obtain the compound 6 with the yield of 60%, ee value of 96.7%, wherein the structure of the compound is confirmed by MS and 1 H NMR .ESI-LRMS m/z:419.2[M+H]+,1H NMR(500MHz,CDCl3)δ:7.75-7.52(m,4H),7.51-7.40(m,2H),7.39-7.26(m,2H),6.34(d,J＝2.0Hz,1H),5.64(s,1H),5.35(dd,J＝12.1,2.0Hz,1H),1.46(s,9H),1.25(d,J＝12.2Hz,3H).
Example 5: synthesis of Compound 6
Under the protection of N 2, 50mmol of compound 5, 65mmol of (S) -tert-butyl sulfonamide and 50mL of THF are sequentially added into a reaction bottle, after stirring and mixing uniformly, 100mmol of B (OCH 2CF3)3) is added dropwise, the temperature of the reaction system is raised to 60 ℃ after the dripping is finished, and the reaction is carried out for 12 hours under heat preservation and stirring.
Example 6: synthesis of Compound 6
Under the protection of N 2, 50mmol of compound 5, 75mmol of (S) -tert-butyl sulfonamide and 50mL of THF are sequentially added into a reaction bottle, after stirring and mixing uniformly, 150mmol of B (OCH 2CF3)3) is added dropwise, the temperature of a reaction system is raised to 60 ℃ after the dripping is finished, and the reaction is carried out for 12 hours under heat preservation and stirring.
Based on the reaction conditions of example 6 (namely, the mol ratio of the compound 5, (S) -tert-butyl sulfonamide to the B (OCH 2CF3)3 is 1:1.5:3.0), the reducing agent NaBH 4 in the reaction can be replaced by LiBH 4,KBH4,Me4NBH4,BH3.THF,LiAlH4 and the like, the temperature of the addition dehydration reaction can be adjusted between 40 ℃ and 80 ℃, other reaction conditions are unchanged, and partial experimental results are shown in Table 1.
Table 1: examples 7 to 13 conditions and results for the preparation of Compound 6
Example 14: synthesis of Compound 7
Under the protection of N 2, adding 50mmol of compound 6 prepared in example 6 and 100mL of THF into a reaction bottle, stirring and mixing uniformly, then adding 100mmol of aluminum trichloride, stirring and mixing uniformly, heating a reaction system to 40 ℃, keeping the temperature and stirring for 3 hours, stopping heating, pouring the reaction mixture into 150mL of ice water under stirring, extracting with 200mL of ethyl acetate for 3 times, combining organic layers, adding ammonia water, adjusting the pH to 8-9, separating out an organic phase, extracting the aqueous phase with 100mL of ethyl acetate for two times, combining the organic layers, drying, steaming under reduced pressure to remove a solvent to obtain a crude solid, adding 50mL of isopropanol into the crude solid, stirring, then adding 200mL of petroleum ether for pulping, filtering the separated solid, and drying to obtain the compound 7 with the yield of 90% and the ee value of 99.2%. The structure was confirmed by MS and 1 H NMR .ESI-LRMS m/z:299.2[M+H]+,1H NMR(500MHz,CDCl3)δ:7.77-7.54(m,4H),7.51-7.39(m,2H),7.32～7.19(m,2H),6.59(d,J＝2.0Hz,1H),4.73(q,J＝12.3,1H),1.98(s,1H),1.65(s,1H),1.27(d,J＝12.2Hz,3H).
Example 15: du Weili Synthesis of Sibutus
60Mmol of Compound 7, 50mmol of hypoxanthine, 150mmol DTBP,2.5mmol Cu (acac) 2 and 300mL of DMF were sequentially added to a reaction flask, and the temperature of the reaction system was raised to 110℃and stirred for reaction for 12h with heat preservation. Stopping the reaction, cooling the reaction liquid to room temperature, adding saturated sodium carbonate solution to adjust the pH to about 8, extracting with 200mL of ethyl acetate for3 times, merging organic phases, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, adding 50mL of ethyl acetate and 200mL of petroleum ether into the residue, stirring at room temperature for 0.5h, filtering the precipitated solid, and drying to obtain Du Weili Xie cloth with the yield of 89% and the purity of 99.2%. Characterization of the Structure by MS and 1 H NMR ,ESI-LRMS m/z:417.2[M+H]+,1H NMR(500MHz,CDCl3)δ:9.30(s,1H),8.24(s,1H),7.83(s,1H),7.68-7.51(m,4H),7.49-7.38(m,2H),7.33-7.21(m,2H),6.46(s,1H),5.65(q,J＝3.9Hz,1H),3.84(s,1H),1.38(d,J＝3.9Hz,3H).
Example 16: du Weili Synthesis of Sibutus
60Mmol of Compound 7, 50mmol of hypoxanthine, 75mmol DTBP,1.5mmol Cu (acac) 2 and 300mL of DMF were added sequentially to the reaction flask, the temperature of the reaction system was raised to 110℃and the reaction was allowed to stand with stirring for 12h. Working up was carried out in the same manner as in example 15, with a yield of 68% and a purity of 97.7%.
Example 17: du Weili Synthesis of Sibutus
60Mmol of Compound 7, 50mmol of hypoxanthine, 150mmol DTBP,4.0mmol Cu (acac) 2 and 300mL of DMF were added sequentially to the reaction flask, the temperature of the reaction system was raised to 110℃and the reaction was allowed to stand with stirring for 12h. The working-up procedure was as in example 15, with a yield of 90% and a purity of 99%.
Example 18: du Weili Synthesis of Sibutus
60Mmol of Compound 7, 50mmol of hypoxanthine, 100mmol DTBP,2.5mmol Cu (acac) 2 and 300mL of DMF were added sequentially to the reaction flask, the temperature of the reaction system was raised to 110℃and the reaction was allowed to stand with stirring for 12h. Working up was carried out in the same manner as in example 15, with a yield of 81% and a purity of 98.9%.
Based on the reaction conditions of example 15 (i.e., the molar ratio of hypoxanthine, compound 7, oxidant and catalyst is 1:1.2:3:0.05), the oxidant DTBP in the reaction can be replaced by TBHP, CHP, m-CPBA, BPO; the temperature of the reaction system can be adjusted between 60 ℃ and 120 ℃; the catalyst Cu (acac) 2 in the reaction can be replaced by CuCl 2、CuBr2、CuI2、Cu(OAc)2, the other reaction conditions are unchanged, and some experimental results are shown in Table 2.
Table 2: examples 19-30 conditions and results for preparing Du Weili Sibs
The foregoing examples merely illustrate embodiments of the invention and are described in more detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.

Claims (5)

1. A Du Weili Sibub synthesis method is characterized in that: the specific preparation route is as follows:
The method comprises the following specific steps:
Step (1): the compound 2 and dimethyl oxalate firstly undergo condensation reaction and then undergo ring closure reaction to obtain a compound 3;
Step (2): carrying out ester hydrolysis reaction on the compound 3 to obtain a compound 4;
Step (3): the compound 4 and acetic anhydride undergo condensation reaction under the action of pyridine to obtain a compound 5;
step (4): the compound 5 and (S) -tert-butyl sulfonamide undergo an addition dehydration reaction under the action of B (OCH 2CF3)3) and then undergo a reduction reaction with a reducing agent to obtain a compound 6;
the reducing agent is selected from LiBH 4、NaBH4、KBH4、Me4NBH4、BH3, THF or LiAlH 4;
step (5): carrying out hydrolysis reaction on the compound 6 to obtain a compound 7;
Step (6): the compound 7 and hypoxanthine undergo an amine alkylation reaction under the action of a catalyst, an oxidant and DMF to obtain Du Weili sibutre;
The catalyst is selected from CuCl 2、CuBr2、CuI2、Cu(OAc)2 or Cu (acac) 2; the oxidant is TBHP, DTBP, CHP, m-CPBA or BPO.
2. A method of synthesizing Du Weili a siberian according to claim 1, wherein: in the step (4), the temperature of the addition dehydration reaction is 40-80 ℃.
3. A method of synthesizing Du Weili a siberian according to claim 1, wherein: in the step (4), the ratio of the compound 5 to the amount of the (S) -tert-butyl sulfonamide and the amount of the B (OCH 2CF3)3 substance) is 1.0:1.0-1.5:1.5-3.0.
4. A method of synthesizing Du Weili a siberian according to claim 1, wherein: the reaction temperature in the step (6) is 60-120 ℃.
5. A method of synthesizing Du Weili a siberian according to claim 1, wherein: in step (6), the ratio of the amount of hypoxanthine to the amount of compound 7, the amount of the oxidizing agent, and the amount of the catalyst substance is: 1.0:1.2:1.5-3:0.03-0.08.
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CN103648499A (en) * 2011-01-10 2014-03-19 无限药品股份有限公司 Processes for preparing isoquinolinones and solid forms of isoquinolinones
CN108699061A (en) * 2015-11-16 2018-10-23 纽弗姆制药有限公司 For treating hematologic malignancies, inflammation and the deuterated compound of autoimmune disease

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