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【结 构 式】 
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【分子编号】19832 【品名】tert-butyl (2S)-2-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C9H17NO2 【 分 子 量 】171.23952 【元素组成】C 63.13% H 10.01% N 8.18% O 18.69% |
合成路线1
该中间体在本合成路线中的序号：(II)It is prepared by hydrolysis with ammonia in methanol of N-(3-acetylthio-2-methylpropanoyl)-L-proline (I). Compound (I) can be obtained in three different ways: 1) The reaction of L-proline tert-butyl ester (II) with 3-acetylthio-2-methyl-propanoic acid (III) by means of dicyclohexylcarbodiimide in CH2Cl2 gives N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester (IV), which is hydrolyzed with trifluoroacetic acid in anisole. 2) By condensation of L-proline (V) with 3-acetylthio-2-methylpropanoyl chloride (VI) (prepared from the corresponding acid (III) with SOCl2) by means of NaOH in water. 3) The condensation of L-proline (V) with methacryloyl chloride (VII) by means of NaHCO3 in water yields N-methacryloyl-L-proline (VIII), which is then treated with thiolacetic acid (A) and azobisisobutyronitrile. The acid (III) is obtained by addition of thiolacetic acid (IX) to methacrylic acid (X) at 100 C.
| 【1】 Cushman, D.W.; Ondetti, M.A.; Azetidine-2-carboxylic acid derivatives. BE 0851361; DD 283999; JP 58189113; JP 58189158; US 4046889; US 4154840 . |
| 【2】 Roberts, P.J.; Castaner, J.; Captopril. Drugs Fut 1978, 3, 11, 795. |
| 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) | 33555 | Thiolacetic acid; Thioacetic acid; ethanethioic O-acid; Ethanethioic acid | 507-09-5 | C2H4OS | 详情 | 详情 |
| (I) | 33552 | (2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid | 65167-28-4 | C11H17NO4S | 详情 | 详情 |
| (II) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (III) | 33556 | 3-(acetylsulfanyl)-2-methylpropionic acid | C6H10O3S | 详情 | 详情 | |
| (IV) | 33551 | tert-butyl (2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-2-pyrrolidinecarboxylate | C15H25NO4S | 详情 | 详情 | |
| (V) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (VI) | 33557 | S-(3-chloro-2-methyl-3-oxopropyl) ethanethioate | C6H9ClO2S | 详情 | 详情 | |
| (VII) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (VIII) | 33554 | (2S)-1-methacryloyl-2-pyrrolidinecarboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (IX) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (X) | 33550 | 2-methylacrylic acid | 79-41-4 | C4H6O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Thermal cyclization of the azidocinnamate (II), obtained from O-benzylsalicylaldehyde (I) by methoxide condensation with ethyl azidoacetate, provides methyl 4-benzyloxyindol-2-carboxylate (III). Debenzylation by catalytic hydrogenolysis and alkylation of the phenol with (2S)-glycidyl tosylate gives the chiral oxirane (IV). Ring opening of (IV) followed by protection of the secondary amine by reaction with di-tert-butyldicarbonate and saponification of the methyl ester gives the key (S)-beta-blocker synthon (V). The required ACE inhibitor svnthon (VIII) is assembled from tert-butyl-N'-benzyloxycarbonyl-(S)-lysinate (VI). Alkylation of the alpha-amino group with the triflate of methyl (R)-lactate and saponification of the methyl ester gives N-[5-benzyloxycarbonylamino-1-(S)-tert-butyloxycarbonylpent-1-yl-(S)-alanine (VII). Condensation of (VII) with tert-butyl-(S)-prolinate. mediated by dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, followed by hydrogenolytic removal of the benzyloxycarbonyl group, provides tert-butyl-N-[5-amino-1-(S)-tert-butyloxycarbonylpent-1-yl]-(S)-alanyl-(S)-prolinate (VIII). Coupling of (V) with (VIII) using dicyclohexylcarbodiimide-1-hydroxybenzotriazole and removal of the tert-butyl protecting groups by acidolysis in trifluoroacetic acid, with ethyl methyl sulfide as a scavenger, gives crude BW-8385C as the bistrifluoroacetate salt. Purification is achieved by ion exchange chromatography on DE52 cellulose, followed by reverse-phase desalting to provide pure BW-B385C as the zwitterionic trihydrate.
| 【1】 Allan, G.; Hardy, G.W.; BW-B385C. Drugs Fut 1988, 13, 3, 203. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 | |
| 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | ||
| 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 | |
| 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 | |
| 63428 | 3-methyl-1H-indole | C9H9N | 详情 | 详情 | ||
| (I) | 21874 | 2-(benzyloxy)benzaldehyde | 5896-17-3 | C14H12O2 | 详情 | 详情 |
| (II) | 21875 | methyl (Z)-2-azido-3-[2-(benzyloxy)phenyl]-2-propenoate | C17H15N3O3 | 详情 | 详情 | |
| (III) | 21876 | methyl 4-(benzyloxy)-1H-indole-2-carboxylate | C17H15NO3 | 详情 | 详情 | |
| (IV) | 21877 | methyl 4-[(2R)oxiranylmethoxy]-1H-indole-2-carboxylate | C13H13NO4 | 详情 | 详情 | |
| (V) | 21878 | 4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indole-2-carboxylic acid | C20H28N2O6 | 详情 | 详情 | |
| (VI) | 21879 | tert-butyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate | C18H28N2O4 | 详情 | 详情 | |
| (VII) | 21880 | (2S)-2-[[(1S)-5-[[(benzyloxy)carbonyl]amino]-1-(tert-butoxycarbonyl)pentyl]amino]propionic acid | C21H32N2O6 | 详情 | 详情 | |
| (VIII) | 21881 | tert-butyl (2S)-1-((2S)-2-[[(1S)-5-amino-1-(tert-butoxycarbonyl)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate | C22H41N3O5 | 详情 | 详情 | |
| (IX) | 21882 | tert-butyl (2S)-1-((2S)-2-[[(1S)-1-(tert-butoxycarbonyl)-5-([[4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indol-2-yl]carbonyl]amino)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate | C42H67N5O10 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 2-(3-pyridinyl)tetrahydrothiopyran-2-carboxylic acid (I) with L-proline tert-butyl ester (II) by means of SOCl2 gives the corresponding amide as a diastereomeric mixture (S,S)-(III) + (R,S)-(III) that is separated by chromatography. The desired isomer (R,S)-(III) is hydrolyzed with conc. HCl to yield 2-(3-pyridinyl)tetrahydrothiopyran-2-carboxylic acid (R)-(IV), which is treated first with SOCl2 and methylamine, and then with Lawesson reagent or P2S5 to afford the thioamide (R)-(V). The reaction of (R)-(V) with methyl iodide, n-BuLi and H2S in pyridine provides the dithioester (R)-(VI), which is carefully oxidized with MCPBA in dichloromethane to provide the corresponding sulfoxide as a diastereomeric mixture (1R,2R)-(VII) + (1S,2R)-(VII) that is separated by chromatography. Finally, the desired isomer (1R,2R)-(VII) is treated with methylamine in ethanol to furnish the target thioamide.
| 【1】 Aloup, J.C.; Farge, D.; James, C.; Mondot, S.; Cavero, I.; 2-(3-PYRIDYL)-TETRAHYDROTHIOPYRAN-2-CARBOTHIOAMIDE DERIVATIVES AND ANALOGUES: A NOVEL FAMILY OF POTENT POTASSIUM CHANNEL OPENERS. Drugs Fut 1990, 15, 11, 1097. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S,S)-(III) | 44401 | tert-butyl (2S)-1-[[(2S)-2-(3-pyridinyl)tetrahydro-2H-thiopyran-2-yl]carbonyl]-2-pyrrolidinecarboxylate | C20H28N2O3S | 详情 | 详情 | |
| (R,S)-(III) | 44402 | tert-butyl (2S)-1-[[(2R)-2-(3-pyridinyl)tetrahydro-2H-thiopyran-2-yl]carbonyl]-2-pyrrolidinecarboxylate | C20H28N2O3S | 详情 | 详情 | |
| (1R,2S)-(VII) | 44406 | methyl (2R)-1-oxo-2-(3-pyridinyl)hexahydro-1lambda(4)-thiopyran-2-carbodithioate | C12H15NOS3 | 详情 | 详情 | |
| (1S,2R)-(VII) | 44407 | methyl (2R)-1-oxo-2-(3-pyridinyl)hexahydro-1lambda(4)-thiopyran-2-carbodithioate | C12H15NOS3 | 详情 | 详情 | |
| (I) | 44400 | 2-(3-pyridinyl)tetrahydro-2H-thiopyran-2-carboxylic acid | C11H13NO2S | 详情 | 详情 | |
| (II) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (IV) | 44403 | (2R)-2-(3-pyridinyl)tetrahydro-2H-thiopyran-2-carboxylic acid | C11H13NO2S | 详情 | 详情 | |
| (V) | 44404 | (2R)-N-methyl-2-(3-pyridinyl)tetrahydro-2H-thiopyran-2-carbothioamide | C12H16N2S2 | 详情 | 详情 | |
| (VI) | 44405 | methyl (2R)-2-(3-pyridinyl)tetrahydro-2H-thiopyran-2-carbodithioate | C12H15NS3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The reaction of 3-phenacyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6(S)-carboxylic acid methyl ester (I) with 2,2-diphenylacetic acid (II) gives 5-(2,2-diphenylacetyl)-3-phenacyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6(S)-carboxylic acid methyl ester (III), which is condensed with 3,5-dibromobenzyl bromide (IV) in acetic acid yielding the corresponding 1-(3,5-dibromobenzyl) derivative (V). The hydrolysis of the ester group of (V) with NaOH affords the expected free acid (VI), which is condensed with L-proline tert-butyl ester (VII) giving the corresponding N-substituted L-proline ester (VIII). Finall this compound is coupled with phenylboronic acid (IX), catalized with palladium tetrakis(triphenylphosphine) complex.
| 【1】 Kim, D.; et al.; Non-peptide ligands of the human C5a receptor: Structure-activity relationship of a series of tetrahydroimidazopyridines. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 088. |
| 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) | 19826 | methyl (6S)-3-(2-oxo-2-phenylethyl)-3a,4,5,6,7,7a-hexahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate | C16H19N3O3 | 详情 | 详情 | |
| (II) | 19827 | 2,2-diphenylacetic acid | 117-34-0 | C14H12O2 | 详情 | 详情 |
| (III) | 19828 | methyl (6S)-5-(2,2-diphenylacetyl)-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate | C30H27N3O4 | 详情 | 详情 | |
| (IV) | 19829 | 1,3-dibromo-5-(bromomethyl)benzene | 56908-88-4 | C7H5Br3 | 详情 | 详情 |
| (V) | 19830 | methyl (6S)-1-(3,5-dibromobenzyl)-5-(2,2-diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate | C29H25Br2N3O3 | 详情 | 详情 | |
| (VI) | 19831 | (6S)-1-(3,5-dibromobenzyl)-5-(2,2-diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid | C28H23Br2N3O3 | 详情 | 详情 | |
| (VII) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (VIII) | 19833 | tert-butyl (2S)-1-[[(6S)-1-(3,5-dibromobenzyl)-5-(2,2-diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-6-yl]carbonyl]-2-pyrrolidinecarboxylate | C37H38Br2N4O4 | 详情 | 详情 | |
| (IX) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Condensation of 4-chloro-3-nitrobenzenesulfonyl chloride (VII) with L-proline tert-butyl ester (VIII) yielded sulfonamide (IX). Displacement of the chloro group of (IX) with hydrazine hydrate furnished the aryl hydrazine (X), which was reacted with benzhydryl isothiocyanate (XI) to produce the thiosemicarbazide (XII). After acid cleavage of the tert-butyl ester of (XII), the resulting carboxylic acid (XIII) was activated with isobutyl chloroformate and then coupled with triamine (VI) to furnish the title amide.
| 【1】 Ritchie, T.J.; Hallett, A.; Dziadulewicz, E.K.; et al.; 1-(2-Nitrophenyl)thiosemicarbazides: A novel class of potent, orally active non-peptide antagonist for the bradykinin B2 receptor. J Med Chem 2000, 43, 5, 769. |
| 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) | 42318 | 4-chloro-3-nitrobenzenesulfonyl chloride | 97-08-5 | C6H3Cl2NO4S | 详情 | 详情 |
| (II) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (III) | 42319 | tert-butyl (2S)-1-[(4-chloro-3-nitrophenyl)sulfonyl]-2-pyrrolidinecarboxylate | C15H19ClN2O6S | 详情 | 详情 | |
| (IV) | 42320 | tert-butyl (2S)-1-[(4-hydrazino-3-nitrophenyl)sulfonyl]-2-pyrrolidinecarboxylate | C15H22N4O6S | 详情 | 详情 | |
| (V) | 42321 | 1-[isothiocyanato(phenyl)methyl]benzene; benzhydryl isothiocyanate | 3550-21-8 | C14H11NS | 详情 | 详情 |
| (VI) | 42322 | tert-butyl (2S)-1-[(4-[2-[(benzhydrylamino)carbothioyl]hydrazino]-3-nitrophenyl)sulfonyl]-2-pyrrolidinecarboxylate | C29H33N5O6S2 | 详情 | 详情 | |
| (VII) | 42323 | (2S)-1-[(4-[2-[(benzhydrylamino)carbothioyl]hydrazino]-3-nitrophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid | C25H25N5O6S2 | 详情 | 详情 | |
| (VIII) | 42317 | N-(2-aminoethyl)-N-[2-(dimethylamino)ethyl]-N-methylamine; N(1)-(2-aminoethyl)-N(1),N(2),N(2)-trimethyl-1,2-ethanediamine | C7H19N3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The title compound has been prepared by solid phase synthesis. Attachment of (R)-2-butylsuccinic acid 1-fluorenylmethyl ester (I) to ArgoGel resin under Mitsunobu conditions affords the succinate-bound resin (II). Subsequent deprotection with piperidine in DMF leads to the acid-resin (III), which is further activated as the pentafluorophenyl ester (IV) upon treatment with pentafluorophenyl trifluoroacetate. Coupling of active ester (IV) with L-proline tert-butyl ester (V) furnishes amide (VI). Finally, cleavage of the resin by means of hydroxylamine in aqueous dioxane provides the target hydroxamic acid.
| 【1】 Jacobs, J.W.; Yuan, Z.; Ni, Z.-J.; Jain, R.; Patel, D.; Novel succinate cpds., compsns. and methods of use and preparation. US 2002115863 . |
| 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) | 61240 | (3R)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]heptanoic acid | C22H24O4 | 详情 | 详情 | |
| (II) | 61240 | (3R)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]heptanoic acid | C22H24O4 | 详情 | 详情 | |
| (III) | 61241 | (2R)-2-butylbutanedioic acid | C8H14O4 | 详情 | 详情 | |
| (IV) | 61242 | (3R)-3-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]heptanoic acid | C14H13F5O4 | 详情 | 详情 | |
| (V) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (VI) | 61243 | C18H31NO5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)In an alternative procedure, (R)-2-butylsuccinic acid 4-methyl ester (I) is coupled to L-proline tert-butyl ester (II) to afford amide (III). Then, displacement of the methyl ester group with hydroxylamine gives rise to the desired hydroxamic acid.
| 【1】 Jacobs, J.W.; Yuan, Z.; Ni, Z.-J.; Jain, R.; Patel, D.; Novel succinate cpds., compsns. and methods of use and preparation. US 2002115863 . |
合成路线8
该中间体在本合成路线中的序号：(I)Acylation of L-proline t-butyl ester (I) with 3,5-dichlorobenzenesulfonyl chloride (II) affords sulfonamide (III). The tert-butyl ester group of (III) is then cleaved by treatment with aqueous trifluoroacetic acid, yielding carboxylic acid (IV). Coupling of sulfonyl proline (IV) with the racemic 3-endo-amino-bicyclo[2.2.1]heptane-2-endo-carboxylate (V) leads to a mixture of four diastereoisomeric amides, resulting from carboxylate group epimerization. This mixture can be separated into two pairs of diastereoisomers (VI) and (VII) by flash chromatography. The desired diastereoisomeric mixture of esters (VII) is then hydrolyzed under alkaline conditions to furnish the title carboxylic acid along with its epimer (VIII).
| 【1】 Chang, L.L.; Truong, Q.; Doss, G.; et al.; Orally active, conformationally constrained small molecule VLA-4 antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 325. |
| 【2】 Hagmann, W.K.; MacCoss, M.; Chang, L. (Merck & Co., Inc.); Cyclic amino acid derivs. as cell adhesion inhibitors. JP 2001523711; US 6271252; WO 9926615 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(V) | 60436 | ethyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (I) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (II) | 59023 | 3,5-dichlorobenzenesulfonyl chloride | C6H3Cl3O2S | 详情 | 详情 | |
| (III) | 60434 | tert-butyl (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylate | C15H19Cl2NO4S | 详情 | 详情 | |
| (IV) | 60435 | (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid | C11H11Cl2NO4S | 详情 | 详情 | |
| (VI) | 60437 | ethyl (1R,3S,4S)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate | C21H26Cl2N2O5S | 详情 | 详情 | |
| (VII) | 60438 | ethyl (1S,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate | C21H26Cl2N2O5S | 详情 | 详情 | |
| (VIII) | 60439 | (1S,2S,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylic acid | C19H22Cl2N2O5S | 详情 | 详情 |