1-butoxyethylene; butyl vinyl ether -Drug Synthesis Database

【结构式】

【分子编号】59983

【品名】1-butoxyethylene; butyl vinyl ether

【CA登记号】111-34-2

【分子式】C₆H₁₂O

【分子量】100.16068

【元素组成】C 71.95% H 12.08% O 15.97%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(A)

Androstenedione (II) was converted to the C-17 cyanohydrin (III) by treatment with either KCN and AcOH or with acetone cyanohydrin and NaOH. Ketalization of the remaining 3-keto group with ethylene glycol and trimethyl orthoformate led to (IV). The C-17 hydroxyl was then protected by formation of the acetaldehyde mixed ketal (V) by treatment with butyl vinyl ether. Addition of methyllithium to the cyano group, followed by acidic ketal hydrolysis furnished the pregnenedione (VI). Subsequent iodination of (VI) by means of iodine and calcium oxide gave iodo ketone (VII), which was further displaced by potassium acetate yielding the C-21 acetate ester (VIII). Finally, dehydration of the C-17 alcohol employing 70% aqueous sulfuric acid produced the title compound.

参考文献中间体

合成目标

【1】 Batist, J.N.M.; Marx, A.F.; Van Zoest, W.J.; Kapur, J.C. (Gist-Brocades NV); 9-alpha-Hydroxy steroids and process for their preparation. EP 0263569; JP 1989500907; WO 8802753 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(A)	59983	1-butoxyethylene; butyl vinyl ether	111-34-2	C₆H₁₂O	详情	详情
(II)	28065	(8S,9R,10S,13S,14S)-9-hydroxy-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione		C₁₉H₂₆O₃	详情	详情
(III)	59973	(8S,9R,10S,13S,14S,17R)-9,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonitrile		C₂₀H₂₇NO₃	详情	详情
(IV)	59974			C₂₂H₃₁NO₄	详情	详情
(V)	59975			C₂₈H₄₃NO₅	详情	详情
(VI)	59976	(8S,9R,10S,13S,14S,17R)-17-acetyl-9,17-dihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₃₀O₄	详情	详情
(VII)	59977	(8S,9R,10S,13S,14S,17R)-9,17-dihydroxy-17-(2-iodoacetyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₉IO₄	详情	详情
(VIII)	59978	2-[(8S,9R,10S,13S,14S,17R)-9,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate		C₂₃H₃₂O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

Amination of 5-bromo-2,4-dichloropyrimidine (VIII) with cyclopentylamine (IX) in EtOH gives 5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine (X), which is then cyclized with crotonic acid (XI) by means of DIEA, TOTP, PdCl2(PhCN)2 in THF at 70 °C followed by treatment with Ac2O to yield the 8H-pyrido[2,3-d]pyrimidinone derivative (XII). Bromination of compound (XII) with Br2 in the presence of NaOAc in AcOH provides the 6-bromopyrido[2,3-d]pyrimidinone derivative (XIII), which is then coupled with the aminopyridine derivative (IV) in the presence of LiHMDS in toluene to afford intermediate (V). Condensation of the bromo derivative (V) with butylvinylether (XIV) in the presence of DIEA, PdCl2(dppf)2.CH2Cl2 complex in n-BuOH at 95 °C affords the 6-(1-butoxyvinyl)dihydropyrido[2,3-d]pyrimidine derivative (XV) . Finally, intermediate (XV) is treated with isethionic acid (XVI) —previously prepared by acidification of sodium isethionate (XVII) with HCl in i-PrOH in MeOH/H2O at 55 °C followed by TEA in MeOH .
The aminopyridine intermediate (IV) can be prepared by condensation of Boc-piperazine (XVIII) with 5-bromo-2-nitropyridine (XIX) in the presence of TEA in DMSO at 65-70 °C to give the nitropyridine derivative (XX), which is then reduced in the presence of H2 over Pd(OH)2/C in i-PrOH .
The key intermediate diarylamine adduct (V) can also be obtained directly by coupling aminopyridine derivative (IV) with the 2-methanesulfonylpyrido[2,3-d]pyrimidinone derivative (XXI) .

参考文献中间体

合成目标

【1】 Toogood, P.L., Harvey, P.J., Repine, J.T. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005, 48(7): 2388-406.
【2】 Barvian, M.R., Quin, J. III, Sheehan, D.J. et al. (Pfizer Inc.). 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 1470124, JP 2005519909, US 2003149001, US 6936612, WO 2003062236.
【4】 Beylin, V.G., Blackburn, A.C., Erdman, D.T., Toogood, P.L. (Pfizer, Inc.).Isethionate salt of a selective CDK4 inhibitor. EP 1648889, JP 2007530425, US 2005059670, WO 2005005426.
【3】 Erdman, D.T., Flamme, C.M., Nelson, J.D. (Pfizer Products, Inc.). Synthesis of 2-(pyridine-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 2069344, JP 2008094834, US 2008125588, US 7781583, WO 2008032157.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	68144	tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate		C₁₄H₂₂N₄O₂	详情	详情
(V)	68145	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		C₂₇H₃₄BrN₇O₃	详情	详情
(VIII)	68146	5-bromo-2,4-dichloropyrimidine	36082-50-5	C₄HBrCl₂N₂	详情	详情
(IX)	28850	cyclopentanamine	1003-03-8	C₅H₁₁N	详情	详情
(X)	68147	5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine;5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine		C₉H₁₁BrClN₃	详情	详情
(XI)	20599	(E)-2-butenoic acid; crotonic acid	3724-65-0	C₄H₆O₂	详情	详情
(XII)	68148	2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one		C₁₃H₁₄ClN₃O	详情	详情
(XIII)	68149	6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one		C₁₃H₁₃BrClN₃O	详情	详情
(XIV)	59983	1-butoxyethylene; butyl vinyl ether	111-34-2	C₆H₁₂O	详情	详情
(XV)	68150	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		C₃₃H₄₅N₇O₄	详情	详情
(XVI)	13359	2-Hydroxy-1-ethanesulfonic acid	107-36-8	C₂H₆O₄S	详情	详情
(XVII)	68151	sodium isethionate；sodium 2-sulfoethanolate		C₂H₅NaO₄S	详情	详情
(XVIII)	13225	N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate	143238-38-4	C₉H₁₈N₂O₂	详情	详情
(XIX)	68152	5-bromo-2-nitropyridine；2-Nitro-5-bromopyridine;3-Bromo-6-nitropyridine	39856-50-3	C₅H₃BrN₂O₂	详情	详情
(XX)	68153	tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate		C₁₄H₂₀N₄O₄	详情	详情
(XXI)	68154	6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one		C₁₄H₁₆BrN₃O₃S	详情	详情

Extended Information