CN112500379B - Olaparib intermediate and preparation method of Olaparib - Google Patents
Olaparib intermediate and preparation method of Olaparib Download PDFInfo
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- CN112500379B CN112500379B CN202011535326.6A CN202011535326A CN112500379B CN 112500379 B CN112500379 B CN 112500379B CN 202011535326 A CN202011535326 A CN 202011535326A CN 112500379 B CN112500379 B CN 112500379B
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- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229960000572 olaparib Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 100
- 238000003756 stirring Methods 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 23
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 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 abstract description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 238000001816 cooling Methods 0.000 claims abstract description 15
- 238000004321 preservation Methods 0.000 claims abstract description 14
- HNZJIWIXRPBFAN-UHFFFAOYSA-N 1-cyclopropylpiperazine Chemical compound C1CC1N1CCNCC1 HNZJIWIXRPBFAN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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 8
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 14
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 231100000614 poison Toxicity 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000007599 discharging Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 239000011345 viscous material Substances 0.000 description 3
- 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 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000005885 boration reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000004886 process control Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- -1 2-fluoro-5- [ (4-oxo-3, 4-dihydropyrazol-1-yl) methyl ] benzoic acid Chemical compound 0.000 description 1
- MOFRJTLODZILCR-UHFFFAOYSA-N 2-fluoro-5-formylbenzonitrile Chemical compound FC1=CC=C(C=O)C=C1C#N MOFRJTLODZILCR-UHFFFAOYSA-N 0.000 description 1
- DYNFCHNNOHNJFG-UHFFFAOYSA-N 2-formylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C=O DYNFCHNNOHNJFG-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 102000011724 DNA Repair Enzymes Human genes 0.000 description 1
- 108010076525 DNA Repair Enzymes Proteins 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 201000001342 Fallopian tube cancer Diseases 0.000 description 1
- 208000013452 Fallopian tube neoplasm Diseases 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
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- KIALFUYSJAAJSU-UHFFFAOYSA-N cyclopropyl(piperazin-1-yl)methanone Chemical compound C1CNCCN1C(=O)C1CC1 KIALFUYSJAAJSU-UHFFFAOYSA-N 0.000 description 1
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- GHEFZYZTGHKBBI-UHFFFAOYSA-N methyl 5-(bromomethyl)-2-fluorobenzoate Chemical compound COC(=O)C1=CC(CBr)=CC=C1F GHEFZYZTGHKBBI-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000011518 platinum-based chemotherapy Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses an Olaparib intermediate and a preparation method of Olaparib, wherein the preparation method comprises the following steps: suspending the compound II in a solvent, adding alkali, heating to a reaction temperature, and reacting to obtain a compound III; mixing the compound III with a solvent, adding hydrazine hydrate and alkali, heating to a reaction temperature, and carrying out heat preservation reaction until a reaction end point to obtain a compound IV; mixing and stirring a compound IV, a catalyst and a solvent, heating to a reaction temperature, adding thionyl chloride, carrying out heat preservation reaction to a reaction end point, cooling, sequentially adding alkali and cyclopropylpiperazine, carrying out heat preservation reaction to complete reaction, and obtaining the Olaparib by the following reaction formula:
Description
Technical Field
The invention relates to an intermediate and a preparation method thereof, in particular to an Olaparib intermediate and a preparation method of Olaparib.
Background
Olaparib is an inhibitor of poly (adenosine diphosphate) ribose polymerase (PARP), a DNA repair enzyme that plays a key role in the DNA repair pathway, and PARPi can exert antitumor activity by synthetic lethal effects.
Olaparis was approved for marketing in europe and the united states at 12, 16, 2014 and 12, 19, respectively, as the first commercially available PARPi worldwide, with the approved indications being recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer that is fully or partially responsive to platinum-based chemotherapy; deleterious or suspected deleterious BRCA mutation (gbgcam) associated advanced ovarian cancer that has been treated with three or more chemotherapies; patients with detrimental or suspected detrimental BRCA mutations (gbgcam), HER 2-negative metastatic breast cancer who received chemotherapy are treated.
At present, the synthesis method of the olapari mainly comprises the following steps:
document j. Med. Chem.2008,51:6581-6591 reports a synthesis method of Olaparib, which comprises the steps of taking o-carboxybenzaldehyde as a raw material, reacting with dimethyl phosphite, reacting the obtained product with 2-fluoro-5-formylbenzonitrile to obtain a condensation intermediate, carrying out alkaline hydrolysis and cyclization with hydrazine hydrate on the condensation intermediate to obtain 2-fluoro-5- [ (4-oxo-3, 4-dihydropyrazol-1-yl) methyl ] benzoic acid, and finally reacting with HBTU and DIPEA to obtain the Olaparib. The last step of the method uses a toxic coupling agent HBTU, so that the raw material cost is high, and the serious wastewater post-treatment cost is brought, and the method does not meet the requirements of environmental protection.
Another synthetic method of Olaparib is reported in the "Olaparib and its analogue synthesis research" by the university of Nanjing Industrial university, 2012, and is prepared by using 2-fluoro-5- [ (4-oxo-3, 4-dihydropyrazin-1-yl) methyl ] benzoic acid as a raw material, chloridizing with oxalyl chloride, and then reacting with 1-cyclopropanecarbonyl piperazine in the presence of DMAP catalyst. The yield of the route is 48% lower, and the route is not suitable for industrial production.
Another synthesis method of olapari is reported in patent CN105820126B, which uses methyl 5-bromomethyl-2-fluorobenzoate as a raw material, and obtains olapari through a boration reaction, a coupling reaction, a hydrolysis reaction, and an aminolysis reaction. In the method, catechol borane is adopted as a raw material in the boration reaction, and the raw material is high in price; the palladium catalyst is adopted in the coupling reaction, so that the cost is high, the post-treatment is difficult, and the industrial production is not facilitated.
Disclosure of Invention
The invention aims to: the first object of the invention is to provide an Olaparib intermediate, and the second object of the invention is to provide a preparation method of Olaparib with cheap and easily available raw materials, mild conditions, simple operation and high purity of the obtained products.
The technical scheme is as follows: the structural formula of the olapari intermediate is as follows:
the preparation method of the olapari comprises the following steps:
(1) Mixing the compound II with a solvent, adding alkali, heating to a reaction temperature, and reacting to obtain a compound III;
(2) Mixing the compound III with a solvent, adding hydrazine hydrate and alkali, heating to a reaction temperature, and carrying out heat preservation reaction until a reaction end point to obtain a compound IV;
(3) Mixing and stirring a compound IV, a catalyst and a solvent, heating to a reaction temperature, adding thionyl chloride, carrying out heat preservation reaction to a reaction end point, cooling, sequentially adding alkali and cyclopropylpiperazine, carrying out heat preservation reaction to complete reaction, and obtaining the Olaparib by the following reaction formula:
further, in the step (1), the solvent is one or more of acetonitrile, THF, DMF, DMSO or water, and the base is an organic base or an inorganic base.
The organic base is one of triethylamine, pyridine or DMAP, and the inorganic base is sodium hydroxide or potassium hydroxide.
In the step (1), the reaction temperature is 20-30 ℃.
In the step (2), the solvent is one or more of acetonitrile, water, THF, DMF or DMSO; the base is an organic base or an inorganic base.
The organic base is one of triethylamine, pyridine or DMAP, and the inorganic base is sodium hydroxide or potassium hydroxide.
In the step (2), the reaction temperature is 90-110 ℃.
In the step (3), the catalyst is one or more of DMF, DMAP, triethylamine or pyridine; the solvent is one or more of toluene, xylene, acetonitrile, chloroform or dichloromethane; the base is one or more of triethylamine, pyridine or DMAP.
In the step (3), the reaction temperature is 70-85 ℃; cooling to 5-20 ℃.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) Provides a brand new Olaparib intermediate, through which Olaparib can be synthesized;
(2) The novel method for synthesizing the olapari is low in cost and easy to obtain raw materials, simple to operate, mild in reaction conditions, high in purity and high in yield of the obtained target product, free of extremely toxic substances, simple in post-treatment, less in three wastes and capable of meeting the production requirements of environmental protection.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1
(1) Preparation of Compound III
50g of compound II and 500g of water are added into a 1L four-mouth bottle, the mixture is stirred and heated to 25-30 ℃, sodium hydroxide aqueous solution (9 g of sodium hydroxide and 250g of water) is rapidly added, the reaction is carried out for 15min under the condition of heat preservation, the system is gradually dissolved, and TLC monitors that the reaction of compound I is complete. Regulating the pH to 1-2 by using 6M hydrochloric acid, standing and separating liquid; the organic phase was washed with 1L of saturated salt water for 2 times and dried over anhydrous sodium sulfate; concentrating under reduced pressure until no solvent is present. 45g of tetrahydrofuran and 250g of water were added, whereupon the system separated out an oil; cooling to 20-25 ℃, enabling the oily matter to become sticky, and dropwise adding a mixed solvent of ethyl acetate (50 mL) and petroleum ether (100 mL); a large amount of solid is precipitated after stirring for 1 h; suction filtering, rinsing the filter cake with water, and drying the filter cake at 50-60 ℃ under reduced pressure until the weight is constant to obtain 48g of solid with the purity of 98.8%. 1 HNMR(DMSO-D6，400MHz):δppm8.15(s，1H)，7.77-7.56(m，7H)，7.41(s，2H)。m/z[M-H] - ：282.17。
(2) Preparation of Compound IV
To a 250mL three-necked flask, 20g of Compound III and 100mL of water were added, 7.1g of potassium hydroxide was added, and the dropwise addition of 7.5g of 85% hydrazine hydrate was started, and the temperature was raised to about 90℃and the reaction was continued overnight at a constant temperature. TLC monitored reaction was complete. Cooling to room temperature, regulating pH to 2-3 with hydrochloric acid, precipitating a great amount of solid, and suction filtering. The filter cake is dried at 60-65 ℃ to obtain 19.5g yellow solid with the purity of 96.4 percent. 1 HNMR(DMSO-D6，400MHz):δppm13.24(brs，1H)，12.59(s，1H)，8.27-8.25(d，1H)，7.67(d，1H)，7.89(t，1H)，7.82(t，2H)，7.58-7.57(d，1H)，7.23(t，1H)，4.35(s，2H)。m/z[M+H] + ：299.10，m/z[M-H] - ：297.17。
(3) Preparation of Compound I (Olaparib)
2.61kg of toluene, 0.50kg of compound IV and 0.021kg of DMAP are added into a 5L reaction flask, stirring is carried out, the temperature is raised to 80-85 ℃, 240g of thionyl chloride is slowly added, the reaction is carried out after dripping, the temperature is maintained, stirring is carried out, and TLC monitors that the compound IV is basically reacted completely. Cooling, controlling the temperature of the reaction system to be between 5 and 20 ℃, starting to slowly dropwise add 0.48kg of DMAP, continuously dropwise adding 0.311kg of toluene solution (0.311 kg of cyclopropylpiperazine and 0.26kg of toluene) of cyclopropylpiperazine into the reaction system after the completion of dropwise adding, controlling the temperature of the reaction system to be between 5 and 20 ℃ in the dropwise adding process, and keeping the dropwise adding time period to be about 1 to 3 hours; after the dripping is finished, the temperature of the reaction system is controlled between 5 ℃ and 20 ℃ to continue stirring reaction, and TLC monitors that the raw material reaction is complete. 3.00kg of water was added dropwise to the reaction system, followed by stirring for 3 to 4 hours. Discharging and centrifuging, recrystallizing the crude product, and drying to obtain 0.65kg of refined product with purity more than 99%. 1 HNMR(DMSO-D6，400MHz):δppm12.61(s,1H),8.26(dd,1H),7.96(d,1H),7.88(t,1H),7.82(m,1H),7.44(m,1H),7.38(d,1H)，7.24(t，1H),4.33(s,2H),3.67(m,4H),3.47(m,2H),3.20(m,2H),1.94(d,1H),0.73(m,4H)。m/z[M-H] - ：433.16。
Example 2
(1) Preparation of Compound III
50g of compound II and 500g of DMF are added into a 1L four-necked flask, the mixture is stirred and heated to 20-25 ℃, 9g of potassium hydroxide is quickly added, the reaction is carried out for 15min under the condition of heat preservation, the system is gradually dissolved, and TLC monitors that the compound I is completely reacted. Regulating pH to 1-2 with 6M hydrochloric acid, standing and separating; the organic phase was washed with 1L of saturated salt water for 2 times and dried over anhydrous sodium sulfate; concentrating under reduced pressure until no solvent is present. 45g of tetrahydrofuran and 250g of water were added, whereupon the system separated out an oil; continuously adding a mixed solvent of ethyl acetate (50 mL) and petroleum ether (100 mL); a large amount of solid is precipitated after stirring for 1 h; suction filtering, rinsing the filter cake with water, and drying the filter cake at 50-60 ℃ under reduced pressure until the weight is constant to obtain 48.5g of solid with the purity of 98.6%.
(2) Preparation of Compound IV
To a 250mL three-necked flask, 20g of Compound III, 100mL of acetonitrile and 13g of triethylamine were added, and then 7.5g of 85% hydrazine hydrate was added dropwise, and the temperature was raised to about 110℃to allow the reaction to proceed overnight. TLC monitored reaction was complete. The solvent was distilled off under reduced pressure, 100mL of water was added, the pH was adjusted to 2-3 with hydrochloric acid, a large amount of solids were precipitated, and suction filtration was performed. The filter cake was dried to give 19.1g of a yellow solid with a purity > 96%.
(3) Preparation of Compound I (Olaparib)
2.5kg of xylene, 0.50kg of compound IV and 0.012kg of DMF are added into a 5L reaction flask, stirred, heated to about 70 ℃, 240g of thionyl chloride is slowly added, the reaction is carried out after dripping, the temperature is maintained, stirring is carried out, and TLC monitors that the compound IV is basically reacted completely. Cooling, controlling the temperature of the reaction system to be between 5 and 20 ℃, starting to slowly dropwise add 0.3kg of pyridine, and continuously dropwise adding 0.311kg of cyclopropylpiperazine (0.311 kg of cyclopropylpiperazine and 0.26kg of toluene) into the reaction system after the dropwise addition is completed, wherein the dropwise addition process controls the temperature of the reaction system to be between 5 and 20 ℃ and the dropwise addition time is about 1 to 3 hours; after the dripping is finished, the temperature of the reaction system is controlled between 5 ℃ and 20 ℃ to continue stirring reaction, and TLC monitors that the raw material reaction is complete. 3.00kg of water was added dropwise to the reaction system, followed by stirring for 3 to 4 hours. Discharging and centrifuging, recrystallizing the crude product, and drying to obtain 0.7kg of refined product with purity more than 99%.
Example 3
(1) Preparation of Compound III
50g of compound II and 500g of acetonitrile are added into a 1L four-necked flask, the mixture is stirred, the temperature is raised to 25-30 ℃, 18g of pyridine is added, the reaction is carried out for 15min under the heat preservation, the system is gradually dissolved, and TLC monitors that the compound I is completely reacted. Regulating pH to 1-2 with 6M hydrochloric acid, standing and separating; the organic phase was washed with 1L of saturated salt water for 2 times and dried over anhydrous sodium sulfate; concentrating under reduced pressure until no solvent is present. 45g of acetonitrile and 250g of water were added, at which time the system precipitated an oil; cooling to 20-25deg.C, making the oily substance into viscous substance, and dripping mixed solvent of ethyl acetate (50 mL) and petroleum ether (100 mL); a large amount of solid is precipitated after stirring for 1 h; suction filtration, rinsing the filter cake with water, and drying the filter cake under reduced pressure to constant weight to obtain 45g of solid with the purity of 98.9%.
(2) Preparation of Compound IV
To a 250mL three-necked flask, 20g of Compound III and 100mL of water were added, 5g of sodium hydroxide was added, and the dropwise addition of 7.3g of 85% hydrazine hydrate was started, and the temperature was raised to about 100℃to allow the reaction to proceed overnight. TLC monitored reaction was complete. Cooling to room temperature, regulating pH to 2-3 with hydrochloric acid, precipitating a great amount of solid, and suction filtering. The filter cake was dried to give 19.8g of a yellow solid with a purity > 96%.
(3) Preparation of Compound I (Olaparib)
2.6kg of acetonitrile, 0.52kg of compound IV and 0.017kg of triethylamine are added into a 5L reaction bottle, stirring is carried out, the temperature is raised to about 80 ℃, 245g of thionyl chloride is slowly added, the reaction is carried out after dripping, the temperature is maintained, stirring is carried out, and TLC monitors that the compound IV basically reacts completely. Cooling, controlling the temperature of the reaction system to be between 5 and 20 ℃, starting to slowly dropwise add 0.40kg of triethylamine, continuously dropwise adding 0.32kg of toluene solution (0.32 kg of cyclopropylpiperazine and 0.26kg of toluene) of cyclopropylpiperazine into the reaction system after the dropwise adding is completed, controlling the temperature of the reaction system to be between 5 and 20 ℃ in the dropwise adding process, and keeping the dropwise adding time period to be about 2 to 3 hours; after the dripping is finished, the temperature of the reaction system is controlled between 5 ℃ and 20 ℃ to continue stirring reaction, and TLC monitors that the raw material reaction is complete. 3.00kg of water was added dropwise to the reaction system, followed by stirring for 3 to 4 hours. Discharging and centrifuging, recrystallizing the crude product, and drying to obtain a refined product of the compound I, wherein the purity is more than 99%.
Example 4
(1) Preparation of Compound III
50g of compound II and 500g of DMSO are added into a 1L four-necked flask, the mixture is stirred and heated to 25-30 ℃, 22g of triethylamine is added, the reaction is carried out for 15min under the heat preservation, the system is gradually dissolved, and TLC monitors that the compound I is completely reacted. Regulating pH to 1-2 with 6M hydrochloric acid, standing and separating; the organic phase was washed with 1L of saturated salt water for 2 times and dried over anhydrous sodium sulfate; concentrating under reduced pressure until no solvent is present. 45g of acetonitrile and 250g of water were added, at which time the system precipitated an oil; cooling to 20-25deg.C, making the oily substance into viscous substance, and dripping mixed solvent of ethyl acetate (50 mL) and petroleum ether (100 mL); a large amount of solid is precipitated after stirring for 1 h; suction filtration, rinsing the filter cake with water, and drying the filter cake under reduced pressure to constant weight to obtain 48.5g of solid with the purity of 98%.
(2) Preparation of Compound IV
To a 250ml three-necked flask, 20g of Compound III and 100mL of HF were added, 9.7g of pyridine was added, and 7.3g (127 mmol,1.8 eq) of 85% hydrazine hydrate was started to be added dropwise, and the temperature was raised to about 95℃and the reaction was allowed to proceed overnight. TLC monitored reaction was complete. The solvent is distilled off under reduced pressure, water is added, the pH is regulated to 2 to 3 by hydrochloric acid, a large amount of solid is separated out, and suction filtration is carried out. The filter cake is dried to obtain 20g of yellow solid with purity more than 96%.
(3) Preparation of Compound I (Olaparib)
2.6kg of toluene, 0.52kg of compound IV and 0.017kg of triethylamine are added into a 5L reaction bottle, stirring is carried out, the temperature is raised to 75-80 ℃, 245g of thionyl chloride is slowly added, the reaction is carried out after dripping, the temperature is maintained, stirring is carried out, and TLC monitors that the compound IV is basically reacted completely. Cooling, controlling the temperature of the reaction system to be between 5 and 20 ℃, starting to slowly dropwise add 0.40kg of triethylamine, continuously dropwise adding 0.32kg of toluene solution (0.32 kg of cyclopropylpiperazine and 0.26kg of toluene) of cyclopropylpiperazine into the reaction system after the dropwise adding is completed, controlling the temperature of the reaction system to be between 5 and 20 ℃ in the dropwise adding process, and keeping the dropwise adding time period to be about 2 to 3 hours; after the dripping is finished, the temperature of the reaction system is controlled between 5 ℃ and 20 ℃ to continue stirring reaction, and TLC monitors that the raw material reaction is complete. 3.00kg of water was added dropwise to the reaction system, followed by stirring for 3 to 4 hours. Discharging and centrifuging, recrystallizing the crude product, and drying to obtain a refined product of the compound I, wherein the purity is more than 99%.
Example 5
(1) Preparation of Compound III
50g of compound II and 500g of DMF are added into a 1L four-necked flask, the mixture is stirred, the temperature is raised to 25-30 ℃, 23g of DMAP is added, the reaction is carried out for 15min under the heat preservation, the system is gradually dissolved, and TLC monitors that the reaction of compound I is complete. Regulating the pH to 1-2 by using 6M hydrochloric acid, standing and separating liquid; the organic phase was washed with 1L of saturated salt water for 2 times and dried over anhydrous sodium sulfate; concentrating under reduced pressure until no solvent is present. 45g of acetonitrile and 250g of water were added, at which time the system precipitated an oil; cooling to 20-25deg.C, making the oily substance into viscous substance, and dripping mixed solvent of ethyl acetate (50 mL) and petroleum ether (100 mL); a large amount of solid is precipitated after stirring for 1 h; suction filtering, rinsing the filter cake with water, and drying the filter cake under reduced pressure until the weight is constant, wherein the purity of the product is 98.4%.
(2) Preparation of Compound IV
To a 250ml three-necked flask, 20g of Compound III (70.6 mmol,1.0 eq) and 100ml of LDMF were added, 15g of DMAP was added, and the dropwise addition of 7.3g (127 mmol,1.8 eq) of 85% hydrazine hydrate was started, and the temperature was raised to about 90℃and the reaction was allowed to stand overnight. TLC monitored reaction was complete. The solvent is distilled off under reduced pressure, water is added, the pH is regulated to 2 to 3 by hydrochloric acid, a large amount of solid is separated out, and suction filtration is carried out. The filter cake was dried to give 20.5g of a yellow solid with a purity > 96%.
(3) Preparation of Compound I (Olaparib)
2.6kg of toluene, 0.52kg of compound IV and 0.014kg of pyridine are added into a 5L reaction bottle, stirring is carried out, the temperature is raised to 70-75 ℃, 245g of thionyl chloride is slowly added, the reaction is carried out after the dripping, the temperature is maintained, stirring is carried out, and TLC monitors that the compound IV is basically reacted completely. Cooling, controlling the temperature of the reaction system to be between 5 and 20 ℃, starting to slowly dropwise add 0.31kg of pyridine, and continuously dropwise adding 0.32kg of cyclopropylpiperazine (0.32 kg of cyclopropylpiperazine and 0.26kg of toluene) into the reaction system after the dropwise addition is completed, wherein the dropwise addition process controls the temperature of the reaction system to be between 5 and 20 ℃ and the dropwise addition time is about 2 to 3 hours; after the dripping is finished, the temperature of the reaction system is controlled between 5 ℃ and 20 ℃ to continue stirring reaction, and TLC monitors that the raw material reaction is complete. 3.00kg of water was added dropwise to the reaction system, followed by stirring for 3 to 4 hours. Discharging and centrifuging, recrystallizing the crude product, and drying to obtain a refined product of the compound I, wherein the purity is more than 99%.
Claims (4)
1. A method for preparing olapari, comprising the steps of:
(1) Mixing a compound II with a solvent, adding alkali, heating to a reaction temperature, and reacting to obtain a compound III, wherein the solvent is one or more of acetonitrile, THF, DMF, DMSO or water, the alkali is organic alkali or inorganic alkali, and the reaction temperature is 20-30 ℃;
(2) Mixing a compound III with a solvent, adding hydrazine hydrate and alkali, heating to a reaction temperature, and carrying out heat preservation reaction until the reaction is ended to obtain a compound IV, wherein the solvent is one or more of acetonitrile, water, THF, DMF or DMSO; the alkali is organic alkali or inorganic alkali, and the reaction temperature is 90-110 ℃;
(3) Mixing and stirring a compound IV, a catalyst and a solvent, heating to a reaction temperature, adding thionyl chloride, carrying out heat preservation reaction to a reaction end point, cooling, sequentially adding alkali and cyclopropylpiperazine, carrying out heat preservation reaction to complete reaction, and obtaining the Olaparib; the reaction temperature is 70-85 ℃; the catalyst is one or more of DMF, DMAP, triethylamine or pyridine; the solvent is one or more of toluene, xylene, acetonitrile, chloroform or dichloromethane; the base is one or more of triethylamine, pyridine or DMAP, and the reaction formula is as follows:
。
2. a process for preparing olapari according to claim 1, wherein: in the step (1), the organic base is one or more of triethylamine, pyridine or DMAP, and the inorganic base is sodium hydroxide or potassium hydroxide.
3. The method of preparing olapari according to claim 1, wherein in the step (2), the organic base is one or more of triethylamine, pyridine or DMAP, and the inorganic base is sodium hydroxide or potassium hydroxide.
4. A process for preparing olapari according to claim 1, wherein: in the step (3), the temperature is reduced to 5-20 ℃.
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