CN112574122A - Preparation method of olaparib key intermediate - Google Patents
Preparation method of olaparib key intermediate Download PDFInfo
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- CN112574122A CN112574122A CN201910925768.2A CN201910925768A CN112574122A CN 112574122 A CN112574122 A CN 112574122A CN 201910925768 A CN201910925768 A CN 201910925768A CN 112574122 A CN112574122 A CN 112574122A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
Abstract
The invention provides an olaparib key intermediate formula (4- (3-bromo-4-fluorobenzyl) -naphthyridin-1 (2H) -ketone (a compound shown in the formula IV) and 5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl]A preparation method of (E) -2-fluorobenzoic acid (compound shown in the formula V). Specifically, taking (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphonate as a raw material to perform Wittig-Horner reaction with 3-bromo-4-fluorobenzaldehyde to obtain a formula III, cyclizing the formula III with hydrazine hydrate to obtain a formula IV, and reacting the formula IV with n-butyl lithium and carbon dioxide to obtain an Olaparib intermediate V. The method is economical and environment-friendly, and the yield is greatly improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of olaparib key intermediates (4- (3-bromo-4-fluorobenzyl) -naphthyridin-1 (2H) -one (a compound in a formula IV) and 5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoic acid (a compound in a formula V).
Background
Olaparib (olaparib), an adenosine polyphosphate ribopolymerase (PARP) inhibitor from AstraZeneca, usa, was approved by FDA in the united states at 12 months 2014 for the treatment of advanced ovarian cancer associated with BRCA gene deficiency. EMEA and FDA in turn grant orphan drug certification for olaparib in the treatment of ovarian cancer.
At present, the method for preparing the intermediate 5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoic acid mainly comprises the following steps: (CN 105085408A):
the method uses 2-fluoro-5-aldehyde benzoic acid, so that the industrial production cost is greatly increased.
Therefore, in the industrial production of olaparib, it is necessary to develop a synthetic route with low cost and high overall yield.
Disclosure of Invention
The present inventors have conducted extensive and intensive studies for a long time to develop a preparation method for synthesizing olaparib key intermediates (4- (3-bromo-4-fluorobenzyl) -naphthyridin-1 (2H) -one (a compound of formula iv) and 5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoic acid (a compound of formula V)) from 3-bromo-4-fluorobenzaldehyde as a raw material, which is low in cost and advantageous for industrial production.
In a first aspect of the invention, there is provided a process for the preparation of a compound of formula IV, said process comprising the steps of:
(ii) reacting the compound shown in the formula III with hydrazine hydrate in an inert solvent to obtain the compound shown in the formula IV.
In another preferred embodiment, in the step (ii), the inert solvent is selected from the group consisting of: tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, or combinations thereof.
In another preferred embodiment, the inert solvent is tetrahydrofuran.
In another preferred embodiment, in the step (ii), the molar ratio of hydrazine hydrate to the compound of formula iii is 1: 1.0-1: 2.0.
in another preferred embodiment, the molar ratio of hydrazine hydrate to compound of formula III is from 1:1.3 to 1: 1.5.
In another preferred example, the step (ii) further includes: acetic acid was used as a catalyst.
In another preferred embodiment, the molar ratio of acetic acid to the compound of formula III is from 0.25 to 1:1. In another preferred embodiment, the acetic acid in step (ii) is added after the hydrazine hydrate is added.
In another preferred embodiment, the reaction time in step (ii) is 5-10 h.
In another preferred embodiment, the method further comprises the steps of:
(i) reacting the compound shown in the formula I with the compound shown in the formula II in an inert solvent under the alkaline condition to obtain the compound shown in the formula III.
In another preferred embodiment, in the step (i), the inert solvent is selected from the group consisting of: methanol, ethanol, tetrahydrofuran, N-dimethylformamide, or a combination thereof.
In another preferred embodiment, in the step (i), the solvent is selected from the group consisting of: methanol, N-dimethylformamide, tetrahydrofuran, or a combination thereof.
In another preferred embodiment, in step (i), the base is selected from the group consisting of: sodium methoxide, sodium tert-butoxide, sodium hydride or triethylamine.
In another preferred embodiment, in step (i), the base is selected from the group consisting of: sodium methoxide, sodium hydride, triethylamine, or a combination thereof.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula V, said process comprising the steps of: (iii) preparation of the Compound of formula IV by step (ii) as described above in 7, and
(iii-1) reacting the compound of formula IV with an organolithium reagent or a Grignard reagent and carbon dioxide in an inert solvent to produce a compound of formula V; or
(iii-2) reacting the compound of formula IV with carbon monoxide in an inert solvent under the action of a catalyst to generate the compound of formula V.
In another preferred embodiment, in the step (iii-1), the carbon dioxide is gaseous or solid carbon dioxide.
In another preferred embodiment, in the step (iii-1): reacting the compound of formula IV with an organolithium reagent and carbon dioxide in an inert solvent to produce the compound of formula V.
In another preferred embodiment, the organolithium is n-butyllithium.
In another preferred embodiment, in the step (iii-1), the molar ratio of n-butyllithium to the compound of formula IV is 0.8-1.2: 1.
In another preferred example, in the step (iii-1), n-butyllithium is added to the solvent in which the compound of formula IV is dissolved.
In another preferred embodiment, in the step (iii-1), the reaction temperature of the compound of formula IV and the organolithium reagent is-40 to-20 ℃.
In another preferred embodiment, in the step (iii-1), the compound of formula IV reacts with an organic lithium reagent to generate an intermediate, and the reaction temperature of the intermediate and carbon dioxide is-40 ℃ to-20 ℃.
In another preferred embodiment, in the step (iii-1), the compound of formula iv reacts with an organolithium reagent to form an intermediate, the intermediate reacts with carbon dioxide, and an acid is added after the reaction is finished.
In another preferred example, in the step (iii-1), the acid added after the reaction is finished is hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid.
In another preferred embodiment, in the step (iii-1), the inert solvent is tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, or a combination thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention has long and intensive researches and provides a preparation method of key intermediates of olaparib, namely (4- (3-bromo-4-fluorobenzyl) -naphthyridin-1 (2H) -one (a compound shown in a formula IV) and 5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoic acid (a compound shown in a formula V), wherein the method has the advantages of low raw material cost and greatly improved total yield.
The synthetic route of the invention is as follows:
the synthesis steps of the compound of formula IV comprise:
(i) reacting a compound shown in a formula I with a compound shown in a formula II in an inert solvent under an alkaline condition to obtain a compound shown in a formula III;
(ii) reacting the compound shown in the formula III with hydrazine hydrate in an inert solvent to obtain the compound shown in the formula IV.
The synthesis method of the compound of the formula V comprises the synthesis of the compound of the formula IV and the following steps:
(iii-1) reacting the compound of formula IV with an organolithium reagent or a Grignard reagent and carbon dioxide in an inert solvent to produce a compound of formula V; or
(iii-2) reacting the compound of formula IV with carbon monoxide in an inert solvent under the action of a catalyst to generate the compound of formula V.
The solvent used in the synthesis step of the present invention may be a solvent commonly used in such reactions in the art, for example, in step (i), the inert solvent may be methanol, ethanol, tetrahydrofuran, N-dimethylformamide, or a combination thereof; in step (ii), the inert solvent may be tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, or a combination thereof; in step (iii-1), the inert solvent is tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, or a combination thereof.
The temperature in the synthesis step of the present invention may be a temperature commonly used in such reactions in the art, for example: in step (i), the temperature may be 20-30 ℃; in step (ii), the temperature may be 20-40 ℃; in the step (iii-1), the step (ii),
the reaction temperature of the compound shown in the formula IV and an organic lithium reagent is-40-20 ℃, the compound shown in the formula IV and the organic lithium reagent react to generate an intermediate, the reaction temperature of the intermediate and carbon dioxide is-40-20 ℃, the compound shown in the formula IV and the organic lithium reagent react to generate the intermediate, the intermediate and the carbon dioxide react, acid is required to be added after the reaction is finished, and the acid added after the reaction is hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.
In addition, in step (ii), an acetic acid catalyst is also required; acetic acid is added after the addition of hydrazine hydrate.
The reaction time in the synthesis step of the present invention can be detected by a conventional detection means until the reaction is completed.
In the synthesis step of the present invention, the reaction conditions in each step may be carried out according to the conditions in the reaction in the art except those specifically mentioned above.
The invention has the advantages that:
1. the raw material adopted in the invention is 3-bromo-4-fluorobenzaldehyde, which is easy to obtain and has low cost.
2. The total yield of the invention is greatly improved.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
EXAMPLE 1 preparation of Compound III
Dissolving a compound (150.0g, 0.62mol) of a formula I in THF (1200mL), adding a compound (113.7g, 0.56mol) of a formula II at 30 ℃ for about 1h, stirring to dissolve the solution, controlling the temperature to be 30 ℃, dropwise adding triethylamine (85.0g, 0.84mol), obviously releasing heat during dropwise adding, separating out a large amount of solid, controlling the temperature to be 30 ℃, and reacting for 5 h. The solvent was removed by concentration under reduced pressure, 95% ethanol (600ml) was added, and the mixture was slurried and stirred at 30 ℃ for 4 hours, followed by filtration to give compound III (171.8g, yield: 97%) as an off-white solid (relative to formula I). Ms (esi): m +1 + 320.20.
EXAMPLE 2 preparation of Compound III
Dissolving a compound (150.0g, 0.62mol) of a formula I in methanol (1500mL), adding a compound (113.7g, 0.56mol) of a formula II, stirring at 30 ℃ to dissolve the compound clearly, controlling the temperature to be 30 ℃, dropwise adding a methanol solution (130mL) of sodium methoxide (54.4g, 1.0mol), obviously releasing heat during dropwise adding, separating out a large amount of solids, and controlling the temperature to be 30 ℃ to react for 5 hours. The solvent was removed by concentration under reduced pressure, 95% ethanol (600ml) was added, slurried at 30 ℃ for 4 hours, filtered, blown at 50 ℃ and dried to obtain Compound III (151.8g, yield: 88.7%) as an off-white solid (referred to formula I). Ms (esi): m +1 + 320.20.
EXAMPLE 3 preparation of Compound IV
Adding a compound (100g, 0.31mol) of a formula III into tetrahydrofuran (500ml) to obtain a white turbid liquid, stirring, controlling the temperature to be 30 ℃, dropwise adding hydrazine hydrate (21g, 0.42mol), clarifying a reaction liquid after adding, keeping the temperature at 30 ℃ for reaction for 1h, dropwise adding acetic acid (9.3g, 0.16mol) into the reaction liquid, heating to reflux, and reacting for 7 h. The temperature was reduced to 15 ℃ and the mixture was filtered, rinsed with tetrahydrofuran and dried by blowing at 50 ℃ to obtain Compound IV (96.0g, yield: 92%) as a beige solid (relative to formula III). Ms (esi): m +1 + 334.16.
EXAMPLE 4 preparation of Compound IV
Adding a compound (100g, 0.31mol) of a formula III into tetrahydrofuran (500ml) to obtain a white turbid liquid, stirring, controlling the temperature to be 30 ℃, dropwise adding hydrazine hydrate (31.2g, 0.62mol), clarifying a reaction liquid after adding, keeping the temperature at 30 ℃, reacting for 1h, dropwise adding acetic acid (9.3g, 0.16mol) into the reaction liquid, heating to reflux, and reacting for 7 h. The temperature was reduced to 15 ℃ and the mixture was filtered, rinsed with tetrahydrofuran and dried by blowing at 50 ℃ to give compound IV (88.0g, yield: 78.7%) as a beige solid (referred to formula III). Ms (esi): m +1 + 334.16.
EXAMPLE 5 preparation of Compound IV
Adding a compound (100g, 0.31mol) of a formula III into tetrahydrofuran (500ml) to obtain a white turbid liquid, stirring, controlling the temperature to be 30 ℃, dropwise adding hydrazine hydrate (15.6g, 0.31mol), clarifying a reaction liquid after adding, keeping the temperature at 30 ℃, reacting for 1h, dropwise adding acetic acid (9.3g, 0.16mol) into the reaction liquid, heating to reflux, and reacting for 7 h. The temperature was reduced to 15 ℃ and the mixture was filtered, rinsed with tetrahydrofuran and dried by blowing at 50 ℃ to obtain Compound IV (82.0g, yield: 84.3%) as a beige solid (referred to formula III). Ms (esi): m +1 + 334.16.
EXAMPLE 6 preparation of Compound V
Adding a compound (100g, 0.30mol) of a formula IV into diethyl ether (1000ml), cooling ethanol dry ice to-40-38 ℃, dropwise adding 187.5ml of 1.6M n-butyllithium n-hexane solution (0.30mol), controlling the temperature, keeping the dropwise adding temperature not more than-30 ℃, keeping the temperature and stirring for 30min after dropwise adding, introducing CO at-30 ℃, adding2After bubbling reaction for 20min, cooling, slowly raising the temperature to about 20 ℃, dropwise adding the reaction solution into 1.2M dilute hydrochloric acid solution (1000ml), stirring for 30min, standing to separate out an organic layer, drying with anhydrous sodium sulfate, filtering, removing anhydrous sodium sulfate, distilling at 30 ℃ under reduced pressure to obtain a white solid, and drying by blowing at 50 ℃ to obtain a white solid compound V (85.0g, yield: 95.1%) (relative to formula IV) MS (ESI): [ M +1]]+＝299.27。
EXAMPLE 7 preparation of Compound V
Adding a compound (100g, 0.30mol) of a formula IV into diethyl ether (1000ml), cooling ethanol dry ice to-40-38 ℃, dropwise adding 243.7ml of 1.6M n-butyllithium n-hexane solution (0.39mol), controlling the temperature, keeping the dropwise adding temperature not more than-30 ℃, keeping the temperature and stirring for 30min after dropwise adding, introducing CO at-30 ℃, adding2After bubbling reaction for 20min, cooling, slowly raising the temperature to about 20 ℃, dropwise adding the reaction solution into 1.2M dilute hydrochloric acid solution (1000ml), stirring for 30min, standing to separate out an organic layer, drying with anhydrous sodium sulfate, filtering, removing anhydrous sodium sulfate, distilling at 30 ℃ under reduced pressure to obtain a white solid, and drying by blowing at 50 ℃ to obtain a white solid compound V (81.2g, yield: 90.7%) (relative to formula IV) MS (ESI): [ M +1]]+＝299.27。
EXAMPLE 8 preparation of Compound V
Adding a compound (100g, 0.30mol) shown in the formula IV into ethanol (600ml), adding into a high-pressure reaction kettle, adding bis (triphenylphosphine) palladium dichloride (8.0g), replacing air in the kettle with carbon monoxide, keeping the carbon monoxide introduced, keeping the air pressure in the kettle at 12atm, heating to 110 ℃, reacting for 6h, cooling to room temperature, filtering to remove a solid catalyst, and concentrating a filtrate under reduced pressure to obtain a solid compound V (63.6g, yield: 71.1%) (relative to formula IV) MS (ESI): m +1 + 299.27.
Comparative example 1 preparation of Compound IV
Adding a compound (100g, 0.31mol) of a formula III into tetrahydrofuran (500ml) to obtain a white turbid liquid, stirring, controlling the temperature to be 30 ℃, dropwise adding hydrazine hydrate (21g, 0.42mol), clarifying a reaction liquid after adding, keeping the temperature at 30 ℃, reacting for 1h, heating to reflux, reacting for 13h, wherein TLC still has a small amount of raw materials which are not completely reacted with an intermediate, and the time for prolonging is not obviously changed. The temperature was reduced to 15 ℃ and the mixture was filtered, rinsed with tetrahydrofuran and dried by blowing at 50 ℃ to give compound IV (73.0g, yield: 69.9%) as a beige solid (referred to formula III). Ms (esi): m +1 + 334.16.
Comparative example 2 preparation of Compound IV
Adding the compound of the formula III (100g, 0.31mol) into ethanol (500ml), stirring, controlling the temperature at 30 ℃, dropwise adding hydrazine hydrate (21g, 0.42mol), heating to reflux, and reacting for 8 h. The temperature was reduced to 20 ℃ and the solvent was distilled off, tetrahydrofuran (250ml) was added, and the mixture was stirred and slurried for 30min, filtered, rinsed with tetrahydrofuran, and dried by blowing at 50 ℃ to obtain Compound IV (81.3g, yield: 77.8%) as a beige solid (relative to formula III). Ms (esi): m +1 + 334.16.
Comparative example 3 preparation of Compound V
Adding a compound (100g, 0.30mol) of a formula IV into diethyl ether (1000ml), cooling ethanol dry ice to-40-38 ℃, dropwise adding 131.2ml of 1.6M n-butyllithium n-hexane solution (0.21mol), controlling the temperature, keeping the dropwise adding temperature not to exceed-30 ℃, keeping the temperature and stirring for 30min after dropwise adding, introducing CO at-30 ℃, and stirring2After bubbling reaction for 20min, cooling, slowly raising the temperature to about 20 ℃, dropwise adding the reaction solution into 1.2M dilute hydrochloric acid solution (1000ml), stirring for 30min, standing to separate out an organic layer, drying by anhydrous sodium sulfate, filtering, removing anhydrous sodium sulfate, distilling under reduced pressure at 30 ℃ to obtain a white solid, and drying by blowing at 50 ℃ to obtain a white solid compound V (74.2g, yield: 82.9%) (relative to formula IV) MS (ESI): [ M +1]]+＝299.27。
Comparative example 4 preparation of Compound V
Adding a compound (100g, 0.30mol) of a formula IV into diethyl ether (1000ml), cooling ethanol dry ice to-40-38 ℃, dropwise adding 187.5ml of 1.6M n-butyllithium n-hexane solution (0.30mol), controlling the temperature, keeping the dropwise adding temperature not more than-10 ℃, keeping the temperature and stirring for 30min after dropwise adding, introducing CO at-10 ℃, adding2Bubbling for 20min, cooling, slowly heating to about 20 deg.C, adding the reaction solution into 1.2M dilute hydrochloric acid solution (1000ml), stirring for 30min, standing to separate organic layer, drying with anhydrous sodium sulfate, filtering, removing anhydrous sodium sulfate, distilling at 30 deg.C under reduced pressure to obtain white solid, and air drying at 50 deg.CCompound V (52.7g, yield: 58.9%) was obtained as a white solid (relative to formula IV), MS (ESI): [ M +1]]+＝299.27。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for preparing a compound of formula IV, comprising the steps of:
(ii) reacting the compound shown in the formula III with hydrazine hydrate in an inert solvent to obtain the compound shown in the formula IV.
2. The process of claim 1, wherein in step (ii), the inert solvent is selected from the group consisting of: tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, or combinations thereof.
3. The process of claim 1, wherein the reaction is carried out in a molar ratio of hydrazine hydrate to the compound of formula iii of 1: 1.0-1: 2.0.
4. the method of claim 1, wherein step (ii) further comprises: acetic acid was used as a catalyst.
5. The method of claim 4, wherein the molar ratio of acetic acid to the compound of formula III is from 0.25 to 1:1.
6. The method of claim 1, wherein said method further comprises the steps of:
(i) reacting the compound shown in the formula I with the compound shown in the formula II in an inert solvent under the alkaline condition to obtain the compound shown in the formula III.
7. The process of claim 6, wherein in step (i), the inert solvent is selected from the group consisting of: methanol, ethanol, tetrahydrofuran, N-dimethylformamide, or a combination thereof.
8. The method of claim 6, wherein in step (i), the base is selected from the group consisting of: sodium methoxide, sodium tert-butoxide, sodium hydride or triethylamine.
9. A process for the preparation of a compound of formula V, said process comprising the steps of: preparing a compound of formula IV with step (ii) as described in claims 1-7, and
(iii-1) reacting the compound of formula IV with an organolithium reagent or a Grignard reagent and carbon dioxide in an inert solvent to produce a compound of formula V; or
(iii-2) reacting the compound of formula IV with carbon monoxide in an inert solvent under the action of a catalyst to generate the compound of formula V.
10. The method of claim 9, wherein the method is: reacting the compound of formula IV with an organolithium reagent and carbon dioxide in an inert solvent to produce the compound of formula V.
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