|
【结 构 式】 
|
【分子编号】16925 【品名】3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one 【CA登记号】1193-65-3 |
【 分 子 式 】C7H11NO 【 分 子 量 】125.17048 【元素组成】C 67.17% H 8.86% N 11.19% O 12.78% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid affords a mixture of two diastereomeric spiroracemates, the (±)-trans (V) and (±)-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid. The (±)-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3. Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane.
| 【1】 Fisher, A.; Grunfeld, Y.; Heldman, E.; Karton, I.; Levy, A. (Israel Institute for Biological Research); Derivs of quinuclidine. EP 0205247; JP 1986280497; US 4855290 . |
| 【2】 Sorbera, L.A.; Castaner, J.; Cevimeline Hydrochloride. Drugs Fut 2000, 25, 6, 558. |
| 【3】 Hayashi, K.; Isogai, T.; Tokumoto, S.; Yoshizawa, H. (Ishihara Sangyo Kaisha, Ltd.); Method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine. EP 0683168; US 5571918 . |
| 【4】 Hara, K.; Koyanagi, T.; Shigehara, I.; Maeda, M.; Haga, T. (Ishihara Sangyo Kaisha, Ltd.); Method for isomerization of trans-form 2-methylspiro-(1,3-oxothiolane-5,3')-quinuclidine or acid addition salts thereof. EP 0298491; US 4861886 . |
| 【5】 Honda, N.; Saito, K.; Ono, T. (Snow Brand Milk Products Co., Ltd.); Preparation method of cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine hydrochloride.1/2 hydrate capable of disgregating easily. JP 1992108792 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| cis-(V) | 37592 | C10H17NOS | 详情 | 详情 | ||
| trans-(V) | 37593 | C10H17NOS | 详情 | 详情 | ||
| (I) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (II) | 37590 | C8H13NO | 详情 | 详情 | ||
| (III) | 37591 | 3-(sulfanylmethyl)-3-quinuclidinol | C8H15NOS | 详情 | 详情 | |
| (IV) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Sabcomeline can be obtained by several related ways: 1) The reaction of N-methoxyquinuclidine-3-carboxamide (I) with triphenylphosphine in refluxing CCl4 or with PCl5 in nitromethane gives N-methoxyquinuclidin-3-ylcarboxyimidoyl chloride (II), which by reaction with NaCN in hot DMSO is converted into 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III). Finally, this compound is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP], or with 2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid [L-DIOG]. 2) The condensation of diethyl cyanomethylphosphonate (IV) with 3-quinuclidinone (V) by means of KOH in water gives 2-(quinuclidin-3-ylidene)acetonitrile (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield 2-(quinuclidin-3-yl)acetonitrile (VII). The nitrosation of (VII) with isoamyl nitrile and potassium tert-butoxide in THF affords 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), which is methylated with methyl p-toluenesulfonate and potassium tert-butoxide in DMSO to give 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III), already obtained. 3) The condensation of 3-quinuclidinone (V) with cyanacetic acid (IX) by means of NaOH in water gives 2-(quinuclidin-3-ylidene)cyanacetic acid (X), which is hydrogenated with H2 over Pd/C in water to yield 2-(3-quinuclidinyl)cyanacetic acid (XI). Finally, this compound is nitrosated with NaNO2/HCl to afford 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), already obtained.
| 【1】 Graul, A.; Prous, J.; Castañer, J.; Sabcomeline Hydrochloride. Drugs Fut 1998, 23, 1, 41. |
| 【2】 Clark, M.S.G.; Bromidge, S.M.; Oriek,B.S.; Cassidy, F.; Eggleston, D.S.; Synthesis and properties of [R-(Z)]-(+)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)-alpha-(methoxyimino) acetonitrile, a novel functionally selective muscarinic partial agonist. J Chem Soc Chem Commun 1994, 18, 18, 2189-90. |
| 【3】 Cassidy, F.; Bromidge, S.M.; Clark, M.S.G.; Brown, F.; Riley, G.J.; Dabbs, S.; Loudon, J.M.; Hawkins, J.; Orlek, B.S.; A novel and selective class of azabicyclic muscarinic agonists incorporating an N-methoxy imidoyl halide or nitrile functionality. Bioorg Med Chem Lett 1992, 2, 8, 791-6. |
| 【4】 Orlek, B.S.; Bromidge, S.M.; Dabbs, S. (SmithKline Beecham plc); Novel cpds. AU 9053159; EP 0392803; JP 1991007285; JP 1997188678; JP 1997188679; US 5278170 . |
| 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) | 16921 | N-methoxy-3-quinuclidinecarboxamide | C9H16N2O2 | 详情 | 详情 | |
| (II) | 16922 | N-methoxy-3-quinuclidinecarboximidoyl chloride | C9H15ClN2O | 详情 | 详情 | |
| (III) | 16923 | N-methoxy-3-quinuclidinecarboximidoyl cyanide | C10H15N3O | 详情 | 详情 | |
| (IV) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (V) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (VI) | 16926 | 2-(1-azabicyclo[2.2.2]oct-3-ylidene)acetonitrile | C9H12N2 | 详情 | 详情 | |
| (VII) | 16927 | 2-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile | C9H14N2 | 详情 | 详情 | |
| (VIII) | 16928 | N-hydroxy-3-quinuclidinecarboximidoyl cyanide | C9H13N3O | 详情 | 详情 | |
| (IX) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (X) | 16930 | 2-(1-azabicyclo[2.2.2]oct-3-ylidene)-2-cyanoacetic acid | C10H12N2O2 | 详情 | 详情 | |
| (XI) | 16931 | 2-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyanoacetic acid | C10H14N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The Horner-Emmons condensation of 3-quinuclidinone (I) with triethyl 2-fluoro-2-phosphonoacetate (II) produced the unsaturated ester (III). The amino-borane complex (IV) was then obtained by treatment of (III) with borane in THF. Ester group of (IV) reduction by means of sodium bis(2-methoxyethoxy)aluminium hydride gave the allylic alcohol (V), which was converted into chloride (VI) by treatment with mesyl chloride in the presence of LiCl. Condensation of chloride (VI) with 2-hydroxycarbazole (VII) yielded ether (VIII). After acid cleavage of the amino-borane complex (VIII), the title compound was isolated as the hydrochloride salt.
| 【1】 Isaka, M.; Ishihara, T.; Matsuda, K.; Kakuta, H.; Moritani, H. (Yamanouchi Pharmaceutical Co., Ltd.); Novel quinuclidine derivs. having tricyclic fused hetero ring. EP 0812840; WO 9626938 . |
| 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) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (II) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
| (III) | 44999 | ethyl 2-(1-azabicyclo[2.2.2]oct-3-ylidene)-2-fluoroacetate | C11H16FNO2 | 详情 | 详情 | |
| (IV) | 45000 | C11H19BFNO2 | 详情 | 详情 | ||
| (V) | 45001 | C9H17BFNO | 详情 | 详情 | ||
| (VI) | 45002 | C9H16BClFN | 详情 | 详情 | ||
| (VII) | 45003 | 9H-carbazol-2-ol | C12H9NO | 详情 | 详情 | |
| (VIII) | 45004 | C21H24BFN2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of 3-quinuclidinone (I) with tert-butyl acetate using LDA in THF at low temperature gave hydroxy ester (II). Acid cleavage of the tert-butyl ester of (II), followed by esterification with MeOH and H2SO4 produced the methyl ester (III), which was transformed to hydrazide (IV) upon treatment with hydrazine in refluxing MeOH. Nitrosation of (IV) with NaNO2 and HCl, followed by Curtius rearrangement of the intermediate acyl azide furnished the target spiro oxazolidinone (V). The required (S)-enantiomer was then isolated by resolution with dibenzoyl-D-tartaric acid.
| 【1】 Mullen, G.; Balestra, M.; Napier, J.; et al.; (-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha7 nicotinic acetylcholine receptor. J Med Chem 2000, 43, 22, 4045. |
| 【2】 Napier, J.; Mack, R.; Loch, J. III; et al.; The synthesis and nicotinic receptor subtype profile of AR-R17779, a conformationally restricted analog of acetylcholine. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.149. |
| 【3】 Murray, R.J.; Gordon, J.C.; Griffith, R.C.; Balestra, M. (AstraZeneca plc); Spiro-azabicyclic cpds. useful in therapy. WO 9606098 . |
| 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) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (II) | 30111 | tert-butyl 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetate | C13H23NO3 | 详情 | 详情 | |
| (III) | 30112 | methyl 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetate | C10H17NO3 | 详情 | 详情 | |
| (IV) | 30113 | 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetohydrazide | C9H17N3O2 | 详情 | 详情 | |
| (V) | 30114 | Spiro[oxazolidine-5,3'-quinuclidin]-2-one | C9H14N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)In an alternative procedure, reaction of quinuclidinone (I) with (R)-2-hydroxy-1,2,2-triphenylethyl acetate (VI) gave adduct (VII) as a single enantiomer. Subsequent ester hydrolysis of (VII) provided the chiral carboxylic acid (VIII). Finally, rearrangement of (VIII) in the presence of diphenyl phosphorylazide yielded the title compound.
| 【1】 Napier, J.; Mack, R.; Loch, J. III; et al.; The synthesis and nicotinic receptor subtype profile of AR-R17779, a conformationally restricted analog of acetylcholine. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.149. |
| 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) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (VI) | 11540 | (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate | 95061-47-5 | C22H20O3 | 详情 | 详情 |
| (VII) | 30115 | (1S)-2-hydroxy-1,2,2-triphenylethyl 2-[(3R)-3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl]acetate | C29H31NO4 | 详情 | 详情 | |
| (VIII) | 30116 | 2-[(3R)-3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl]acetic acid | C9H15NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Addition of lithium trimethylsilylacetylide (II) to quinuclidin-3-one (I) in THF at -70 C afforded the O-silylated ethynyl quinuclidinol (III). Subsequent palladium-catalyzed coupling of (III) with 4,4'-dibromobenzophenone (IV) gave adduct (V). Finally, the Meyer-Schuster rearrangement of (V) in concentrated H2SO4 furnished the title unsaturated ketone.
| 【1】 Brown, G.R.; Stokes, E.S.E.; Hollinshead, D.M.; et al.; Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: Optimization from lipid profiles. J Med Chem 1999, 42, 7, 1306. |
| 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) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (II) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (III) | 34446 | 3-ethynyl-3-[(trimethylsilyl)oxy]quinuclidine; 3-ethynyl-1-azabicyclo[2.2.2]oct-3-yl trimethylsilyl ether | C12H21NOSi | 详情 | 详情 | |
| (IV) | 34447 | bis(4-bromophenyl)methanone | 3988-03-2 | C13H8Br2O | 详情 | 详情 |
| (V) | 34448 | (4-bromophenyl)[4-(2-[3-[(trimethylsilyl)oxy]-1-azabicyclo[2.2.2]oct-3-yl]ethynyl)phenyl]methanone | C25H28BrNO2Si | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)N-(2-Butynyloxy)phthalimide (III) was obtained by the Mitsunobu coupling between 2-butyn-1-ol (II) and N-hydroxyphthalimide (I). Subsequent hydrazinolysis of (III) gave the O-alkynyl hydroxylamine (IV). This was finally condensed with quinuclidin-3-one (V) in methanol to furnish the corresponding oxime.
| 【1】 Go, M.-L.; Loke, W.-K.; Sim, M.-K.; Somanadhan, B.; Quinuclidinone O-alkynyloximes with muscarinic agonist activity. Bioorg Med Chem 2002, 10, 1, 207. |
| 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) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (II) | 42514 | 2-butyn-1-ol | 764-01-2 | C4H6O | 详情 | 详情 |
| (III) | 59686 | 2-(2-butynyloxy)-1H-isoindole-1,3(2H)-dione | C12H9NO3 | 详情 | 详情 | |
| (IV) | 59687 | 1-(aminooxy)-2-butyne; O-(2-butynyl)hydroxylamine | C4H7NO | 详情 | 详情 | |
| (V) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |