阅读说明：本技术 奥拉帕利杂质中间体、奥拉帕利杂质及其制备方法 (Olapari impurity intermediate, Olapari impurity and preparation method thereof ) 是由 周步高 张明雨 惠舰 宁武松 徐光辉 于 2020-12-23 设计创作，主要内容包括：本发明公开了奥拉帕利杂质中间体、奥拉帕利杂质及其制备方法,所述奥拉帕利杂质中间体分别具有式2、式3的结构,所述奥拉帕利杂质具有式I的结构,该杂质以3-氰基-4-氟苯甲醛为起始物料,经氨基化、缩合反应制备得到式2的奥拉帕利杂质中间体,然后经环合反应制备得到式3的杂质中间体,最后经重氮化-还原反应制备得到式I的奥拉帕利杂质,制备所得杂质纯度和得量稳定,可用于奥拉帕利中间体及原料药质量控制,通过对特定杂质定量,提升原料药质量。(The invention discloses an olaparide impurity intermediate, an olaparide impurity and a preparation method thereof, wherein the olaparide impurity intermediate has structures shown in formula 2 and formula 3 respectively, the olaparide impurity has a structure shown in formula I, the impurity takes 3-cyano-4-fluorobenzaldehyde as a starting material, the olaparide impurity intermediate shown in formula 2 is prepared through amination and condensation reactions, then the impurity intermediate shown in formula 3 is prepared through cyclization reactions, and finally the olaparide impurity shown in formula I is prepared through diazotization-reduction reactions.)

1. An olaparide impurity intermediate, characterized in that the impurity intermediate has the following structure:

2. an olaparide impurity intermediate, characterized in that the impurity intermediate has the following structure:

3. an olaparide impurity having the structure of formula I:

4. a method for preparing the olapari impurity of claim 3, characterized in that it comprises the following steps:

the 3-cyano-4-fluorobenzaldehyde is subjected to amination, condensation, cyclization and diazotization-reduction reaction to prepare the olaparide impurity with the structure shown in the formula I.

5. The method for preparing olaparide impurity according to claim 4, characterized in that the reaction solvent of the amination is one or more of acetonitrile, tetrahydrofuran, toluene, DMF, DMSO; the amination reagent is ammonia gas or ammonia water; the reaction temperature is 80-150 ℃.

6. The method of claim 5, wherein the amination reagent of the amination reaction is ammonia water; the reaction temperature is 90-110 ℃.

7. The method of claim 4, wherein the condensation reaction is carried out with a reaction catalyst selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate; the reaction solvent is one or two of acetonitrile and water; the reaction temperature is 20-40 ℃.

8. The method of claim 7, wherein the condensation reaction is carried out using sodium bicarbonate or potassium bicarbonate as a reaction catalyst.

9. The method for preparing olaparide impurity according to claim 4, wherein the reaction solvent of the cyclization reaction is one or more of water, N-dimethylformamide, and tetrahydrofuran; the catalyst is sodium hydroxide or potassium hydroxide; the adding temperature of the catalyst is 60-70 ℃, and the reaction temperature is 90-110 ℃.

10. The process for the preparation of olapari impurities according to claim 4, characterized in that the diazotizing agent of the diazotization-reduction reaction is a nitrite; the reaction temperature is-20 to-10 ℃.

Technical Field

The invention relates to an olaparib impurity intermediate, an olaparib impurity and a preparation method thereof, in particular to an olaparib impurity intermediate, an olaparib impurity and a preparation method thereof, which can accurately control the content of specific impurities and improve the quality of raw material medicines.

Background

Olaparide is an inhibitor of poly (adenosine diphosphate ribose) polymerase (PARP), a DNA repair enzyme that plays a key role in the DNA repair pathway, and PARPi can produce anti-tumor activity through synthetic lethal effects.

Olaparide is approved for marketing in europe and the united states at 16 days 12/2014 and 19 days 12/2014, respectively, is the first worldwide marketed PARPi, and approved indications are recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer that is fully or partially responsive to platinum-based chemotherapy; advanced ovarian cancer associated with mutations in BRCA (gBRCAm) that are harmful or suspected to be harmful that have been treated with three or more chemotherapeutics; treating metastatic breast cancer patients who have been treated with harmful or suspected harmful mutations in BRCA (gBRCAm), HER 2-negative chemotherapy.

Currently, the general synthetic route of olaparide is as follows:

in the olaparide raw material medicine prepared by the method, a plurality of unknown process impurities generated by the preparation process often exist, so that the difficulty of controlling the quality of the olaparide intermediate and the raw material medicine is improved.

Disclosure of Invention

The purpose of the invention is as follows: the first purpose of the invention is to provide an olaparide impurity intermediate, the second purpose is to provide an olaparide impurity, and the third purpose is to provide a preparation method of the olaparide impurity.

The technical scheme is as follows: the intermediate of the impurities of the olaparide has the following structure:

another olaparide impurity intermediate prepared from the above olaparide impurity intermediate has the following structure:

the olaparide impurity prepared from the above impurity intermediate has the structure of formula I:

in a conventional preparation method of olaparide, the applicant finds that fluorine atom groups in structures of a compound 4 and a compound 5 can perform nucleophilic substitution reaction with hydrazine hydrate to generate impurity intermediates, the impurity intermediates can form stable impurities in a formula I through subsequent reaction, and the impurities can participate in the subsequent reaction of olaparide synthesis to form more derivatization impurities, so that the purity of the olaparide bulk drug is influenced, and therefore, the content of the impurities needs to be monitored, and the quality of the olaparide bulk drug is ensured. The impurity of formula I is one of the main process impurities of olaparide, has low content and is not easy to separate in the synthesis process of olaparide, a large amount of high-purity impurities are difficult to obtain, and qualitative and quantitative detection on the impurities cannot be carried out.

The preparation method of the olapari impurity comprises the following steps:

the 3-cyano-4-fluorobenzaldehyde is subjected to amination, condensation, cyclization and diazotization-reduction reaction to prepare the olapari impurity with the structure shown in the formula I.

Firstly, dissolving 3-cyano-4-fluorobenzaldehyde, adding ammonia, heating to a certain temperature, and reacting to obtain a compound 1;

secondly, adding the compound 1, dimethyl (3-oxo-1, 3-dihydroisobenzofuran-1-yl) phosphate and a solvent into a reaction kettle, stirring, adding alkali at a certain temperature, and carrying out heat preservation reaction until the reaction end point (the HPLC content of the compound 1 is lower than 2%) to obtain a compound 2;

thirdly, adding the compound 2 and a solvent into a reaction kettle, stirring, heating to a certain temperature, adding alkali, and continuously heating to a certain temperature to react to obtain a compound 3;

fourthly, adding the compound 3 and hydrochloric acid into a reaction kettle, cooling to a certain temperature, adding nitrite, and reacting to obtain a compound I;

wherein, the reaction solvent of the amination reaction in the step (1) is one or more of acetonitrile, tetrahydrofuran, toluene, DMF and DMSO; the amination reagent is ammonia gas or ammonia water; the reaction temperature is 80-150 ℃.

Further preferably, the amination reagent for the amination reaction in the step (1) is ammonia water; the reaction temperature is 90-110 ℃.

The reaction catalyst of the condensation reaction in the step (2) is sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate; the reaction solvent is one or two of acetonitrile and water; the reaction temperature is 20-40 ℃.

Further preferably, the reaction catalyst for the condensation reaction in step (2) is sodium bicarbonate or potassium bicarbonate.

The reaction solvent of the cyclization reaction in the step (3) is one or more of water, N-dimethylformamide and tetrahydrofuran; the catalyst is sodium hydroxide or potassium hydroxide; the adding temperature of the catalyst is 60-70 ℃, and the reaction temperature is 90-100 ℃.

The diazotization reagent of the diazotization-reduction reaction in the step (4) is nitrite, preferably sodium nitrite or potassium nitrite; the reaction temperature is-20 to-10 ℃.

Has the advantages that: compared with the prior art, the invention has the following remarkable advantages:

(1) the impurities generated in the preparation process of the olaparide are subjected to structure confirmation, the impurities with purity (higher than 95%) and quantity (the batch yield of the impurities reaches gram level) meeting the detection requirements are prepared, the corresponding impurities in the olaparide intermediate and the bulk pharmaceutical chemicals can be accurately determined qualitatively and quantitatively, and the product quality is improved;

(2) the preparation method of the impurities is simple and convenient, and the purity and yield of the obtained impurities are stable.

Detailed Description

The technical solution of the present invention is further illustrated by the following examples.

Example 1

(1) Preparation of Compound 1

80.0g (0.54mol, 1eq) of 3-cyano-4-fluorobenzaldehyde, 1.2L of tetrahydrofuran and 416mL (6.11mol, 11.3eq) of ammonia water are added into a 5L autoclave, heated to 90 ℃, and stirred for reaction for 3-4 h. And (3) cooling, layering the reaction solution, removing a water layer, and concentrating the organic phase under reduced pressure until the organic phase is dry to obtain a yellow solid. The solid was washed 2 times with 500mL dichloromethane slurry and dried to give 65.3g of a yellow solid with 95% purity.¹H NMR(DMSO-D6,400MHz):δppm 9.64(s,1H),8.01(d,1H),7.78-7.75(dd,1H),7.16(s,2H),6.87(d,1H).m/z[M]⁺:146.12.

(2) Preparation of Compound 2

56.7g (0.23mol, 1.0eq) of dimethyl (3-oxo-1, 3-dihydroisobenzofuran-1-yl) phosphate, 132.5 g (0.22mol, 0.95eq) of the compound, 89.4g of acetonitrile and 113.35g of water were charged into a 1L four-necked flask. Stirring, heating to 20 deg.C, adding 9.0% sodium bicarbonate (0.281mol, 1.2eq) water solution dropwise for 40min, and keeping the temperature at 20 deg.C for reaction. And (2) carrying out suction filtration, leaching a filter cake with water to obtain a yellow solid, pulping the solid for 3h at 40-50 ℃ by using a mixed solution of 50g of acetonitrile and 300g of water, filtering, refining and pulping for 2h at 45 ℃ by using a mixed solution of 20g of sodium bisulfite and 400mL of water, filtering, and drying to obtain 38.5g of yellow solid.¹H NMR (DMSO-D6,400MHz) As Compound 2 has Z/E configuration, the ratio of the two configurations is about 2.63: 1 by HPLC, the total integration is about 12.5H equivalent to 10H, and is consistent with the structure of Compound 2, specifically, Δ ppm 8.02(d,1H),7.95(t,1H),7.86(t,1.23H),7.86-7.80(M,2.23H),7.66-7.58(M,2.08H),6.90(d,1.53H),6.90-6.86(M,1.53H),7.95(s,1H),6.54(s,1.90H),6.46(s,0.57H), M/Z [ M + H ], [ M + H ]]⁺:263.21.

(3) Preparation of Compound 3

Weighing 235 g (0.134mol, 1eq) of the compound, adding into a 1L four-mouth bottle, adding 250g of water, stirring, heating to 60-70 ℃, and starting dropwise adding an aqueous solution (7.48g of sodium hydroxide dissolved in 0.187mol, 1.4eq) of sodium hydroxide35mL of water), the dripping time is 15min, the temperature is continuously increased to 90-100 ℃, and the stirring is carried out for 25min under the condition of heat preservation. 14.95g of hydrazine hydrate (0.239mol, 1.4eq) is added dropwise for 10min, and after the addition is finished, the mixture is heated to 90-100 ℃ and stirred overnight. Cooling, adjusting pH to 4-5 with glacial acetic acid, separating out solid, filtering, leaching filter cake with water, pulping with 300mL ethanol, washing, filtering, washing filtrate with 200mL ethyl acetate for 2 times, adjusting acidity of water phase, and filtering. The filter cake was slurried with 250mL of ethanol, washed, filtered and dried to give 29.6g of a pale yellow solid.¹H NMR(DMSO-D6,400MHz):δppm12.54(s,1H),8.26(brs,2H),7.94-7.63(m,3H),7.63(d,1H),7.20(d,1H),6.68(d,1H),4.13(s,1H).m/z[M+H]⁺:296.2.

(4) Preparation of Compound I

310.0 g (33.9mmol, 1eq) of compound is weighed and added into a 500mL four-mouth bottle, 150mL of 2N hydrochloric acid is added, the mixture is stirred, the temperature is reduced to-10 ℃, 2.83g of sodium nitrite (40.6mmol, 1.2eq) aqueous solution is added dropwise, and the reaction is kept for 1h after the dropwise addition. After the reaction was complete, stannous chloride (101.6mmol, 3eq) in hydrochloric acid (19.3g stannous chloride dissolved in 50mL water and 5mL 2N hydrochloric acid) was started dropwise. And keeping the temperature for reaction for 2 hours. Filtering, pulping the filter cake with 200mL of 1N hydrochloric acid at-5 ℃ for 1h, filtering, pulping the filter cake with 150mL of 15% hydrochloric acid ethanol solution for 3-4 times, filtering, leaching with a small amount of ethanol, and drying by air blow at 45 ℃ overnight to obtain 8.7g of a light yellow solid product I with the HPLC purity of 96.8%.¹H NMR(DMSO-D6,400MHz):δppm 12.59(s,1H),10.49-10.29(brs,2H),8.98(s,1H),8.26(dd,1H),7.98(d,1H),7.91-7.80(m,3H),7,57(dd,1H),7.13(d,1H),4.24(t,2H),3.62-3.41(m,2H).m/z[M-HCl+H]⁺:311.24,m/z[M-HCl-H]^-:309.24.

Example 2

(1) Preparation of Compound 1

80.0g (0.54mol, 1eq) of 3-cyano-4-fluorobenzaldehyde, 1.2L of acetonitrile and 416mL (6.11mol, 11.3eq) of ammonia water are added into a 5L autoclave, heated to 110 ℃, and stirred for reaction for 3-4 h. And (3) cooling, layering the reaction solution, removing a water layer, and concentrating the organic phase under reduced pressure until the organic phase is dry to obtain a yellow solid. The solid was washed 2 times with 500mL dichloromethane slurry and dried to give 65.5g of a yellow solid with 95% purity.

(2) Preparation of Compound 2

56.7g (0.23mol, 1.0eq), 132.5 g (0.22mol, 0.95eq), and 150g of acetonitrile were charged to a 1L four-necked flask. Stirring, heating to 40 deg.C, adding 9.0% potassium bicarbonate (0.281mol, 1.2eq) water solution dropwise for 40min, and keeping the temperature at 40 deg.C for reaction. And (2) carrying out suction filtration, leaching a filter cake with water to obtain a yellow solid, pulping the solid for 3h at 40-50 ℃ by using a mixed solution of 50g of acetonitrile and 300g of water, filtering, refining and pulping for 2h at 45 ℃ by using a mixed solution of 20g of sodium bisulfite and 400mL of water, filtering, and drying to obtain 38.2g of yellow solid.

(3) Preparation of Compound 3

Weighing 235 g (0.134mol, 1eq) of the compound, adding the compound into a 1L four-mouth bottle, adding 250g of DMF, stirring, heating to 60-70 ℃, starting to dropwise add an aqueous solution (10.5g of potassium hydroxide is dissolved in 35mL of water) of potassium hydroxide (0.187mol, 1.4eq), adding for 15min, continuing to heat to 100-. 14.95g of hydrazine hydrate (0.239mol, 1.4eq) is added dropwise for 10min, and after the addition is finished, the mixture is heated to 100 ℃ and stirred at 110 ℃ overnight. Cooling, adjusting pH to 4-5 with glacial acetic acid, separating out solid, filtering, leaching filter cake with water, pulping with 300mL ethanol, washing, filtering, washing filtrate with 200mL ethyl acetate for 2 times, adjusting acidity of water phase, and filtering. The filter cake was slurried with 250mL of ethanol, washed, filtered and dried to give 29.5g of a pale yellow solid.

(4) Preparation of Compound I

310.0 g (33.9mmol, 1eq) of compound is weighed and added into a 500mL four-mouth bottle, 150mL of 2N hydrochloric acid is added, the mixture is stirred, the temperature is reduced to-20 ℃, 3.45g of potassium nitrite (40.6mmol, 1.2eq) aqueous solution is added dropwise, and the reaction is kept for 1.5h after the dropwise addition. After the reaction was complete, stannous chloride (101.6mmol, 3eq) in hydrochloric acid (19.3g stannous chloride dissolved in 50mL water and 5mL 2N hydrochloric acid) was started dropwise. And keeping the temperature for reaction for 2 hours. Filtering, pulping the filter cake with 200mL of 1N hydrochloric acid at-5 ℃ for 1h, filtering, pulping the filter cake with 150mL of 15% hydrochloric acid ethanol solution for 3-4 times, filtering, leaching with a small amount of ethanol, and drying by air blow at 45 ℃ overnight to obtain 8.8g of a light yellow solid product I with the HPLC purity of 96.8%.

Comparative example 1

(1) Preparation of Compound 1

80.0g (0.54mol, 1eq) of 3-cyano-4-fluorobenzaldehyde, 1.2L of acetonitrile, and 416mL (6.11mol, 11.3eq) of ammonia water were added to a 5L autoclave, and the mixture was heated to 50 ℃ and stirred for 10 hours. And (3) cooling, layering the reaction solution, removing a water layer, and concentrating the organic phase under reduced pressure until the organic phase is dry to obtain a yellow solid. The solid was washed 2 times with 500mL dichloromethane slurry and dried to give 36.8g of a yellow solid with an HPLC purity of about 80%.

(2) Preparation of Compound 2

56.7g (0.23mol, 1.0eq), 132.5 g (0.22mol, 0.95eq), and 150g of acetonitrile were charged to a 1L four-necked flask. Stirring, heating to 50 deg.C, adding 9.0% sodium hydroxide (0.281mol, 1.2eq) water solution dropwise for 40min, and keeping the temperature at 50 deg.C for reaction. And (3) carrying out suction filtration, leaching a filter cake with water to obtain a yellow solid, pulping the solid for 3h at 40-50 ℃ by using a mixed solution of 50g of acetonitrile and 300g of water, filtering, refining and pulping for 2h at 45 ℃ by using a mixed solution of 20g of sodium bisulfite and 400mL of water, filtering, and drying to obtain 30.3g of yellow solid with the HPLC purity of about 80%.

(3) Preparation of Compound 3

Weighing 235 g (0.134mol, 1eq) of the compound, adding into a 1L four-mouth bottle, adding 250g of DMF, stirring, heating to 60-70 ℃, starting to dropwise add aqueous solution of potassium hydroxide (0.187mol, 1.4eq) (10.5g of potassium hydroxide is dissolved in 35mL of water), adding for 15min, continuing to heat to 130 ℃, preserving heat and stirring for 25 min. 14.95g of hydrazine hydrate (0.239mol, 1.4eq) is added dropwise for 10min, and after the addition is finished, the mixture is heated to 150 ℃ and stirred overnight. Cooling, adjusting pH to 4-5 with glacial acetic acid, separating out solid, filtering, leaching filter cake with water, pulping with 300mL ethanol, washing, filtering, washing filtrate with 200mL ethyl acetate for 2 times, adjusting acidity of water phase, and filtering. The filter cake is beaten and washed by 250mL of ethanol, filtered and dried to obtain 25.4g of light yellow solid with the HPLC purity of about 85 percent.

(4) Preparation of Compound I

310.0 g (33.9mmol, 1eq) of the compound is weighed and added into a 500mL four-mouth bottle, 150mL of 2N hydrochloric acid is added, the mixture is stirred, the temperature is controlled to be 0-10 ℃, 3.45g of potassium nitrite (40.6mmol, 1.2eq) aqueous solution is started to be dripped, and the reaction is kept for 1.5h after the dripping is finished. After the reaction was complete, stannous chloride (101.6mmol, 3eq) in hydrochloric acid (19.3g stannous chloride dissolved in 50mL water and 5mL 2N hydrochloric acid) was started dropwise. And keeping the temperature for reaction for 2 hours. Filtering, pulping the filter cake with 200mL of 1N hydrochloric acid at-5 ℃ for 1h, filtering, pulping the filter cake with 150mL of 15% hydrochloric acid ethanol solution for 3-4 times, filtering, leaching with a small amount of ethanol, and drying by air blow at 45 ℃ overnight to obtain 6.8g of a light yellow solid product I with the HPLC purity of 90%.