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【结 构 式】 
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【分子编号】37404 【品名】(3-carboxypropyl)(triphenyl)phosphonium bromide 【CA登记号】17857-14-6 |
【 分 子 式 】C22H22BrO2P 【 分 子 量 】429.293242 【元素组成】C 61.55% H 5.17% Br 18.61% O 7.45% P 7.22% |
合成路线1
该中间体在本合成路线中的序号：(XII)The Wittig reaction of (XI) with (4-carboxybutyl)triphenylphosphonium bromide (XII) in HMPT gives nat-11R,16,16-trimethyl-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoic acid (XIII), which is oxidized with Jones reagent (CrO3-H2SO4) affording the corresponding 9-oxo compound (XIV). Finally, this compound is hydrolyzed with acetic acid in a mixture THF-water.
| 【1】 Holland, G.W.; et al.; US 4112225 . |
| 【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; RO-21-6937/000. Drugs Fut 1981, 6, 1, 42. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 37403 | (3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-ol | C24H42O4 | 详情 | 详情 | |
| (XII) | 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 |
| (XIII) | 37405 | (Z)-7-((1R,2R,3R,5S)-2-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-methylcyclopentyl)-5-heptenoic acid | C29H50O5 | 详情 | 详情 | |
| (XIV) | 37406 | (Z)-7-((1R,2R,3R)-2-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-3-methyl-5-oxocyclopentyl)-5-heptenoic acid | C29H48O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Resolution of bicyclo[3.2.0]hept-2-en-6-one (I) via the R-(+)-alpha-methylbenzylamine-bisulfite (A) addition complex provides the 1S-(-)-enantiomer (II), which affords the 3-endo-acetoxy-2-exo-bromobicyclo[3.2.0]heptan-6-one (III) on treatment with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). Reaction with piperidine followed by hydrolysis gives the hydroxynorbornanone (IV), which is alkylated with biphenylmethylbromide (B) under phase-transfer catalysis to yield the norbornanone (V). Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VII), which is then homologated to the aldehyde (VIII) using methoxymethylene-phosphorane and subsequent treatment with 2N HCl. Condensation of (VIII) with carboxypropyltriphenylphosphorane in tetrahydrofuran followed by esterification with tritylchloride gives the ester (IX). The alcohol stereochemistry in (IX) is inverted via oxidation with pyridine-sulfur trioxide complex in dimethylsulfoxide followed by reduction with Dibal in the presence of 2,6-di-tert-butyl-4-methylphenol. Finally, the ester is hydrolyzed with hydrochloric acid to give the required acid.
| 【1】 Coleman, M.J.; et al.; Baeyer-villiger oxidation of 5-endo-(biphenyl-4-ylmethoxy)-7-anti-piperidinobicyclo[2.2.1] process development and scale-Up. Org Process Res Dev 1997, 1, 1, 20. |
| 【2】 Lumley, P.; Finch, H.; Collington, E.W.C.; Humphrey, P.P.A.; VAPIPROST HYDROCHLORIDE < Rec INNM; BAN >. Drugs Fut 1990, 15, 11, 1087. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 | |
| (A) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (I), (II) | 24421 | (1S,5R)bicyclo[3.2.0]hept-2-en-6-one | C7H8O | 详情 | 详情 | |
| (B) | 31210 | 4-(bromomethyl)-1,1'-biphenyl | 2567-29-5 | C13H11Br | 详情 | 详情 |
| (III) | 31208 | (1R,2S,3S,5R)-2-bromo-6-oxobicyclo[3.2.0]hept-3-yl acetate | C9H11BrO3 | 详情 | 详情 | |
| (IV) | 31209 | 5-hydroxy-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one | C12H19NO2 | 详情 | 详情 | |
| (V) | 31211 | 5-([1,1'-biphenyl]-4-ylmethoxy)-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one | C25H29NO2 | 详情 | 详情 | |
| (VI) | 31212 | 6-([1,1'-biphenyl]-4-ylmethoxy)-8-(1-piperidinyl)-2-oxabicyclo[3.2.1]octan-3-one | C25H29NO3 | 详情 | 详情 | |
| (VII) | 31213 | 2-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]acetaldehyde | C25H31NO3 | 详情 | 详情 | |
| (VIII) | 31214 | 3-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]propanal | C26H33NO3 | 详情 | 详情 | |
| (IX) | 31215 | trityl (Z)-7-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoate | C49H53NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)In an alternative method, (-)-myrtenol (VI) was heated with triethyl orthoacetate to produce an intermediate allyl vinyl ether (VII), which underwent Claisen rearrangement to the unsaturated ester (VIII). Ozonization of the olefin (VIII), followed by reductive treatment with trimethyl phosphite, furnished ketone (IX). Conversion of ketone (IX) into the required amine (XI) was effected via previous formation of either the oxime (XII) or the O-methyl oxime (X). Simultaneous reduction of the O-methyl oxime and ester functions of (X) was carried out by using NaBH4 in the presence of AlCl3 or, alternatively, with sodium metal and n-propanol, to produce the desired (2R,3R)-amino alcohol (XI) as the major diastereoisomer. Isolation of (XI) from the reaction mixture was achieved through formation of the corresponding benzoate salt. Amino alcohol (XI) was also obtained by reduction of oxime (XII) with NaBH4 in the presence of either boron trifluoride ethearate or TiCl4. Optionally, (X) was reduced in a two-step process by first conversion to alcohol (XIII) and subsequent reduction of the oxime function. Acid chloride (XIV) was prepared from 5-hydroxybenzothiophene-3-carboxylic acid (I) by sulfonylation of the phenolic hydroxyl with benzenesulfonyl chloride, followed by treatment with SOCl2. Condensation of acid chloride (XIV) with amine (XI) produced the corresponding amide (XV). The alcohol function of (XV) was oxidized to aldehyde (XVI) using NaOCl in the presence of catalytic amounts of TEMPO and KBr. Then Wittig condensation of aldehyde (XVI) with (4-carboxybutyl)triphenylphosphonium bromide (XVII), followed by basic hydrolysis of the phenylsulfonyl protecting group, gave rise to the title compound.
| 【1】 Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume, H.; Mitsumori, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino, J.; Ohtani, M.; Bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists. J Med Chem 1997, 40, 22, 3504. |
| 【2】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 . |
| 【3】 Arimura, A. (Shionogi & Co. Ltd.); Remedies for itching containing PGD2 antagonists. EP 1084711; WO 9962555 . |
| 【4】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 . |
| 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) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (VI) | 51423 | [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol | C10H16O | 详情 | 详情 | |
| (VII) | 52245 | (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl 1-(ethyloxy)ethenyl ether; 2-({[1-(ethyloxy)ethenyl]oxy}methyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene | C14H22O2 | 详情 | 详情 | |
| (VIII) | 52246 | ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate | C14H22O2 | 详情 | 详情 | |
| (IX) | 52247 | ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate | C13H20O3 | 详情 | 详情 | |
| (X) | 52248 | ethyl 2-{6,6-dimethyl-2-[(methyloxy)imino]bicyclo[3.1.1]hept-3-yl}acetate | C14H23NO3 | 详情 | 详情 | |
| (XI) | 52250 | 2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol | C11H21NO | 详情 | 详情 | |
| (XII) | 52251 | ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate | C13H21NO3 | 详情 | 详情 | |
| (XIII) | 52249 | 3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime | C12H21NO2 | 详情 | 详情 | |
| (XIV) | 52252 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate | C15H9ClO4S2 | 详情 | 详情 | |
| (XV) | 52253 | 3-({[3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate | C26H29NO5S2 | 详情 | 详情 | |
| (XVI) | 52254 | 3-({[6,6-dimethyl-3-(2-oxoethyl)bicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate | C26H27NO5S2 | 详情 | 详情 | |
| (XVII) | 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)A new large-scaleable synthesis of TAK-779 has been developed: The reduction of 4'-methylbiphenyl-4-carbonitrile (I) with sodium bis(2-methoxyethoxy)aluminum hydride (SBMEA) in THF gives the corresponding aldehyde (II), which is submitted to a Wittig condensation with the phosphonium bromide (III) by means of NaOMe in methanol to yield the pentenoic acid derivative (IV). Reduction of the double bond of (IV) with H2 over Pd/C in THF, followed by cyclization with hot PPA affords the benzocycloheptanone (V), which is treated with refluxing dimethyl carbonate and NaOMe to provide the beta-ketoester (VI). The reduction of (VI) with NaBH4 in THF gives the hydroxyester (VII), which is dehydrated with Ms-Cl and DBU and hydrolyzed with NaOH to yield 8-(4-methylphenyl)benzocyclohept-1-ene-2-carboxylic acid (VIII). Condensation of (VIII) with 4-aminobenzyl alcohol (IX) by means of (COCl)2 and TEA in THF affords the corresponding amide (X), which is treated with SOCl2 in THF to provide the chloromethyl derivative (XI). Finally, this compound is condensed with 4-(dimethylamino)tetrahydropyran (XII) in hot DMF to furnish the target ammonium salt. The tertiary amine (XII) has been obtained by reductive condensation of tetrahydropyran-4-one (XIII) with dimethylamine by means of H2 over Pd/C in THF.
| 【1】 Ikemoto, T.; Hashimoto, H.; Kaarasaki, T.; Tomimatsu, K.; Ito, T.; Nishiguchi, A.; Wakimasu, M.; Mitsudera, H.; Development of a new synthetic route of a non-peptide CCR5 antagonist, TAK-779, for large-scale preparation. Org Process Res Dev 2000, 4, 6, 520. |
| 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) | 45764 | 4'-methyl[1,1'-biphenyl]-4-carbonitrile | C14H11N | 详情 | 详情 | |
| (II) | 18985 | 4'-methyl[1,1'-biphenyl]-4-carbaldehyde | C14H12O | 详情 | 详情 | |
| (III) | 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 |
| (IV) | 45765 | (Z)-5-(4'-methyl[1,1'-biphenyl]-4-yl)-4-pentenoic acid | C18H18O2 | 详情 | 详情 | |
| (V) | 31555 | 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H18O | 详情 | 详情 | |
| (VI) | 33422 | methyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H20O3 | 详情 | 详情 | |
| (VII) | 45766 | methyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H22O3 | 详情 | 详情 | |
| (VIII) | 31560 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid | C19H18O2 | 详情 | 详情 | |
| (IX) | 34430 | (4-aminophenyl)methanol | 623-04-1 | C7H9NO | 详情 | 详情 |
| (X) | 33424 | N-[4-(hydroxymethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C26H25NO2 | 详情 | 详情 | |
| (XI) | 33425 | N-[4-(chloromethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C26H24ClNO | 详情 | 详情 | |
| (XII) | 33426 | N,N-dimethyltetrahydro-2H-pyran-4-amine; N,N-dimethyl-N-tetrahydro-2H-pyran-4-ylamine | C7H15NO | 详情 | 详情 | |
| (XIII) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |