1038915-60-4

Basic information

• Product Name: Niraparib
• Synonyms: (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide;MK-4827,(S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxaMide;Niraparib;2-[4-((3S)-3-Piperidinyl)phenyl]-2H-indazole-7-carboxamide;MK4827 (Niraparib);2H-Indazole-7-carboxamide, 2-[4-(3S)-3-piperidinylphenyl]-;(S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide hydrocholoride;Niraparib (MK-4827)
• CAS NO: 1038915-60-4
• Molecular Formula: C₁₉H₂₀N₄O
• Molecular Weight: 320.3883
• Product Categories: API;Anti-cancer&immunity
• Mol File: 1038915-60-4.mol
• Article Data: 14

Chemical Properties

• Boiling Point: 463.619 °C at 760 mmHg
• Flash Point: 234.188 °C
• Appearance: /
• Density: 1.34
• Storage Temp.: 2-8°C(protect from light)
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 15.36±0.30(Predicted)
• CAS DataBase Reference: Niraparib(CAS DataBase Reference)
• NIST Chemistry Reference: Niraparib(1038915-60-4)
• EPA Substance Registry System: Niraparib(1038915-60-4)

Safety Data

• Hazardous Substances Data: 1038915-60-4(Hazardous Substances Data)

Usage

Uses

Niraparib is a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.

Description

(S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide is also known as MK-4827(Niraparib) tosylate is a selective inhibitor of PARP1/PARP2 (The poly(ADP-ribose) polymerase) with great activity in cancer cells with mutant BRCA-1 and BRCA-2. It has been recently approved by FDA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death.

Pharmacology

The synthesis and initial pharmacology of niraparib have been published. Niraparib has affinity for PARP 1 and 2 inhibition (IC50 = 3.8 and 2.1 nM, respectively) and inhibits the proliferation of cancer cells with mutant BRCA1 and BRCA2 with IC50 values in the 10–100 nM range in vitro. Niraparib demonstrated efficacy as a single agent in a xenograft model of BRCA1-deficient cancer. Niraparib has also been reported to act as a preclinical radiosensitiser and has entered into clinical oncology trials.

in vitro

mk-4827displayed excellent parp 1 and 2 inhibition with ic50 of 3.8 and 2.1 nm, respectively. in a whole cell assay, mk-4827 inhibited parp activity with ec50 of 4 nm. mk-4827 also inhibited proliferation of cancer cells with mutant brca-1 and brca-2 with cc50 in the 10-100 nm range[1].

in vivo

in a variety of human tumor xenografts of differing p53 status,mk-4827 showed high potential to improve the efficacy of radiotherapy,such as calu-6 (p53 null), a549 (p53 wild-type [wt]) and h-460 (p53 wt) lung cancers and triple negative mda-mb-231 human breast carcinoma [3].

References

https://newdrugapprovals.org/2016/12/22/niraparib-mk-4827/ https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm548487.htm https://www.drugbank.ca/drugs/DB11793 Sandhu, Shahneen K, et al. "The poly (ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA, mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial." Lancet Oncology14.9 (2013):882. Jones, P, et al. "Niraparib: A Poly (ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination. " Journal of Medicinal Chemistry 58.8(2015):3302-14.

Synthetic route

C27H36N4O2S → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 40℃; for 3h;	95%

C19H20N4O*C11H13NO4 → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
With sodium hydroxide In water; ethyl acetate at 20℃;	94.2%

formaldehyd (50-00-0) + (S)-2-{[4-(piperidin-3-yl)phenyl]azo}benzamide → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; cobalt(III) acetylacetonate In 1,4-dioxane at 100℃; for 0.333333h; Temperature; Reagent/catalyst; Solvent; Microwave irradiation;	93%

2-[4-(3-piperidinyl)phenyl]-2H-indazole-7-carboxamide → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
With N-Ac-Leu In methanol at 70℃; for 1h;	91.2%

2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonic acid salt (1038915-73-9) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
With sodium hydroxide In 2-methyltetrahydrofuran at 20℃; for 0.5h;	75.9%
With sodium hydroxide In 2-methyltetrahydrofuran; water at 20℃; for 0.5h;	75.9%

racemic 3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidinium chloride (1038915-56-8) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4) + 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (1038915-58-0)

Conditions	Yield
With diethylamine In isopropyl alcohol at 35℃; under 75007.5 Torr; Purification / work up; Resolution of racemate;
With carbon dioxide Resolution of racemate; Supercritical conditions; optical yield given as %ee;

tert-butyl 3-[4-({[3-(methoxycarbonyl)-2-nitrophenyl]methylene}amino)phenyl]piperidine-1-carboxylate (1038915-99-9) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethyl phosphite / 24 h / 92 °C 2: formamide; sodium methylate / N,N-dimethyl-formamide / 3.5 h / 0 - 40 °C 3: trifluoroacetic acid / dichloromethane / 20 h 4: N-Ac-Leu / methanol / 1 h / 70 °C View Scheme

methyl 2-{4-[1-(tert-butoxycarbonyl)piperidin-3-yl]phenyl}-2H-indazole-7-carboxylate (1038915-90-0) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: formamide; sodium methylate / N,N-dimethyl-formamide / 3.5 h / 0 - 40 °C 2: trifluoroacetic acid / dichloromethane / 20 h 3: N-Ac-Leu / methanol / 1 h / 70 °C View Scheme
Multi-step reaction with 4 steps 1: sodium methylate / N,N-dimethyl-formamide / 3.5 h / 40 °C 2: trifluorormethanesulfonic acid / dichloromethane 3: ethanol / 0.5 h / Reflux 4: sodium hydroxide / water; ethyl acetate / 20 °C View Scheme

3-methyl-2-nitrobenzoic acid (5437-38-7) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 7 steps 1: sulfuric acid / 58 °C 2: manganese(IV) oxide; nitric acid / 40 °C 3: sodium hydrogencarbonate; acetic acid / 2 h / 40 °C 4: triethyl phosphite / 24 h / 92 °C 5: formamide; sodium methylate / N,N-dimethyl-formamide / 3.5 h / 0 - 40 °C 6: trifluoroacetic acid / dichloromethane / 20 h 7: N-Ac-Leu / methanol / 1 h / 70 °C View Scheme

methyl 3-methyl-2-nitrobenzoate (5471-82-9) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: manganese(IV) oxide; nitric acid / 40 °C 2: sodium hydrogencarbonate; acetic acid / 2 h / 40 °C 3: triethyl phosphite / 24 h / 92 °C 4: formamide; sodium methylate / N,N-dimethyl-formamide / 3.5 h / 0 - 40 °C 5: trifluoroacetic acid / dichloromethane / 20 h 6: N-Ac-Leu / methanol / 1 h / 70 °C View Scheme
Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide / 18 h / 130 °C 2.1: sodium periodate / N,N-dimethyl-formamide / 3.5 h / 20 °C 3.1: hexane / 18 h / Reflux 4.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 5.1: ammonium bicarbonate / methanol / 12 h / 100 °C 5.2: 3 h / 20 °C / pH Ca. 3 View Scheme
Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide / 18 h / 130 °C 2.1: sodium periodate / N,N-dimethyl-formamide / 3.5 h / 20 °C 3.1: hexane / 18 h / Reflux 4.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 5.1: ammonium bicarbonate / methanol / 12 h / 100 °C 5.2: 3 h / 20 °C / pH Ca.3 View Scheme

3-formyl-2-nitrobenzoic acid methyl ester (138229-59-1) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydrogencarbonate; acetic acid / 2 h / 40 °C 2: triethyl phosphite / 24 h / 92 °C 3: formamide; sodium methylate / N,N-dimethyl-formamide / 3.5 h / 0 - 40 °C 4: trifluoroacetic acid / dichloromethane / 20 h 5: N-Ac-Leu / methanol / 1 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1.1: hexane / 18 h / Reflux 2.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 3.1: ammonium bicarbonate / methanol / 12 h / 100 °C 3.2: 3 h / 20 °C / pH Ca. 3 View Scheme
Multi-step reaction with 3 steps 1.1: hexane / 18 h / Reflux 2.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 3.1: ammonium bicarbonate / methanol / 12 h / 100 °C 3.2: 3 h / 20 °C / pH Ca.3 View Scheme

β-(dimethylamino)-3-carbomethoxy-2-nitrostyrene (68109-89-7, 93247-79-1) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium periodate / N,N-dimethyl-formamide / 3.5 h / 20 °C 2.1: hexane / 18 h / Reflux 3.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 4.1: ammonium bicarbonate / methanol / 12 h / 100 °C 4.2: 3 h / 20 °C / pH Ca. 3 View Scheme
Multi-step reaction with 4 steps 1.1: sodium periodate / N,N-dimethyl-formamide / 3.5 h / 20 °C 2.1: hexane / 18 h / Reflux 3.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 4.1: ammonium bicarbonate / methanol / 12 h / 100 °C 4.2: 3 h / 20 °C / pH Ca.3 View Scheme

18-(nitrobenzylideneamino)phenylpiperidine-1-carboxylate (1312106-32-3) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 2.1: ammonium bicarbonate / methanol / 12 h / 100 °C 2.2: 3 h / 20 °C / pH Ca. 3 View Scheme

2-[4-((3S)-(tertbutoxycarbonyl)piperidin-3-yl)phenyl]-2H-indazole-7-carboxylic acid methyl ester (1196713-67-3) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Stage #1: 2-[4-((3S)-(tertbutoxycarbonyl)piperidin-3-yl)phenyl]-2H-indazole-7-carboxylic acid methyl ester With ammonium bicarbonate In methanol at 100℃; for 12h; Stage #2: With hydrogenchloride In methanol; water at 20℃; for 3h; pH=Ca. 3;	8.2 g
Stage #1: 2-[4-((3S)-(tertbutoxycarbonyl)piperidin-3-yl)phenyl]-2H-indazole-7-carboxylic acid methyl ester With ammonium bicarbonate In methanol at 100℃; for 12h; Stage #2: With hydrogenchloride In water at 20℃; for 3h; pH=Ca.3;	8.2 g

3-(4'-nitrophenyl)pyridine (4282-46-6) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 10 h / 110 °C 2.1: sodium tetrahydroborate; methanol / 8.5 h / 3 - 20 °C 2.2: 24 h / 9120.61 Torr / Autoclave 3.1: L-Tartaric acid / acetonitrile / 10 °C / Reflux 4.1: sodium hydroxide; triethylamine; dmap / dichloromethane / 8 h / 20 °C 5.1: hexane / 18 h / Reflux 6.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 7.1: ammonium bicarbonate / methanol / 12 h / 100 °C 7.2: 3 h / 20 °C / pH Ca. 3 View Scheme

1-benzyl-3-(4-nitrophenyl)pyridinium bromide → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium tetrahydroborate; methanol / 8.5 h / 3 - 20 °C 1.2: 24 h / 9120.61 Torr / Autoclave 2.1: L-Tartaric acid / acetonitrile / 10 °C / Reflux 3.1: sodium hydroxide; triethylamine; dmap / dichloromethane / 8 h / 20 °C 4.1: hexane / 18 h / Reflux 5.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 6.1: ammonium bicarbonate / methanol / 12 h / 100 °C 6.2: 3 h / 20 °C / pH Ca. 3 View Scheme

(3S)-3-(4-aminophenyl)piperidine (1196713-21-9) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide; triethylamine; dmap / dichloromethane / 8 h / 20 °C 2.1: hexane / 18 h / Reflux 3.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 4.1: ammonium bicarbonate / methanol / 12 h / 100 °C 4.2: 3 h / 20 °C / pH Ca. 3 View Scheme

3-(4-aminophenyl)piperidine (19733-56-3) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: L-Tartaric acid / acetonitrile / 10 °C / Reflux 2.1: sodium hydroxide; triethylamine; dmap / dichloromethane / 8 h / 20 °C 3.1: hexane / 18 h / Reflux 4.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 5.1: ammonium bicarbonate / methanol / 12 h / 100 °C 5.2: 3 h / 20 °C / pH Ca. 3 View Scheme
Multi-step reaction with 4 steps 1.1: acetonitrile / 10 °C / Reflux 1.2: 0.33 h 1.3: 8 h / 20 °C 2.1: hexane / 18 h / Reflux 3.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 4.1: ammonium bicarbonate / methanol / 12 h / 100 °C 4.2: 3 h / 20 °C / pH Ca.3 View Scheme

(3S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (1171197-20-8) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hexane / 18 h / Reflux 2.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 3.1: ammonium bicarbonate / methanol / 12 h / 100 °C 3.2: 3 h / 20 °C / pH Ca. 3 View Scheme
Multi-step reaction with 3 steps 1.1: hexane / 18 h / Reflux 2.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 3.1: ammonium bicarbonate / methanol / 12 h / 100 °C 3.2: 3 h / 20 °C / pH Ca.3 View Scheme

tert-butyl 3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}-piperidine-1-carboxylate (1038915-92-2) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: trifluorormethanesulfonic acid / dichloromethane 2: ethanol / 0.5 h / Reflux 3: sodium hydroxide / water; ethyl acetate / 20 °C View Scheme

1-benzyl-3-piperidone (40114-49-6) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / -60 °C / Inert atmosphere 1.2: 8 h / Inert atmosphere; Reflux 2.1: acetonitrile / 10 °C / Reflux 2.2: 0.33 h 2.3: 8 h / 20 °C 3.1: hexane / 18 h / Reflux 4.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 5.1: ammonium bicarbonate / methanol / 12 h / 100 °C 5.2: 3 h / 20 °C / pH Ca.3 View Scheme

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nitrobenzene (171364-83-3) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / -60 °C / Inert atmosphere 1.2: 8 h / Inert atmosphere; Reflux 2.1: acetonitrile / 10 °C / Reflux 2.2: 0.33 h 2.3: 8 h / 20 °C 3.1: hexane / 18 h / Reflux 4.1: sodium azide; 2,6-dimethylpyridine / N,N-dimethyl-formamide / 24 h / 120 °C 5.1: ammonium bicarbonate / methanol / 12 h / 100 °C 5.2: 3 h / 20 °C / pH Ca.3 View Scheme

C25H28BrNO5 → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions

Yield

Multi-step reaction with 6 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 2: triethylamine / dichloromethane / 2 h / 0 °C / Inert atmosphere 3: ammonia / acetonitrile / 2 h / 105 °C 4: sodium hydroxide / water / 20 - 35 °C 5: potassium carbonate; copper(I) bromide; 8-quinolinol; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane / N,N-dimethyl acetamide / 24 h / 110 °C / Inert atmosphere 6: methanesulfonic acid / o-xylene / 3 h / 40 °C View Scheme

C13H19BrO6S2 → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: ammonia / acetonitrile / 2 h / 105 °C 2: sodium hydroxide / water / 20 - 35 °C 3: potassium carbonate; copper(I) bromide; 8-quinolinol; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane / N,N-dimethyl acetamide / 24 h / 110 °C / Inert atmosphere 4: methanesulfonic acid / o-xylene / 3 h / 40 °C View Scheme

4-(3S-piperidine-3-yl)bromobenzene (1335523-82-4) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / water / 20 - 35 °C 2: potassium carbonate; copper(I) bromide; 8-quinolinol; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane / N,N-dimethyl acetamide / 24 h / 110 °C / Inert atmosphere 3: methanesulfonic acid / o-xylene / 3 h / 40 °C View Scheme

(S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester (1476776-55-2) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; copper(I) bromide; 8-quinolinol; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane / N,N-dimethyl acetamide / 24 h / 110 °C / Inert atmosphere 2: methanesulfonic acid / o-xylene / 3 h / 40 °C View Scheme

C8H6N2O2 → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 20 - 35 °C 1.2: 3 h / 45 °C 2.1: potassium carbonate; copper(I) bromide; 8-quinolinol; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane / N,N-dimethyl acetamide / 24 h / 110 °C / Inert atmosphere 3.1: methanesulfonic acid / o-xylene / 3 h / 40 °C View Scheme

C12H15N3O → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; copper(I) bromide; 8-quinolinol; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane / N,N-dimethyl acetamide / 24 h / 110 °C / Inert atmosphere 2: methanesulfonic acid / o-xylene / 3 h / 40 °C View Scheme

(S)-tert-butyl 3-(4-(7-(tert-butylcarbamoyl)-2H-indazol-2-yl)phenyl)piperidine-1-carboxylate (1476776-84-7) → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions	Yield
With methanesulfonic acid In o-xylene at 40℃; for 3h;

C11H15BrO2 → (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4)

Conditions

Yield

Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 2 h / 0 °C / Inert atmosphere 2: ammonia / acetonitrile / 2 h / 105 °C 3: sodium hydroxide / water / 20 - 35 °C 4: potassium carbonate; copper(I) bromide; 8-quinolinol; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane / N,N-dimethyl acetamide / 24 h / 110 °C / Inert atmosphere 5: methanesulfonic acid / o-xylene / 3 h / 40 °C View Scheme

(3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4) + toluene-4-sulfonic acid (104-15-4) → 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonic acid salt (1038915-73-9)

Conditions	Yield
In Isopropyl acetate; dimethyl sulfoxide; isopropyl alcohol at 5 - 70℃; Inert atmosphere;	85%
In water at 20 - 30℃; for 4h; Inert atmosphere;	110 g

(3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4) + D-(+)-camphoric acid (124-83-4) → 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (1R,3S)-(+)-camphorate

Conditions	Yield
In tetrahydrofuran; methanol at 20 - 40℃; for 72h;	75%

(3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4) + (R)-Mandelic Acid (611-71-2) → 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (R)-(-)-mandelate

Conditions	Yield
In tetrahydrofuran; acetonitrile at 20 - 40℃; for 80h;	50.6%

(3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4) + (1S)-10-camphorsulfonic acid (3144-16-9) → 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (1S)-(+)-camsylate

Conditions	Yield
In tetrahydrofuran; acetonitrile at 20 - 40℃;	37%

(3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (1038915-60-4) → (3S)-3-[4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl]piperidinium chloride (1038915-64-8)

Conditions	Yield
With hydrogenchloride In water for 0.25h;

Upstream product

• 108-86-1 bromobenzene 
• 1038915-56-8 racemic 3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidinium chloride 
• 1038915-73-9 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonic acid salt 
• 50-00-0 formaldehyd 
• 41841-16-1 (4-bromo-phenyl)-acetic acid methyl ester 
• 1476776-84-7 (S)-tert-butyl 3-(4-(7-(tert-butylcarbamoyl)-2H-indazol-2-yl)phenyl)piperidine-1-carboxylate 
• 1476776-55-2 (S)-3-(4-bromophenyl)piperidine-1-carboxylic acid tert-butyl ester 
• 1335523-82-4 4-(3S-piperidine-3-yl)bromobenzene 
• 171364-83-3 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nitrobenzene 

Downstream Products

• 1038915-73-9 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonic acid salt 
• 1038915-64-8 (3S)-3-[4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl]piperidinium chloride 

Relevant articles and documents

Niraparib preparation method

The invention provides a niraparib preparation method, which comprises: carrying out photocatalysis on a compound 1 and bromobenzene under a Pd catalyst to obtain a niraparib key intermediate; carrying out chiral resolution on the niraparib key intermediate, and coupling the niraparib key intermediate with NBoc-1H-indazole-7-carboxamide under the catalysis of copper bromide to obtain protected niraparib; and removing the protective color of the protected niraparib under the action of methanesulfonic acid, and obtaining the target product niraparib under tetrahydrofuran pulping. The preparation method of niraparib is simple in synthesis process route, high in preparation efficiency, small in damage to human bodies and the environment and low in synthesis cost.

NIRAPARIB SALTS

Novel salts of niraparib are provided. Also provided are pharmaceutical compositions comprising those salts, as well as methods and uses pertaining to the same.

COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATMENT OF DISEASES INVOLVING ACIDIC OR HYPOXIC DISEASED TISSUES

Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.