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【结 构 式】 
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【分子编号】25151 【品名】phenylmethanesulfonyl chloride 【CA登记号】1939-99-7 |
【 分 子 式 】C7H7ClO2S 【 分 子 量 】190.65008 【元素组成】C 44.1% H 3.7% Cl 18.6% O 16.78% S 16.82% |
合成路线1
该中间体在本合成路线中的序号：(XVII)N-Boc glutamic acid delta-benzyl ester (VI) was treated with carbonyldiimidazole (CDI) in THF, and to the resulting acyl imidazole was added MeOH to provide alpha-methyl ester (VII). Further hydrogenolysis of (VII) in the presence of palladium on carbon cleaved the benzyl ester to give acid (VIII). Treatment of (VIII) with ethanethiol in the presence of EDC and DMAP yielded thioester (IX) and this was then reduced with triethylsilane in the presence of Pd-C to glutamic semialdehyde (X), which was shown to exist predominately in the hemiaminal form (XI). Condensation of this aldehyde (XI) with cysteine (XII) led, via the intermediate thiazolidine (XIII), to the bicyclic lactam (XIV) after equilibration to the more stable isomer. Formation of methyl ester (XV) via the acyl imidazole intermediate, followed by trifluoroacetic acid-catalyzed deprotection of the Boc group of (XV) afforded the amine salt (XVI). This was treated with benzylsulfonyl chloride (XVII) in the presence of collidine to give sulfonamide (XVIII), and subsequent ester hydrolysis provided acid (XIX). Coupling of this acid with amino acetal (V) by treatment with EDC and HOBt yielded amide (XX). Finally, hydrolysis of the acetal of (XX) with dilute HCl in acetonitrile, with simultaneous deblocking of both guanidino-Boc groups and cyclization afforded the title compound, which was purified by reverse phase HPLC, and converted to the trifluoroacetate salt.
| 【1】 Kogel, B.; et al.; HZ2, a selective kappa-opioid agonist. CNS Drug Rev 1998, 4, 1, 54. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25140 | tert-butyl (Z)-[[(4S)-4-amino-5,5-diethoxypentyl]amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C20H40N4O6 | 详情 | 详情 | |
| (VI) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (VII) | 25142 | 5-benzyl 1-methyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate | C18H25NO6 | 详情 | 详情 | |
| (VIII) | 25143 | (4S)-4-[(tert-butoxycarbonyl)amino]-5-methoxy-5-oxopentanoic acid | C11H19NO6 | 详情 | 详情 | |
| (IX) | 25144 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(ethylsulfanyl)-5-oxopentanoate | C13H23NO5S | 详情 | 详情 | |
| (X) | 25145 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoate | C11H19NO5 | 详情 | 详情 | |
| (XI) | 25146 | 1-(tert-butyl) 2-methyl (2S)-5-hydroxy-1,2-pyrrolidinedicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (XIII) | 25147 | (4R)-2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-methoxy-4-oxobutyl]-1,3-thiazolidine-4-carboxylic acid | C14H24N2O6S | 详情 | 详情 | |
| (XIV) | 25148 | (3R,6S,8aS)-6-[(tert-butoxycarbonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid | C13H20N2O5S | 详情 | 详情 | |
| (XV) | 25149 | methyl (3R,6S,8aS)-6-[(tert-butoxycarbonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate | C14H22N2O5S | 详情 | 详情 | |
| (XVI) | 25150 | methyl (3R,6S,8aS)-6-amino-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate | C9H14N2O3S | 详情 | 详情 | |
| (XVII) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (XVIII) | 25152 | methyl (3R,6S,8aS)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate | C16H20N2O5S2 | 详情 | 详情 | |
| (XIX) | 25153 | (3R,6S,8aS)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid | C15H18N2O5S2 | 详情 | 详情 | |
| (XX) | 25154 | tert-butyl (Z)-([(3S)-3-[([(3R,6S,8aS)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl]carbonyl)amino]-4,4-diethoxybutyl]amino)[(tert-butoxycarbonyl)amino]methylidenecarbamate | C34H54N6O10S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Solid-phase synthesis: Reduction of the carboxylic acid moiety of Boc-Arg(NO2)-OH (I) by first treatment with CDI followed by LiAlH4 affords aldehyde (II), which is then condensed with compound (III) in aqueous NaOAc and refluxing EtOH to yield semicarbazone linker (IV). Loading of (IV) onto aminomethyl polystyrene resin provides anchored arginine derivative (V), which is subjected to the following pathway to provide anchored peptide (VI): (i) Boc removal with TFA/CH2Cl2; (ii) incorporation of Boc-Gly-OH (A) by means of coupling agents HOBt, HBTU and DIEA in DMF; (iii) again Boc removal; and finally (iv) coupling of Boc-D-Arg(NO2)-OH (B) with HOBt, HBTU and DIEA in DMF. Deprotection of (VI) with TFA/CH2Cl2 and capping with benzylsulfonyl chloride (VII) and DIEA furnishes anchored derivative (VIII), which is cleaved by means of HOAc, aqueous formaldehyde and HCl in THF and finally hydrogenolyzed over Pd/C. The synthesis can also be performed in an analogous way by substitution of Boc-Arg(NO2)-OH for Boc-Arg(Cbz)2-OH.
| 【1】 Marlowe, C.K.; Sinha, U.; Scarborough, R.M.; Gunn, A.C.; Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: Structures based on the (D)-Arg-Gly-Arg tripeptide sequence. Bioorg Med Chem Lett 2000, 10, 1, 13. |
| 【2】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. US 5721214 . |
| 【3】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. EP 0846125; JP 1999507626; US 5919765; WO 9640743 . |
| 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) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (B) | 39364 | Omega-nitro-Boc-D-arginine | 50913-12-7 | C11H21N5O6 | 详情 | 详情 |
| (I) | 29372 | N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (II) | 43535 | C11H21N5O5 | 详情 | 详情 | ||
| (III) | 43536 | 4-[[(hydrazinocarbonyl)amino]methyl]cyclohexanecarboxylic acid | C9H17N3O3 | 详情 | 详情 | |
| (IV) | 43537 | C20H36N8O7 | 详情 | 详情 | ||
| (V) | 43538 | C20H37N9O6 | 详情 | 详情 | ||
| (VI) | 43539 | C28H51N15O10 | 详情 | 详情 | ||
| (VII) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VIII) | 43540 | C30H49N15O10S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Coupling of thiazolopyridine (I) with amine (II) in the presence of EDC and HOBt provided amide (III). Deprotection of the Fmoc group of (III) was effected with piperidine in CH2Cl2 and the resulting amine (IV) was condensed with benzylsulfonyl chloride (V) to afford sulfonamide (VI). Finally, both Boc protecting groups of (VI) were removed with TFA to yield the title guanidine as the bis(trifluoroacetate) salt.
| 【1】 Wagner, J.; Kallen, J.; Ehrhardt, C.; Evenou, J.-P.; Wagner, D.; Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors. J Med Chem 1998, 41, 19, 3664. |
| 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) | 26832 | (3R,6S,8aS)-6-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid | C23H22N2O5S | 详情 | 详情 | |
| (II) | 26836 | tert-butyl (Z)-[(3-aminopropyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C14H28N4O4 | 详情 | 详情 | |
| (III) | 26833 | 9H-fluoren-9-ylmethyl (3R,6S,8aS)-3-[(Z)-7-[(tert-butoxycarbonyl)amino]-11,11-dimethyl-9-oxo-10-oxa-2,6,8-triaza-7-dodecen-1-anoyl]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridin-6-ylcarbamate | C37H48N6O8S | 详情 | 详情 | |
| (IV) | 26834 | tert-butyl (Z)-[[3-([[(3R,6S,8aS)-6-amino-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl]carbonyl]amino)propyl]amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C22H38N6O6S | 详情 | 详情 | |
| (V) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VI) | 26835 | tert-butyl (Z)-([3-[([(3R,6S,8aS)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl]carbonyl)amino]propyl]amino)[(tert-butoxycarbonyl)amino]methylidenecarbamate | C29H44N6O8S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The intermediate 2-[3-(benzylsulfonamido)-6-methyl-2-oxo-1,2-dihydropyridin-1-yl]acetic acid (VI) has been obtained as follows: The reaction of 2-hydroxy-6-methylpyridine-3-carboxylic acid (IX) with diphenylphosphoryl azide (DPPA), triethylamine and benzyl alcohol in refluxing dioxane gives 3-(benzyloxycarbonylamino)-6-methylpyridin-2(1H)-one (X), which is condensed with tert-butyl bromoacetate (II) by means of NaH in THF yielding the expected condensation product (XI). The deprotection od the amino group of (XI) with H2 over Pd/C in ethanol/water gives the aminopyridone (XII), which is acylated with benzylsulfonylchloride (XIII) in pyridine yielding the sulfonamide (XIV). Finally, the tert-butyl ester group of (XIV) is hydrolyzed with HCl in ethyl acetate to afford the target intermediate (VI).
| 【1】 Naylor-Olsen, A.M.; Newton, C.L.; Isaacs, R.C.A.; Dorsey, B.D. (Merck & Co., Inc.); Thrombin inhibitors. EP 0969840; US 5932606; WO 9842342 . |
| 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) | 26599 | 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid | C15H16N2O5S | 详情 | 详情 | |
| (IX) | 26602 | 2-hydroxy-6-methylnicotinic acid | 38116-61-9 | C7H7NO3 | 详情 | 详情 |
| (X) | 26603 | benzyl 6-methyl-2-oxo-1,2-dihydro-3-pyridinylcarbamate | C14H14N2O3 | 详情 | 详情 | |
| (XI) | 26604 | tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C20H24N2O5 | 详情 | 详情 | |
| (XII) | 26605 | tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C12H18N2O3 | 详情 | 详情 | |
| (XIII) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (XIV) | 26606 | tert-butyl 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C19H24N2O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)6-Methoxy-alpha-tetralone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine in the presence of sodium acetate. Subsequent Beckmann rearrangement of (II) employing polyphosphoric acid produced a mixture of two regioisomeric lactams from which the required 1-benzazepine (III) was isolated by flash chromatography. Iodination of (III) to give (IV) was carried out following a previously described metodolgy. Displacement of the iodolactam (IV) with ammonia in aqueous ethanol furnished the racemic primary amine, which was resolved by means of L-pyroglutamic acid. The desired (S)-amine (V) was protected as the benzyl carbamate (VII) by treatment with N-(benzyloxycarbonyloxy)succinimide (VI). Then, selective alkylation of the lactam ring nitrogen of (VII) with tert-butyl bromoacetate in the presence of lithium hexamethyldisilazide provided ester (VIII). After hydrogenolysis of the carbobenzoy moiety of (VIII), the resulting amino lactam (IX) was condensed with benzylsulfonyl chloride (X) to give sulfonamide (XI). Deprotection of the tert-butyl ester of (XI) with trifluoroacetic acid afforded carboxylic acid (XII), which was coupled with nitroargininal ethyl aminal (XIII), yielding amide (XIV).
| 【1】 Tamura, S.Y.; Goldman, E.A.; Semple, J.E.; Bergum, P.W.; Novel benzo-fused lactam scaffolds as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 17, 2573. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 17594 | 6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone | 1078-19-9 | C11H12O2 | 详情 | 详情 |
| (II) | 38125 | 6-methoxy-3,4-dihydro-1(2H)-naphthalenone oxime | C11H13NO2 | 详情 | 详情 | |
| (III) | 38126 | 7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H13NO2 | 详情 | 详情 | |
| (IV) | 38127 | 3-iodo-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H12INO2 | 详情 | 详情 | |
| (V) | 38128 | (3S)-3-amino-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H14N2O2 | 详情 | 详情 | |
| (VI) | 30663 | N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione | 13139-17-8 | C12H11NO5 | 详情 | 详情 |
| (VII) | 38129 | benzyl (3S)-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate | C19H20N2O4 | 详情 | 详情 | |
| (VIII) | 38130 | tert-butyl 2-((3S)-3-[[(benzyloxy)carbonyl]amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C25H30N2O6 | 详情 | 详情 | |
| (IX) | 38131 | tert-butyl 2-[(3S)-3-amino-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C17H24N2O4 | 详情 | 详情 | |
| (X) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (XI) | 38132 | tert-butyl 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C24H30N2O6S | 详情 | 详情 | |
| (XII) | 38133 | 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C20H22N2O6S | 详情 | 详情 | |
| (XIII) | 38136 | C8H17N5O3 | 详情 | 详情 | ||
| (XIV) | 38134 | C28H37N7O8S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Nalpha-(Benzyloxycarbonyl)-1,4-diaminobutyric acid (I) was protected as the Nomega-Boc derivative (II) and then coupled to glycine ethyl ester (III) by means of EDC and HOBt to produce dipeptide (IV). Hydrogenolysis of the benzyloxycarbonyl group of (IV) to give (V), followed by condensation with alpha-toluenesulfonyl chloride (VI) gave sulfonamide (VII). Side-chain deprotection of (VII) with HCl liberated amine (VIII), which was acylated with 2-pyrazinecarboxylic acid (IX) to afford amide (X). Saponification of the ethyl ester of (X) with LiOH gave carboxylic acid (XI).
| 【1】 Ho, J.Z.; et al.; Exploration solid-phase synthesis of factor Xa inhibitors: Discovery and application of P3-heterocyclic amides as novel types of non-basic arginine surrogates. Bioorg Med Chem Lett 1999, 9, 24, 3459. |
| 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) | 37250 | (2R)-4-amino-2-[[(benzyloxy)carbonyl]amino]butyric acid | 62234-40-6 | C12H16N2O4 | 详情 | 详情 |
| (II) | 37251 | (2R)-2-[[(benzyloxy)carbonyl]amino]-4-[(tert-butoxycarbonyl)amino]butyric acid | C17H24N2O6 | 详情 | 详情 | |
| (III) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (IV) | 37252 | ethyl 2-([(2R)-2-[[(benzyloxy)carbonyl]amino]-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate | C21H31N3O7 | 详情 | 详情 | |
| (V) | 37253 | ethyl 2-([(2R)-2-amino-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate | C13H25N3O5 | 详情 | 详情 | |
| (VI) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VII) | 37254 | ethyl 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate | C20H31N3O7S | 详情 | 详情 | |
| (VIII) | 37255 | ethyl 2-([(2R)-4-amino-2-[(benzylsulfonyl)amino]butanoyl]amino)acetate | C15H23N3O5S | 详情 | 详情 | |
| (IX) | 37256 | 2-pyrazinecarboxylic acid; Pyrazinoic acid | 98-97-5 | C5H4N2O2 | 详情 | 详情 |
| (X) | 37257 | ethyl 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(2-pyrazinylcarbonyl)amino]butanoyl]amino)acetate | C20H25N5O6S | 详情 | 详情 | |
| (XI) | 37258 | 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(2-pyrazinylcarbonyl)amino]butanoyl]amino)acetic acid | C18H21N5O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)Coupling of Boc-d-nitroarginine (I) with sarcosine methyl ester (II) in the presence of EDC and HOBt gave dipeptide (III). Subsequent deprotection of the Boc group of (III) afforded amine (IV), which was coupled with benzylsulfonyl chloride (V), yielding sulfonamide (VI). Then, saponification of the methyl ester of (VI) with LiOH furnished carboxylic acid (VII).
| 【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193. |
| 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) | 39364 | Omega-nitro-Boc-D-arginine | 50913-12-7 | C11H21N5O6 | 详情 | 详情 |
| (II) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
| (III) | 39347 | C15H28N6O7 | 详情 | 详情 | ||
| (IV) | 39348 | C10H20N6O5 | 详情 | 详情 | ||
| (V) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VI) | 39349 | C17H26N6O7S | 详情 | 详情 | ||
| (VII) | 39350 | C16H24N6O7S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)In an alternative procedure, d-nitroarginine methyl ester (VIII) was condensed with sulfonyl chloride (V) giving sulfonamide (IX). The hydrolysis of the ester group of (IX) with LiOH produced carboxylic acid (X). Conversion of (X) to arginine lactam (XI) was effected by treatment with EDC and HOBt. Subsequent opening of the lactam ring of (XI) with sarcosine tert-butyl ester (XII) in the presence of AlMe3 gave rise to dipeptide (XIII). The tert-butyl ester of (XIII) was then cleaved by treatment with trifluoroacetic acid.
| 【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VII) | 39350 | C16H24N6O7S | 详情 | 详情 | ||
| (VIII) | 39351 | D-Ornithine, N5-(imino(nitroamino)methyl)-, methyl ester; N5-(Imino(nitroamino)methyl)-D-ornithine methyl ester | 141968-19-6 | C7H15N5O4 | 详情 | 详情 |
| (IX) | 39352 | C14H21N5O6S | 详情 | 详情 | ||
| (X) | 39353 | C13H19N5O6S | 详情 | 详情 | ||
| (XI) | 39354 | C13H17N5O5S | 详情 | 详情 | ||
| (XII) | 39355 | tert-butyl 2-(methylamino)acetate | C7H15NO2 | 详情 | 详情 | |
| (XIII) | 39356 | C20H32N6O7S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The tosylation of 2-amino-5-chlorobenzophenone (I) with tosyl chloride (II) in pyridine gives 2-tosylamido-5-chlorobenzophenone (III), which is methylated with dimethyl sulfate and sodium methoxide in toluene yielding N-methyl-2-tosylamido-5-chlorobenzophenone (IV). Hydrolysis of (IV) with aqueous sulfuric acid affords 2-methylamino-5-chlorobenzophenone (V), which is acylated with bromoacetyl chloride (VI) in benzene to give N-methyl-2-(bromoacetylamido)-5-chlorobenzophenone (VII). Finally this compound is condensed with 2-methylallylamine (VIII) in acetone
| 【1】 Mouzin, G.; Cousse, H.; Stenger, A.; Casadio, S. (Pierre Fabre S.A.); US 4372975 . |
| 【2】 Serradell, M.N.; Castaner, J.; Souto, M.; Dinazafone. Drugs Fut 1984, 9, 7, 501. |
| 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) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (II) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (III) | 61085 | N-(2-benzoyl-4-chlorophenyl)(phenyl)methanesulfonamide | C20H16ClNO3S | 详情 | 详情 | |
| (IV) | 61086 | N-(2-benzoyl-4-chlorophenyl)-N-methylphenylmethanesulfonamide | C21H18ClNO3S | 详情 | 详情 | |
| (V) | 33972 | [5-chloro-2-(methylamino)phenyl](phenyl)methanone | 1022-13-5 | C14H12ClNO | 详情 | 详情 |
| (VI) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VII) | 33973 | N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-methylacetamide | C16H13BrClNO2 | 详情 | 详情 | |
| (VIII) | 61087 | 2-methyl-2-propen-1-amine; 2-methyl-2-propenylamine | C4H9N | 详情 | 详情 |