Olaparil intermediate impurity and preparation method thereof
By reacting compound II with the catalyst and the base in a specific molar ratio and reaction solvent under alkaline conditions, the olaparib intermediate impurity compound I was prepared, which solved the problem of lack of the synthesis of the impurity in the prior art, achieved high purity preparation, and improved the quality of the raw materials.
Patent Information
- Application Number
- CN202311590258.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-27
- Publication Date
- 2025-05-27
AI Technical Summary
There are no reports on the synthesis of olaparib intermediate impurity compound I in the prior art, and the lack of corresponding preparation methods makes it difficult to obtain high-purity reference products during the synthesis of olaparib, affecting the quality of the raw materials.
Olaparib intermediate impurity compound I was prepared by reacting compound II with a catalyst and a base in a specific molar ratio and a reaction solvent under basic conditions. The method includes stirring to form a reaction system, adding compound II dropwise and controlling the reaction temperature, and then purifying with liquid separation and column chromatography to obtain high purity compound I.
The efficient preparation of olaparib intermediate impurity compound I was achieved, with high conversion rate and a yield of 70%, and the purity of more than 98% was achieved through column chromatography, which solved the problem of quality control of raw materials.
Smart Images
Figure CN120040318A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of chemical synthesis, and in particular to an olaparib intermediate impurity and a preparation method thereof. Background Art
[0002] Olaparib is a poly(ADP-ribose) polymerase inhibitor (PARPi). Poly(ADP-ribose) polymerase is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARPi can produce anti-tumor activity through synthetic lethality.
[0003] Olaparib was approved for marketing in Europe and the United States on December 16, 2014 and December 19, 2014, respectively. It is the world's first PARPi to be marketed. The approved indications are recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer that has a complete or partial response to platinum-based chemotherapy; advanced ovarian cancer associated with deleterious or suspected deleterious BRCA mutations (gBRCAm) that have been treated with three or more chemotherapy regimens; and treatment of patients with deleterious or suspected deleterious BRCA mutations and HER2-negative metastatic breast cancer who have received chemotherapy.
[0004] Currently, the commonly used synthesis route of Olaparib is as follows:
[0005]
[0006] In the process of synthesizing compound V, compound IV and compound II undergo Wittig-Horner reaction under alkaline conditions, which will produce impurity compounds, and the impurities are difficult to remove in the process. Eventually, they will participate in the synthesis of Olaparib, thereby affecting the purity of the raw material Olaparib. It is necessary to monitor and detect the impurity compounds during the synthesis of Olaparib to control the quality of the raw material Olaparib. The impurity compounds are low in content and difficult to separate during the synthesis of Olaparib, and there is no report on the synthesis of impurity compound I in the prior art. It is difficult for people to obtain a large amount of high-purity compound I, and there is a lack of corresponding reference substances. It is difficult to qualitatively and quantitatively detect the impurity during the synthesis of Olaparib. Summary of the invention
[0007] The purpose of the present invention is to establish an olaparib intermediate impurity and a preparation method thereof, so as to solve the technical problems that there is no report on the synthesis of impurity compound I in the prior art, there is a lack of a preparation method for olaparib impurity compound I, and the content of impurity compound I is low during the synthesis of olaparib, and it is difficult to separate and obtain a high-purity reference compound I.
[0008] The present invention provides compound I:
[0009]
[0010] The preparation method of compound I comprises:
[0011]
[0012] In the step of preparing compound I from compound II, a base, a catalyst and a solvent are first stirred to form a reaction system, and then compound II dissolved in the solvent is added dropwise to the reaction system to react and obtain compound I.
[0013] In the step of preparing compound I from compound II, the catalyst is 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide or vitamin B1.
[0014] In the step of preparing compound I from compound II, the base is a strong base.
[0015] In the step of preparing compound I from compound II, the strong base is potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene or cesium carbonate.
[0016] In the step of preparing compound I from compound II, the molar ratio of compound II: catalyst: base is 1:0.1-0.7:0.8-1.
[0017] In the step of preparing compound I from compound II, the molar ratio of compound II: catalyst: base is 1:0.1:1.
[0018] In the step of preparing compound I from compound II, the reaction solvent is one or more of acetonitrile, tetrahydrofuran, methanol and ethanol.
[0019] In the step of preparing compound I from compound II, the reaction temperature ranges from -10 to 30°C.
[0020] In the step of preparing compound I from compound II, the reaction solvent is tetrahydrofuran; the base is 1,8-diazabicyclo[5.4.0]undec-7-ene; and the reaction temperature ranges from 0 to 10°C.
[0021] Beneficial effects of the present application: The present invention provides an olaparib intermediate impurity and a preparation method thereof. The raw materials of the present invention are cheap and easily available, the operation is simple, the reaction conditions are mild, the conversion rate of the obtained target product is high, and the yield can be as high as 70%. The purity can reach more than 98% by column chromatography purification. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] In order to more clearly illustrate the technical solution of the present application, the drawings required for use in the embodiments are briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.
[0023] Figure 1 For compound Ⅰ 1 HNMR spectrum. DETAILED DESCRIPTION
[0024] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.
[0025] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.
[0026] Herein, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible secondary ranges and individual values within the range (including integers and fractions).
[0027] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.
[0028] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.
[0029] The following examples use conventional instruments and equipment in the art. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions or under conditions recommended by the manufacturer. The various raw materials used in the following examples are conventional commercial products unless otherwise specified, and their specifications are conventional specifications in the art. In the specification of the present invention and the following examples, unless otherwise specified, "%" means weight percentage, "part" means weight part, and ratio means weight.
[0030] The following is a further description of an olaparib intermediate impurity and a preparation method thereof provided in the present application in conjunction with specific examples.
[0031] Example 1
[0032]
[0033] Preparation of compound Ⅰ:
[0034] Add tetrahydrofuran (15 mL, 3 v / m), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazole bromide (0.86 g, 0.0034 mol, 0.1 eq), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.2 g, 0.034 mol, 1.0 eq) to a four-necked flask (50 mL). Stir, cool to 0-10 ° C, stir for 1.0 h, prepare a solution of compound II (5.0 g, 0.034 mol, 1.0 eq) and tetrahydrofuran (10 mL), slowly drop it into the reaction system, drop it for 0.2 h, and keep it at 0-10 ° C for 1 h.
[0035] After the reaction of compound II was complete, water (15 mL, 3 v / m) and dichloromethane (30 mL, 6 v / m) were added to the system and stirred for 0.5 h. The liquids were separated and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and made into sand using 200-300 mesh silica gel (15 g). The mixture was subjected to column chromatography with an eluent ratio of petroleum ether: ethyl acetate of 10:1. The off-white solid compound I (6.7 g) was obtained after column chromatography with a yield of 70%. 1 HNMR (DMSO-D6, 400 MHz) Figure 1 As shown, specifically δppm 10.03 (s, 0.99H), 8.51 (d, 1.03H), 8.20-8.19 (t, 1.00H), 8.18-8.07 (m, 1.03H), 7.91-7.89 (q, 1.06H), 7.67-7.59 (m, 2.00H), 5.82 (s, 1.98H).
[0036] Example 2
[0037] Preparation of compound Ⅰ:
[0038] Add tetrahydrofuran (15 mL, 3 v / m), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazole bromide (6.02 g, 0.0238 mol, 0.7 eq), 1,8-diazabicyclo[5.4.0]undec-7-ene (4.16 g, 0.027 mol, 0.8 eq) to a four-necked flask (50 mL). Stir, cool to 0-10 ° C, stir for 1.0 h, prepare a solution of compound II (5.0 g, 0.034 mol, 1.0 eq) and tetrahydrofuran (10 mL), slowly drop it into the reaction system, drop it for 0.2 h, and keep it at 0-10 ° C for 1 h.
[0039] After the reaction of compound II was complete, water (15 mL, 3 v / m) and dichloromethane (30 mL, 6 v / m) were added to the system and stirred for 0.5 h. The liquids were separated and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and made into sand using 200-300 mesh silica gel (15 g). The mixture was subjected to column chromatography with an eluent ratio of petroleum ether: ethyl acetate of 10:1. The off-white solid compound I (6.0 g) was obtained after column chromatography with a yield of 63%.
[0040] Example 3
[0041] Preparation of compound Ⅰ:
[0042] Add tetrahydrofuran (15 mL, 3 v / m), vitamin B1 (7.14 g, 0.0238 mol, 0.7 eq), 1,8-diazabicyclo[5.4.0]undec-7-ene (4.16 g, 0.027 mol, 0.8 eq) to a four-necked flask (50 mL). Stir, cool to 0-10 °C, stir for 1.0 h, prepare a solution of compound II (5.0 g, 0.034 mol, 1.0 eq) and tetrahydrofuran (10 mL), slowly dropwise add to the reaction system, dropwise for 0.2 h, keep warm at 0-10 °C for 1 h.
[0043] After the reaction of compound II was complete, water (15 mL, 3 v / m) and dichloromethane (30 mL, 6 v / m) were added to the system and stirred for 0.5 h. The liquids were separated and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and made into sand using 200-300 mesh silica gel (15 g). The mixture was subjected to column chromatography with an eluent ratio of petroleum ether: ethyl acetate of 10:1. The off-white solid compound I (6.3 g) was obtained after column chromatography with a yield of 66%.
[0044] Although the present invention has been disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the definition of the claims.
Claims
1. Compound I structural formula:
2. A method for preparing the compound I according to claim 1, include:
3. The preparation method according to claim 2, Features: In the step of preparing compound I from compound II, a base, a catalyst and a solvent are first stirred to form a reaction system, and then compound II dissolved in the solvent is added dropwise to the reaction system to react and obtain compound I.
4. The preparation method according to claim 2, Features: In the step of preparing compound I from compound II, the catalyst is 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide or vitamin B1.
5. The preparation method according to claim 2, Features: In the step of preparing compound I from compound II, the base is a strong base.
6. The preparation method according to claim 4, Features: In the step of preparing compound I from compound II, the strong base is potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene or cesium carbonate.
7. The preparation method according to claim 2, Features: In the step of preparing compound I from compound II, the molar ratio of compound II: catalyst: base is 1:0.1-0.7:0.8-1.
8. The preparation method according to claim 2, Features: In the step of preparing compound I from compound II, the reaction solvent is one or more of acetonitrile, tetrahydrofuran, methanol and ethanol.
9. The preparation method according to claim 2, Features: In the step of preparing compound I from compound II, the reaction temperature ranges from -10 to 30°C.
10. The preparation method according to claim 2, Features: In the step of preparing compound I from compound II, the reaction solvent is tetrahydrofuran; the base is 1,8-diazabicyclo[5.4.0]undec-7-ene; and the reaction temperature ranges from 0 to 10°C.