571190-30-2

Basic information

• Product Name: OTAVA-BB 1115529
• Synonyms: Palbociclib API;palbociclib (OTAVA-BB 1115529);6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-;6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylammino)-8H-pyrido-[2,3-d]-pyrimidin-7-one;Palbociclib, >=98%;tert-butyl 4-(6-(8-cyclopentyl-5-Methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2,3-d]pyriMidin-2-ylaMino)pyridin-3-yl)piperazine-1-carboxylate (CAS No.866084-31-3);Prabhu past Lieb;6-Acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one
• CAS NO: 571190-30-2
• Molecular Formula: C₂₄H₂₉N₇O₂
• Molecular Weight: 447.54
• EINECS: 1592732-453-0
• Product Categories: Inhibitors;Anticancer;API
• Mol File: 571190-30-2.mol

Chemical Properties

• Melting Point: 200 ºC
• Boiling Point: 711.5 °C at 760 mmHg
• Flash Point: 384.1°C
• Appearance: /
• Density: 1.313 g/cm³
• Vapor Pressure: 4.32E-20mmHg at 25°C
• Refractive Index: 1.647
• Storage Temp.: room temp
• Solubility: Soluble in DMSO (up to 2 mg/ml with warming)
• PKA: 8.66±0.10(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: OTAVA-BB 1115529(CAS DataBase Reference)
• NIST Chemistry Reference: OTAVA-BB 1115529(571190-30-2)
• EPA Substance Registry System: OTAVA-BB 1115529(571190-30-2)

Safety Data

• Hazardous Substances Data: 571190-30-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
OTAVA-BB 1115529 is used as a cyclin-dependent kinase (CDK) 4 and CDK6 inhibitor for the treatment of hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-) metastatic breast cancer. It is administered in combination with letrozole as the first-line hormonal-based therapy in postmenopausal women or with fulvestrant in women with disease progression following hormonal therapy.
Additionally, Pfizer is studying the effectiveness of OTAVA-BB 1115529 in a variety of other cancers at various stages in the clinic, which may lead to its use in different application types and industries in the future.

Indications

Palbociclib (Ibrane(R), Pfizer), a selective CDK4 and CDK6 inhibitor, received accelerated approval from FDA in 2015 for women with estrogen receptor-positive and HER2-negative breast cancer in combination with letrozole.

Biochem/physiol Actions

PF-00080665 (Palbociclib; PD 0332991) is an orally active and highly specific inhibitor against cyclin-dependent kinase 4 & 6 (IC50 = 9, 11, 15 nM, respectively, using CDK4/cycD3, CDK4/cycD1, CDK6/cycD2; IC50 >10 μM against 36 other kinases) that potently suppresses Cdk4/6-dependent cellular Rb phosphorylation (IC50 = 66 nM/pSer780 & 63 nM/pSer795; MDA-MB-435). PF-00080665 exhibits selective antiproliferation activity against Rb-positive human breast/colon/lung/leukemia cancer cultures (IC50 = 40-400 nM; IC50 >3 μM/Rb-negative MDA-MB-468 & H2009) and displays in vivo efficacy against various advanced stage human tumor xenografts in mice (12.5-150 mg/kg/day p.o.).

Clinical Use

Protein kinase inhibitor: Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative locally advanced or metastatic breast cancer

Synthesis

Numerous syntheses of palbociclib have been reported,149,150 and the commercial scale process published by scientists at Pfizer is described herein. The amino-pyridylpiperazine fragment 212 was prepared in two steps. Commercial piperazine 209 was added to 5-bromo-2-nitropyridine (210) to give nitro-pyridine 211 in 93% yield. Hydrogenation of the nitro group using catalytic palladium on carbon provided the amino-pyridylpiperazine 212 in 96% yield. As such, cyclopentylamine (214) was added to 5-bromo-2,4-dichloropyrimidine (213) to give 5-bromo-2-chloro-6-cyclopentylaminopyrimidine (215) in 84% yield. Heck reaction with crotonic acid followed by treating the resulting product with acetic anhydride formed the mixed anhydride under elevated temperatures, and this resulted in cyclization to give pyrimidinone 214 in 81% yield. Bromination using N-bromosuccinimide (NBS) provided coupling partner 217 in 88% yield. Next, aminopyridine 212 was treated with cyclohexylmagnesium chloride and then reacted with 217 to give the SNAr product 218 in 88% yield. A second Heck reaction between bromide 218 and butyl vinyl ether (219) using palladium acetate/bis(2- diphenylphosphinophenyl)ether (DPEPhos) as the catalyst provided enol ether 220 in 84% yield. Exposure of 220 to acidic conditions removed the Boc group from the piperazine while converting the enol ether to the corresponding ketone, providing palbociclib (XXVII) in 90% yield.

Enzyme inhibitor

This orally active, non-ATP-competitive cyclin kinase-directed inhibitor (FW = 483.99 g/mol (mono-HCl); CASs = 827022-32-2 (mono- hydrochloride, 571190-30-2 (free base); Solubility: 10 mg/mL DMSO; 30 mg/mL Water; Formulation: Dissolved in sodium lactate buffer (50 mM, ? pH 4.0) ), also known as PD-0332991, Ibrance, and 6-acetyl-8-cyclopentyl- 5-methyl-2- (5- (piperazin-1-yl) pyridin-2-ylamino) pyrido[2,3-d]pyrimidin- 7 (8H) -one hydrochloride, targets Cdk-4 (Cyclin D1) and Cdk-6 (Cyclin D2), enzymes that participate in the so-called CDK4/6-retinoblastoma signaling pathway governing the cell-cycle restriction point. Palbociclib induces rapid G1 cell-cycle arrest in primary human myeloma cells. This agent also shows significant efficacy in a broad spectrum of human tumor xenografts in vivo, resulting in complete regression in some tumors with no evidence of acquired resistance or ability to circumvent the growth inhibitory properties of this agent. Ibrance received FDA approval in 2015 for combined use with letrozole to treat postmenopausal women with estrogen receptor- positive, (HER2) -negative advanced breast cancer as an initial endocrine- based therapy for metastatic disease. Cyclin Target Selectivity: Cdk1 (weak, if any), Cdk2 (weak, if any), Cdk3 (weak, if any), Cdk4 (IC50 = 11 nM), Cdk5 (weak, if any), Cdk6 (IC50 = 16 nM), Cdk7 (weak, if any), Cdk8 (weak, if any), Cdk9 (weak, if any), Cdk10 (weak, if any).

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration possibly increased by clarithromycin - avoid or reduce palbociclib dose; concentration reduced by rifampicin - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid. Antifungals: concentration possibly increased by itraconazole, ketoconazole, posaconazole and voriconazole - avoid or reduce palbociclib dose. Antipsychotics: increased risk of agranulocytosis with clozapine - avoid. Antivirals: concentration possibly increased by indinavir, lopinavir, ritonavir, saquinavir and telaprevir - avoid or reduce palbociclib dose. Cytotoxics: concentration possibly reduced by enzalutamide - avoid. Grapefruit juice: concentration possibly increased - avoid

Metabolism

Palbociclib undergoes extensive hepatic metabolism. The main metabolic pathways for palbociclib involved oxidation and sulphonation, with acylation and glucuronidation contributing as minor pathways. Unchanged drug accounts for 2.3% and 6.9% of radioactivity in faeces and urine, respectively. In faeces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose.

References

1) El-Rayes?et al.?(2004),?Cyclooxygenase-2-dependent and –independent effects of celecoxib in pancreatic cancer cell lines; Mol. Cancer Ther.,?3?1427 2) Menu?et al.?(2008),?A novel therapeutic combination using PD 0332991 and bortezomib: study in 5T33MM myeloma model; Cancer Res.,?68?5519 3) Valenzuela?et al.?(2017),?Palbociclib-induced autophagy and senescence in gastric cancer cells; Exp. Cell Res.,?360?390 4) Palanisamy?et al.?(2016),?Palbociclib: A new hope in the treatment of breast cancer; J. Cancer Res. Ther.,?12?1220 5) Goel?et al.?(2017),?CDK4/6 inhibition triggers anti-tumour immunity; Nature?548?471 6)6) AbuHammad?et al.?(2019),?Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma; Proc. Natl. Acad. Sci. USA?116?179909

InChI:InChI=1/C24H29N7O2/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29)

Synthetic route

C24H28ClN7O2 → PD 0332991 (571190-30-2)

Conditions	Yield
With hydrogen; sodium hydroxide In ethanol at 40 - 50℃; for 4h; Reagent/catalyst; Solvent;	98.6%
With hydrogen; sodium hydroxide; palladium dichloride In ethanol at 40 - 50℃; for 4h;	97.1%

4-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridine-3-yl]piperazine-1-carboxylic acid tert-butyl ester → PD 0332991 (571190-30-2)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 25 - 30℃; for 5h;	98.5%
With methanesulfonic acid In water; acetone at 55 - 70℃; for 8h; Reagent/catalyst;	95%
With hydrogenchloride In water; butan-1-ol at 70℃; for 2h;	84.8%

tert‑butyl 4‑(6‑((6‑(1‑butoxyvinyl)‑8‑cyclopentyl‑5‑methyl‑7‑oxo‑7,8‑dihydropyrido[2,3‑d]pyrimidin‑2‑yl)amino)pyridin‑3‑yl)piperazine‑1‑carboxylate → PD 0332991 (571190-30-2)

Conditions	Yield
With methanesulfonic acid In water; acetone at 45 - 55℃; Solvent; Reagent/catalyst; Large scale;	98%
With methanesulfonic acid In water; acetone at 55℃; Reagent/catalyst;	98%
With methanesulfonic acid In water; acetone at 45 - 55℃; for 0.5h;	96.2%

6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one isethionate → PD 0332991 (571190-30-2)

Conditions	Yield
With water; sodium carbonate at 30℃; for 1h; Reagent/catalyst; Temperature;	97%
With sodium hydroxide In methanol; water at 25 - 35℃; pH=10;	32.2 g

6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride → PD 0332991 (571190-30-2)

Conditions	Yield
With water; sodium hydroxide at 100℃;	96%
With sodium hydroxide In water pH=10 - Ca. 11; Concentration;	90%
With sodium hydroxide In water pH=11 - 12.5; Large scale;

6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-5,6-dihydropyrido[2,3-d]pyrimidyl-7(8H)-one → PD 0332991 (571190-30-2)

Conditions	Yield
With tetrahydropyridine dichromate nickel (II); acetic acid at 25 - 35℃; for 8h; Temperature;	95.3%
With sodium selenate In dimethyl sulfoxide at 150 - 160℃;	94%

6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride (827022-32-2) → PD 0332991 (571190-30-2)

Conditions	Yield
With sodium hydroxide In ethanol; water for 1h; pH=9; Solvent;	95%
Stage #1: 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride In water at 55℃; for 1.5h; Stage #2: With ammonia at -5 - 0℃; for 4h;	84.2%
With triethylamine In water at 0 - 40℃;	65%

6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one acetate → PD 0332991 (571190-30-2)

Conditions	Yield
With sodium hydroxide In water pH=10 - Ca. 11;	95%

palbociclib dihydrochloride dihydrate → PD 0332991 (571190-30-2)

Conditions	Yield
With sodium hydroxide In ethanol; water at 19 - 25℃; for 21h;	94%

C24H29N7O2*2CH4O3S → PD 0332991 (571190-30-2)

Conditions	Yield
With sodium hydroxide In water; acetone at 28℃; for 1.75h; pH=12; Large scale;	92%

1-(4-ethoxy-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-5-yl)ethanone + ethyl acetoacetate (141-97-9) + Cyclopentamine (1003-03-8) → PD 0332991 (571190-30-2)

Conditions	Yield
Stage #1: 1-(4-ethoxy-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-5-yl)ethanone; Cyclopentamine In isopropyl alcohol for 4h; Reflux; Stage #2: With sodium ethanolate In isopropyl alcohol for 0.5h; Stage #3: ethyl acetoacetate In isopropyl alcohol for 3h; Reagent/catalyst; Solvent; Reflux;	91.89%
Stage #1: 1-(4-ethoxy-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-5-yl)ethanone; Cyclopentamine In isopropyl alcohol at 20 - 60℃; for 4h; Reflux; Stage #2: With sodium ethanolate In isopropyl alcohol for 0.5h; Stage #3: ethyl acetoacetate In isopropyl alcohol for 3h; Reflux;	91.85%

4-{6-[8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino]pyridin-3-yl}piperazine-1-carboxylic acid tert-butyl ester (571189-10-1) → PD 0332991 (571190-30-2)

Conditions	Yield
With hydrogenchloride In dichloromethane	91%
With hydrogenchloride In dichloromethane	91%

palbociclib trifluoroacetic acid → PD 0332991 (571190-30-2)

Conditions	Yield
With sodium hydroxide In water pH=10 - Ca. 11;	89%
With sodium hydroxide In methanol; water at 40℃; pH=9.5 - 10;	2.6 g

N-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-6-ethynylpyrido[2,3-d]pyrimidin-7-one → PD 0332991 (571190-30-2)

Conditions	Yield
With sulfuric acid; gold(I) chloride In water at 75℃; for 2h; Temperature;	88.7%

4-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester hydrochloride → PD 0332991 (571190-30-2)

Conditions	Yield
Stage #1: 4-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester hydrochloride With hydrogenchloride In ethanol; water at 70℃; for 4.25h; Inert atmosphere; Stage #2: With sodium hydroxide at 20 - 35℃; for 20.14h;	87.7%
Stage #1: 4-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester hydrochloride With hydrogenchloride In ethanol; water at 70℃; for 3h; Inert atmosphere; Stage #2: With sodium hydroxide Inert atmosphere;

tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (571188-59-5) + 1-(2-chloro-8-cyclopentyl-5-methyl-7-oxo-1,3,8-triaza-8H-naphth-6-yl)-1-ethanone → PD 0332991 (571190-30-2)

Conditions	Yield
Stage #1: tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate With lithium hexamethyldisilazane In tetrahydrofuran; tert-butyl methyl ether for 0.5h; Stage #2: 1-(2-chloro-8-cyclopentyl-5-methyl-7-oxo-1,3,8-triaza-8H-naphth-6-yl)-1-ethanone In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 1h; Solvent; Reagent/catalyst;	86.6%
Stage #1: tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate; 1-(2-chloro-8-cyclopentyl-5-methyl-7-oxo-1,3,8-triaza-8H-naphth-6-yl)-1-ethanone With lithium hexamethyldisilazane In toluene at 50 - 55℃; Inert atmosphere; Stage #2: With hydrogenchloride In dichloromethane; water at 20℃; for 12h; Inert atmosphere;	82.6%

6-acetyl-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (850628-86-3) + tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (571188-59-5) → PD 0332991 (571190-30-2)

Conditions	Yield
Stage #1: 6-acetyl-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one; tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate With lithium hexamethyldisilazane In toluene at 70 - 75℃; Inert atmosphere; Stage #2: With hydrogenchloride In dichloromethane; water at 20℃; for 12h; Inert atmosphere;	85%

C24H29N7O2*2C2H6O4S → PD 0332991 (571190-30-2)

Conditions	Yield
In methanol; water at 20℃; for 3h; pH=> 8;	84.5%

N-cyclopentyl-3-acetyl-4-methyl-6-formyl-5-chloro-2-pyridone + N-(5-(4-N-tert-butoxycarbonyl-1-N-hexahydro-pyrazinyl)2-pyridyl)guanidine sulphate → PD 0332991 (571190-30-2)

Conditions	Yield
Stage #1: N-cyclopentyl-3-acetyl-4-methyl-6-formyl-5-chloro-2-pyridone; N-(5-(4-N-tert-butoxycarbonyl-1-N-hexahydro-pyrazinyl)2-pyridyl)guanidine sulphate With sodium methylate In methanol at 60 - 65℃; for 5h; Stage #2: With water; sodium hydroxide at 20℃; for 3h;	83.8%

C28H35N7O5 + acetic anhydride (108-24-7) → PD 0332991 (571190-30-2)

Conditions	Yield
Stage #1: C28H35N7O5; acetic anhydride With pyridine at 80℃; for 4h; Stage #2: With hydrogenchloride In methanol; water at 5 - 45℃; for 3h; Reagent/catalyst; Temperature;	83%

palbociclib acetic acid → PD 0332991 (571190-30-2)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.366667h;	71%

6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride → PD 0332991 (571190-30-2)

Conditions	Yield
With sodium hydroxide

tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (571188-59-5) → PD 0332991 (571190-30-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: isopropylmagnesium chloride / tetrahydrofuran / 20 - 60 °C / Inert atmosphere 2: palladium diacetate; N-ethyl-N,N-diisopropylamine; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 2.5 h / 95 °C / Inert atmosphere 3: methanesulfonic acid / water; acetone / 45 - 55 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 1.2: 1.91 h / 10 - 20 °C 2.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 28 h / Heating; Inert atmosphere 3.1: hydrogenchloride / ethanol / 50 °C / Inert atmosphere 3.2: 20 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 1.2: 1.91 h / 10 - 20 °C 2.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 24 h / Inert atmosphere; Heating 2.2: 3 h / 20 °C 3.1: hydrogenchloride / water; ethanol / 4.25 h / 70 °C / Inert atmosphere 3.2: 20.14 h / 20 - 35 °C View Scheme

Cyclopentamine (1003-03-8) → PD 0332991 (571190-30-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: triethylamine / ethanol / 4 h / 25 °C 2.1: palladium diacetate; triethylamine / 1-methyl-pyrrolidin-2-one / 65 °C / Inert atmosphere 2.2: 65 °C / Inert atmosphere 3.1: N-Bromosuccinimide; oxalic acid / acetonitrile / 60 °C 4.1: isopropylmagnesium chloride / tetrahydrofuran / 20 - 60 °C / Inert atmosphere 5.1: palladium diacetate; N-ethyl-N,N-diisopropylamine; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 2.5 h / 95 °C / Inert atmosphere 6.1: methanesulfonic acid / water; acetone / 45 - 55 °C / Large scale View Scheme
Multi-step reaction with 6 steps 1.1: ethanol / 3 h / 10 - 20 °C 2.1: tris-(o-tolyl)phosphine; bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 h / 75 °C / Inert atmosphere 2.2: 2 h / 75 °C 3.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 7 h / 15 °C / Inert atmosphere; Heating 4.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 4.2: 1.91 h / 10 - 20 °C 5.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 28 h / Heating; Inert atmosphere 6.1: hydrogenchloride / ethanol / 50 °C / Inert atmosphere 6.2: 20 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: ethanol / 3 h / 10 - 20 °C 2.1: tris-(o-tolyl)phosphine; bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 h / 75 °C / Inert atmosphere 2.2: 2 h / 75 °C 3.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 7 h / 15 °C / Inert atmosphere; Heating 4.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 4.2: 1.91 h / 10 - 20 °C 5.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 24 h / Inert atmosphere; Heating 5.2: 3 h / 20 °C 6.1: hydrogenchloride / water; ethanol / 4.25 h / 70 °C / Inert atmosphere 6.2: 20.14 h / 20 - 35 °C View Scheme

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → PD 0332991 (571190-30-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: palladium diacetate; triethylamine / 1-methyl-pyrrolidin-2-one / 65 °C / Inert atmosphere 1.2: 65 °C / Inert atmosphere 2.1: N-Bromosuccinimide; oxalic acid / acetonitrile / 60 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 20 - 60 °C / Inert atmosphere 4.1: palladium diacetate; N-ethyl-N,N-diisopropylamine; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 2.5 h / 95 °C / Inert atmosphere 5.1: methanesulfonic acid / water; acetone / 45 - 55 °C / Large scale View Scheme
Multi-step reaction with 5 steps 1.1: tris-(o-tolyl)phosphine; bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 h / 75 °C / Inert atmosphere 1.2: 2 h / 75 °C 2.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 7 h / 15 °C / Inert atmosphere; Heating 3.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 3.2: 1.91 h / 10 - 20 °C 4.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 24 h / Inert atmosphere; Heating 4.2: 3 h / 20 °C 5.1: hydrogenchloride / water; ethanol / 4.25 h / 70 °C / Inert atmosphere 5.2: 20.14 h / 20 - 35 °C View Scheme
Multi-step reaction with 5 steps 1.1: tris-(o-tolyl)phosphine; bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 h / 75 °C / Inert atmosphere 1.2: 2 h / 75 °C 2.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 7 h / 15 °C / Inert atmosphere; Heating 3.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 3.2: 1.91 h / 10 - 20 °C 4.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 28 h / Heating; Inert atmosphere 5.1: hydrogenchloride / ethanol / 50 °C / Inert atmosphere 5.2: 20 h / 20 °C / Inert atmosphere View Scheme

2-chloro-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydro-7-one (1013916-37-4) → PD 0332991 (571190-30-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-Bromosuccinimide; oxalic acid / acetonitrile / 60 °C 2: isopropylmagnesium chloride / tetrahydrofuran / 20 - 60 °C / Inert atmosphere 3: palladium diacetate; N-ethyl-N,N-diisopropylamine; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 2.5 h / 95 °C / Inert atmosphere 4: methanesulfonic acid / water; acetone / 45 - 55 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 7 h / 15 °C / Inert atmosphere; Heating 2.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 2.2: 1.91 h / 10 - 20 °C 3.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 28 h / Heating; Inert atmosphere 4.1: hydrogenchloride / ethanol / 50 °C / Inert atmosphere 4.2: 20 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 7 h / 15 °C / Inert atmosphere; Heating 2.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 2.2: 1.91 h / 10 - 20 °C 3.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 24 h / Inert atmosphere; Heating 3.2: 3 h / 20 °C 4.1: hydrogenchloride / water; ethanol / 4.25 h / 70 °C / Inert atmosphere 4.2: 20.14 h / 20 - 35 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium acetate; bromine; acetic acid / 35 h / 50 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / toluene / 0.5 h / 0 - 20 °C 2.2: 0.67 h / 0 - 20 °C 3.1: palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene; N-ethyl-N,N-diisopropylamine / butan-1-ol / 20 h / 95 °C / Inert atmosphere 4.1: hydrogenchloride / dichloromethane; water / 1 h / 20 °C 5.1: trifluoroacetic acid / dichloromethane / 15 h View Scheme
Multi-step reaction with 3 steps 1: aluminum (III) chloride / chloroform / 5 h / 0 - 60 °C 2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 3: hydrogenchloride / acetone; water / 10 h / 50 °C View Scheme

PD 0332991 (571190-30-2) + chloroacetyl chloride (79-04-9) → 6-acetyl-2-(5-(4-(2-chloroacetyl)piperazin-1-yl)pyridin-2-ylamino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

Conditions	Yield
With dmap In dichloromethane at 0 - 20℃; for 3h;	99%
With dmap In dichloromethane at 0 - 20℃;	86%
Stage #1: PD 0332991 With triethylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: chloroacetyl chloride In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere;	75%

PD 0332991 (571190-30-2) + suberic acid monomethyl ester (3946-32-5) → methyl 8-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-8-oxooctanoate

Conditions	Yield
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃;	98%

PD 0332991 (571190-30-2) + bromoacetic acid methyl ester (96-32-2) → C27H33N7O4

Conditions	Yield
With potassium carbonate Inert atmosphere;	98%

PD 0332991 (571190-30-2) + bromoacetic acid tert-butyl ester (5292-43-3) → tert-butyl 2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetate

Conditions	Yield
Stage #1: PD 0332991 With potassium carbonate In 1-methyl-pyrrolidin-2-one for 0.166667h; Stage #2: bromoacetic acid tert-butyl ester In 1-methyl-pyrrolidin-2-one at 50℃; for 12h;	96%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;	88%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;	85%

PD 0332991 (571190-30-2) + 2,2'-oxybis-acetic acid (110-99-6) → 2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)acetic acid

Conditions	Yield
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; dimethyl sulfoxide at 20℃;	96%

PD 0332991 (571190-30-2) + C30H40N4O6S → (2S,4R)-1-((S)-2-((E)-8-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-8-oxooct-4-enamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃;	95%

PD 0332991 (571190-30-2) + tert-Butyl acrylate (1663-39-4) → tert-butyl 3-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3 -d]pyrimidin-2-ylamino)pyridin-3-yl)piperazin-1-yl)propanoate

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 5h;	94%

PD 0332991 (571190-30-2) + acetic acid (64-19-7) → palbociclib acetic acid

Conditions	Yield
In water	93%

PD 0332991 (571190-30-2) + maleic acid (110-16-7) → palbociclib maleate

Conditions	Yield
In acetonitrile at 20℃; for 48h; Solvent; Reflux;	92.7%

PD 0332991 (571190-30-2) + 2-hydroxyethanesulfonic acid (107-36-8) → PD 0332991 isethionate

Conditions	Yield
In methanol at -8 - 20℃; Conversion of starting material;	91.8%
In methanol at 20℃; for 3h;	52.5%
In methanol; water pH=5.2;
In methanol; water pH=5.2;

PD 0332991 (571190-30-2) + propoxycarbonyl chloride (109-61-5) → propyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate

Conditions	Yield
With dmap In dichloromethane at 0 - 20℃;	91%

PD 0332991 (571190-30-2) + [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (76-26-6, 3144-16-9, 5872-08-2, 35963-20-3) → palbociclib camsylate

Conditions	Yield
In acetone at 20℃; for 24h; Reflux;	91%

PD 0332991 (571190-30-2) → 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride (827022-32-2)

Conditions	Yield
With hydrogenchloride In ethanol; water at 20℃; for 93h; Heating;	90.8%

PD 0332991 (571190-30-2) + naphthalene-2-sulfonate (120-18-3) → palbociclib napsylate

Conditions	Yield
In acetone at 20℃; for 48h; Solvent; Reflux;	90.3%

PD 0332991 (571190-30-2) + carbonochloridic acid, butyl ester (592-34-7) → butyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate

Conditions	Yield
With dmap In dichloromethane at 0 - 20℃;	90%

PD 0332991 (571190-30-2) + 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide → tert-butyl (2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyI-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)carbamate

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile at 80℃; for 16h; Inert atmosphere;	90%
With potassium carbonate; potassium iodide In acetone Reflux;	85%
With potassium carbonate; potassium iodide In acetone Reflux;	85%

PD 0332991 (571190-30-2) + tert-butyl 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy) ethoxy)ethoxy)propanoate → 4-((2-(2-(2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione

Conditions	Yield
Stage #1: tert-butyl 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy) ethoxy)ethoxy)propanoate With formic acid at 20℃; Stage #2: PD 0332991 With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; dimethyl sulfoxide at 20℃;	90%

Upstream product

• 827022-32-2 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride 
• 571188-59-5 tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 
• 1003-03-8 Cyclopentamine 
• 733039-20-8 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine 
• 1013916-37-4 2-chloro-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydro-7-one 
• 39856-50-3 5-bromo2-nitropyridine 
• 1016636-76-2 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridine[2,3-d]pyrimidin-8-hydro-7-one 
• 866084-31-3 tert?butyl 4?(6?((6?(1?butoxyvinyl)?8?cyclopentyl?5?methyl?7?oxo?7,8?dihydropyrido[2,3?d]pyrimidin?2?yl)amino)pyridin?3?yl)piperazine?1?carboxylate 
• 571189-16-7 4-(6-nitropyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester 
• 571188-82-4 tert?butyl 4?(6?((6?bromo?8?cyclopentyl?5?methyl?7?oxo?7,8?dihydropyrido[2,3?d]pyrimidin?2?yl)amino)pyridin?3?yl)piperazine?1?carboxylate 
• 5909-24-0 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester 
• 211245-64-6 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde 
• 211245-62-4 4-cyclopentylamino-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester 
• 211245-63-5 [4-cyclopentylamino-2-(methylsulfanyl)pyrimidine-5-yl]methanol 

Downstream Products

• 827022-33-3 PD 0332991 isethionate 
• 1376615-91-6 8-cyclopentyl-6-(1-hydroxyethyl)-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one 
• 827022-33-3 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one isethionate 
• 827022-32-2 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride 
• 2361493-16-3 N-(2-(2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide 
• 2349356-09-6 N-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide 

Relevant articles and documents

Preparation method of palbociclib

The invention provides a preparation method of palbociclib. Specifically, ethyl acetoacetate and acetaldehyde are subjected to condensation hydrolysis to prepare 2-acetyl-2-butenoic acid instead of crotonic acid, and tedious steps such as acetyl group loading are not needed, so a synthesis route is simplified. The preparation method is simple and safe, product purity is high, and product yield is improved.

Preparation method and process of palbociclib

The invention relates to a preparation method of palbociclib. The preparation method comprises the steps of 1 reacting a compound I with a compound II to obtain an intermediate I; 2 carrying out a coupling reaction on the intermediate I and vinyl n-butyl ether to obtain an intermediate II; 3 removing a protecting group from the intermediate II under the action of an acid reagent to obtain palbociclib silicate; and 4 carrying out alkali replacement on the palbociclib silicate to obtain palbociclib.

Low-cost preparation method of palbociclib

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PHARMACEUTICAL COMPOSITION COMPRISING PALBOCICLIB

The present invention relates to a pharmaceutical granulate composition comprising Palbociclib free base, having improved bioavailability.

A new route for the synthesis of Palbociclib

Abstract: In this paper, a novel synthetic method for Palbociclib was reported. It was synthesized in eight steps from 2-(methylthio) pyrimidin-4-(3H)-one with approximately 10% overall yield. This protocol started material 2-(methylthio) pyrimidin-4-(3H)-one, involved nucleophilic substitution by thionyl chloride, bromination, nucleophilic substitution by cyclopentylamine, a one pot-two step method (Heck reaction, ring close sequence), oxidation and bromination, cross-coupling reaction, Heck reaction, aqueous workup to afford Palbociclib. This synthetic route used inexpensive raw material and reagents, involved readily controllable reaction conditions and reduced environmental hazards. Graphic abstract: Synthesis of Palbociclib, a small molecule CDK inhibitor, starting from 2-(methylthio) pyrimidin-4-(3H)-one by 8 steps reaction. This method afforded the Palbociclib in 10% yield. [Figure not available: see fulltext.].

Preparation method and product of palbociclib

The invention discloses a preparation method of palbociclib. The preparation method comprises the following steps: 1) dissolving 4-(6-aminopyridine-3-yl)-piperazine-1-tertiary butyl carboxylate into asolvent A, adding an alkali reagent, activating at 0-20 DEG C, adding 6-bromine-2-chlorine-8-cyclopentyl-5-methyl-pyridino-[2,3-D]-pyrimidine-7(8H)-ketone, adjusting the solution to acid after a reaction is completed, cooling and filtering, taking filter cakes, and drying the filter cakes to obtain an intermediate I; 2) in the presence of an inert atmosphere, dissolving the intermediate I and butyl vinyl ether into a solvent B, catalyzing with a catalyst at 95-105 DEG C, cooling and separating a crystal after the reaction is completed, filtering, and taking the filter cakes, and drying the filter cakes to obtain an intermediate II; 3) dissolving the intermediate II into a solvent C, adding an acid, adjusting the solution to acid after the reaction is completed, filtering, and taking and centrifuging filtrate to obtain a target product, namely palbociclib. By adjusting reaction parameters and optimizing preparation process procedures, the preparation method is high in product yield, good in purity, simple and mild in process conditions and applicable to industrial large-scale production.

Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders

A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.

A PROCESS FOR MAKING PALBOCICLIB

The presented invention relates to a process for preparation of compound of formula (1) or a salt thereof (i.e.) palbociclib: The invention also relates to a solid crystalline form of intermediate of formula (2) used in the process:

Method for synthesizing palbociclib

The invention discloses a method for synthesizing palbociclib. The method comprises the following steps: 1, carrying out a coupled reaction on a compound as shown in a formula (II) and a compound as shown in a formula (III) under the action of cyclohexylmagnesium chloride to obtain a compound as shown in a formula (IV); 2, reacting the compound as shown in the formula (IV) with magnesium metal toprepare a Grignard reagent, then, carrying out a Grignard reaction on the Grignard reagent and carbon dioxide, and carrying out hydrolysis to prepare a compound as shown in a formula (V); and 3, reacting the compound as shown in the formula (V) with acetic anhydride under the action of alkaline to obtain a crude product, and deprotecting the crude product under the action of an acid to prepare a target product. The method for synthesizing palbociclib, disclosed by the invention, is cheap and available in raw materials, high in synthesis efficiency, few in impurity, easy to control and suitablefor industrial production and provides a new approach for synthesizing palbociclib.

Simple preparation method of palmemonil (by machine translation)

The invention provides a simple preparation method, and belongs to the field of preparation. 2 -acetyl -3 -methyl -2 -methylpyridine 3 -1 - (1H, 5H) - diketone (III), and a hydroformylation reagent are then condensed to prepare -4 -acetyl -2-cyclopentyl 6 -methyl 3 -dialkylaminopyridylpyridine -1 -5 - 6 -2 -4 - (1H, 5H) - diketone (IV) . Further to N - [5 - (4 -tert-butoxycarbonyl piperazine -1 -yl) pyridin -2 -yl] guanidine (V) is cyclized to obtain Boc-protected pbast (VI) . deBoc protecting group gave palbotanil (I). The method is short, simple and convenient to operate, easy to implement, low in cost, less in three wastes, and high in product purity and yield. (by machine translation)