2,4-Dichloropyrimidine -Drug Synthesis Database

【结构式】

【分子编号】54377

【品名】2,4-Dichloropyrimidine

【CA登记号】3934-20-1

【分子式】C₄H₂Cl₂N₂

【分子量】148.97876

【元素组成】C 32.25% H 1.35% Cl 47.59% N 18.8%

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：(VII)

The synthesis can be performed by two related ways: 1) The condensation of 2-(methylsulfanyl)pyrimidin-4-ol (I) with 4-aminobenzonitrile (II) in hot diglyme gives 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (III), which is treated with POCl3 to yield the corresponding chloro derivative (IV). Finally, this compound is condensed with 2,4,6-trimethylaniline (V) in dioxane to afford the target 4-aminobenzonitrile derivative. 2) Condensation of 2,4,6-trimethylaniline (VI) with 2,4-dichloropyrimidine (VII) by means of DIEA in refluxing 1,4-dioxane, followed by chromatographic purification furnishes intermediate (VIII), which is finally converted into the desired compound by condensation with 4-aminobenzonitrile (II) in refluxing water by means of HCl in 2-propanol.

参考文献中间体

合成目标

【2】 Heeres, J.; Kukla, M.J.; Andries, K.J.L.M.; Janssen, P.A.J.; Ho, C.Y.; Janssen, M.A.C.; Ludovici, D.W.; de Corte, B.; de Jonge, M.R.; Koymans, L.M.H.; van Aken, K.J.A. (Janssen Pharmaceutica NV); HIV inhibiting pyrimidine derivs.. EP 0945442; EP 0945443; US 6197779; US 6440986; WO 9950250 .
【1】 Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; et al.; Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorg Med Chem Lett 2001, 11, 17, 2235.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	54374	2-Methylsulfanylpyrimidin-4-ol; 2-Methylthio-4-hydroxy pyrimidine	124700-70-5	C₅H₆N₂OS	详情	详情
(II)	15361	4-Aminobenzonitrile	873-74-5	C₇H₆N₂	详情	详情
(III)	54375	4-[(4-hydroxy-2-pyrimidinyl)amino]benzonitrile; 4-[(1,4-Dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile	189956-45-4	C₁₁H₈N₄O	详情	详情
(IV)	54376	4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile	244768-32-9	C₁₁H₇ClN₄	详情	详情
(V)	28804	2,4,6-trimethylaniline	88-05-1	C₉H₁₃N	详情	详情
(VII)	54377	2,4-Dichloropyrimidine	3934-20-1	C₄H₂Cl₂N₂	详情	详情
(VIII)	54378	2-chloro-N-mesityl-4-pyrimidinamine; N-(2-chloro-4-pyrimidinyl)-N-mesitylamine		C₁₃H₁₄ClN₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

O-Alkylation of 5-nitrosalicylaldehyde (I) with 1,2-dichloroethane (IIa) or 1-bromo-2-chloroethane (IIb) (3) by means of K2CO3 in DMF at 100-5 °c or 60 °c affords 2-(2-chloroethoxy)-5-nitrobenzaldehyde (III), which by reduction with nabH4 in THF or MeoH yields the corresponding alcohol (IV). O-Alkylation of alcohol (IV) with allyl bromide (V) and KoH and Bu4NHSo4 or Bu4Ni at 40 °c gives 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (VI), which is then reduced with Fe in the presence of nH4cl in EtoH to yield the corresponding aniline (VII). condensation of amine (VII) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine (VIII) by means of Hcl in buoH at 80 °c affords the 2-anilinopyrimidine derivative (IX), which then undergoes ring-closing metathesis in the presence of Grubbs’ second-generation catalyst and HCl in CH2Cl2 at 40-45 °c to yield macrocycle (X). Finally, compound (X) is submitted to microwave-assisted condensation with pyrrolidine (XI) in dimethylacetamide at 80 °c .
intermediate (VIII) can be prepared by Suzuki coupling of 2,4-dichloropyrimidine (XII) with 3-(hydroxymethyl)phenylboronic acid (XIII) in the presence of Pd(OAc)2, PPh3 and na2co3 in THF at 70 °c or Pd(PPh3)4 and Na2CO3 in DME at 80-5 °c to give [3-(2-chloropyrimidin-4-yl)phenyl]methanol (XIV), which is finally O-alkylated with allyl bromide (V) and KOH and Bu4NHSO4 or Cs2CO3 in DMF at 40 °c .

参考文献中间体

合成目标

【1】 William, A.D., Lee, A.c., blanchard, S. et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med chem 2011, 54(13): 4638-58.
【2】 Lee, A., William, A., Poulsen, A. et al. Design, synthesis and SAR studies leading to SB1518, a novel macrocyclic JAK2/FLT3 inhibitor in phase 2 clinical trials for myelofibrosis and lymphoma. 102nd Annu Meet Am Assoc cancer Res (AAcR) (April 2-6, orlando) 2011, Abst 3564.
【3】 blanchard, S., Lee, c.H.A., nagaraj, H.K.M., Poulsen, A., Sun, E.t., tan, Y.L.E., William, A.D. (S*bio Pte. Ltd.). EP 1951729, JP 2009515954, US 8153632, Wo 2007058627.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIa)	16170	1,2-dichloroethane	107-06-2	C₂H₄Cl₂	详情	详情
(IIb)	24271	1-bromo-2-chloroethane	107-04-0	C₂H₄BrCl	详情	详情
(IX)	68053	N-(3-((allyloxy)methyl)-4-(2-chloroethoxy)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine		C₂₆H₂₈ClN₃O₃	详情	详情
(I)	42307	2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde	97-51-8	C₇H₅NO₄	详情	详情
(III)	68048	2-(2-chloroethoxy)-5-nitrobenzaldehyde		C₉H₈ClNO₄	详情	详情
(IV)	68049	(2-(2-chloroethoxy)-5-nitrophenyl)methanol		C₉H₁₀ClNO₄	详情	详情
(V)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(VI)	68050	2-((allyloxy)methyl)-1-(2-chloroethoxy)-4-nitrobenzene		C₁₂H₁₄ClNO₄	详情	详情
(VII)	68051	3-((allyloxy)methyl)-4-(2-chloroethoxy)aniline		C₁₂H₁₆ClNO₂	详情	详情
(VIII)	68052	4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine		C₁₄H₁₃ClN₂O	详情	详情
(X)	68054			C₂₄H₂₄ClN₃O₃	详情	详情
(XI)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(XII)	54377	2,4-Dichloropyrimidine	3934-20-1	C₄H₂Cl₂N₂	详情	详情
(XIII)	68055	3-(hydroxymethyl)phenylboronic acid；(3-Hydroxymethyl)phenylboronic acid;(m-Hydroxymethyl)phenylboronic acid;3-Hydroxymethylbenzeneboronic acid	87199-15-3	C₇H₉BO₃	详情	详情
(XIV)	68056	[3-(2-chloropyrimidin-4-yl)phenyl]methanol		C₁₁H₉ClN₂O	详情	详情

Extended Information