合成路线1
该中间体在本合成路线中的序号:
(I) The condensation of benzophenone (I) with chloroacetic acid methyl ester (II) by means of sodium methoxide in THF gives the epoxide (III), which is treated with methanol/BF3.Et2O, yielding 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is hydrolyzed with NaOH in hot dioxane/water to give the corresponding free acid (VII). Finally, this compound is submitted to optical resolution, affording LU-135252.
Optical resolution of (VIII), the free acid derivative of (IV), with (R)-phenylethylamine, L-proline methyl ester, (S)-1-(4-nitrophenyl)ethylamine or (S)-1-(4--chlorophenyl)ethylamine leads to the enantiomerically pure (S)-enatiomer (IX), which by reaction with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) directly affords LU-135252.
【1】
Jansen, R.; et al.; Structural similarity and its suprises: Endothelin receptor antagonists - Process research and development report. Org Process Res Dev 2001, 5, 1, 16.
|
【2】
Riechers, H.; Albrecht, H.-P.; Amberg, W.; et al.; Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem 1996, 39, 11, 2123.
|
【3】
Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; LU-135252. Drugs Fut 1999, 24, 2, 141.
|
【4】
Riechers, H.; Klinge, D.; Amberg, W.; Kling, A.; Müller, S.; Baumann, E.; Rheinheimer, J.; Vogelbacher, U.J.; Wernet, W.; Unger, L.; Raschack, M. (BASF AG); New carboxylic acid derivs., their preparation and their use. EP 0785926; JP 1998507190; WO 9611914 . |
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) |
18732 |
benzophenone
|
119-61-9 |
C13H10O |
详情 | 详情
|
(III) |
21148 |
methyl 3,3-diphenyl-2-oxiranecarboxylate
|
|
C16H14O3 |
详情 |
详情
|
(IV) |
21149 |
methyl 2-hydroxy-3-methoxy-3,3-diphenylpropanoate
|
|
C17H18O4 |
详情 |
详情
|
(V) |
21150 |
4,6-dimethoxy-2-(methylsulfonyl)pyrimidine; 4,6-dimethoxy-2-pyrimidinyl methyl sulfone
|
|
C7H10N2O4S |
详情 |
详情
|
(VI) |
21151 |
methyl 2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoate
|
|
C23H24N2O6 |
详情 |
详情
|
(VII) |
21152 |
2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropionic acid
|
|
C22H22N2O6 |
详情 |
详情
|
(VIII) |
21153 |
2-hydroxy-3-methoxy-3,3-diphenylpropionic acid
|
|
C16H16O4 |
详情 |
详情
|
(IX) |
21154 |
(2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid
|
|
C16H16O4 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(VIII) A pilot plant process was further developed for the (S)-enantiomer. Darzens condensation of benzophenone (VIII) with methyl chloroacetate gave the glycidic ester (X). Epoxide opening in (X) with trimethylaluminum furnished methyl 2-hydroxy-3,3-diphenylbutyrate (XI), which was hydrolyzed to the corresponding acid (VI) by using KOH in isopropanol. Treatment of the racemic acid (VI) with (S)-1-(4-chlorophenyl)ethylamine (XII) provided the desired (S)-acid salt (XIII). This was finally condensed with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (XIV) in the presence of lithium amide to yield the title compound.
【1】
Jansen, R.; et al.; Structural similarity and its suprises: Endothelin receptor antagonists - Process research and development report. Org Process Res Dev 2001, 5, 1, 16.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VI) |
48526 |
2-hydroxy-3,3-diphenylbutyric acid
|
|
C16H16O3 |
详情 |
详情
|
(VIII) |
18732 |
benzophenone
|
119-61-9 |
C13H10O |
详情 | 详情
|
(IX) |
10257 |
methyl 2-chloroacetate; methyl chloroacetate
|
96-34-4 |
C3H5ClO2 |
详情 | 详情
|
(X) |
21148 |
methyl 3,3-diphenyl-2-oxiranecarboxylate
|
|
C16H14O3 |
详情 |
详情
|
(XI) |
48528 |
methyl 2-hydroxy-3,3-diphenylbutanoate
|
|
C17H18O3 |
详情 |
详情
|
(XII) |
48529 |
(S)-4-Chloro-alpha-methylbenzylamine; 1-(4-Chlorophenyl)ethylamine
|
4187-56-8 |
C8H10ClN |
详情 | 详情
|
(XIII) |
48530 |
(1S)-1-(4-chlorophenyl)-1-ethanaminium (2S)-2-hydroxy-3,3-diphenylbutanoate
|
|
C24H26ClNO3 |
详情 |
详情
|
(XIV) |
38714 |
4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone
|
|
C7H10N2O2S |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(IX) Alkylation of diethyl malonate (I) with chloroethyl ether (II) in the presence of NaOEt in refluxing EtOH provided tetrahydropyran dicarboxylate (III). Hydrolysis of diester (III) with ethanolic KOH, and decarboxylation of the resulting diacid (IV) at 180 C gave tetrahydropyran-4-carboxylic acid (V). This was reduced to the alcohol (VI) on treatment with LiAlH4 in refluxing THF, and then converted into mesylate (VII) by reaction with metanesulfonyl chloride and triethylamine in THF. 3-(Aminomethyl)pyridine (VIII) was protected as the imine (X) by reaction with benzophenone (IX) in refluxing benzene with a Dean-Stark trap. Alkylation of imine (X) with mesylate (VII) in the presence of LDA in cold THF gave intermediate (XI) which, on acidic hydrolysis provided amine (XII). Reaction of (XII) with saturated aqueous HBr at 100 C in a pressure tube formed dibromide (XIII), which was basified with K2CO3 and heated to 80 C to provide the target quinuclidine.
【1】
Bencherif, M.; Lippiello, P.M.; Caldwell, W.S. (R.J. Reynolds Tobacco Co.); Depolarizing skeletal muscle relaxants. WO 9607410 .
|
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) |
16829 |
Diethyl malonate
|
105-53-3 |
C7H12O4 |
详情 | 详情
|
(II) |
12060 |
Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether
|
111-44-4 |
C4H8Cl2O |
详情 | 详情
|
(III) |
18726 |
diethyl tetrahydro-4H-pyran-4,4-dicarboxylate
|
|
C11H18O5 |
详情 |
详情
|
(IV) |
18727 |
tetrahydro-4H-pyran-4,4-dicarboxylic acid
|
|
C7H10O5 |
详情 |
详情
|
(V) |
18728 |
tetrahydro-2H-pyran-4-carboxylic acid
|
|
C6H10O3 |
详情 |
详情
|
(VI) |
18729 |
tetrahydro-2H-pyran-4-ylmethanol
|
|
C6H12O2 |
详情 |
详情
|
(VII) |
18730 |
tetrahydro-2H-pyran-4-ylmethyl methanesulfonate
|
|
C7H14O4S |
详情 |
详情
|
(VIII) |
18731 |
3-pyridinylmethanamine; 3-pyridinylmethylamine
|
3731-52-0 |
C6H8N2 |
详情 | 详情
|
(IX) |
18732 |
benzophenone
|
119-61-9 |
C13H10O |
详情 | 详情
|
(X) |
18733 |
N-(dibenzylene)(3-pyridinyl)methanamine; N-(dibenzylene)-N-(3-pyridinylmethyl)amine
|
|
C19H16N2 |
详情 |
详情
|
(XI) |
18734 |
N-(dibenzylene)-N-[1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-ylethyl]amine; N-(dibenzylene)-1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-yl-1-ethanamine
|
|
C25H26N2O |
详情 |
详情
|
(XII) |
18735 |
1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-ylethylamine; 1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-yl-1-ethanamine
|
|
C12H18N2O |
详情 |
详情
|
(XIII) |
18736 |
5-bromo-3-(2-bromoethyl)-1-(3-pyridinyl)-1-pentanamine; 5-bromo-3-(2-bromoethyl)-1-(3-pyridinyl)pentylamine
|
|
C12H18Br2N2 |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(I) The reaction of benzophenone (I) with succinodinitrile (II) by means of potassium tert-butoxide in refluxing tert-butanol, followed by a treatment with refluxing 10% sulfuric acid gives 3-(diphenylmethylene)pyrrolidine-2,5-dione (III), which is then consdensed with 4-[3-(trifluoromethyl)phenyl]piperazine (IV) and formaldehyde in refluxing ethanol.
【1】
López-Rodríguez, M.L.; Morcillo, M.J.; Rovat, T.K.; Fernández, E.; Sanz, A.M.; Orensanz, L.; 1-[omega-(4-Arylpiperazin-1-yl)alkyl]-3-diphenylmethylene-2,5-pyrrolidinediones as 5-HT1A receptor ligands: Study of the steric requirements of the terminal amide fragment on 5-HT1A affinity/selectivity. Bioorg Med Chem Lett 1998, 8, 6, 581. |
【2】
López-Rodríguez, M.L.; Morcillo, M.J.; Rovat, T.K.; Fernandez, E.; Vicente, B.; Sanz, A.M.; Hernandez, M.; Orensanz, L.; Synthesis and structure-activity relationships of a new model of arylpiperazines. 4. 1-[omega-(4-Arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene)-2,5-pyrrolidinediones and -3-(9H-fluoren-9-ylidene)-2,5-pyrrolidinediones: Study of the steric requirements of. J Med Chem 1999, 42, 1, 36. |
【3】
K. Rovat, T.; Oesanz Muno, L.M.; Fernandez Velando, E.; Lopez Rodriguez, M.L.; Rosado Samitier, M.L.; Morcillo Ortega, M.J. (Universidad Complutense de Madrid); New imidapiperazine derivs.. ES 2094690 .
|
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) |
18732 |
benzophenone
|
119-61-9 |
C13H10O |
详情 | 详情
|
(II) |
28669 |
3-(dibenzylene)-2,5-pyrrolidinedione
|
|
C17H13NO2 |
详情 |
详情
|
(III) |
28669 |
3-(dibenzylene)-2,5-pyrrolidinedione
|
|
C17H13NO2 |
详情 |
详情
|
(IV) |
16172 |
1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine
|
15532-75-9 |
C11H13F3N2 |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(I) The condensation of benzophenone (I) with methyl 2-chloroacetate (II) by means of NaOMe in THF gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester (III), which by treatment with BF3/Et2O and methanol, followed by optical resolution, yielded the pure enantiomer 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is finally hydrolyzed with KOH in hot dioxane to afford the target propionic acid as a racemic mixture.
【1】
Riechers, H.; Albrecht, H.-P.; Amberg, W.; et al.; Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem 1996, 39, 11, 2123.
|
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) |
18732 |
benzophenone
|
119-61-9 |
C13H10O |
详情 | 详情
|
(II) |
10257 |
methyl 2-chloroacetate; methyl chloroacetate
|
96-34-4 |
C3H5ClO2 |
详情 | 详情
|
(III) |
21148 |
methyl 3,3-diphenyl-2-oxiranecarboxylate
|
|
C16H14O3 |
详情 |
详情
|
(IV) |
38710 |
methyl (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoate
|
|
C17H18O4 |
详情 |
详情
|
(V) |
38714 |
4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone
|
|
C7H10N2O2S |
详情 |
详情
|
(VI) |
56710 |
methyl (2S)-2-[(4,6-dimethyl-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoate
|
|
C23H24N2O4 |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(I) Horner-Emmons condensation of benzophenone (I) with triethyl phosphonoacetate provides the unsaturated ester (II), which is further reduced with DIBAL in toluene to the allylic alcohol (III). Reaction of alcohol (III) with methanesulfonyl chloride and Et3N leads to chloride (IV). Finally, alkylation of 3-propionyl-3,9-diazabicyclo[3.3.1]nonane (V) with the allyl chloride (IV) furnishes the title compound.
【1】
Pinna, G.A.; Cignarella, G.; Loriga, G.; Murineddu, G.; Mussinu, J.-M.; Ruiu, S.; Fadda, P.; Fratta, W.; N-3(9)-Arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes as mu-opioid receptor agonists. Effects on mu-affinity of arylalkenyl chain modifications. Bioorg Med Chem 2002, 10, 6, 1929. |
【2】
Cignarella, G.; Pinna, G.A. (Centro Consortile Ricerche Neuropsicofarmacologiche a.r.l); 3,9-Diazabicyclo[3.3.1]nonane derivs. with analgesic activity. EP 1259511; WO 0160823 .
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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) |
10019 |
Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate
|
867-13-0 |
C8H17O5P |
详情 | 详情
|
(I) |
18732 |
benzophenone
|
119-61-9 |
C13H10O |
详情 | 详情
|
(II) |
61015 |
ethyl 3,3-diphenylacrylate
|
|
C17H16O2 |
详情 |
详情
|
(III) |
61016 |
3,3-diphenyl-2-propen-1-ol
|
|
C15H14O |
详情 |
详情
|
(IV) |
61017 |
1-(3-chloro-1-phenyl-1-propenyl)benzene
|
|
C15H13Cl |
详情 |
详情
|
(V) |
61018 |
1-(3,9-diazabicyclo[3.3.1]non-3-yl)-1-propanone
|
|
C10H18N2O |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(I)
【1】
Jansen R, Knopp M, Amberg W, et al. 2001. Structural similarity and its surprises: endothelin receptor antagonists-process research and development report. Org Proc Res Dev, 5(1):16~22. |
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) |
18732 |
benzophenone
|
119-61-9 |
C13H10O |
详情 | 详情
|
(II) |
10257 |
methyl 2-chloroacetate; methyl chloroacetate
|
96-34-4 |
C3H5ClO2 |
详情 | 详情
|
(III) |
21148 |
methyl 3,3-diphenyl-2-oxiranecarboxylate
|
|
C16H14O3 |
详情 |
详情
|
(IV) |
21149 |
methyl 2-hydroxy-3-methoxy-3,3-diphenylpropanoate
|
|
C17H18O4 |
详情 |
详情
|
(V) |
21153 |
2-hydroxy-3-methoxy-3,3-diphenylpropionic acid
|
|
C16H16O4 |
详情 |
详情
|
(VI) |
67028 |
(S)-1-(p-tolyl)ethanamine |
27298-98-2 |
C9H13N |
详情 | 详情
|
(VII) |
67029 |
|
|
C16H16O4.C9H13N |
详情 | 详情
|
(VIII) |
21150 |
4,6-dimethoxy-2-(methylsulfonyl)pyrimidine; 4,6-dimethoxy-2-pyrimidinyl methyl sulfone
|
|
C7H10N2O4S |
详情 |
详情
|