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【结 构 式】 
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【分子编号】24271 【品名】1-bromo-2-chloroethane 【CA登记号】107-04-0 |
【 分 子 式 】C2H4BrCl 【 分 子 量 】143.41046 【元素组成】C 16.75% H 2.81% Br 55.72% Cl 24.72% |
合成路线1
该中间体在本合成路线中的序号：(II)The alkylation of 5,5-pentamethylenehydantoin (I) with 1-bromo-2-chloroethane (II) by means of KOH in refluxing ethanol gives 3-(2-chloroethyl)-5,5-pentamethylenehydantoin (II), which is condensed with diethanolamine (IV) by means of NaI in hot DMF yielding 3-[2-[bis(2 hydroxyethyl)amino]ethyl] 5,5-pentamethylenehydantoin (V) Finally, this compound is treated with hot POCl3.
| 【1】 Peng, G.W.; et al.; Potential central nervous system antitumor agents. Hydantoin derivatives. J Med Chem 1975, 18, 8, 846. |
| 【2】 Prous, J.; Castaner, J.; Spiromustine. Drugs Fut 1986, 11, 9, 773. |
| 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) | 24270 | 1,3-diazaspiro[4.5]decane-2,4-dione | 702-62-5 | C8H12N2O2 | 详情 | 详情 |
| (II) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (III) | 24272 | 3-(2-chloroethyl)-1,3-diazaspiro[4.5]decane-2,4-dione | C10H15ClN2O2 | 详情 | 详情 | |
| (IV) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (V) | 24274 | 3-[2-[bis(2-hydroxyethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione | C14H25N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The cyclization of ethyl isocyanate (I) with sodium azide (II) by means of AlCl3 in refluxing THF gives 1-ethyl-1,4-dihydro-5H-tetrazol-5-one (III), which is alkylated with 1-chloro-2-bromoethane (IV) by means of Na2CO3 and KI in refluxing 4-methyl-2-pentanone to afford 1-ethyl-4-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one (V). Finally, this compound is condensed with N-(4-methoxymethyl-4-piperidinyl)propionanilide (VI) by means of Na2CO4 - KI in refluxing 4-methyl-2-pentanone.
| 【1】 Janssen, F. (Janssen Pharmaceutica NV); N-Phenyl-N-(4-piperidinyl)amides. DE 2819873; ES 469473; FR 2389622; GB 1598872; JP 53149980 . |
| 【2】 Castaner, J.; Leeson, P.A.; Blancafort, P.; Mealy, N.E.; Serradell, M.N.; Alfentanil hydrochloride. Drugs Fut 1981, 6, 6, 335. |
| 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) | 28738 | ethyl isocyanate | 109-90-0 | C3H5NO | 详情 | 详情 |
| (III) | 32218 | 1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | 69048-98-2 | C3H6N4O | 详情 | 详情 |
| (IV) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (V) | 32219 | 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C5H9ClN4O | 详情 | 详情 | |
| (VI) | 32220 | N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide | C16H24N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The preparation of the precursor aldehyde (IX) is illustrated in Scheme 1. Alkylation of 3-hydroxy-4-(difluoromethoxy)benzaldehyde (I) with 1-bromo-2-chloroethane (II) affords the chloroethyl ether (III). After reduction of the aldehyde function of (III) with NaBH4, the resulting alcohol (IV) is protected as the corresponding silyl ether (V) with triisopropylsilyl triflate and 2,6-lutidine. Dehydrohalogenation of the chloroethyl ether moiety of (V) with NaOH under phase-transfer conditions, followed by resilylation with triisopropylsilyl triflate, leads to the vinyl ether (VI). This is converted into the cyclopropyl derivative (VII) following the Simmons-Smith procedure in the presence of chloroiodomethane and diethylzinc. Desilylation of (VII) with tertbutylammonium fluoride yields the benzylic alcohol (VIII), which is again oxidized to aldehyde (IX) employing MnO2 in CH2Cl2.
| 【1】 Girard, M.; Frenette, R.; Hamel, P.; Guay, D.; Ducharme, Y.; Blouin, M.; Friesen, R.; Cote, B.; Martins, E.; Laliberte, S. (Merck Frosst Canada Inc.); Tri-aryl-substd.-ethane PDE4 inhibitors. EP 1272488; US 6399636; WO 0170738 . |
| 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) | 59742 | 4-(difluoromethoxy)-3-hydroxybenzaldehyde | C8H6F2O3 | 详情 | 详情 | |
| (II) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (III) | 59743 | 3-(2-chloroethoxy)-4-(difluoromethoxy)benzaldehyde | C10H9ClF2O3 | 详情 | 详情 | |
| (IV) | 59744 | [3-(2-chloroethoxy)-4-(difluoromethoxy)phenyl]methanol | C10H11ClF2O3 | 详情 | 详情 | |
| (V) | 59745 | 3-(2-chloroethoxy)-4-(difluoromethoxy)benzyl triisopropylsilyl ether; {[3-(2-chloroethoxy)-4-(difluoromethoxy)benzyl]oxy}(triisopropyl)silane | C19H31ClF2O3Si | 详情 | 详情 | |
| (VI) | 59746 | {[4-(difluoromethoxy)-3-(vinyloxy)benzyl]oxy}(triisopropyl)silane; 2-(difluoromethoxy)-5-{[(triisopropylsilyl)oxy]methyl}phenyl vinyl ether | C19H30F2O3Si | 详情 | 详情 | |
| (VII) | 59747 | cyclopropyl 2-(difluoromethoxy)-5-{[(triisopropylsilyl)oxy]methyl}phenyl ether; {[3-(cyclopropyloxy)-4-(difluoromethoxy)benzyl]oxy}(triisopropyl)silane | C20H32F2O3Si | 详情 | 详情 | |
| (VIII) | 59748 | [3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methanol | C11H12F2O3 | 详情 | 详情 | |
| (IX) | 59749 | 3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde | C11H10F2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Alkylation of ethyl isonipecotate (I) with 1-bromo-2-chloroethane (II) in the presence of K2CO3 in acetone yields ethyl 1-(2-chloro-ethyl)piperidine-4-carboxylate (III), which by treatment with LDA in THF cyclizes to the quinuclidine derivative (IV) . Alternatively, quinuclidine (IV) can be prepared by alkylation of Boc-protected ethyl nipecotate (V) with 1-bromo-2-chloroethane (II) using LiHMDS in toluene to yield the 4-(2-chloroethyl)piperidine derivative (VI), which is then N-deprotected with HCl in water/dioxane, followed by cyclization of the resulting chloro amine (VII) by means of K2CO3 in refluxing toluene . Addition of phenyl lithium (VIII) to ester (IV) in THF affords 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IX), which finally undergoes quaternization with benzyl 2-bromoethyl ether (X) in acetonitrile/chloroform .
| 【1】 Lainé, D.I., McCleland, B., Thomas, S. et al. Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009, 52(8): 2493-505. |
| 【2】 Lainé, D.I., Palovich, M.R., McCleland, B.W., Neipp, C.E., Thomas, S.M.(GlaxoSmithKline plc). Muscarinic acetylcholine receptor antagonists. CA 2564742, CN 102040602, EP 1740177, JP 2007534769, KR 2011010841, US 200785155, US 7498440, US 8183257, US 2012157491, US 8309572, US 2013030015, WO 2005104745. |
| 【3】 Carangio, A., Cheung, I., D’Souza, E.C.F., Leahy, J.H., Strachan, J.B. (GlaxoSmithKline plc). Methods of preparation of muscarinic acetylcholine receptor antagonists. WO 2011029896. |
| 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) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (II) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (III) | 67994 | ethyl 1-(2-chloroethyl)piperidine-4-carboxylate | C10H18ClNO2 | 详情 | 详情 | |
| (IV) | 67995 | ethyl quinuclidine-4-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (V) | 49847 | 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine | 142851-03-4 | C13H23NO4 | 详情 | 详情 |
| (VI) | 67996 | 1-tert-butyl 4-ethyl 4-(2-chloroethyl)piperidine-1,4-dicarboxylate | C15H26ClNO4 | 详情 | 详情 | |
| (VII) | 67997 | ethyl 4-(2-chloroethyl)piperidine-4-carboxylate hydrochloride | C10H18ClNO2.HCl | 详情 | 详情 | |
| (VIII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (IX) | 67998 | diphenyl(quinuclidin-4-yl)methanol;1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol | C20H23NO | 详情 | 详情 | |
| (X) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IIb)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 .
| 【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 |
合成路线6
该中间体在本合成路线中的序号：(IX)Methoxycarbonylation of 5-bromo-2,2-difluoro-1,3-benzodioxole (I) under CO atmosphere in the presence of Pd(PPh3)4 and Et3N in MeOH/acetonitrile at 75 °C produces the benzodioxole carboxylate (II), which is reduced to primary alcohol (III) using LiAlH4 in THF . Similarly, alcohol (III) can be obtained by reduction of 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (IV) with Red-Al in toluene . Chlorination of alcohol (III) with SOCl2, optionally in the presence of DMAP, in CH2Cl2 or MTBE affords 5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole (V), which upon cyanation with NaCN in DMSO produces nitrile (VI) . In an alternative procedure, coupling of bromo benzodioxole (I) with ethyl cyanoacetate (VII) by means of Pd(dba)2, t-Bu3P and Na3PO4 in toluene/H2O at 70 °C yields the 2-cyanoacetate derivative (VIII), which undergoes decarboethoxylation to compound (VI) by means of HCl in DMSO/H2O at 75 °C . Dialkylation of nitrile (VI) with 1-bromo-2-chloroethane (IX) in the presence of either NaOH and BnNEt3Cl or KOH and Oct4NBr at 70 °C yields 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonitrile (X). After hydrolysis of nitrile (X) with NaOH in boiling H2O or EtOH, the resulting carboxylic acid (XI) is chlorinated with SOCl2 in the presence of DMF toluene at 60 °C to provide the acid chloride (XII) . Condensation of the cyclopropanecarbonyl chloride (XII) with 6-amino-2-chloro-3-methylpyridine (XIII) in pyridine at 110 °C affords the N-pyridyl amide (XIV), which finally undergoes Suzuki coupling with pinacol 3-carboxyphenylboronate (XV) by means of Pd(dppf)Cl2 and K2CO3 in hot DMF/H2O to furnish lumacaftor .
Alternatively, condensation of acid chloride (XII) with the biaryl amine (XVI) in the presence of Et3N and DMAP in toluene generates the tert-butyl ester (XVII), which is finally hydrolized by treatment with HCl in acetonitrile/water , followed by dissolving the obtained amino acid hydrochloride salt in aqueous NaOH or H2O, or by direct hydrolysis of ester (XVII) with HCOOH at 60-80 °C .
| 【1】 Hadida Rua, S., Hamilton, M., Miller, M., Grootenhuis, P.D.J., Bear, B., McCarthy, J., Zhou, J. (Vertex Pharmaceuticals, Inc.). Heterocyclic modulators of ATP-binding cassette transporters. EP 1945632, EP 2395002, EP 2404919, JP 2009514962, US 2008113985, US 7741321, US 7973038, US 2011172229, US 2011312958, US 2012232059, WO 2007056341. |
| 【2】 Siesel, D. (Vertex Pharmaceuticals, Inc.). Processes for producing cycloalkylcarboxamido-pyridine benzoic acids. CN 101910134, EP 2231606, JP 2011506332, KR 201010132, US 2009176989, US 8124781, US 2012190856, WO 2009076142. |
| 【3】 Pilewski, J.M., Frizzell, R.A. Role of CFTR in airway disease. Physiol Rev 1999, 79(1, Suppl.): S215-55. |
| 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) | 57609 | 5-Bromo-2,2-difluoro-1,3-benzodioxole；4-Bromo-1,2-[(difluoromethylene)dioxy]benzene | 33070-32-5 | C7H3BrF2O2 | 详情 | 详情 |
| (II) | 68629 | methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate | 773873-95-3 | C9H6F2O4 | 详情 | 详情 |
| (III) | 68630 | (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol | C8H6F2O3 | 详情 | 详情 | |
| (IV) | 68631 | 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid;2,2-difluoro-1,3-benzodioxole-5-carboxylic acid | C8H4F2O4 | 详情 | 详情 | |
| (V) | 68632 | 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole;5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole | C8H5ClF2O2 | 详情 | 详情 | |
| (VI) | 68633 | 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile | C9H5F2NO2 | 详情 | 详情 | |
| (VII) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (VIII) | 68634 | ethyl 2-cyano-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetate | C12H9F2NO4 | 详情 | 详情 | |
| (IX) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (X) | 68635 | 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile | C11H7F2NO2 | 详情 | 详情 | |
| (XI) | 68636 | 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid | C11H8F2O4 | 详情 | 详情 | |
| (XII) | 68637 | 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride | C11H7ClF2O3 | 详情 | 详情 | |
| (XIII) | 68639 | 6-amino-2-chloro-3-methylpyridine;2-Amino-6-chloro-5-methylpyridine;6-chloro-5-methyl-2-Pyridinamine | 442129-37-5 | C6H7ClN2 | 详情 | 详情 |
| (XIV) | 68638 | N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide | C17H13ClF2N2O3 | 详情 | 详情 | |
| (XV) | 68641 | 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid;3-Carboxyphenylboronic acid pinacol ester | 269409-73-6 | C13H17BO4 | 详情 | 详情 |
| (XVI) | 68642 | tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate | C17H20N2O2 | 详情 | 详情 | |
| (XVII) | 68640 | tert-butyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoate | C28H26F2N2O5 | 详情 | 详情 |