CN114644604A - Olapari impurity and preparation process thereof - Google Patents
Olapari impurity and preparation process thereof Download PDFInfo
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- CN114644604A CN114644604A CN202011510081.1A CN202011510081A CN114644604A CN 114644604 A CN114644604 A CN 114644604A CN 202011510081 A CN202011510081 A CN 202011510081A CN 114644604 A CN114644604 A CN 114644604A
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- 239000012535 impurity Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- WCNBTJKIKZOKHO-UHFFFAOYSA-N C(=O)N1CCNCC1.C1CC1 Chemical compound C(=O)N1CCNCC1.C1CC1 WCNBTJKIKZOKHO-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 239000007821 HATU Substances 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 5
- 238000007112 amidation reaction Methods 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- KIALFUYSJAAJSU-UHFFFAOYSA-N cyclopropyl(piperazin-1-yl)methanone Chemical compound C1CNCCN1C(=O)C1CC1 KIALFUYSJAAJSU-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JMHGATOBRPWPBZ-UHFFFAOYSA-N 3-cyano-4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(C#N)=C1 JMHGATOBRPWPBZ-UHFFFAOYSA-N 0.000 description 1
- LTZZZXXIKHHTMO-UHFFFAOYSA-N 4-[[4-fluoro-3-[4-(4-fluorobenzoyl)piperazine-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one Chemical compound FC1=C(C=C(CC2=NNC(C3=CC=CC=C23)=O)C=C1)C(=O)N1CCN(CC1)C(C1=CC=C(C=C1)F)=O LTZZZXXIKHHTMO-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 201000001342 Fallopian tube cancer Diseases 0.000 description 1
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 1
- -1 Hexafluorophosphate Chemical compound 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000026149 Primary peritoneal carcinoma Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- 230000002083 iodinating effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
Abstract
The invention discloses an olaparide impurity and a preparation process thereof, wherein the compound has a structure shown in a formula I, and is obtained by taking a compound II as a raw material and performing hydrolysis and amidation reactions.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an olapari impurity and a preparation process thereof.
Background
Olaparide is a poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor and has anti-tumor activity. 12 months 2014, oralapari is approved to be listed in europe and the united states in sequence, is the first PARPi to be listed on the world, and has indications of recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer which completely or partially respond to platinum 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 for olapari is as follows:
the olaparide bulk drug obtained through the synthetic route has various unknown impurities brought by the process, and the impurities are difficult to separate due to low content, so that a lot of troubles are brought to the purity analysis of the olaparide bulk drug.
Disclosure of Invention
The purpose of the invention is as follows: the first purpose of the invention is to provide an impurities of olapari, and the second purpose is to provide a preparation process of the impurities.
The technical scheme is as follows: the impurities of the invention have the following structure:
the preparation process of the olapari impurity has the following reaction route:
4-fluoro-3-cyanobenzoic acid (compound II) is used as a raw material, and the compound I is obtained through hydrolysis and amidation reactions.
Dissolving a compound II in water, adding alkali and a catalyst, heating to a certain temperature, and reacting to obtain a compound III.
And secondly, adding the compound III into a solvent, sequentially adding alkali and a condensing agent, and adding cyclopropane formyl piperazine to react to obtain the compound III.
Wherein, the alkali used in the first-step hydrolysis reaction is inorganic strong alkali, preferably sodium hydroxide or potassium hydroxide, and the feeding molar ratio of the alkali to the compound II is 2-2.5: 1. the catalyst is potassium iodide, sodium iodide or cuprous iodide, and the mass ratio of the catalyst to the compound II is (0.01-0.5): 1. the reaction temperature is 90-100 ℃.
The solvent for the second amidation reaction is acetonitrile, toluene or tetrahydrofuran. The base is triethylamine, pyridine or N, N-diisopropylethylamine, and the feeding molar ratio of the base to the compound III is 1.2-1.5: 1. the reaction temperature is 30-40 ℃. The condensing agent is O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU) or 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), and the feeding molar ratio of the condensing agent to the compound III is 1-1.05: 1. the feeding molar ratio of the cyclopropane formyl piperazine to the compound III is 2-2.5: 1.
the technical effects are as follows: compared with the prior art, the invention has the following remarkable effects:
(1) the impurities generated in the preparation process of the olaparide are subjected to structural confirmation, impurity standard samples with purity (more than 95%) and quantity (the batch yield reaches more than gram level) meeting the detection requirements are prepared, and corresponding impurities in the olaparide bulk drug can be accurately qualitatively and quantitatively analyzed;
(2) in the impurity preparation process, the cyano hydrolysis reaction is carried out under the catalysis of an iodinating reagent, so that the yield and the purity of the product are greatly improved (the purity is improved from 84.2 percent to 97.48 percent).
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
(1) Process for the preparation of compound III
A500 mL four-necked flask was charged with 20g of Compound II, 100mL of water, 9.68g of sodium hydroxide, and 10g of potassium iodide. Stirring is started, the temperature is increased to 90 ℃, after 1 hour of reaction, TLC monitoring is carried out until the raw material point disappears, the temperature is reduced to 20-30 ℃, hydrochloric acid is used for adjusting the pH value to 2-3, stirring is continued, white solid is separated out from the system, and filtering is carried out, so that 21.4g of compound III with the purity of 97.48% is obtained.1HNMR（DMSO-D6，400MHz）：δppm11.19-11.15(br, 2H)，8.37-8.35(dd, 1H)，8.06-8.03 (m,1H)，7.33-7.28 (dd, 1H)。m/z[M-CO2H]-：139.07。
(2) Process for the preparation of compounds I
Into a 100mL four-necked flask were added in this order compound III5.5g, acetonitrile 110mL, HBTU11.33g, and triethylamine 3.6 g. Starting stirring, heating to 30 ℃, adding 11.51g of cyclopropane formyl piperazine in batches, and adding the mixture to the systemAnd (3) stirring the mixture to react for 2-3 h, and monitoring the disappearance of the raw material point by TLC after 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure until no fraction was present, washed twice with 100mL of dichloromethane, then twice with 100mL of saturated aqueous sodium bicarbonate solution, the organic phase was concentrated, and purified by column chromatography to give 12g of a tan oil with a purity of 95.96%.1HNMR（DMSO-D6，400MHz）:δppm7.61-7.58 (m, 1H)，7.54-7.53(d, 1H)，7.44-7.40 (t,1H)，3.71-3. 48 (m,16H)，2.10-1.85（m, 2H），0.77-0.72（s, 8H）。m/z[M +H]+：457.39m/z。
Example 2
In a 500mL four-necked flask, 20g of Compound II, 100mL of water, 16.94g (2.5 eq) of potassium hydroxide and 0.2g of cuprous iodide were placed, stirred, heated to 100 ℃ and reacted for 1 hour, followed by TLC until the starting material spot disappeared. And cooling to 20-30 ℃, adjusting the pH to 2-3 by using hydrochloric acid, continuously stirring, separating out a white solid from the system, and filtering to obtain 22g of a compound III. 22g of the compound III obtained, 400mL of toluene, 47.91g of HATU and 14.2g of pyridine are added into another reaction kettle, the stirring is started, the temperature is increased to 40 ℃, 9.2g of cyclopropylformylpiperazine is added in portions, the system is in a brown turbid state after the addition is finished, the reaction is stirred for 2h, and the disappearance of the raw material point is monitored by TLC after 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure until no fraction was present, washed twice with 200mL of dichloromethane, then washed twice with 200mL of saturated aqueous sodium bicarbonate solution, the aqueous phase was discarded, the organic phase was concentrated, and purified by column chromatography to obtain 49g of a brown-yellow oily substance with a purity of 96.6%.
Example 3
A500 mL four-necked flask was charged with 20g (0.121 mol, 1.0 eq) of Compound II, 100mL of water, 16.94g (2.5 eq) of potassium hydroxide, and 5g of sodium iodide. Stirring was started, the temperature was raised to 94 ℃ and after 1h of reaction, TLC was monitored until the starting material spot disappeared. And (3) cooling to 20-30 ℃, adjusting the pH to 2-3 by using hydrochloric acid, continuing stirring, separating out a white solid from the system, and filtering to obtain 21.5g of a compound III. Adding 21.5g of the obtained compound III, 400mL of tetrahydrofuran, 45.96g of HBTU and 20g N, N-diisopropylethylamine into another reaction kettle, starting stirring, heating to 36 ℃, adding 10.6g of cyclopropylformyl piperazine in batches, stirring for reacting for 2h, and finishing the reaction, wherein the system is in a brown turbid state after the addition is finished. The reaction solution was concentrated under reduced pressure until no fraction was present, washed twice with 200mL of dichloromethane, then twice with 200mL of saturated aqueous sodium bicarbonate solution, the aqueous phase was discarded, the organic phase was concentrated and purified by column chromatography to give 48g of a tan oil with a purity of 96%.
Comparative example 1
A500 mL four-necked flask was charged with 20g of Compound II, 100mL of water, and 16.94g of potassium hydroxide. Stirring is started, the temperature is increased to 100 ℃, and after 5 hours of reaction, TLC monitors until the raw material point disappears. And (3) cooling to 20-30 ℃, adjusting the pH to 2-3 with hydrochloric acid, continuing stirring, separating out white solid from the system, and filtering to obtain 15g of a compound III with the purity of 84.2%.
The comparative experiment results are as follows: in the hydrolysis reaction, when no iodinating agent is added, the yield and the purity of the product are both greatly reduced.
Claims (9)
1. An olapari impurity, characterized by the following structure:
2. a process for the preparation of a compound according to claim 1, wherein the process comprises:
dissolving a compound II in water, adding alkali and a catalyst, heating to a certain temperature, and reacting to obtain a compound III; and secondly, adding the compound III into a solvent, sequentially adding alkali and a condensing agent, and adding cyclopropane formyl piperazine for reaction to obtain a compound I.
3. The process according to claim 2, wherein the alkali in the first step is sodium hydroxide or potassium hydroxide, and the molar ratio of the alkali to the compound II is 2-2.5: 1.
4. The process of claim 2, wherein the catalyst in the first step is sodium iodide, potassium iodide or cuprous iodide, and the mass ratio of the catalyst to the compound II is 0.01-0.5: 1.
5. the process according to claim 2, wherein the reaction temperature in the first step is 90 to 100 ℃.
6. The process of claim 2, wherein the solvent in the second step is acetonitrile, toluene or tetrahydrofuran.
7. The process according to claim 2, wherein the base in the second step is triethylamine, pyridine or N, N-diisopropylethylamine, and the molar ratio of the base to the compound III is 1.2-1.5: 1.
8. the process of claim 2, wherein the condensing agent in the second step is HBTU or HATU, and the molar ratio of the condensing agent to the compound III is 1-1.05: 1.
9. the process according to claim 2, wherein the reaction temperature in the second step is 30-40 ℃, and the molar ratio of the cyclopropane formyl piperazine to the compound III is 2-2.5: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011510081.1A CN114644604A (en) | 2020-12-19 | 2020-12-19 | Olapari impurity and preparation process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011510081.1A CN114644604A (en) | 2020-12-19 | 2020-12-19 | Olapari impurity and preparation process thereof |
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| Publication Number | Publication Date |
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| CN114644604A true CN114644604A (en) | 2022-06-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011510081.1A Pending CN114644604A (en) | 2020-12-19 | 2020-12-19 | Olapari impurity and preparation process thereof |
Country Status (1)
| Country | Link |
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| CN (1) | CN114644604A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107266370A (en) * | 2017-08-14 | 2017-10-20 | 山东裕欣药业有限公司 | A kind of process for purification of olaparib compound |
| CN111732547A (en) * | 2020-07-31 | 2020-10-02 | 北京鑫开元医药科技有限公司 | Refining method and application of olapari |
-
2020
- 2020-12-19 CN CN202011510081.1A patent/CN114644604A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107266370A (en) * | 2017-08-14 | 2017-10-20 | 山东裕欣药业有限公司 | A kind of process for purification of olaparib compound |
| CN111732547A (en) * | 2020-07-31 | 2020-10-02 | 北京鑫开元医药科技有限公司 | Refining method and application of olapari |
Non-Patent Citations (1)
| Title |
|---|
| 陆毅;余浩;黄璐;: "PARP抑制剂奥拉帕尼的专利分析", 中国新药杂志, no. 11, pages 1281 - 1286 * |
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