CN105085407A - Preparation method of Olaparib and analogue of Olaparib - Google Patents

Preparation method of Olaparib and analogue of Olaparib Download PDF

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CN105085407A
CN105085407A CN201510651102.4A CN201510651102A CN105085407A CN 105085407 A CN105085407 A CN 105085407A CN 201510651102 A CN201510651102 A CN 201510651102A CN 105085407 A CN105085407 A CN 105085407A
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substituting group
piperazine
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reaction
carbonyl
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王立强
邱飞
岳海涛
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Guangzhou Youmijian Pharmaceutical Technology Co Ltd
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Guangzhou Youmijian Pharmaceutical Technology Co Ltd
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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 discloses a preparation method of Olaparib and an analogue of the Olaparib. 2-fluoro-5-formyl benzoic acid is taken as a raw material and reacts with 1-substitutent piperazine to produce 3-(4-substitutent)piperazine-1-carbonyl)-4-fluorobenzalde which reacts with (3-oxo-1,3-dihydro-isobenzofuran-1-yl)dialkyl phosphate to produce 1-(substitutent)-4-[5-(3-oxo-3H-isobenzofuran-1-yl-methylene)-2-fluorobenzoyl]piperazine, then the 1-(substitutent)-4-[5-(3-oxo-3H-isobenzofuran-1-yl-methylene)-2-fluorobenzoyl]piperazine reacts with hydrazine hydrate to produce the Olaparib (Ia,R=cyclopropyl formyl) and the analogue (Ib,R=BOC) of the Olaparib; or 3-(4-substitutent)paperazine-1-carbonyl)-4-fluorobenzalde reacts with phthalide to produce 1-(substituent)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indene-2-yl)-2-fluorobenzoyl]piperazine which reacts with the hydrazine hydrate to produce the Olaparib (Ia,R=cyclopropyl formyl) and the analogue (Ib,R=BOC) of the Olaparib.

Description

The preparation method of a kind of Aura handkerchief Buddhist nun and analogue thereof
Technical field
The present invention relates to bulk drug preparing technical field, be specifically related to the preparation method of Aura handkerchief Buddhist nun (Olaparib) and analogue thereof.
Background technology
Aura handkerchief Buddhist nun (English name Olaparib, trade(brand)name Lynparza), be a Poly ADP-Ribose Polymerase [poly (ADP-ribose) polymerase] (PARP) inhibitor that the U.S. is researched and developed by Astrazeneca.This medicine and in December, 2014 obtain FDA and ratify to go on the market, for the ovarian cancer of BRCA genetic flaw and the treatment of mammary cancer.The chemistry of Aura handkerchief Buddhist nun (Olaparib) is called: 1-(cyclopropane carbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine, and its structural formula is:
Document J.Med.Chem., 2008,51:6581-6591 report the synthetic method of Aura handkerchief Buddhist nun, see following formula:
This route take 2-carboxybenzaldehyde as raw material, successively to react with dimethylphosphite and 2-fluoro-5-formyl radical cyanophenyl is reacted and generated the fluoro-5-of intermediate 2-(3-oxo-3H-isobenzofuran-1-methylene) cyanophenyl (III), this intermediate in the basic conditions cyan-hydrolysis becomes carboxyl, and hydrazine hydrate carries out cyclization obtains the fluoro-5-of intermediate 2-[(4-oxo-3, 4-dihydro phenol piperazine-1-base) methyl] phenylformic acid (IV), last and 1-cyclopropane carbonyl piperazine is at O-benzotriazole-tetramethyl-urea hexafluorophosphate (HBTU), N, Aura handkerchief Buddhist nun (I) is obtained under N-diisopropylethylamine (DIPEA) effect.This route final step adopts O-benzotriazole-tetramethyl-urea hexafluorophosphate (HBTU), DIPEA (DIPEA) reacts, and raw materials cost is higher, and product, through preparation liquid phase purifying, is unfavorable for suitability for industrialized production.
Chinese patent CN101528714 reports an other synthetic route, the fluoro-5-of intermediate (IV) 2-[(4-oxo-3, 4-dihydro phenol piperazine-1-base) methyl] phenylformic acid and 1-tert-butoxycarbonyl-piperazine be at O-benzotriazole-tetramethyl-urea hexafluorophosphate (HBTU), N, intermediate 4-[the fluoro-5-of 2-(4-oxo-3.4-dihydro-phenol piperazine-1-ylmethyl)-benzoyl]-piperazine-1-t-butyl formate (V) is obtained under N-diisopropylethylamine (DIPEA) effect, then tertbutyloxycarbonyl is sloughed in acid condition, Aura handkerchief Buddhist nun (I) is obtained by reacting again with Cyclopropyl carbonyl chloride.This route is long, and also adopt O-benzotriazole-tetramethyl-urea hexafluorophosphate (HBTU) when preparing intermediate V, DIPEA (DIPEA) reacts, and raw materials cost is higher, is unfavorable for suitability for industrialized production simultaneously.
Nanjing University of Technology's Master's thesis " Aura handkerchief Buddhist nun and analogue study on the synthesis thereof " report in 2012,
Intermediate (IV) obtains acid chloride intermediate through oxalyl chloride acidylate, then under the catalysis of DMAP, obtains target product Aura handkerchief Buddhist nun with 1-cyclopropane carbonyl piperazine, but yield is lower.
Document J.Am.Chem.Soc.2014,136,6142-6147 report that intermediate 4-(the bromo-4-fluorophenyl of 3-)-phenol piperazine-1 (2H)-one and 1-cyclopropane carbonyl piperazine obtain Aura handkerchief Buddhist nun under Organometallic Palladium catalyst.The method reaction is complicated, and the palladium catalyst of employing is expensive, is not suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to for defect of the prior art, provide a kind of and have that raw material is easy to get, concise in technology, environmental protection and economy and be applicable to the preparation method of industrialized Aura handkerchief Buddhist nun and analogue thereof, be applied to the preparation of Aura handkerchief Buddhist nun and analogue thereof.
The invention discloses the preparation method of a kind of Aura handkerchief Buddhist nun (Olaparib) and analogue thereof, with the fluoro-5-formylbenzoate of 2-for raw material prepares Aura handkerchief Buddhist nun (Olaparib) and analogue thereof, comprise the steps: a), with the fluoro-5-formylbenzoate of 2-to generate 3-(4-substituting group) piperazinyl-1-carbonyl for raw material and 1-substituting group piperazine react)-4-fluorobenzaldehyde, i.e. intermediate (VI); B), 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (intermediate (VI)) and (3-oxo-1,3-dihydro-isobenzofuran-1-base) phosphoric acid dialkyl is obtained by reacting 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine, i.e. intermediate (VII); C), 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine (intermediate (VII)) and hydrazine hydrate are obtained by reacting Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC); Or d), 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (intermediate (VI)) and phthalide be obtained by reacting 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine, i.e. intermediate (VIII); E), 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine (intermediate (VIII)) and hydrazine hydrate be obtained by reacting Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC); See reaction equation (I).
The preparation method of Aura handkerchief Buddhist nun and analogue thereof, comprises the steps:
A), the fluoro-5-formylbenzoate of 2-is dissolved in chloride reagent, subzero 10-90 DEG C of reaction, until raw material reaction is complete, removes excessive chloride reagent, obtains 2-fluoro-5-formyl radical Benzoyl chloride; 1-substituting group piperazine is dissolved in organic solvent A, and add alkali B, the solution that 2-fluoro-5-formyl radical Benzoyl chloride is dissolved in organic solvent A is dripped at subzero 10-40 DEG C, drip off, subzero 10-100 DEG C of reaction, until raw material reaction is complete, obtains intermediate (VI) through aftertreatment purifying: 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde;
B), intermediate (VI): 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde and (3-oxo-1,3-dihydro-isobenzofuran-1-base) in phosphoric acid dioxane ester solution organic solvent C, alkali B is dripped at subzero 10-100 DEG C, drip off and continue reaction until raw material reaction is complete, through aftertreatment, obtain intermediate (VII): 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine;
C), intermediate (VII): 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine is dissolved in solvent D, hydrazine hydrate reaction is added at subzero 10-100 DEG C, until raw material reaction is complete, through aftertreatment, obtain Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC);
D), 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (intermediate (VI)) and phthalide add in organic solvent A, add highly basic E, subzero 10-100 DEG C of reaction is until raw material reaction is complete, 1-(substituting group)-4-[5-(2 is obtained through aftertreatment purifying, 3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine, i.e. intermediate (VIII);
E), 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine (intermediate (VIII)) is dissolved in solvent D, hydrazine hydrate reaction is added at subzero 10-100 DEG C, until raw material reaction is complete, through aftertreatment, obtain Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC);
Organic solvent A is a kind of in methylene dichloride, chloroform, toluene, dimethylbenzene, ethyl acetate, propyl acetate, Iso Butyl Acetate, tetrahydrofuran (THF), ether, isopropyl ether, acetone, dioxane, acetonitrile and DMF or their mixture;
Alkali B is organic bases or mineral alkali, is especially a kind of in diisopropylethylamine, triethylamine, pyridine, DMAP, N-methylmorpholine, sodium hydride, sodium bicarbonate (potassium), sodium carbonate (potassium), cesium carbonate or their mixture;
Organic solvent C is a kind of in tetrahydrofuran (THF), ether, isopropyl ether, dioxane, methylene dichloride, chloroform, ethanol, methyl alcohol, Virahol, butanols, toluene, dimethylbenzene, acetone, ethyl acetate, propyl acetate, acetonitrile and DMF or their mixture;
Solvent D is a kind of in water, ethanol, methyl alcohol, Virahol, butanols, tetrahydrofuran (THF), dioxane or their mixture.
Highly basic E is sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, sodium hydride.
The chloride reagent that 2-fluoro-5-formylbenzoate makes 2-fluoro-5-formyl radical Benzoyl chloride is: sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene, two phosgene, triphosgene, oxalyl chloride; Especially be sulfur oxychloride; The amount of substance ratio that the fluoro-5-formylbenzoate of 2-and chloride reagent react is 1: 0.1-10, is especially 1: 1-1.5; Temperature of reaction is-50 DEG C-200 DEG C, is especially 0-90 DEG C; Reaction is the organic solvents such as methylene dichloride, chloroform, toluene, tetrahydrofuran (THF), dioxane without the need for machine solvent or solvent, is especially methylene dichloride and chloroform; Add a small amount of DMF catalyzed reaction simultaneously.
Step a) in, the amount of substance ratio that 2-fluoro-5-formyl radical Benzoyl chloride and 1-substituting group piperazine react is 1: 0.1-10, is especially 1: 0.5-2.
Step b) in, (3-oxo-1,3-dihydro-isobenzofuran-1-base) phosphoric acid dialkyl is (3-oxo-1,3-dihydro-isobenzofuran-1-base) dimethyl phosphate or (3-oxo-1,3-dihydro-isobenzofuran-1-base) diethyl phosphoric acid.
Step a) in the fluoro-5-formylbenzoate of 2-and 1-substituting group piperazine at dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, and be obtained by reacting intermediate (VI) under alkali B existence: 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde; The amount of substance ratio that the fluoro-5-formylbenzoate of 2-and 1-substituting group piperazine react is 1: 0.1-10, is especially 1: 0.5-2;
Alkali B is organic bases or mineral alkali, is especially a kind of in diisopropylethylamine, triethylamine, pyridine, DMAP, N-methylmorpholine, sodium hydride, sodium bicarbonate (potassium), sodium carbonate (potassium), cesium carbonate or their mixture.
Step b) in; intermediate 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (VI) and (3-oxo-1; 3-dihydro-isobenzofuran-1-base) phosphoric acid dialkyl reaction amount of substance ratio be 1: 0.1-10, be especially 1: 0.5-2.
Step c) in, the amount of substance ratio that intermediate 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine (VII) reacts with hydrazine hydrate is 1: 0.1-50, is especially 1: 0.5-10.
Steps d) in, 3-(4-substituting group) piperazinyl-1-carbonyl) the amount of substance ratio that reacts with phthalide of-4-fluorobenzaldehyde (intermediate (VI)) is 1: 0.1-10, is especially 1: 0.5-2.
Step e) in, 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] the amount of substance ratio that reacts with hydrazine hydrate of piperazine (intermediate (VIII)) is 1: 0.1-50, is especially 1: 0.5-10.
3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde; namely intermediate (VIa) can be obtained by following steps: 3-(4-tertbutyloxycarbonyl) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde sloughs tertbutyloxycarbonyl; then be obtained by reacting with Cyclopropyl carbonyl chloride, square formula 2.
Technique scheme can be found out, compared to prior art, and the preparation method of Aura handkerchief Buddhist nun involved in the present invention, there is raw material be easy to get, the feature such as concise in technology and environmental protection and economy, so the industrialization being beneficial to Aura handkerchief Buddhist nun bulk drug is produced, promotes the development of its economic technology.
Accompanying drawing explanation
Fig. 1 is chemical equation of the present invention.
Embodiment
Embodiment one:
The preparation method of Aura handkerchief Buddhist nun, comprises the following steps:
A) 2-fluoro-5-formylbenzoate 1.68g, is added in round-bottomed flask; sulfur oxychloride 5mL; drip several N; dinethylformamide, room temperature reaction, until raw material reaction is complete; decompression removing sulfur oxychloride; obtain oily matter 1.8g, 2-fluoro-5-formyl radical Benzoyl chloride, next step reaction can be directly used in.
B), 1-cyclopropane carbonyl piperazine 1.65g is dissolved in 20mL methylene dichloride; add triethylamine 1.5mL; the 2-fluoro-5-formyl radical Benzoyl chloride dripping upper step preparation at 0 DEG C is dissolved in the solution of 10mL methylene dichloride; drip off; room temperature reaction is until raw material reaction is complete; respectively through 1M salt acid elution; saturated sodium carbonate washs; saturated common salt water washing organic layer; anhydrous sodium sulfate drying, filters, obtains intermediate (VIa): 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl after concentrating under reduced pressure)-4-fluorobenzaldehyde; 2.56g, yield 84%.ESI-MS，m/z：305.1[M+H] +，327.1[M+Na] +。
C), by 3g intermediate (VIa): 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde and 2.5g (3-oxo-1, 3-dihydro-isobenzofuran-1-base) dimethyl phosphate is dissolved in 50mL dioxane, 1.4mL triethylamine is dripped at 0 DEG C, drip off and continue reaction until raw material reaction is complete, underpressure distillation is except desolventizing, add water and stir 1 hour, suction filtration, dry, obtain solid 3.2g, i.e. intermediate (VIIa): 1-(cyclopropane carbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine, yield, 76%.ESI-MS，m/z：443.1[M+Na] +，421.1[M+H] +。
D), 4.2g intermediate (VIIa): 1-(cyclopropane carbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine is dissolved in 20mL ethanol; 8mL hydrazine hydrate is added under room temperature; back flow reaction, until raw material reaction is complete, concentrating under reduced pressure is except desolventizing; add water; extraction into ethyl acetate, concentrated after dry, re-crystallizing in ethyl acetate; obtain Aura handkerchief Buddhist nun (Ia) 3.3g, yield 77%.ESI-MS，m/z：457.1[M+Na] +，435.1[M+H] +。
Embodiment two:
The preparation method of Aura handkerchief Buddhist nun, comprises the following steps:
A) 2-fluoro-5-formylbenzoate 3.4g, is added in round-bottomed flask; 30mL methylene dichloride; sulfur oxychloride 3mL, drips several DMFs; back flow reaction; until raw material reaction is complete, removal of solvent under reduced pressure, obtains oily matter 3.7g; 2-fluoro-5-formyl radical Benzoyl chloride, can be directly used in next step reaction.
1-cyclopropane carbonyl piperazine 3.3g is dissolved in 20mL dioxane; add diisopropylethylamine 4mL; the 2-fluoro-5-formyl radical Benzoyl chloride dripping upper step preparation at 0 DEG C is dissolved in the solution of 10mL dioxane; drip off; back flow reaction is until raw material reaction is complete; respectively through salt acid elution; saturated sodium carbonate washs; saturated common salt water washing organic layer; anhydrous sodium sulfate drying, filters, obtains intermediate (VIa): 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl after concentrating under reduced pressure)-4-fluorobenzaldehyde; 5.5g, yield 91%.
B), by 4.5g intermediate (VIa): 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde and 4g (3-oxo-1, 3-dihydro-isobenzofuran-1-base) diethyl phosphoric acid is dissolved in 100mL chloroform, 1.4mL diisopropylethylamine is dripped under room temperature, drip off temperature rising reflux reaction until raw material reaction is complete, underpressure distillation is except desolventizing, add water and stir 1 hour, suction filtration, dry, obtain solid 5.0g, i.e. intermediate (VIIa): 1-(cyclopropane carbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine, yield, 79.3%.
C), 2.8g intermediate (VIIa): 1-(cyclopropane carbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine is dissolved in 20mL dioxane; 5mL hydrazine hydrate is added under room temperature; back flow reaction, until raw material reaction is complete, concentrating under reduced pressure is except desolventizing; add water; extraction into ethyl acetate, concentrated after dry, re-crystallizing in ethyl acetate; obtain Aura handkerchief Buddhist nun (Ia) 2.0g, yield 69%.
Embodiment three:
The preparation method of Aura handkerchief Buddhist nun, comprises the following steps:
A) 2-fluoro-5-formylbenzoate 1.68g, is added in round-bottomed flask; 30mL methylene dichloride; triphosgene 1g, drips several DMFs; back flow reaction; until raw material reaction is complete, removal of solvent under reduced pressure, obtains oily matter 1.8g; 2-fluoro-5-formyl radical Benzoyl chloride, can be directly used in next step reaction.
1-cyclopropane carbonyl piperazine 1.5g is dissolved in 20mL toluene; add N-methylmorpholine 1.1mL; the 2-fluoro-5-formyl radical Benzoyl chloride dripping upper step preparation under room temperature is dissolved in the solution of 10mL toluene; drip off; back flow reaction is until raw material reaction is complete; respectively through salt acid elution; saturated sodium carbonate washs; saturated common salt water washing organic layer; anhydrous sodium sulfate drying, filters, obtains intermediate (VIa): 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl after concentrating under reduced pressure)-4-fluorobenzaldehyde; 1.7g, yield 56%.
B), by 4.5g intermediate (VIa): 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde, 2g phthalide be dissolved in 100mL ethyl propionate; drip the solution that 4g sodium methylate is dissolved in 20 methyl alcohol under room temperature, during dropping, keep temperature not higher than 30 DEG C with ice-water bath.Drip off temperature rising reflux, reaction is until raw material reaction is complete, and underpressure distillation is except desolventizing, add water and stir 1 hour, suction filtration, filter cake ethyl acetate is washed, acetum acidifying, stirs, and filters after washing, dry, obtain solid 3.6g, i.e. intermediate (VIIIa), 1-(cyclopropyl formyl radical)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine, yield; 57.3%.
C), 2.8g intermediate (VIIIa): 1-(cyclopropyl formyl radical)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine is dissolved in 20mL ethanol; 10mL hydrazine hydrate is added under room temperature; back flow reaction, until raw material reaction is complete, concentrating under reduced pressure is except desolventizing; add water; extraction into ethyl acetate, concentrated after dry, re-crystallizing in ethyl acetate; obtain Aura handkerchief Buddhist nun (Ia) 1.8g, yield 61%.
Embodiment four: the preparation of Aura handkerchief Buddhist nun analogue 1-(tertbutyloxycarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine (Ib), comprises the following steps:
A), intermediate (VIb): 3-(4-tertbutyloxycarbonyl) piperazinyl-1-carbonyl) preparation of-4-fluorobenzaldehyde: add 2-fluoro-5-formylbenzoate 1.84g in round-bottomed flask; 1-tert-butoxycarbonyl-piperazine 1.86g; dioxane 20ml; dicyclohexylcarbodiimide 2.26g is added after entirely molten; DMAP 1.30g, stirring at room temperature reaction is until 1-tert-butoxycarbonyl-piperazine raw material reaction is complete.Cross and filter precipitation, concentrated filtrate, add ethyl propionate, 1M salt acid elution, saturated sodium carbonate washs, saturated common salt water washing, dry organic layer, concentrate and obtain intermediate (VIb): 3-(4-tertbutyloxycarbonyl) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde, 2.3g, yield 68.0%.
D), by 1g intermediate (VIb): 3-(4-tertbutyloxycarbonyl) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde and 0.8g (3-oxo-1, 3-dihydro-isobenzofuran-1-base) dimethyl phosphate is dissolved in 20mL dioxane, 0.5mL triethylamine is dripped at 0 DEG C, drip off and continue reaction until raw material reaction is complete, underpressure distillation is except desolventizing, add water and stir 1 hour, suction filtration, dry, obtain solid 0.8g, i.e. intermediate (VIIb): 1-(tertbutyloxycarbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine, yield, 59.2%.ESI-MS，m/z：475.1[M+Na] +，453.1[M+H] +。
E), 0.6g intermediate (VIIb): 1-(tertbutyloxycarbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine is dissolved in 10mL ethanol, 2mL hydrazine hydrate is added under room temperature, back flow reaction, until raw material reaction is complete, concentrating under reduced pressure is except desolventizing, add water, extraction into ethyl acetate, concentrated after dry, re-crystallizing in ethyl acetate, obtain 1-(tertbutyloxycarbonyl)-4-[5-[(3, 4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoyl] piperazine (Ib) 0.4g, yield 65%.ESI-MS，m/z：489.1[M+Na] +，467.1[M+H] +。
Embodiment five:
3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl) preparation of-4-fluorobenzaldehyde
1-tert-butoxycarbonyl-piperazine 1.85g is dissolved in 20mL methylene dichloride, adds triethylamine 1.5mL, and the 2-fluoro-5-formyl radical Benzoyl chloride dripping 2g at 0 DEG C is dissolved in the solution of 10mL methylene dichloride; drip off; room temperature reaction is until raw material reaction is complete, and respectively through 1M salt acid elution, saturated sodium carbonate washs; saturated common salt water washing organic layer; anhydrous sodium sulfate drying, filters, obtains 3-(4-tertbutyloxycarbonyl) piperazinyl-1-carbonyl after concentrating under reduced pressure)-4-fluorobenzaldehyde; 2.4g, yield 71%.ESI-MS，m/z：337.1[M+H] +，359.1[M+Na] +。
3.36g3-(4-tertbutyloxycarbonyl) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde is dissolved in 30mL methylene dichloride, and add 5mL trifluoroacetic acid, stirring at room temperature is until raw material reaction is complete.Decompression steams trifluoroacetic acid and solvent, obtains 2.35g3-(piperazinyl-1-carbonyl)-4-fluorobenzaldehyde, yield 99%, directly carries out next step reaction.
Upper step 3-(piperazinyl-1-carbonyl)-4-fluorobenzaldehyde is dissolved in methylene dichloride; add triethylamine 1.5mL; the Cyclopropyl carbonyl chloride dripping 1.2g at 0 DEG C is dissolved in the solution of 10mL methylene dichloride; drip off; room temperature reaction is until raw material reaction is complete; respectively through 1M salt acid elution; saturated sodium carbonate washs; saturated common salt water washing organic layer; anhydrous sodium sulfate drying; filter, after concentrating under reduced pressure, obtain 2.8g3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde, yield 92%.

Claims (11)

1. the preparation method of an Aura handkerchief Buddhist nun (Olaparib) and analogue thereof, it is characterized in that with the fluoro-5-formylbenzoate of 2-for raw material prepares Aura handkerchief Buddhist nun (Olaparib) and analogue thereof, comprise the steps: a), with the fluoro-5-formylbenzoate of 2-to generate 3-(4-substituting group) piperazinyl-1-carbonyl for raw material and 1-substituting group piperazine react)-4-fluorobenzaldehyde, i.e. intermediate (VI); B), 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (intermediate (VI)) and (3-oxo-1,3-dihydro-isobenzofuran-1-base) phosphoric acid dialkyl is obtained by reacting 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine, i.e. intermediate (VII); C), 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine (intermediate (VII)) and hydrazine hydrate are obtained by reacting Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC); Or d), 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (intermediate (VI)) and phthalide be obtained by reacting 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine, i.e. intermediate (VIII); E), 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine (intermediate (VIII)) and hydrazine hydrate be obtained by reacting Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC); See reaction equation (I),
2. the preparation method of Aura handkerchief Buddhist nun according to claim 1 and analogue thereof, is characterized in that comprising the steps:
A), the fluoro-5-formylbenzoate of 2-is dissolved in chloride reagent, subzero 10-90 DEG C of reaction, until raw material reaction is complete, removes excessive chloride reagent, obtains 2-fluoro-5-formyl radical Benzoyl chloride; 1-substituting group piperazine is dissolved in organic solvent A, and add alkali B, the solution that 2-fluoro-5-formyl radical Benzoyl chloride is dissolved in organic solvent A is dripped at subzero 10-40 DEG C, drip off, subzero 10-100 DEG C of reaction, until raw material reaction is complete, obtains intermediate (VI) through aftertreatment purifying: 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde;
B), intermediate (VI): 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde and (3-oxo-1,3-dihydro-isobenzofuran-1-base) in phosphoric acid dioxane ester solution organic solvent C, alkali B is dripped at subzero 10-100 DEG C, drip off and continue reaction until raw material reaction is complete, through aftertreatment, obtain intermediate (VII): 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine;
C), intermediate (VII): 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine is dissolved in solvent D, hydrazine hydrate reaction is added at subzero 10-100 DEG C, until raw material reaction is complete, through aftertreatment, obtain Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC);
D), 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (intermediate (VI)) and phthalide add in organic solvent A, add highly basic E, subzero 10-100 DEG C of reaction is until raw material reaction is complete, 1-(substituting group)-4-[5-(2 is obtained through aftertreatment purifying, 3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine, i.e. intermediate (VIII);
E), 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] piperazine (intermediate (VIII)) is dissolved in solvent D, hydrazine hydrate reaction is added at subzero 10-100 DEG C, until raw material reaction is complete, through aftertreatment, obtain Aura handkerchief Buddhist nun (Ia, R=cyclopropyl formyl radical) and analogue (Ib, R=BOC);
Described organic solvent A is a kind of in methylene dichloride, chloroform, toluene, dimethylbenzene, ethyl acetate, propyl acetate, Iso Butyl Acetate, tetrahydrofuran (THF), ether, isopropyl ether, acetone, dioxane, acetonitrile and DMF or their mixture;
Described alkali B is organic bases or mineral alkali, is especially a kind of in diisopropylethylamine, triethylamine, pyridine, DMAP, N-methylmorpholine, sodium hydride, sodium bicarbonate (potassium), sodium carbonate (potassium), cesium carbonate or their mixture;
Described organic solvent C is a kind of in tetrahydrofuran (THF), ether, isopropyl ether, dioxane, methylene dichloride, chloroform, ethanol, methyl alcohol, Virahol, butanols, toluene, dimethylbenzene, acetone, ethyl acetate, propyl acetate, acetonitrile and DMF or their mixture;
Described solvent D is a kind of in water, ethanol, methyl alcohol, Virahol, butanols, tetrahydrofuran (THF), dioxane or their mixture, and described highly basic E is sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, sodium hydride.
3. according to the preparation method of the Aura handkerchief Buddhist nun described in claim 2 and analogue thereof, it is characterized in that the chloride reagent that 2-fluoro-5-formylbenzoate makes 2-fluoro-5-formyl radical Benzoyl chloride is: sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene, two phosgene, triphosgene, oxalyl chloride; Especially be sulfur oxychloride; The amount of substance ratio that the fluoro-5-formylbenzoate of 2-and chloride reagent react is 1: 0.1-10, is especially 1: 1-1.5; Temperature of reaction is-50 DEG C-200 DEG C, is especially 0-90 DEG C; Reaction is the organic solvents such as methylene dichloride, chloroform, toluene, tetrahydrofuran (THF), dioxane without the need for machine solvent or solvent, is especially methylene dichloride and chloroform; Add a small amount of DMF catalyzed reaction simultaneously.
4. according to the preparation method of the Aura handkerchief Buddhist nun described in claim 1 and 2 and analogue thereof; in it is characterized in that described step a); the amount of substance ratio that 2-fluoro-5-formyl radical Benzoyl chloride and 1-substituting group piperazine react is 1: 0.1-10, is especially 1: 0.5-2.
5. according to the preparation method of the Aura handkerchief Buddhist nun described in claim 1 and 2 and analogue thereof, it is characterized in that described step b) in, (3-oxo-1,3-dihydro-isobenzofuran-1-base) phosphoric acid dialkyl is (3-oxo-1,3-dihydro-isobenzofuran-1-base) dimethyl phosphate or (3-oxo-1,3-dihydro-isobenzofuran-1-base) diethyl phosphoric acid.
6. the preparation method of Aura handkerchief Buddhist nun according to claim 1 and analogue thereof, it is characterized in that: described step a) in the fluoro-5-formylbenzoate of 2-and 1-substituting group piperazine at dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, and be obtained by reacting intermediate (VI) under alkali B existence: 3-(4-substituting group) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde; The amount of substance ratio that the fluoro-5-formylbenzoate of 2-and 1-substituting group piperazine react is 1: 0.1-10, is especially 1: 0.5-2;
Alkali B is organic bases or mineral alkali, is especially a kind of in diisopropylethylamine, triethylamine, pyridine, DMAP, N-methylmorpholine, sodium hydride, sodium bicarbonate (potassium), sodium carbonate (potassium), cesium carbonate or their mixture.
7. the Aura handkerchief Buddhist nun according to claim 1 and 2 and the preparation method of analogue thereof; it is characterized in that: described step b) in; intermediate 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde (VI) and (3-oxo-1; 3-dihydro-isobenzofuran-1-base) phosphoric acid dialkyl reaction amount of substance ratio be 1: 0.1-10, be especially 1: 0.5-2.
8. the Aura handkerchief Buddhist nun according to claim 1 and 2 and the preparation method of analogue thereof, it is characterized in that: described step c) in, the amount of substance ratio that intermediate 1-(substituting group)-4-[5-(3-oxo-3H-isobenzofuran-1-methylene)-2-fluorobenzoyl] piperazine (VII) reacts with hydrazine hydrate is 1: 0.1-50, is especially 1:0.5-10.
9. the Aura handkerchief Buddhist nun according to claim 1 and 2 and the preparation method of analogue thereof, it is characterized in that: described steps d) in, 3-(4-substituting group) piperazinyl-1-carbonyl) the amount of substance ratio that reacts with phthalide of-4-fluorobenzaldehyde (intermediate (VI)) is 1: 0.1-10, is especially 1: 0.5-2.
10. the Aura handkerchief Buddhist nun according to claim 1 and 2 and the preparation method of analogue thereof, it is characterized in that: described step e) in, 1-(substituting group)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indenes-2-base)-2-fluorobenzoyl] the amount of substance ratio that reacts with hydrazine hydrate of piperazine (intermediate (VIII)) is 1: 0.1-50, is especially 1: 0.5-10.
The preparation method of 11. Aura handkerchief Buddhist nuns according to claim 1 and 2 and analogue thereof; it is characterized in that: 3-(4-cyclopropyl formyl radical) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde; namely intermediate (VIa) can be obtained by following steps: 3-(4-tertbutyloxycarbonyl) piperazinyl-1-carbonyl)-4-fluorobenzaldehyde sloughs tertbutyloxycarbonyl; then be obtained by reacting with Cyclopropyl carbonyl chloride; square formula 2
CN201510651102.4A 2015-09-29 2015-09-29 Preparation method of Olaparib and analogue of Olaparib Pending CN105085407A (en)

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CN105254572A (en) * 2015-11-09 2016-01-20 北京科莱博医药开发有限责任公司 Crystal form, preparing method and application of Olaparib
CN105503739A (en) * 2016-02-24 2016-04-20 上海今寅生物科技有限公司 Preparation method of high-purity olaparib
CN105820126A (en) * 2016-05-12 2016-08-03 山东罗欣药业集团恒欣药业有限公司 Preparing method for Olaparib
CN106083741A (en) * 2016-02-22 2016-11-09 南京中医药大学 2 sulfur are for quinazolinedione derivatives
CN106905243A (en) * 2017-02-13 2017-06-30 广州仁恒医药科技股份有限公司 A kind of preparation method of olaparib
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
CN107325055A (en) * 2017-08-14 2017-11-07 山东裕欣药业有限公司 A kind of synthetic method of olaparib compound
TWI639593B (en) * 2016-08-24 2018-11-01 台灣神隆股份有限公司 Processes for preparing olaparib
CN110790710A (en) * 2019-11-07 2020-02-14 东南大学 Synthetic method of olaparib
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
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CN105254572A (en) * 2015-11-09 2016-01-20 北京科莱博医药开发有限责任公司 Crystal form, preparing method and application of Olaparib
CN106083741A (en) * 2016-02-22 2016-11-09 南京中医药大学 2 sulfur are for quinazolinedione derivatives
CN105503739A (en) * 2016-02-24 2016-04-20 上海今寅生物科技有限公司 Preparation method of high-purity olaparib
CN105503739B (en) * 2016-02-24 2018-09-11 合肥启旸生物科技有限公司 A kind of preparation method of olaparib
CN105820126B (en) * 2016-05-12 2018-01-12 山东罗欣药业集团恒欣药业有限公司 A kind of preparation method of olaparib
CN105820126A (en) * 2016-05-12 2016-08-03 山东罗欣药业集团恒欣药业有限公司 Preparing method for Olaparib
TWI639593B (en) * 2016-08-24 2018-11-01 台灣神隆股份有限公司 Processes for preparing olaparib
CN106905243A (en) * 2017-02-13 2017-06-30 广州仁恒医药科技股份有限公司 A kind of preparation method of olaparib
CN107325055A (en) * 2017-08-14 2017-11-07 山东裕欣药业有限公司 A kind of synthetic method of olaparib compound
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
CN110790710A (en) * 2019-11-07 2020-02-14 东南大学 Synthetic method of olaparib
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
CN111732547B (en) * 2020-07-31 2020-12-11 北京鑫开元医药科技有限公司 Refining method and application of olapari
WO2023017393A1 (en) * 2021-08-09 2023-02-16 Glenmark Life Sciences Limited Process for the preparation of olaparib, and crystalline form thereof

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