|
【结 构 式】 
|
【分子编号】16583 【品名】(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride 【CA登记号】39637-74-6 |
【 分 子 式 】C10H13ClO3 【 分 子 量 】216.66412 【元素组成】C 55.44% H 6.05% Cl 16.36% O 22.15% |
合成路线1
该中间体在本合成路线中的序号：(XV)Efavirenz has been obtained by two related ways: 1) The acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by means of Na2CO3 in toluene gives the expected anilide (III), which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords the protected acetophenone (VI), which is regioselectively condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium in cyclohexane] by means of butyllithium in THF in the presence of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the (S)-isomer of the tertiary alcohol (X) exclusively. The cyclization of (X) with phosgene and triethylamine or K2CO3 in toluene/THF yields the benzoxazinone (XI), which is finally deprotected with ceric ammonium nitrate in acetonitrile/water. 2) The condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV) with cyclopropylacetylene (VIII) by means of butyllithium or ethylmagnesium bromide in THF gives (?-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (XII). The cyclization of (XII) with carbonyldiimidazole (XIII) in hot THF yields the racemic benzoxazinone (XIV). Compound (XIV) is submitted to optical resolution by condensation with (S)-(-)-camphanoyl chloride by means of dimethylaminopyridine (DMAP) in dichloromethane to give the acyl derivative (XVI) as a diastereomeric mixture that is resolved by crystallization and finally decomposed with HCl in ethanol or butanol.
| 【1】 Choudhury, A.; Moore, J.R.; Pierce, M.E.; Fortunak, J.M.; Valvis, I.; Confalone, P.N.; In situ recycling of chiral ligand and surplus nucleophile for a noncatalytic reaction: Amplification of process throughput in the asymmetric addition step of efavirenz (DMP 266). Org Process Res Dev 2003, 7, 3, 324. |
| 【2】 Britcher, S.F.; Tran, L.O.; Young, S.D.; L-743,726 (DMP-266): A novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995, 39, 12, 2602-5. |
| 【3】 Corley, E.G.; Thompson, A.S.; Huntington, M.F.; Grabowski, E.J.J.; Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: Asymmetric synthesis of the reverse transcriptase inhibitor L-743,726. Tetrahedron Lett 1995, 36, 49, 8937-40. |
| 【4】 Graul, A.; Rabasseda, X.; Castañer, J.; Efavirenz. Drugs Fut 1998, 23, 2, 133. |
| 【5】 Young, S.D.; Britcher, S.F.; Payne, L.S.; Tran, L.O.; Lumma, W.C. Jr. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. WO 9520389 . |
| 【6】 Young, S.D.; Tran, L.O.; Britcher, S.F.; Lumma, W.C. Jr.; Payne, L.S. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. EP 0582455; JP 1994184124; WO 9403440 . |
| 【7】 Thompson, A.S.; Corley, E.G.; Huntington, M. (Merck & Co., Inc.); Improved synthesis of cyclopropylacetylene. JP 1998512880; WO 9622955 . |
| 【8】 Thompson, A.S.; Corley, E.G.; Grabowski, E.J.J.; Yasuda, N. (Merck & Co., Inc.); Asymmetric synthesis of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one. WO 9637457 . |
| 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) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 16571 | 4'-Chloro-2,2-dimethylpropionanilide; N-(4-Chlorophenyl)-2,2-dimethylpropanamide | 65854-91-3 | C11H14ClNO | 详情 | 详情 |
| (IV) | 16572 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone | C8H5ClF3NO | 详情 | 详情 | |
| (V) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (VI) | 16574 | 1-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-2,2,2-trifluoro-1-ethanone | C16H13ClF3NO2 | 详情 | 详情 | |
| (VII) | 16575 | 1-ethynylcyclopropane; cyclopropyl acetylene | 6746-94-7 | C5H6 | 详情 | 详情 |
| (VIII) | 16576 | 5-chloro-1-pentyne | 14267-92-6 | C5H7Cl | 详情 | 详情 |
| (IX) | 16577 | (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol | C13H19NO | 详情 | 详情 | |
| (X) | 16578 | (2S)-2-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | C21H19ClF3NO2 | 详情 | 详情 | |
| (XI) | 16579 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C22H17ClF3NO3 | 详情 | 详情 | |
| (XII) | 16580 | 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | 168834-43-3 | C13H11ClF3NO | 详情 | 详情 |
| (XIII) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (XIV) | 16582 | 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C14H9ClF3NO2 | 详情 | 详情 | |
| (XV) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (XVI) | 16584 | 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one | C24H21ClF3NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III), which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV). Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI), which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)]. Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of ()-EMD-53998 (EMD-57439) and the camphanoyl amide (X), which are separated by chromatography. Finally, the (+)-enantiomer, EMD-57033, is isolated by further treatment of amide (X) with morpholine in methylene chloride.
| 【1】 Strube, J.; Jupke, A.; Schmidt-Traub, H.; Schulte, M.; Epping, A.; Devant, R.; Design, optimization, and operation of SMB chromatography in the production of enantiomerically pure pharmaceuticals. Chirality 1999, 11, 440. |
| 【2】 Castaner, J.; Doggrell, S.A.; Brown, L.; EMD-57033. Drugs Fut 2002, 27, 1, 14. |
| 【3】 Jonas, R.; Piulats, J.; Lues, I.; Klockow, M. (Merck Patent GmbH); Thiadiazinones. AU 8816646; DE 3719031; DE 3744149; EP 0294647; JP 1988310886; US 4916128 . |
| 【4】 Klockow, M.; Lues, I.; Jonas, R.; Preparation of the enantiomers of the novel Ca-sensitizer EMD 53 998. Bioorg Med Chem Lett 1992, 2, 6, 589. |
| 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) | 51475 | 1-[3,4-dihydro-1(2H)-quinolinyl]-1-ethanone | C11H13NO | 详情 | 详情 | |
| (II) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (III) | 51476 | 1-(1-acetyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-chloro-1-propanone | C14H16ClNO2 | 详情 | 详情 | |
| (IV) | 51477 | 2-chloro-1-(1,2,3,4-tetrahydro-6-quinolinyl)-1-propanone | C12H14ClNO | 详情 | 详情 | |
| (V) | 51478 | O-ethyl 1-hydrazinecarbothioate | C3H8N2OS | 详情 | 详情 | |
| (VI) | 51479 | 6-methyl-5-(1,2,3,4-tetrahydro-6-quinolinyl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one | C13H15N3OS | 详情 | 详情 | |
| (VII) | 13488 | (2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol | 2914-69-4 | C4H6O | 详情 | 详情 |
| (VIII) | 51480 | 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one | C22H23N3O4S | 详情 | 详情 | |
| (IX) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (X) | 51481 | 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one | C32H35N3O7S | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)Vilsmeier formylation of orcinol (I) by means of POCl3 and DMF afforded 2,4-dihydroxy-6-methylbenzaldehyde (II). Coumarin (V) was then prepared by Wittig condensation of (II) with carbethoxymethylene triphenylphosphorane (III) followed by intramolecular cyclization in refluxing xylene. Alkylation of (V) with 3-chloro-3-methyl-1-butyne (VI) in the presence of K2CO3 and KI produced the corresponding alpha,alpha-dimethylpropargyl ether (VII), and subsequent thermal cyclization in refluxing N,N-diethylaniline gave rise to the tricyclic system (VIII). Osmium-catalyzed asymmetric dihydroxylation of (VIII) in the presence of the enantioselective ligand hydroquinone 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2-PYR] produced the required (R,R)-(+)-cis-diol (IX). This was finally acylated with (S)-(-)-camphanic chloride (X) in the presence of pyridine to produce the target dicamphanoyl ester.
| 【1】 Takeuchi, Y.; Xie, L.; Lee, K.-H.; Cosentino, L.M.; Anti-AIDS agents. 37.(1) synthesis and structure-activity relationships of (3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents. J Med Chem 1999, 42, 14, 2662. |
| 【2】 Xie, L.; Takeuchi, Y.; Cosentino, L.M.; Lee, K.-H.; Anti-AIDS agent 33. Synthesis and anti-HIV activity of mono-methyl substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogues. Bioorg Med Chem Lett 1998, 8, 16, 2151. |
| 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) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (II) | 34435 | 2,4-dihydroxy-6-methylbenzaldehyde | C8H8O3 | 详情 | 详情 | |
| (III) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (IV) | 34436 | ethyl (E)-3-(2,4-dihydroxy-6-methylphenyl)-2-propenoate | C12H14O4 | 详情 | 详情 | |
| (V) | 34437 | 7-hydroxy-5-methyl-2H-chromen-2-one | C10H8O3 | 详情 | 详情 | |
| (VI) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (VII) | 34438 | 7-[(1,1-dimethyl-2-propynyl)oxy]-5-methyl-2H-chromen-2-one | C15H14O3 | 详情 | 详情 | |
| (VIII) | 34439 | 5,8,8-trimethyl-2H,8H-pyrano[2,3-f]chromen-2-one | C15H14O3 | 详情 | 详情 | |
| (IX) | 34440 | (9R,10R)-9,10-dihydroxy-5,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C15H16O5 | 详情 | 详情 | |
| (X) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Friedel Crafts' condensation of phloroglucinol (I) with 3,3-dimethylacrylic acid (II) in the presence of boron trifluoride etherate gave the dihydroxy chromanone (III). Selective alkylation of the 7-hydroxyl group of (III) with iodomethane in the presence of K2CO3 furnished the methyl ether (IV). The carbonyl group of (IV) was subsequently reduced with NaBH4 in refluxing THF under basic conditions to produce chroman (V). The lactone ring of (VII) was then formed by a Pechmann reaction of (V) using ethyl acetoacetate (VI) and boron trifluoride to afford the tricyclic compound (VII). Dehydrogenation of (VII) employing DDQ in refluxing dioxan gave (VIII). The target 3'R,4'R-dihydroxylated derivative (IX) was obtained by Sharpless asymmetric dihydroxylation of (VIII) with hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2-PYR) as the chiral catalyst. Diol (IX) was finally esterified with (-)-S-camphanoyl chloride (X) to afford the title diester.
| 【1】 Takeuchi, Y.; McPhail, A.T.; Cosentino, L.M.; Lee, K.-H.; Xie, L.; Anti-AIDS agents.42. Synthesis and anti-HIV activity of disubstituted (3'R, 4'R)-3',4'-Di-O-(S)-camphanoyl-(+)-cis-khellactone analogues. J Med Chem 2001, 44, 5, 664. |
| 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) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (II) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (III) | 22422 | 5,7-dihydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C11H12O4 | 详情 | 详情 | |
| (IV) | 47784 | 5-hydroxy-7-methoxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C12H14O4 | 详情 | 详情 | |
| (V) | 47785 | 7-methoxy-2,2-dimethyl-5-chromanol | C12H16O3 | 详情 | 详情 | |
| (VI) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (VII) | 47786 | 5-methoxy-4,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C16H18O4 | 详情 | 详情 | |
| (VIII) | 47787 | 5-methoxy-4,8,8-trimethyl-2H,8H-pyrano[2,3-f]chromen-2-one | C16H16O4 | 详情 | 详情 | |
| (IX) | 47788 | (9R,10R)-9,10-dihydroxy-5-methoxy-4,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C16H18O6 | 详情 | 详情 | |
| (X) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Alkylation of 2-pyridin-4-ylethanol (I) with 4-fluorobenzyl chloride (II), followed by reduction of the resultant pyridinium salt (III) with NaBH4 leads to the tetrahydropyridine (IV). Acid-catalyzed condensation of alcohol (IV) with benzhydrol (V) then provides the benzhydryl ether (VI) (1). Hydroboration of tetrahydropyridine (VI) and subsequent oxidative work up gives rise to the racemic trans piperidinol rac-(VII) (1,2). Resolution of (VII) is accomplished via esterification with (-)-camphanic chloride (VIII), followed by HPLC separation of the resulting diastereoisomers. The desired isomer (IX) is finally hydrolyzed employing K2CO3 in MeOH to provide the target enantiomer
| 【1】 Ghorai, S.K.; Cook, C.; Davis, M.; Venkataraman, S.K.; George, C.; Beardsley, P.M.; Reith, M.E.A.; Dutta, A.K.; High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: Stereospecific interactions in vitro and in vivo. J Med Chem 2003, 46, 7, 1220. |
| 【2】 Dutta, A.K. (Wayne State University); N- and O-substd. 4-[2-(diphenylmethoxy)-ethyl]-1-[(phenyl)methyl]piperidine analogs and methods of treating CNS disorders therewith. WO 0198266 . |
| 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) | 52533 | 2-(4-Pyridinyl)-1-ethanol; 2-Pyridin-4-ylethanol | C7H9NO | 详情 | 详情 | |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 63533 | 1-[(4-fluorophenyl)methyl]-4-(2-hydroxyethyl)pyridinium chloride | C14H15ClFNO | 详情 | 详情 | |
| (IV) | 63534 | 2-{1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-ethanol | C14H18FNO | 详情 | 详情 | |
| (V) | 11845 | Diphenylmethanol; Benzhydrol | 91-01-0 | C13H12O | 详情 | 详情 |
| (VI) | 63535 | diphenylmethyl 2-{1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydro-4-pyridinyl}ethyl ether; 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydropyridine | C27H28FNO | 详情 | 详情 | |
| (VII) | 63536 | 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-3-piperidinol | C27H30FNO2 | 详情 | 详情 | |
| (VIII) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (IX) | 63537 | 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-3-piperidinyl 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C37H42FNO5 | 详情 | 详情 |