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【结 构 式】 
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【分子编号】20178 【品名】propionic acid 【CA登记号】79-09-4 |
【 分 子 式 】C3H6O2 【 分 子 量 】74.07944 【元素组成】C 48.64% H 8.16% O 43.2% |
合成路线1
该中间体在本合成路线中的序号：(B)The reaction of 3-bromoanisole (I) with magnesium in THF gives 3-methoxyphenylmagnesium bromide (II), which is condensed with 3-bromopyridine (III) in THF by means of dichlorobis(triphenylphosphine)nickel yielding 3-(3-pyridinyl)anisole (IV). The alkylation of (IV) with propylbromide (A) in acetone at 110 C (under pressure) affords N-propyl-3-(3-methoxyphenyl)pyridinium bromide (V), which is reduced with H2 over Pt in methanol to give 1-propyl-3-(3-methoxyphenyl)piperidine (VI). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr. The reduction of (IV) with H2 over Pt in methanol gives 3-(3-methoxyphenyl)piperidine (VII), which is acylated and reduced simultaneously with propionic acid (B) and NaBH4 in refluxing benzene to yield (VI), already obtained.
| 【1】 Arvidsson, F.L.E.; et al.; EP 0030526 . |
| 【2】 Sanchez, D.; Nilsson, J.L.G.; Hacksell, U.; Lindberg, P.; Carlsson, A.; Arvidsson, L.E.; Svensson, U.; Hjorth, S.; Wikstroem, H.; 3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity. J Med Chem 1981, 24, 12, 1475-82. |
| 【3】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (B) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (I) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (II) | 35984 | bromo(3-methoxyphenyl)magnesium | 36282-40-3 | C7H7BrMgO | 详情 | 详情 |
| (III) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (IV) | 35985 | 3-(3-methoxyphenyl)pyridine; methyl 3-(3-pyridinyl)phenyl ether | C12H11NO | 详情 | 详情 | |
| (V) | 35986 | 3-(3-methoxyphenyl)-1-propylpyridinium bromide | C15H18BrNO | 详情 | 详情 | |
| (VI) | 35987 | 3-(3-methoxyphenyl)-1-propylpiperidine; methyl 3-(1-propyl-3-piperidinyl)phenyl ether | C15H23NO | 详情 | 详情 | |
| (VII) | 35988 | 3-(3-methoxyphenyl)piperidine; methyl 3-(3-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The condensation of 2-amino-7-hydroxy-1,8-naphthyridine (I) with 5,6-dihydro-1,7-dithiin-2,3-dicarboxylic acid anhydride (II) in biphenyl-diphenyl ether at 230 C gives 5,7-dioxo-8-(7-hydroxy-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (III), which by reaction with POCl3 at 100 C is converted to the corresponding 7-chloro derivative (IV). Partial reduction of (IV) with KBH4 in methanol yields 6-(7-chloro-1,8-naphthyridin 2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (V), which is condensed with 4-chlorocarbonyl-1-(tert-butoxycarbonyl)piperazin (VI) by means of NaH in DMF affording 5-[(4-tert-butoxycarbonylpiperazin-1-yl)carbonyloxy]-6-(7-chloro-1,8-naphthyndin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (VII) Deprotection of (VII) by means of trifluoroacetic acid gives 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-[(piperazin-1-yl)carbonyloxy]-2,3,6,7-tetrahydro-5H-1,4-dithino[2,3-c]pyrrole (VIII), which is finally acetylated with propionic acid (IX) by means of dicyclohexylcarbodiimide in methylene chloride. The piperazine derivative (VI) is prepared as follows: The condensation of piperazine (X) with tert-butyl azidoformate (XI) in aqueous HCl gives 1-(tert-butoxycarbonyl)piperazine (XII), which is then condensed with phosgene in anhydrous toluene.
| 【1】 Cotrel, C.; Crisan, C.; Jeanmart, C.; Messer, M.N. (Aventis Pharma SA); Heterocyclic compounds. BE 0835325; DE 2550111; FR 2313060; FR 2322600; FR 2322601; FR 2322602; GB 1468497; JP 7670776; JP 7733685; JP 7998790; JP 8040671; JP 8051087; US 4220646 . |
| 【2】 Serradell, M.N.; Castaner, J.; Suproclone. Drugs Fut 1985, 10, 1, 45. |
| 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) | 28994 | 7-amino[1,8]naphthyridin-2-ol | C8H7N3O | 详情 | 详情 | |
| (II) | 28995 | 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C6H5NO2S2 | 详情 | 详情 | |
| (III) | 28996 | 6-(7-hydroxy[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H9N3O3S2 | 详情 | 详情 | |
| (IV) | 28997 | 6-(7-chloro[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H8ClN3O2S2 | 详情 | 详情 | |
| (V) | 28998 | 6-(7-chloro[1,8]naphthyridin-2-yl)-7-hydroxy-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-one | C14H10ClN3O2S2 | 详情 | 详情 | |
| (VI) | 28999 | tert-butyl 4-(chlorocarbonyl)-1-piperazinecarboxylate | C10H17ClN2O3 | 详情 | 详情 | |
| (VII) | 29000 | 1-(tert-butyl) 4-[6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl] 1,4-piperazinedicarboxylate | C24H26ClN5O5S2 | 详情 | 详情 | |
| (VIII) | 29001 | 6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl 1-piperazinecarboxylate | C19H18ClN5O3S2 | 详情 | 详情 | |
| (IX) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (X) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (XI) | 29002 | 2-[(azidocarbonyl)oxy]-2-methylpropane | C5H9N3O2 | 详情 | 详情 | |
| (XII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(D)The 1alpha,3beta-diol (Ia) derived from ergosterol was used as the starting material. The alcohol (Ia) was converted to methoxymethyl derivative (Ib) by reaction with chloromethyl methyl ether (4 eq) in dichloromethane for 16 h, which was oxidized with 3 eq of N-methylmorpholine N-oxide in the presence of osmium tetroxide (0.5 eq) in tert-butanol:tetrahydrofuran:water (10:3:1) for 4 h at room temperature to afford the 22,23-diol. The resulting diol was then cleaved by sodium metaperiodate (2.5 eq) in aqueous tetrahydrofuran (5 h, room temperature) to give the 22-aldehyde (IIa) in 30% yield from (Ia). Reaction of (IIa) with 6 eq of vinyl magnesium bromide (tetrahydrofuran, 0 C to room temperature, 2 h) gave the allyl alcohol (IIb) as a mixture of C-22 diastereoisomers. The Claisen reaction of (IIb) with 10 eq of triethyl orthopropionate and a catalytic amount of propionic acid (benzene reflux, 16 h) gave gamma,delta-unsaturated ester (IIa) in 70% yield from (IIa). The lithium enolate of (IIIa) generated by lithium N-isopropylcyclohexylamide in tetrahydrofuran at -78 C was reacted with oxygen for 1 h and subsequent reduction with triethyl phosphine at -78 C gave the 25-hydroxy ester (IIIb) in 87% yield. (IIIb) was shown to be a 1:1 mixture of C-25 diastereoisomers by high-pressure liquid chromatographic (HPLC) analysis. Alkaline hydrolysis (KOH, methanol, 60 C, 2.5 h) of the ester gave the hydroxy acid (IIIc) in 87% yield. (IIIc) was treated with 6 eq of I2 in dichloromethane in the presence of pyridine (15 eq) to give the iodolactone (IVa) in 74% yield, which was separated into isomers by silica gel column chromatography in a 1.5:1 ratio.
| 【1】 Morris, D.S.; Norris, A.F.; Williams, D.H.; Structure and synthesis of 25-hydroxycholecalciferol-26,23-lactone, a metabolite of vitamin D3. J Org Chem 1981, 46, 3422-28. |
| 【2】 Seino, Y.; Ishizuka, S.; 23(S),25(R)-1alpha,25-(OH)2-D3-26,23-Lactone. Drugs Fut 1992, 17, 8, 655. |
| 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) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (D) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (Ia) | 31263 | (1S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C28H46O2 | 详情 | 详情 | |
| (A) | 31264 | 4-methylmorpholin-4-ium-4-olate | C5H11NO2 | 详情 | 详情 | |
| (Ib) | 31265 | (1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene; (1S,8S,9S,10R,13R,14S,17R)-1-(methoxymethoxy)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl methoxymethyl ether | C32H54O4 | 详情 | 详情 | |
| (IIa) | 31266 | (2S)-2-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]propanal | C26H42O5 | 详情 | 详情 | |
| (IIb) | 31267 | (4S)-4-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-penten-3-ol | C28H46O5 | 详情 | 详情 | |
| (E) | 31268 | N-Cyclohexyl-N-methylamide lithium salt | C9H18LiN | 详情 | 详情 | |
| (IIIa) | 31269 | ethyl (E,6R)-6-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-4-heptenoate | C33H54O6 | 详情 | 详情 | |
| (IIIb) | 31270 | ethyl (E,6R)-6-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-hydroxy-2-methyl-4-heptenoate | C33H54O7 | 详情 | 详情 | |
| (IIIc) | 31271 | (E,6R)-6-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-hydroxy-2-methyl-4-heptenoic acid | C31H50O7 | 详情 | 详情 | |
| (IVa) | 31272 | 5-[(2S)-2-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-iodopropyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C31H49IO7 | 详情 | 详情 | |
| (C) | 10395 | 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate | 115-80-0 | C9H20O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：Nitrosation of 5,6-dimethoxy-1-indanone (I) with n-butyl nitrite and HCl in MeOH at 40 C provided oxime (II). Subsequent catalytic hydrogenation of ketone and oxime groups of (II) afforded the 2-aminoindan (III). Reductive alkylation of (III) using propionic acid and NaBH4 then gave the target dipropylamino compound, which was isolated as the hydrochloride salt after separation of some unreacted material by treatment with phenyl isocyanate.
| 【1】 Cannon, J.G.; et al.; Conformationally restricted congeners of dopamine derived from 2-aminoindan. J Med Chem 1982, 25, 12, 1442. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 | |
| 31340 | butyl nitrite | 544-16-1 | C4H9NO2 | 详情 | 详情 | |
| (I) | 13430 | 5,6-Dimethoxy-1-indanone; 2,3-Dihydro-5,6-dimethoxy-1H-inden-1-one | 2107-69-9 | C11H12O3 | 详情 | 详情 |
| (II) | 27302 | 5,6-dimethoxy-1H-indene-1,2(3H)-dione 2-oxime | C11H11NO4 | 详情 | 详情 | |
| (III) | 27303 | 5,6-dimethoxy-2,3-dihydro-1H-inden-2-ylamine | C11H15NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)1) The reaction of undecanal (I) with vinylmagnesium bromide (II) in THF gives 1-tridecen-3-ol (III), which is condensed with propionic acid (IV) by means of triethyl orthoacetate in refluxing xylene yielding 4(E)-pentadecenoic acid ethyl ester (V). The reaction of (V) with AD-mix-beta and methanesulfonamide in tert-butanol affords (R,R)-5-(1-hydroxyundecyl)tetrahydrofuran-2-one (VI), which by reaction with p-nitrobenzoic acid and triphenylphosphine in benzene gives the corresponding ester (VII). The reaction of (VII) first with LiAlH4 in ether, followed by a treatment with acetone and p-toluenesulfonic acid yields the acetonide (VIII), which by oxidation of its primary alcohol with pyridinium chlorochromate (PCC) in dichloromethane affords the corresponding aldehyde (IX). The reaction of (IX) with vinylmagnesium bromide (II) in ether gives the allyl alcohol (X), which by condensation with proionic acid (IV) and triethyl orthoacetate yields (4E,8R,9S)-8,9-(isopropylidenedioxy)-4-nonadecenoic acid ethyl ester (XI), The reduction of (XI) with diisobutylaluminum hydride (DIBAL) in toluene affords the corresponding aldehyde (XII), which is condensed with triethyl phosphonoacetate (XIII) by means of NaH in toluene giving (2E,6E,10R,11S)-10,11-(isopropylidenedioxy)-heneicosa-2,6-dienoic acid ethyl ester (XIV).
| 【1】 Yazbak, A.; et al.; Total synthesis of uvaricin. J Org Chem 1998, 63, 17, 5863. |
| 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) | 20175 | undecanal | 112-44-7 | C11H22O | 详情 | 详情 |
| (II) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (III) | 20177 | 1-tridecen-3-ol | C13H26O | 详情 | 详情 | |
| (IV) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (V) | 20179 | ethyl (E)-4-pentadecenoate | C17H32O2 | 详情 | 详情 | |
| (VI) | 20180 | (5R)-5-[(1R)-1-hydroxyundecyl]dihydro-2(3H)-furanone | C15H28O3 | 详情 | 详情 | |
| (VII) | 20181 | (1R)-1-[(2S)-4-oxo-1,3-dioxolan-2-yl]undecyl 4-nitrobenzoate | C21H29NO7 | 详情 | 详情 | |
| (VIII) | 20182 | 3-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-1-propanol | C18H36O3 | 详情 | 详情 | |
| (IX) | 20183 | 3-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]propanal | C18H34O3 | 详情 | 详情 | |
| (X) | 20184 | (3S)-5-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-1-penten-3-ol | C20H38O3 | 详情 | 详情 | |
| (XI) | 20185 | ethyl (E)-7-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-4-heptenoate | C24H44O4 | 详情 | 详情 | |
| (XII) | 20186 | (E)-7-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-4-heptenal | C22H40O3 | 详情 | 详情 | |
| (XIII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XIV) | 20188 | ethyl (2E,6E)-9-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2,6-nonadienoate | C26H46O4 | 详情 | 详情 |