|
【结 构 式】 
|
【分子编号】29492 【品名】tert-butyl (3S)-2-oxopyrrolidinylcarbamate 【CA登记号】 |
【 分 子 式 】C9H16N2O3 【 分 子 量 】200.23772 【元素组成】C 53.99% H 8.05% N 13.99% O 23.97% |
合成路线1
该中间体在本合成路线中的序号：(VI)The iodination of 2-hydroxybenzaldehyde (I) with iodine chloride in dichloromethane gives 2-hydroxy-5-iodobenzaldehyde (II), which is protected with Mem-Cl by means of NaH and 1,3-dimethylperhydropyrimidin-2-one (DMPU) in THF yielding the ether derivative (III). The reduction of (III) with NaBH4 in THF affords the benzyl alcohol (IV), which is brominated with NBS and triphenylphosphine in THF to give the benzyl bromide (V). The condensation of (V) with the protected aminopyrrolidinone (VI) by means of NaH and DMPU in THF yields the benzylpyrrolidinone (VII), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to provide the benzonitrile (VIII). The deprotection of (VIII) with HCl gas in ethyl acetate gives the primary amine (IX), which is sulfonated with 5-(3-pyridyl)thiophene-2-sulfonyl chloride (X) in pyridine yielding the sulfonamide (XI). Finally, this compound is treated first with HCl gas in ethanol, and then with NH3 in methanol to convert the cyano group of (XI) into the amidino group of the target compound. The intermediate sulfonyl chloride (X) has been obtained as follows: The condensation of 3-bromopyridine (XII) with 2-bromothiophene (XIII) by means of Mg and NiCl2 in refluxing ethyl ether gives 2-(3-pyridyl)thiophene (XIV), which is chlorosulfonated by means of BuLi, SO2 and SO2Cl2 in THF to yield intermediate (X).
| 【1】 McGarry, D.G.; Choi-Sledeski, Y.M.; Green, D.M.; et al.; Sulfonamidopyrrolidinone factor Xa inhibitors: Potency and selectivity enhancements via P-1 and P-2 optimization. J Med Chem 1999, 42, 18, 3572. |
| 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) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
| (III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
| (IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
| (V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
| (VI) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
| (VIII) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
| (IX) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 | |
| (X) | 31678 | 5-(3-pyridinyl)-2-thiophenesulfonyl chloride | C9H6ClNO2S2 | 详情 | 详情 | |
| (XI) | 31679 | N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]-5-(3-pyridinyl)-2-thiophenesulfonamide | C21H18N4O4S2 | 详情 | 详情 | |
| (XII) | 13625 | 2-[(3-Methoxyphenyl)sulfanyl]benzoic acid | C14H12O3S | 详情 | 详情 | |
| (XIII) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
| (XIV) | 31680 | 3-(2-thienyl)pyridine | C9H7NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The reduction of 5-bromothiophene-3-carbaldehyde (I) with NaBH4 in THF gives the corresponding carbinol (II), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to yield 4-(hydroxymethyl)thiophene-2-carbonitrile (III). The reaction of (III) with tetrabromomethane and triphenylphosphine affords the corresponding bromomethyl derivative (IV), which is condensed with 3(S)-(tert-butoxycarbonylamino)pyrrolidin-2-one (V) by means of NaH in THF/DMF to give the expected addition product (VI). The deprotection of the amino group of (VI) with HCl in ethyl acetate yields the primary amine (VII), which is acylated with 7-methoxynaphthalene-2-sulfonyl chloride (VIII) and triethylamine in dichloromethane providing the sulfonamide (IX). The methylation of (IX) with methyl iodide and K2CO3 in DMF affords the N-methylsulfonamide (X), which is finally treated first with HCl in ethanol, and then with NH3 in methanol to convert the cyano group of (X) into the amidino group of the target compound.
| 【1】 Ewing, W.R.; Manetta, V.E.; Becker, M.R.; et al.; Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa. J Med Chem 1999, 42, 18, 3557. |
| 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) | 31660 | 5-bromo-3-thiophenecarbaldehyde | C5H3BrOS | 详情 | 详情 | |
| (II) | 31661 | (5-bromo-3-thienyl)methanol | C5H5BrOS | 详情 | 详情 | |
| (III) | 31662 | 4-(hydroxymethyl)-2-thiophenecarbonitrile | C6H5NOS | 详情 | 详情 | |
| (IV) | 31663 | 4-(bromomethyl)-2-thiophenecarbonitrile | C6H4BrNS | 详情 | 详情 | |
| (V) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VI) | 31664 | tert-butyl (3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinylcarbamate | C15H19N3O3S | 详情 | 详情 | |
| (VII) | 31665 | 4-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-2-thiophenecarbonitrile | C10H11N3OS | 详情 | 详情 | |
| (VIII) | 31666 | 7-methoxy-2-naphthalenesulfonyl chloride | C11H9ClO3S | 详情 | 详情 | |
| (IX) | 31667 | N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-2-naphthalenesulfonamide | C21H19N3O4S2 | 详情 | 详情 | |
| (X) | 31668 | N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-N-methyl-2-naphthalenesulfonamide | C22H21N3O4S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The reaction of 3-(4-methylphenyl)-2-propenoic acid (I) with ethyl chloroformate or with SOCl2 and then with sodium azide gives the corresponding azide (II), which is cyclized termally yielding 7-methylisoquinolin-1(2H)-one (III). The reaction of (III) with refluxing POCl3 affords 1-chloro-7-methylisoquinoline (IV), which is brominated with NBS and benzoyl peroxide in refluxing CCl4 giving the bromomethyl derivative (V). The condensation of (V) with 3(S)-(tert-butoxycarbonylamino)pyrrolidin-2-one (VI) (obtained by cyclization of the diaminobutyric acid (VII) by means of HOBT in THF) by means of NaH in THF/DMF yields the N-substituted pyrrolidone (VIII), which is deprotected with HCl affording the 3(S)-aminopyrrolidone (IX). The acylation of (IX) with thieno [3,2-b]pyridine-2-sulfonyl chloride (X) by means of triethylamine in acetonitrile gives the sulfonamide (XI), which is finally treated with ammonium acetate in hot phenol. The intermediate sulfonyl chloride (X) has been obtained as follows: The reaction of 2-ethynylpyridine (XII) with benzylthiol and sodium ethoxide in ethanol gives 2-[2-(benzylsulfanyl)vinyl]pyridine (XIII), which is cyclized at 625 C yielding thieno[3,2-bpyridine (XIV). Finally, this compound is chlorosulfonated by reaction with BuLi, SO2 and SO2Cl2 in THF.
| 【1】 Guo, L.; Pan, Y.; Rohrer, S.; Schaeffer, J.; patchett, A.A.; Mosley, R.; Yang, L.; Pastemak, A.; Birzin, E.; 2,4-Bis(aminomethyl)pyridine derived highly potent and selective human somatostatin receptor subtype-2 (hsst2) agonists. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 141. |
| 【2】 Choi-Sledeski, Y.M.; Pauls, H.W.; Green, D.M.; Barton, J.N.; Becker, M.R.; Ewing, W.R. (Aventis Pharmaceuticals, Inc.); Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide cpds.. EP 0944386; WO 9825611 . |
| 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) | 29487 | (E)-3-(4-methylphenyl)-2-propenoic acid | 1866-39-3 | C10H10O2 | 详情 | 详情 |
| (II) | 29488 | (E)-3-(4-methylphenyl)-2-propenoyl azide | C10H9N3O | 详情 | 详情 | |
| (III) | 29489 | 7-methyl-1(2H)-isoquinolinone | C10H9NO | 详情 | 详情 | |
| (IV) | 29490 | 1-chloro-7-methylisoquinoline | C10H8ClN | 详情 | 详情 | |
| (V) | 29491 | 7-(bromomethyl)-1-chloroisoquinoline | C10H7BrClN | 详情 | 详情 | |
| (VI) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VII) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
| (VIII) | 29494 | tert-butyl (3S)-1-[(1-chloro-7-isoquinolinyl)methyl]-2-oxopyrrolidinylcarbamate | C19H22ClN3O3 | 详情 | 详情 | |
| (IX) | 29495 | (3S)-3-amino-1-[(1-chloro-7-isoquinolinyl)methyl]-2-pyrrolidinone | C14H14ClN3O | 详情 | 详情 | |
| (X) | 29496 | thieno[3,2-b]pyridine-2-sulfonyl chloride | C7H4ClNO2S2 | 详情 | 详情 | |
| (XI) | 29497 | N-[(3S)-1-[(1-chloro-7-isoquinolinyl)methyl]-2-oxopyrrolidinyl]thieno[3,2-b]pyridine-2-sulfonamide | C21H17ClN4O3S2 | 详情 | 详情 | |
| (XII) | 29498 | 2-ethynylpyridine | 1945-84-2 | C7H5N | 详情 | 详情 |
| (XIII) | 29499 | benzyl (Z)-2-(2-pyridinyl)ethenyl sulfide; 2-[(Z)-2-(benzylsulfanyl)ethenyl]pyridine | C14H13NS | 详情 | 详情 | |
| (XIV) | 29500 | thieno[3,2-b]pyridine | C7H5NS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The reaction of 3-acetamido-4-methylbenzaldehyde (I) with malonic acid by means of piperidine in hot pyridine gives 3-(3-acetamido-4-methylphenyl)-2(E)-propenoic acid (II), which by reaction first with ethyl chloroformate and then with sodium azide yields the corresponding azide (III). The thermal cyclizaton of (III) affords the isoquinolinone (IV), which is treated with HCl in refluxing ethanol to give 6-amino-7-methylisoquinolin-1(2H)-one (V). The reaction of (V) with refluxing POCl3 yields the 1-chloroisoquinoline (VI), which is protected by reaction with phenzophenoneimine and HCl in methanol to afford 1-chloro-6-(diphenylmethyleneamino)-7-metylisoquinoline (VII). The bromination of (VII) with NBS and benzoyl peroxide in refluxing CCl4 gives the bromomethyl derivative (VIII), which is condensed with 3(S)-(tert-butoxycarbonylamino)pyrrolidin-2-one (IX) (obtained by cyclization of the diaminobutyric acid (X) by means of HOBT in THF) by means of NaH in THF/DMF yielding the N-substituted pyrrolidone (XI). The deprotection of (XI) with HCl afford the diamino intermediate (XII), which is selectively acylated with thieno[3,2-b]pyridine-2-sulfonyl chloride (XIII) by means of triethylamine in acetonitrile giving the sulfonamidde (XIV). Finally, this compound is treated with ammonium acetate in hot phenol. The intermediate sulfonyl chloride (XIII) has been obtained as follows: The reaction of 2-ethynylpyridine (XV) with benzylthiol and sodium ethoxide in ethanol gives 2-[2-(benzylsulfanyl)vinyl]pyridine (XVI), which is cyclized at 625 C yielding thieno[3,2-bpyridine (XVII). Finally, this compound is chlorosulfonated by reaction with BuLi, SO2 and SO2Cl2 in THF.
| 【1】 Green, D.M.; Choi-Sledeski, Y.M.; Becker, M.R.; et al.; Aminoisoquinolines: Design and synthesis of an orally active benzamidine isostere for the inhibition of factor Xa. Bioorg Med Chem Lett 1999, 9, 17, 2539. |
| 【2】 Choi-Sledeski, Y.M.; Pauls, H.W.; Green, D.M.; Barton, J.N.; Becker, M.R.; Ewing, W.R. (Aventis Pharmaceuticals, Inc.); Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide cpds.. EP 0944386; WO 9825611 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 | |
| 32024 | diphenylmethanimine | 1013-88-3 | C13H11N | 详情 | 详情 | |
| (I) | 29501 | N-(5-formyl-2-methylphenyl)acetamide | C10H11NO2 | 详情 | 详情 | |
| (II) | 29502 | (E)-3-[3-(acetamido)-4-methylphenyl]-2-propenoic acid | C12H13NO3 | 详情 | 详情 | |
| (III) | 29503 | (E)-3-[3-(acetamido)-4-methylphenyl]-2-propenoyl azide | C12H12N4O2 | 详情 | 详情 | |
| (IV) | 29504 | N-(7-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)acetamide | C12H12N2O2 | 详情 | 详情 | |
| (V) | 29505 | 6-amino-7-methyl-1(2H)-isoquinolinone | C10H10N2O | 详情 | 详情 | |
| (VI) | 29506 | 1-chloro-7-methyl-6-isoquinolinylamine; 1-chloro-7-methyl-6-isoquinolinamine | C10H9ClN2 | 详情 | 详情 | |
| (VII) | 29507 | N-(1-chloro-7-methyl-6-isoquinolinyl)-N-(dibenzylene)amine; 1-chloro-N-(dibenzylene)-7-methyl-6-isoquinolinamine | C23H17ClN2 | 详情 | 详情 | |
| (VIII) | 29508 | N-[7-(bromomethyl)-1-chloro-6-isoquinolinyl]-N-(dibenzylene)amine; 7-(bromomethyl)-1-chloro-N-(dibenzylene)-6-isoquinolinamine | C23H16BrClN2 | 详情 | 详情 | |
| (IX) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (X) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
| (XI) | 29509 | tert-butyl (3S)-1-([1-chloro-6-[(dibenzylene)amino]-7-isoquinolinyl]methyl)-2-oxopyrrolidinylcarbamate | C32H31ClN4O3 | 详情 | 详情 | |
| (XII) | 29510 | (3S)-3-amino-1-[(6-amino-1-chloro-7-isoquinolinyl)methyl]-2-pyrrolidinone | C14H15ClN4O | 详情 | 详情 | |
| (XIII) | 29496 | thieno[3,2-b]pyridine-2-sulfonyl chloride | C7H4ClNO2S2 | 详情 | 详情 | |
| (XIV) | 29511 | N-[(3S)-1-[(6-amino-1-chloro-7-isoquinolinyl)methyl]-2-oxopyrrolidinyl]thieno[3,2-b]pyridine-2-sulfonamide | C21H18ClN5O3S2 | 详情 | 详情 | |
| (XV) | 29498 | 2-ethynylpyridine | 1945-84-2 | C7H5N | 详情 | 详情 |
| (XVI) | 29499 | benzyl (Z)-2-(2-pyridinyl)ethenyl sulfide; 2-[(Z)-2-(benzylsulfanyl)ethenyl]pyridine | C14H13NS | 详情 | 详情 | |
| (XVII) | 29500 | thieno[3,2-b]pyridine | C7H5NS | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)3-(tert-Butoxycarbonylamino)-2-pyrrolidinone (II), obtained by cyclization of (S)-Boc-2,4-diaminobutyric acid (I) in the presence of EDC, was regioselectively alkylated with propargyl bromide and NaH to give the N-propargyl pyrrolidinone (III). Subsequent acid-promoted deprotection of the Boc group of (III) provided aminopyrrolidinone (IV). Sulfonyl chloride (VII) was prepared by lithiation of thienopyridine (V), followed by addition of SO2, and further chlorination of the resulting sulfinic acid (VI) with sulfuryl chloride. This sulfonyl chloride (VII) was then coupled with aminopyrrolidinone (III), yielding sulfonamide (VIII). Lithiation of 3-(tert-butoxycarbonylamino)pyridine (IX) and subsequent treatment with iodine in cold THF provided the iodopyridine derivative (X). Palladium-mediated coupling of (X) with propargyl pyrrolidinone (VIII) furnished adduct (XI), which was cyclized to the pyrrolopyridine system (XII) upon treatment with DBU. Finally, the Boc protecting group of (XII) was removed using trifluoroacetic acid.
| 【1】 Choi-Sledeski, Y.M.; Becker, M.R.; Pauls, H.W.; et al.; Azaindole pyrrolidinone inhibitors of factor Xa: SAR, synthesis, and X-ray crystal structure of a novel surrogate for basic P1 moieties. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 33. |
| 【2】 Choi-Sledeski, Y.M.; Pauls, H.W.; Green, D.M.; Barton, J.N.; Becker, M.R.; Ewing, W.R. (Aventis Pharmaceuticals, Inc.); Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide cpds.. EP 0944386; WO 9825611 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 | |
| (I) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
| (II) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (III) | 35566 | tert-butyl (3S)-2-oxo-1-(2-propynyl)pyrrolidinylcarbamate | C12H18N2O3 | 详情 | 详情 | |
| (IV) | 35567 | (3S)-3-amino-1-(2-propynyl)-2-pyrrolidinone | C7H10N2O | 详情 | 详情 | |
| (V) | 29500 | thieno[3,2-b]pyridine | C7H5NS | 详情 | 详情 | |
| (VI) | 35568 | thieno[3,2-b]pyridine-2-sulfonic acid | C7H5NO3S2 | 详情 | 详情 | |
| (VII) | 29496 | thieno[3,2-b]pyridine-2-sulfonyl chloride | C7H4ClNO2S2 | 详情 | 详情 | |
| (VIII) | 35569 | N-[(3S)-2-oxo-1-(2-propynyl)pyrrolidinyl]thieno[3,2-b]pyridine-2-sulfonamide | C14H13N3O3S2 | 详情 | 详情 | |
| (IX) | 35570 | tert-butyl 3-pyridinylcarbamate | 56700-70-0 | C10H14N2O2 | 详情 | 详情 |
| (X) | 35571 | tert-butyl 4-iodo-3-pyridinylcarbamate | C10H13IN2O2 | 详情 | 详情 | |
| (XI) | 35572 | tert-butyl 4-(3-[(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]-1-propynyl)-3-pyridinylcarbamate | C24H25N5O5S2 | 详情 | 详情 | |
| (XII) | 35573 | tert-butyl 2-([(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]methyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate | C24H25N5O5S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).
| 【1】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
| 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) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
| (III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
| (IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
| (V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
| (VI) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VIII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
| (IX) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
| (X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).
| 【1】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40670 | 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride | 3970-21-6 | C4H9ClO2 | 详情 | 详情 | |
| (I) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
| (III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
| (IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
| (V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
| (VI) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VIII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
| (IX) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
| (X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 |