CN106831708A - A kind of synthetic method of new oral cancer therapy drug Nirapairb - Google Patents
A kind of synthetic method of new oral cancer therapy drug Nirapairb Download PDFInfo
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- CN106831708A CN106831708A CN201611031551.XA CN201611031551A CN106831708A CN 106831708 A CN106831708 A CN 106831708A CN 201611031551 A CN201611031551 A CN 201611031551A CN 106831708 A CN106831708 A CN 106831708A
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- 0 CC(C)(C)OC(N(CCC1)CC1c(cc1)ccc1-[n]1nc2c(C(*)=O)cccc2c1)=O Chemical compound CC(C)(C)OC(N(CCC1)CC1c(cc1)ccc1-[n]1nc2c(C(*)=O)cccc2c1)=O 0.000 description 1
- PCHKPVIQAHNQLW-AWEZNQCLSA-N NC(c1cccc2c[n](-c3ccc([C@@H]4CNCCC4)cc3)nc12)=O Chemical compound NC(c1cccc2c[n](-c3ccc([C@@H]4CNCCC4)cc3)nc12)=O PCHKPVIQAHNQLW-AWEZNQCLSA-N 0.000 description 1
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
A kind of synthetic method of new oral cancer therapy drug Nirapairb, the method includes oxidized initiation material 3 methyl, 2 methyl-bromobenzoates, aldimine condensation, cyclization, and the series reaction such as amidatioon, de- BOC, chiral resolution obtains the optical voidness Niraparib that purity is up to 98.2%.The method is simple to operate, and synthesis step is few, easily-controlled reaction conditions, it is adaptable to industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of synthesis side of new oral cancer therapy drug Nirapairb
Method.
Background technology
Nirapairb is a kind of oral Poly ADP-ribose polymerase researched and developed by biotech company of U.S. Tesaro
(PARP) inhibitor, its chemical name is 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides, can be suppressed thin
Reparation of the born of the same parents to DNA damage, it is adaptable to the cancer of BRCA1/2 gene mutations, such as oophoroma and breast cancer.For with BRCA
For the cancer cell of gene mutation, if PARP activity is further suppressed, a large amount of DNA will be produced during these cell divisions
Damage, cause cancer cell death.In a completed key name is for the III clinical trial phases of NOVA, researcher has recruited 500
Whether there is the patient of recurrence in the several oophoromas after platinum-based chemotherapy, and carry BRCA gene mutations according to reproduction cell, will suffer from
Person has been divided into two groups.In group of the reproduction cell with BRCA mutation, after first time chemotherapy, if keeping daily oral
Once, " middle position Progression free survival time " is 21 months to Niraparib, and control group is using the patient of placebo, only short
5.5 months.This clinical effectiveness shows that Nirapairb is opened up in reproduction cell in the treatment of cancer treatment with BRCA gene mutations
Extremely good curative effect is showed.
At present, the relevant patent document of synthetic method in the prior art for Niraparib includes Preparation
of pharmaceutically acceptable salts of(3S)-3-[4-[7-(aminocarbonyl)-2H-
indazol-2-yl]phenyl]piperidines as inhibitors of poly(ADP-ribose)polymerase
(PARP), Preparation of piperidinylphenylindazolylcarboxamide for use as poly
(ADP-ribose) polymerase inhibitors etc., disclose a pharmaceutical chemistry synthetic route and to Niraparib's
Discovery procedure has carried out detailed discussion.Specific synthetic route is as follows：
The synthetic route with 3- methyl -2- nitrobenzoic acids as initiation material, by with methyl alcohol under conditions of acyl chlorides ester
Change obtains compound A, A in benzoyl peroxide and the CCl of NBS4It is heated to reflux in solution 12 hours, bromination obtains compound B.B with
Acetonitrile and the oxidation of N-methylmorpholine-N- oxide water solutions obtain intermediate C.The compound C and tert-butyl group -3- (4- aminophenyls)
Piperidines -1- carboxylic acid tert-butyl esters are stirred at reflux in ethanol solution and obtain intermediate D.Compound D and sodium azide and DMF mixtures
Reaction, cyclization forms intermediate E.Compound E is passed through NH in methanol solution360 DEG C of acylated intermediate F of heating.Compound F
Hydrochloric acid is added in ethyl acetate and dioxane, BOC groups is sloughed and is obtained intermediate G, through Chiralpak AS-H positives
Chiral chromatographic column splits and obtains target compound S type rotamers Niraparib.The synthetic route is more long, is difficult to realize greatly
The industrial production of scale.
The content of the invention
In order to overcome the above-mentioned deficiencies of the prior art, it is an object of the invention to provide a kind of new oral cancer therapy drug
The synthetic method of Nirapairb, simple to operate, synthesis step is few, easily-controlled reaction conditions, it is adaptable to industrialized production.
To achieve these goals, the technical solution adopted by the present invention is：
A kind of synthetic method of new oral cancer therapy drug Nirapairb, synthetic route is as follows：
The synthetic method of described intermediate (I), takes a certain amount of initiation material 3- methyl -2- methyl-bromobenzoates and is placed in three
Mouth flask, selenium dioxide is dissolved in Isosorbide-5-Nitrae-dioxane, and in the lower addition reaction material of stirring, reflux oxidation causes 3 at 80 DEG C
Position methyl is converted into aldehyde radical and obtains intermediate (I).
The synthetic method of described intermediate (II), by intermediate (I) and compoundWith anhydrous second
Alcohol makees solvent, then be slowly added dropwise a certain amount of glacial acetic acid as catalyst heating reflux reaction 2 hours intermediate (II).
The structure such as formula (III) of described intermediate (III)：
Synthesis step：Intermediate (II) and NaN3Reagent is being heated under conditions of CuI is as catalyst in solvent DMSO
Back flow reaction obtains intermediate (III) in 12 hours.
The structure such as formula (IV) of described intermediate (IV)：
Synthesis step：Intermediate (III) is solvent in the presence of sodium methoxide, formamide with methyl alcohol, and methyl esters ammonification is formed
Acid amides.
Described intermediate (III) obtains intermediate (V) in dichloromethane with the de- BOC groups of TFMS reaction.
The fractionation of described Niraparib, Niraparib structures such as formula Niraparib：
Synthesis step：Niraparib crude products are dissolved in the dissolving that flowed back in organic solvent, N- acetyl-L-tyrosines, drop is added
Warm crystallization, separates solid crystal, obtains NiraparibN- acetyl-L-tyrosine salt.It is dissolved in pure water, is hydrogenated with oxygen
Change sodium solution alkalization, be subsequently adding ethyl acetate point liquid extraction, washing is drying to obtain Niraparib.
N- acetyl-L-tyrosines have been used in described crystallization process.
The synthetic method of described intermediate (V), described de- Boc protection reactions prepare the solvent used by intermediate (V)
Selected from methyl alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, adjacent diformazan
One kind in benzene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, POCl3
Or several mixtures, preferably dichloromethane, it is room temperature to take off BOC institutes temperature in use.
More detailed step is described as follows：
1) preparation of intermediate (I)：Initiation material is prepared after intermediate (I) can use the halogenation of 3 methyl elder generations and is hydrolyzed into alcohol
Reoxidize or oxidant direct oxidation, optional oxidant has acid KMnO4Aldehyde, SeO are oxidized to Deng strong oxidizer control2, brand-new
MnO4Deng preferably SeO2；
2) intermediate (I) and reactantFlowed back 2 hours in absolute ethyl alcohol, while ice vinegar is added dropwise
Acid obtains intermediate (II) as catalyst reaction；
3) intermediate (II) and NaN3Reagent selects DMSO to heat to obtain intermediate (III) for solvent under CuI catalytic action；
4) in the presence of sodium methoxide, formamide, methyl esters ammonification forms acid amides to intermediate (III), obtains intermediate (IV)；
5) the de- BOC groups of intermediate (IV) obtain compound (V), the preferred TFMS of reaction reagent, described de- BOC
Solvent selection is dichloromethane；
6) mol ratio of material is compound (IV) during above-mentioned de- BOC：DCM：TfOH=1:1.5:1, it is slowly added dropwise
TfOH, it is complete to be stirred at room temperature reaction in about 2 hours or so, to be evaporated that obtain be compound (V)；
7) fractionation of Niraparib：Niraparib crude products are dissolved in the dissolving that flowed back in organic solvent, N- acetyl-L- is added
Tyrosine, crystallization of lowering the temperature, separates solid crystal, dries, and obtains optical voidness Niraparib.Preferred N- acetyl-L-tyrosines with
The mass ratio of Niraparib crude products is 3~4:1；
8) N- acetyl-L-tyrosines of the present invention and the mass ratio of Niraparib crude products are 0.5~5:1, preferably 3
~4:1.
The beneficial effects of the invention are as follows：
Synthetic route is short, and processing step is simple, and reaction condition is gentle, and without complicated purification process, invention route is novel,
Obtain multiple brand-new intermediates in building-up process, and intermediate is stable in properties, post-processes simple and convenient, versus environmental friend
It is good.Target product yield and purity are higher, it is adaptable to industrialized production.
Brief description of the drawings
Fig. 1 is Niraparib HPLC chromatograms.
Specific embodiment
The present invention is further discussed below with reference to embodiments, but the present invention is not limited to following examples.
Compound (I)Synthesis
Weigh reaction initiation material 3- methyl 2- methyl-bromobenzoates 50ml (218mmol) to be placed in there-necked flask, just
Selenium dioxide 5g (45mmol) is dissolved in Isosorbide-5-Nitrae-dioxane 50ml (568mmol), is added dropwise in reaction solution under stirring, will be reacted
Temperature rises to 80 DEG C and is heated to reflux 5 hours, and reaction is cooled to room temperature after terminating, and reaction solution is washed with pure water, is dried, evaporation solvent
Purified after column chromatography afterwards, obtain final products about 21.5g, molar yield is 88.5%, column chromatography condition:N-hexane：Ethyl acetate
=10:1.
1H-NMR(400MHz,DMSO-d6)δ:10.36(1H,s),8.22(1H,d),7.99(1H,d),7.58(1H,t),
3.89(3H,s)；13C-NMR(100MHz,DMSO-d6)δ:191.0,165.5,139.9,136.4,132.2,132.1,
128.1,125.9,51.5；HRMS(ESI)calcd.for C9H7BrO3[M+H]+,242.9579；found,242.9581.
Compound (II)Synthesis
By compound (I) about 20g (82mmol), reactantAbout 25g (90mmol) is dissolved in 300ml
In absolute ethyl alcohol, reaction temperature rises to 70 DEG C or so, is heated to reflux 2h, and reaction stands reactant (II) crude product of filtering after terminating
About 21.5g, molar yield 81% will be filtrated to get during crude product is dissolved in absolute ethyl alcohol and be heated to reflux two hours, stand recrystallization, obtain
Crystallization product.(compound (II))
1H-NMR(400MHz,DMSO-d6)(ppm)δ:8.50 (2H, q, J=7.5Hz, J=7.6Hz) 8.25 (1H, d, J
=8.1Hz) 8.19 (1H, q, J=7.5Hz, J=7.6Hz), 8.11 (1H, d, J=8.1Hz) 7.86 (1H, q, J=7.6Hz, J
=7.5Hz), 7.50 (2H, q, J=7.6Hz, J=7.5Hz), 3.89 (3H, s), 3.62 (2H, d, J=8.2Hz), 3.34 (2H,
D, J=8.2Hz), 2.78 (1H, m), 1.79 (2H, m), 1.48 (2H, m), 1.38 (9H, s)；13C-NMR(75MHz,DMSO-d6)
δ(ppm):164.3,153.7,149.9,141.3,133.3,128.4,127.8,122.8,116.9,79.8,57.0,49.0,
40.5,30.5,28.4,22.7；HRMS(ESI)for(M+H)+:calcd:407.22,found:408.22
Compound (III)Synthesis
By 25g (60mmol) compound (II) reactant NaN3About 20g (307mmol) is dissolved in 250mlDMSO solvents, together
When add catalyst CUI about 10g (53mmol) to be sufficiently mixed after, reaction temperature is risen into 120 DEG C of heating reflux reactions 12 hours,
Reaction is cooled to room temperature after terminating.Cooling mixed liquid is poured into 300ml ethyl acetate, is washed, MgSO4 is dried, under reduced pressure
Purified by column chromatography after evaporation solvent, obtain final products about 22.4g, molar yield is 86.7%.Column chromatography condition:Just oneself
Alkane：Ethyl acetate=10:1
1H-NMR(400MHz,CDCl3,300K)d 8.51(1H,s),8.13(1H,d),7.95(1H,d,),7.91(2H,
d),7.39(2H,d),7.18(1H,t),4.30-4.10(2H,m),4.00(3H,s),2.85-2.70(3H,m),2.11-2.03
(1H,m),1.83-1.75(1H,m),1.73-1.53(2H,m),1.48(9H,s).
13C-NMR(75MHz,DMSO-d6)δ(ppm):167.1,153.2,145.6,136.9,128.7,124.3,
120.6,112.0,79.8,57.0,51.5,49.0,40.5,30.5,28.4,22.7；HRMS(ESI)for(M+H)+:calcd:
435.22,found:436.22
Compound (IV)Synthesis
17.2g (41mmol) compound (III) is dissolved in 100mL dry DMFs at 0 DEG C, to adding 13mL in this solution
(328mmol) formamide, 3.3g (62mmol) sodium methoxide, are warming up to 40 DEG C of reaction 3.5h.Reaction solution is cooled to room temperature, is poured into
In 400mL water, stir 1 hour, suction filtration, dry, obtain compound (IV) crude product 17.23g (theoretical yield is 13.78g), mole receipts
Rate is 87%.Compound (IV) crude product 10.0g is added to 80mL dioxane-water (volume ratio 8 at room temperature:1) mixing is molten
In agent, 101 DEG C are warming up to, complete molten rear addition 0.2g (mass fraction 2%) activated carbon of solid continues to flow back 0.5 hour, takes out while hot
Filter, filtrate is cooled to 0 DEG C, stands 2 hours (precipitation white needle-like crystals), and suction filtration is dried, and separates out crystal (compound (IV)).
1H NMR (400MHz, CDCl3,300K) d 9.04 (1H, br.s), 8.51 (1H, s), 8.31 (1H, d, J=
8.3Hz), 7.91 (1H, d, J=8.3Hz), 7.84 (2H, d, J=8.2Hz), 7.42 (2H, d, J=8.2Hz), 7.31-7.22
(1H,m),5.95(1H,br.s),4.40-4.05(2H,m),2.90-2.70(3H,m),2.15-2.00(1H,m),1.85-
1.75(1H,m),1.75-1.50(2H,m),1.48(9H,s).13CNMR(75MHz,DMSO-d6)δ(ppm):168.0,
153.2,143.2,136.9,128.7,126.7,125.0,124.1,120.8,115.0,79.8,57.0,49.0,
30.5,40.5,28.4,22.7,HRMS(ESI)for(M+H)+:calcd:420.22,found:421.22
Compound (V)Synthesis
18g compounds (III) (42mmol) are added in 180ml dichloromethane, TFMS solution, stirring is added dropwise
Overnight, sodium hydrate aqueous solution is added, organic phase is collected, is dried, be concentrated to give 11.2g compounds (V), molar yield is
83.33%.
1H NMR(400MHz,DMSO-d6,300K)d 9.32(1H,s),9.12(1H,br.s),8.87(1H,br.s),
8.55 (1H, br.s), 8.13 (2H, d, J=8.6Hz), 8.06 (1H, J=7.0Hz), 8.02 (1H, d, J=8.4Hz), 7.89
(1H, br.s), and 7.55 (2H, d, J=8.6Hz), 7.27 (1H, dd, J=8.4,7.0Hz), 3.43-3.27 (2H, m), 3.17-
3.03(2H,m),3.00-2.85
(1H,m),2.00-1.70(4H,m).13CNMR(75MHz,DMSO-d6)δ(ppm):168.0,143.2,136.9,
128.7,126.7,124.1,120.8,115.0,52.4,48.6,43.3,30.5,25.5.HRMS(ESI)for(M+H)+:
calcd:320.16,found:321.16
NiraparibSynthesis
100g compounds (IV) are added in 1000ml absolute ethyl alcohols, add 350g N- acetyl-L-tyrosines to be heated to
Back flow reaction 0.5 hour, is then cooled to -10~0 DEG C of crystallization by system, is filtrated to get solid；By solid 200ml pure water essence
System, obtains the N- acetyl-L-tyrosine salt 97.6g of Niraparib, molar yield 66.39%.
During the N- acetyl-L-tyrosine salt 4.5g of Niraparib added into 25ml pure water, then under the conditions of normal temperature water-bath plus
Enter sodium hydroxide solution 1.3g, be subsequently adding ethyl acetate 45.0ml, be stirred at room temperature to clarification.Liquid, water is divided mutually to use 45.0ml again
Ethyl acetate is extracted, and merges organic phase；Washed with water 15ml and saturated nacl aqueous solution 15ml successively, use anhydrous sulphur
Sour sodium is filtered after drying, and filtrate is concentrated to dryness, and solid taken out after forced air drying to obtain into Niraparib 2.88g, yield 94.2%,
HPLC purity 98.2% (chromatogram below figure 1), is obtained using the Spherisorb ODS2 150mmx4.6mm of Waters companies
Ee values are 99.7%.
1H-NMR (400MHz, DMSO-d6,300K) d 8.52 (1H, s), 8.17 (1H, br, d), 8.03 (1H, d, J=
7.2Hz), 7.66 (1H, q, J=8.4Hz), 7.54 (2H, t), 7.50 (2H, br.s), 7.30 (2H, d, J=8.4Hz), 3.15-
2.90(2H,d),2.78(1H,m),
2.76-2.73(2H,t),2.0(1H,m),1.92-1.67(2H,q),1.53-1.43(2H,m).13C-NMR
(75MHz,DMSO-d6)
δ(ppm):168.0,143.2,136.9,128.7,126.7,125.0,124.1,115.0,52.4,43.3,
48.6,30.5,25.5,HRMS(ESI)for(M+H)+:calcd:352.14,found:353.1。
Claims (9)
1. a kind of synthetic method of new oral cancer therapy drug Nirapairb, it is characterised in that synthetic route is as follows：
2. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 1, it is characterised in that
The synthetic method of intermediate (I), takes a certain amount of initiation material 3- methyl -2- methyl-bromobenzoates and is placed in there-necked flask, by dioxy
Change selenium to be dissolved in Isosorbide-5-Nitrae-dioxane, in the lower addition reaction material of stirring, reflux oxidation causes that 3 methyl are converted into aldehyde at 80 DEG C
Base obtains intermediate (I).
3. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 1, it is characterised in that
The synthetic method of intermediate (II), by intermediate (I) and compoundSolvent is done with absolute ethyl alcohol, then
It is slowly added dropwise a certain amount of glacial acetic acid and obtains intermediate (II) within 2 hours as catalyst heating reflux reaction.
4. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 1, it is characterised in that
The structure such as formula (III) of intermediate (III)：
Synthesis step：Intermediate (II) and NaN3Reagent is being heated to reflux instead under conditions of CuI is as catalyst in solvent DMSO
Answer 12 hours to obtain intermediate (III).
5. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 1, it is characterised in that
The structure such as formula (IV) of intermediate (IV)：
Synthesis step：Intermediate (III) is solvent in the presence of sodium methoxide, formamide with methyl alcohol, and methyl esters ammonification forms acid amides.
6. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 1, it is characterised in that
Intermediate (III) obtains intermediate (V) in dichloromethane with the de- BOC groups of TFMS reaction.
7. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 1, it is characterised in that
The fractionation of Niraparib, Niraparib structures such as formula Niraparib：
Synthesis step：Niraparib crude products are dissolved in the dissolving that flowed back in organic solvent, N- acetyl-L-tyrosines, cooling analysis is added
Crystalline substance, separates solid crystal, obtains NiraparibN- acetyl-L-tyrosine salt.It is dissolved in pure water, is hydrogenated with sodium oxide molybdena
It is basified, ethyl acetate point liquid extraction is subsequently adding, washing is drying to obtain Niraparib.
8. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 7, it is characterised in that
N- acetyl-L-tyrosines have been used in crystallization process.
9. the synthetic method of a kind of new oral cancer therapy drug Nirapairb according to claim 6, it is characterised in that
The synthetic method of intermediate (V), the solvent that described de- Boc protections reaction is prepared used by intermediate (V) be selected from methyl alcohol, ethanol,
Normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, two
One or more mixtures in toluene, DMF, DMA, acetonitrile, POCl3, preferably
Dichloromethane, it is room temperature to take off BOC institutes temperature in use.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A kind of new method preparing Ni Lapani and its intermediate |
| US20200017462A1 (en) | 2017-03-27 | 2020-01-16 | Tesaro, Inc. | Niraparib compositions |
| US11730725B2 (en) | 2017-09-26 | 2023-08-22 | Tesaro, Inc. | Niraparib formulations |
-
2016
- 2016-11-22 CN CN201611031551.XA patent/CN106831708A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20200017462A1 (en) | 2017-03-27 | 2020-01-16 | Tesaro, Inc. | Niraparib compositions |
| US11091459B2 (en) | 2017-03-27 | 2021-08-17 | Tesaro, Inc. | Niraparib compositions |
| US11673877B2 (en) | 2017-03-27 | 2023-06-13 | Tesaro, Inc. | Niraparib compositions |
| US11730725B2 (en) | 2017-09-26 | 2023-08-22 | Tesaro, Inc. | Niraparib formulations |
| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A kind of new method preparing Ni Lapani and its intermediate |
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