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【结 构 式】

【分子编号】18066

【品名】N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid

【CA登记号】4530-20-5

【 分 子 式 】C7H13NO4

【 分 子 量 】175.18456

【元素组成】C 47.99% H 7.48% N 8% O 36.53%
与该中间体有关的原料药合成路线共 21 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21

合成路线1

该中间体在本合成路线中的序号：(VIII)

The syntheses of remacemide [13C]-, [14C]-, [2H]-,and [3H]-labeled in several different positions have been described: The Friedel Crafts condensation of benzene with acetyl chloride (II) by means of AlCl3 in CS2 gives acetophenone (III), which by a Grignard condensation with benzylmagnesium chloride (IV) in THF yields 1,2-diphenyl-3-propanol (V). Reaction of (V) with NaCN and sulfuric acid in acetic acid affords the formamide (VI), which is hydrolyzed with refluxing aqueous HCl to give the amine (VII). The condensation of (VII) with N-Boc-glycine (VIII) and DCC or with the N-Boc-glycine mixed anhydride (IX) and TEA in dichloromethane yields the protected glycinamide (X), which is finally deprotected with HCl in refluxing methanol. Alternatively, condensation of amine (VII) with chloroacetyl chloride (XI) by means of pyridine in dichloromethane provides the chloroacetamide (XII), which is finally treated with ammonia in ethanol/dichloromethane. In this reaction sequence, the use of [carbonyl-14C]-acetophenone (III), [13C6]-benzene (I), [13C2]-acetyl chloride (II), the [1-13C]-glycines (VIII) and (IX) or the [2-3H]-glycine (VIII) as starting materials affords remacemide labeled in the corresponding positions. [2H or 3H]-remacemide labeled in 2,6-positions of the 1-phenyl ring is obtained by submitting the amine (VII) to isotopic exchange with 2H2O/RhCl3, 2H2/Iridium complex, or 3H2/Iridium complex.

参考文献 中间体
合成目标
【1】 Dawson, G.E.; Coombs, M.E.; Fedorchuk, M.; et al.; Preparation of remacemide hydrochloride labelled with carbon-14, carbon-13, deuterium and tritium. J Label Compd Radiopharm 2000, 43, 6, 533.
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) 13364 Benzene 71-43-2 C6H6 详情 详情
(II) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(III) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(IV) 18327 benzyl(chloro)magnesium 6921-34-2 C7H7ClMg 详情 详情
(V) 41763 1,2-diphenyl-2-propanol 5342-87-0 C15H16O 详情 详情
(VI) 41764 1-methyl-1,2-diphenylethylformamide C16H17NO 详情 详情
(VII) 41765 1-methyl-1,2-diphenylethylamine; 1,2-diphenyl-2-propanamine C15H17N 详情 详情
(VIII) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(IX) 41766 [(tert-butoxycarbonyl)amino]acetic 1,1-dimethylpropionic anhydride C12H21NO5 详情 详情
(X) 41767 tert-butyl 2-[(1-methyl-1,2-diphenylethyl)amino]-2-oxoethylcarbamate C22H28N2O3 详情 详情
(XI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XII) 41768 2-chloro-N-(1-methyl-1,2-diphenylethyl)acetamide C17H18ClNO 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The hydrolysis of the spicamycin mixture (I) with R = alkyl by means of HCl in alcohol or water gives 6-(spicaminylamino)purine (II). (The hydrolysis can also be performed with other inorganic acids such as H2SO4 or organic ones such as acetic acid or formic acid.) The condensation of (II) with N-(tert-butoxycarbonyl)glycine (III) by the active ester method yields the protected glycyl derivative (IV), which is deprotected with TFA (or methanolic HCl) to afford the glycyl derivative (V). Finally, this compound is condensed with tetradeca-2(E),4(E)-dienoic acid (VI) by the active ester method to provide the target carboxamide derivative.

参考文献 中间体
合成目标
【1】 Otake, N.; Kawai, H.; Kawasaki, T.; Odagawa, A.; Kamishohara, M.; Sakai, T. (Kirin Brewery Co., Ltd.); Spicamycin derivs. and the use thereof. EP 0525479; JP 1993186494; US 5461036; US 5631238 .
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) 54226 N-(2-{[(2R,3R,4R,5R,6S)-2-[(1R)-1,2-dihydroxyethyl]-4,5-dihydroxy-6-(9H-purin-6-ylamino)tetrahydro-2H-pyran-3-yl]amino}-2-oxoethyl)-14-methylpentadecanamide n/a C30H51N7O7 详情 详情
(II) 54227 (2S,3R,4R,5R,6R)-5-amino-6-[(1R)-1,2-dihydroxyethyl]-2-(9H-purin-6-ylamino)tetrahydro-2H-pyran-3,4-diol n/a C12H18N6O5 详情 详情
(III) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(IV) 54228 tert-butyl 2-{[(2R,3R,4R,5R,6S)-2-[(1R)-1,2-dihydroxyethyl]-4,5-dihydroxy-6-(9H-purin-6-ylamino)tetrahydro-2H-pyran-3-yl]amino}-2-oxoethylcarbamate n/a C19H29N7O8 详情 详情
(V) 54229 2-amino-N-[(2R,3R,4R,5R,6S)-2-[(1R)-1,2-dihydroxyethyl]-4,5-dihydroxy-6-(9H-purin-6-ylamino)tetrahydro-2H-pyran-3-yl]acetamide n/a C14H21N7O6 详情 详情
(VI) 54230 5,8-Tetradecadienoic acid 10390-16-6 C14H24O2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XV)

The Wittig condensation of decanal (I) with phosphorane (II) in benzene gives trans-2-dodecenoic acid methyl ester (III), which by thermal Michael addition of benzylamine yields the protected beta-aminoester (IV). The debenzylation of (IV) with H2 over Pd/C in methanol affords the free aminoester (V), which is condensed with N-(tert-butoxycarbonyl)-L-valine (VI) by means of 1-[3-(dimethylamino)propyl]-1-ethyl carbodiimide (WSC) in dichloromethane to give the dipeptide (VII) as a diastereomeric mixture, from which the desired isomer (VIII) is isolated by crystallization. The deprotection of the amino group of (VIII) with TFA in dichloromethane affords the peptide (IX), which is coupled with the conveniently protected glycyl-L-lysine dipeptide (X) by means of WSC as before to give the tetrapeptide (XI). The hydrolysis of the methyl ester group of (XI) with LiOH in THF/methanol/water yields the acidic tetrapeptide (XII). The intermediate glycyl-L-lysine dipeptide (X) has been obtained by coupling N-(tert-butoxycarbonyl)glycine (XV) with Nomega-(benzyloxycarbonyl)-L-lysine methyl ester (XVI) by means of WSC as before to give dipeptide (XVI), which is submitted to alkaline hydrolysis to provide the intermediate dipeptide (X).

参考文献 中间体
合成目标
【1】 Sakai, K.; Yoshioka, T.; Agematu, H.; Chiba, H.; Dobashi, K.; Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from Rhodococcus sp. III. Synthetic study of rhodopeptins. J Antibiot 1999, 52, 8, 710.
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) 31059 decanal 112-31-2 C10H20O 详情 详情
(II) 14686 2-phenyl-1,3-dioxane C10H12O2 详情 详情
(III) 31060 methyl (E)-2-dodecenoate C13H24O2 详情 详情
(IV) 31061 methyl 3-(benzylamino)dodecanoate C20H33NO2 详情 详情
(V) 31062 methyl 3-aminododecanoate C13H27NO2 详情 详情
(VI) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VII) 31063 methyl 3-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)dodecanoate C23H44N2O5 详情 详情
(VIII) 31064 methyl (3R)-3-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)dodecanoate C23H44N2O5 详情 详情
(IX) 31065 methyl (3R)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]dodecanoate C18H36N2O3 详情 详情
(X) 31066 (2S)-6-[[(benzyloxy)carbonyl]amino]-2-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)hexanoic acid C21H31N3O7 详情 详情
(XI) 31067 methyl (9S,12S,15R)-9-(4-[[(benzyloxy)carbonyl]amino]butyl)-12-isopropyl-2,2-dimethyl-15-nonyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazaheptadecan-17-oate C39H65N5O9 详情 详情
(XII) 31068 (9S,12S,15R)-9-(4-[[(benzyloxy)carbonyl]amino]butyl)-12-isopropyl-2,2-dimethyl-15-nonyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazaheptadecan-17-oic acid C38H63N5O9 详情 详情
(XV) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XVI) 31069 methyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate C15H22N2O4 详情 详情
(XVII) 31070 methyl (2S)-6-[[(benzyloxy)carbonyl]amino]-2-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)hexanoate C22H33N3O7 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XIII)

Compound (X) was submitted to successive coupling cycles (deprotection with TFA, and coupling with DIPCDI) to introduce sequentially the following amino acids: (XIb), (XIII) and (XV) yielding the following resins: (XII),(XIV) and (XVI), respectively.

参考文献 中间体
合成目标
【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIb) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(X) 19053 methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-amino-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate C41H59N7O9S 详情 详情
(XII) 19056 methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentano C50H68N8O10S 详情 详情
(XIII) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XIV) 19058 methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-([(2S)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino)-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate C52H71N9O11S 详情 详情
(XV) 19059 (2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid 54631-81-1 C17H23NO5 详情 详情
(XVI) 19060 methyl (2S)-2-[([(2S,3aS,7aS)-1-[((2R,4S)-1-[(2S)-3-(benzyloxy)-2-[((2S)-2-[[2-([[(2S,4R)-4-(benzyloxy)pyrrolidinyl]carbonyl]amino)acetyl]amino]-3-phenylpropanoyl)amino]propanoyl]-4-propoxypyrrolidinyl)carbonyl]octahydro-1H-indol-2-yl]carbonyl)amino C64H84N10O13S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VII)

Cilengitide is synthesized using solid-phase Merrifield-type methods by sequentially adding N-Boc-N-Me-L-Val (I), N-Boc-D-Phe (III), N-Boc-4-O-t-Bu-L-Asp (V), N-Boc-Gly (VII) and Nalpha-Fmoc-Nomega-Mtr-L-Arg (IX) in a stepwise manner to a 4-hydroxymethylphenoxymethyl-polystyrene resin (Wang type resin), yielding peptide-resin intermediates (II), (IV), (VI), (VIII) and (X), respectively. Elimination of the resin from the peptide chain with a 1:1 mixture of TFA/dichloromethane results in the linear peptide (XI), which is then deprotected at the amino-terminal group by removing the Fmoc group with a 1:1 mixture of piperidine/DMF, to give peptide (XII).

参考文献 中间体
合成目标
【1】 Graul, A.; Sorbera, L.A.; Castañer, J.; Cilengitide. Drugs Fut 2000, 25, 7, 674.
【2】 Jonczyk, A.; Goodman, S.; Diefenbach, B.; Sutter, A.; Holzmann, G.; Kessler, H.; Dechantsreiter, M. (Merck Patent GmbH); Cyclic adhesion inhibitors. DE 19534177; EP 0770622; JP 1997132593; US 6001961 .
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),(II) 27154 (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid 45170-31-8 C11H21NO4 详情 详情
(X),(XI) 37627 (8S,14S,17R,20S)-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid C66H76N8O11 详情 详情
(III) 22184 (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid C14H19NO4 详情 详情
(IV) 37622 (2S)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl](methyl)amino]-3-methylbutyric acid C20H30N2O5 详情 详情
(V) 37623 (2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid C13H23NO6 详情 详情
(VI) 37624 (6S,9R,12S)-9-benzyl-6-[2-(tert-butoxy)-2-oxoethyl]-12-isopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C28H43N3O8 详情 详情
(VII) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(VIII) 37625 (9S,12R,15S)-12-benzyl-9-[2-(tert-butoxy)-2-oxoethyl]-15-isopropyl-2,2,14-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid C30H46N4O9 详情 详情
(IX) 37626 (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]pentanoic acid C41H40N4O5 详情 详情
(XII) 37628 (8S,14S,17R,20S)-8-amino-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid C51H66N8O9 详情 详情

合成路线6

该中间体在本合成路线中的序号：

Alkylation of methyl 4-oxo-3-piperidinecarboxylate (I) with ethyl bromoacetate provided piperidineacetate (II). Subsequent decarbomethoxylation of (II) using LiCl in boiling DMF produced piperidone (III). On the other hand, coupling between 4-aminobenzonitrile (IV) and N-Boc-glycine (V) via activation with carbonyldiimidazole gave amide (V). The Boc group of (V) was then deprotected with HCl in EtOAc to yield 2-amino-N-(4-cyanophenyl)acetamide (VI). Reductive condensation of amine (VI) with piperidone (III) employing NaBH(OAc)3 furnished adduct (VII), which was further reductocondensed with chloroacetaldehyde to give chloroethyl amine (VIII). Cyclization of (VIII) in the presence of NaH generated piperazinone (IX). Finally, addition of hydroxylamine to the cyano group of (IX) provided the corresponding hydroxyamidine.

参考文献 中间体
合成目标
【1】 Suzuki, K.; Tsukamoto, S.; Yanagisawa, I.; Matsumoto, Y.; Ichihara, M.; Akamatsu, S.; Kaku, S.; Kawasaki, T.; Novel orally active GPIIb/IIIa antagonists: Synthesis and structure-activity relationship studies of oxopiperazine derivatives. Symp Med Chem 1999, Abst 1P-02.
【2】 Matsumoto, Y.; Akamatsu, S.; Ichihara, M.; Kawasaki, T.; Kaku, S.; Yanagisawa, I. (Merck Patent GmbH; Yamanouchi Pharmaceutical Co., Ltd.); Substd. amidinobenzene derivs. and medicinal compsns. thereof. EP 0905129; US 6057324; WO 9745413 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(I) 28106 methyl 4-oxo-3-piperidinecarboxylate 56026-52-9 C7H11NO3 详情 详情
(II) 37983 methyl 1-(2-ethoxy-2-oxoethyl)-4-oxo-3-piperidinecarboxylate C11H17NO5 详情 详情
(III) 37984 ethyl 2-(4-oxo-1-piperidinyl)acetate C9H15NO3 详情 详情
(IV) 15361 4-Aminobenzonitrile 873-74-5 C7H6N2 详情 详情
(V) 37985 tert-butyl 2-(4-cyanoanilino)-2-oxoethylcarbamate C14H17N3O3 详情 详情
(VI) 37986 2-amino-N-(4-cyanophenyl)acetamide C9H9N3O 详情 详情
(VII) 37988 ethyl 2-(4-[[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate C18H24N4O3 详情 详情
(VIII) 37987 ethyl 2-(4-[(2-chloroethyl)[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate C20H27ClN4O3 详情 详情
(IX) 37989 ethyl 2-[4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidinyl]acetate C20H26N4O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(A)

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.

参考文献 中间体
合成目标
【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8

该中间体在本合成路线中的序号：(V)

Alkylation of 3-nitrophenol (I) with methyl bromoacetate (II) in the presence of K2CO3 provided phenoxyacetate (III). Then, reduction of the nitro group of (III) by hydrogenation on Pd/C gave amine (IV), which was subsequently condensed with N-tert-butoxycarbonyl glycine (V) on treatment with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) to afford amide (VI). Alkylation with bromoacetamide (VII) in the presence of NaH in THF provided (VIII), and removal of the Boc protecting group with trifluoroacetic acid gave amine (IX). This amine was condensed with 3-tolyl isocyanate (X) to give urea (XI). Then, alkaline hydrolysis of the ester group afforded acid (XII), which was finally condensed with N-methylaniline (XIII) to yield the target compound.

参考文献 中间体
合成目标
【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .
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) 18076 Metanitrophenol; 3-nitrophenol 554-84-7 C6H5NO3 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 18077 methyl 2-(3-nitrophenoxy)acetate C9H9NO5 详情 详情
(IV) 18078 methyl 2-(3-aminophenoxy)acetate C9H11NO3 详情 详情
(V) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(V) 18068 2-bromo-N-methyl-N-phenylacetamide C9H10BrNO 详情 详情
(VI) 18079 methyl 2-[3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)phenoxy]acetate C16H22N2O6 详情 详情
(VIII) 18080 methyl 2-(3-[[2-[(tert-butoxycarbonyl)amino]acetyl][2-(methylanilino)-2-oxoethyl]amino]phenoxy)acetate C25H31N3O7 详情 详情
(IX) 18081 methyl 2-(3-[(2-aminoacetyl)[2-(methylanilino)-2-oxoethyl]amino]phenoxy)acetate C20H23N3O5 详情 详情
(X) 18071 m-Tolyl Isocyanate; 1-isocyanato-3-methylbenzene; 3-methylphenyl isocyanate 621-29-4 C8H7NO 详情 详情
(XI) 18082 methyl 2-[3-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetate C28H30N4O6 详情 详情
(XII) 18083 2-[3-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetic acid C27H28N4O6 详情 详情
(XIII) 10409 N-Methyl-N-phenylamine; N-methylaniline; Monomethylaniline 100-61-8 C7H9N 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

2-Benzyloxyaniline (I) was acylated with N-tert-butoxycarbonyl glycine (II) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.HCl (EDC) to give amide (III). Alkylation with bromoacetamide (IV) in the presence of NaH in THF provided (V), and then removal of the Boc protecting group with trifluoroacetic acid gave amine (VI). This amine was condensed with 3-tolyl isocyanate (VII) to give the phenylurea (VIII). Cleavage of the benzyl group by hydrogenolysis on Pd/C provided phenol (IX), which was alkylated with methyl bromoacetate in the presence of K2CO3 to give ether (X). Alkaline hydrolysis of the ester group gave acid (XI), which was finally condensed with N-methylaniline (XII) by means of EDC to yield the target compound.

参考文献 中间体
合成目标
【1】 Takeda, Y.; et al.; Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of gastrin/cholecystokinin-B receptors. Chem Pharm Bull 1998, 46, 3, 434-444.
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) 18065 2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine C13H13NO 详情 详情
(II) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(III) 18067 tert-butyl 2-[2-(benzyloxy)anilino]-2-oxoethylcarbamate C20H24N2O4 详情 详情
(IV) 18068 2-bromo-N-methyl-N-phenylacetamide C9H10BrNO 详情 详情
(V) 18069 tert-butyl 2-[2-(benzyloxy)[2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate C29H33N3O5 详情 详情
(VI) 18070 2-amino-N-[2-(benzyloxy)phenyl]-N-[2-(methylanilino)-2-oxoethyl]acetamide C24H25N3O3 详情 详情
(VII) 18071 m-Tolyl Isocyanate; 1-isocyanato-3-methylbenzene; 3-methylphenyl isocyanate 621-29-4 C8H7NO 详情 详情
(VIII) 18072 2-(2-(benzyloxy)[2-[(3-toluidinocarbonyl)amino]acetyl]anilino)-N-methyl-N-phenylacetamide C32H32N4O4 详情 详情
(IX) 18073 2-(2-hydroxy[2-[(3-toluidinocarbonyl)amino]acetyl]anilino)-N-methyl-N-phenylacetamide C25H26N4O4 详情 详情
(X) 18074 methyl 2-[2-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetate C28H30N4O6 详情 详情
(XI) 18075 2-[2-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetic acid C27H28N4O6 详情 详情
(XII) 10409 N-Methyl-N-phenylamine; N-methylaniline; Monomethylaniline 100-61-8 C7H9N 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The N-alkylation of N-(tert-butoxycarbonyl)glycine (I) with benzyl bromide (II) by means of NaH in THF gives N-benzyl-N-(tert-butoxycarbonyl)glycine (III), which is condensed with 4-aminoacetophenone (IV) by means of isobutyl chloroformate and TEA in dichloromethane yielding the corresponding glycinamide (V). The cyclization of (V) with thiourea (VI) by means of I2 in refluxing isopropanol affords, after work up, the N-benzyl-glycinamide (VII), which is finally acylated with pyridine-4-carbonyl chloride by means of TEA and DMAP in dichloromethane.

参考文献 中间体
合成目标
【1】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
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) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 27846 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid C14H19NO4 详情 详情
(IV) 27847 1-(4-aminophenyl)-1-ethanone 99-92-3 C8H9NO 详情 详情
(V) 27848 tert-butyl 2-(4-acetylanilino)-2-oxoethyl(benzyl)carbamate C22H26N2O4 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 27849 N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]-2-(benzylamino)acetamide C18H18N4OS 详情 详情
(VIII) 27850 isonicotinoyl chloride 39178-35-3 C6H4ClNO 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Coupling of 2-benzyloxyaniline (I) with N-Boc-glycine (II) by means of EDC aforded amide (III). Subsequent N-alkylation of (III) with N-methyl-N-phenyl-2-bromoacetamide (IV) in the presence of NaH provided diamide (V). Hydrogenolysis of the benzyl ether of (V) over Pd/C gave phenol derivative (VI) (1). Phenol (VI) was then alkylated with bromoamide (IV) to furnish ether (VII). After cleavage of the Boc group of (VII) with trifluoroacetic acid, the resulting amine (VIII) was reacted with carbonyldiimidazole to produce imidazolide (IX), which was subsequently coupled with aniline (X) yielding urea (XI). Finally, basic hydrolysis of the methyl ester group of (XI) gave the title carboxylic acid.

参考文献 中间体
合成目标
【1】 Yokomizo, A.; Takeda, Y.; Kawagoe, K.; et al.; Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of gastrin/cholecystokinin-B receptors. II. Chem Pharm Bull 1998, 46, 6, 951.
【2】 Yokohama, S.; Kawagoe, K.; Takeda, Y.; Yokomizo, Y.; Yokomizo, A. (Daiichi Pharmaceutical Co., Ltd.); Aminophenol derivs.. EP 0985660; US 5919824; WO 9628416 .
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) 18065 2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine C13H13NO 详情 详情
(II) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(III) 18067 tert-butyl 2-[2-(benzyloxy)anilino]-2-oxoethylcarbamate C20H24N2O4 详情 详情
(IV) 18068 2-bromo-N-methyl-N-phenylacetamide C9H10BrNO 详情 详情
(V) 18069 tert-butyl 2-[2-(benzyloxy)[2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate C29H33N3O5 详情 详情
(VI) 41107 tert-butyl 2-[2-hydroxy[2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate C22H27N3O5 详情 详情
(VII) 41108 tert-butyl 2-[2-[2-(methylanilino)-2-oxoethoxy][2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethylcarbamate C31H36N4O6 详情 详情
(VIII) 41109 2-amino-N-[2-[2-(methylanilino)-2-oxoethoxy]phenyl]-N-[2-(methylanilino)-2-oxoethyl]acetamide C26H28N4O4 详情 详情
(IX) 41110 N-(2-[2-[2-(methylanilino)-2-oxoethoxy][2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethyl)-1H-imidazole-1-carboxamide C30H30N6O5 详情 详情
(X) 41111 methyl 2-(3-aminophenyl)acetate C9H11NO2 详情 详情
(XI) 41112 methyl 2-[3-([[(2-[2-[2-(methylanilino)-2-oxoethoxy][2-(methylanilino)-2-oxoethyl]anilino]-2-oxoethyl)amino]carbonyl]amino)phenyl]acetate C36H37N5O7 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XXIII)

Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI), N-Boc-glycine (XXIII), N-Boc-4-hydroxyproline (XXV), N-Boc-proline (XXVII), Nalpha-Boc-Ngamma-tosyl-arginine (XXIX) and Nalpha-Boc-Ngamma-nitro-D-arginine (XXXI) to produce peptide resins (XXII), (XXIV), (XXVI), (XXVIII), (XXX) and (XXXII), respectively. The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.

参考文献 中间体
合成目标
【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193.
【2】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 39383 (2S)-2-([2-[(3S)-3-[[(2S)-2-amino-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C35H43N7O8S2 详情 详情
(XXI) 16888 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine 78452-55-8 C12H17NO4S 详情 详情
(XXII) 39385 (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-[[(2S)-2-[[(2S)-2-amino-3-(2-thienyl)propanoyl]amino]-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid C42H50N8O9S3 详情 详情
(XXIII) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XXIV) 39386 　 C44H53N9O10S3 详情 详情
(XXV) 19043 (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid C10H17NO5 详情 详情
(XXVI) 39387 　 C49H60N10O12S3 详情 详情
(XXVII) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(XXVIII) 39388 　 C54H67N11O13S3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

Hexahydroazepine (I) was coupled with N-Boc-glycine (II) by means of EDC and HOBt, and the resulting amide (III) was reduced with LiAlH4 to give diamine (IV). Subsequent coupling of (IV) with 3,4-dichlorophenylacetic acid (V) in the presence of DCC afforded amide (VI). Finally, reduction of (VI) with aluminum hydride in THF provided the title compound.

参考文献 中间体
合成目标
【1】 de Costa, B.R.; et al.; Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the sigma receptor. J Med Chem 1992, 35, 1, 38.
【2】 De Costa, B.R.; Radesca, L.; Bowen, W.; Long, J.; Walker, J.M.; Rice, K.C.; Gray, N.M.; Contreras, P.C. (Pharmacia Corp.); N-(Arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine derivs. for CNS disorders. EP 0518216; WO 9222279 .
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) 18672 azepane 111-49-9 C6H13N 详情 详情
(II) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(III) 30416 tert-butyl 2-(1-azepanyl)-2-oxoethylcarbamate C13H24N2O3 详情 详情
(IV) 30417 N-[2-(1-azepanyl)ethyl]-N-methylamine; 2-(1-azepanyl)-N-methyl-1-ethanamine C9H20N2 详情 详情
(V) 30414 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid 5807-30-7 C8H6Cl2O2 详情 详情
(VI) 30418 N-[2-(1-azepanyl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide C17H24Cl2N2O 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VI)

Coupling of N-Boc-glycine (VI) with glycine benzyl ester hydrochloride (VII) by means of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) gave the protected dipeptide (VIII). After deprotection of the Boc group of (VIII) with HCl, the resulting amine (IX) was condensed with the thioacylating compound (V) to furnish thioamide (X). Finally, the Boc and benzyl protecting groups of (X) were cleaved using HF.

参考文献 中间体
合成目标
【1】 Zackarie, B.; et al.; Thioamides: Synthesis, stability, and immunological activities of thioanalogues of imreg. Preparation Of new thioacylating agents using fluorobenzimidazolone derivatives. J Med Chem 1999, 42, 11, 2046.
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) 30400 tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-(6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-2-thioxoethylcarbamate C28H28FN3O4S 详情 详情
(VI) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(VII) 13601 benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride 1738-68-7 C9H11NO2 详情 详情
(VIII) 30401 benzyl 2-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)acetate C16H22N2O5 详情 详情
(IX) 30402 benzyl 2-[(2-aminoacetyl)amino]acetate C11H14N2O3 详情 详情
(X) 30403 benzyl (6S)-6-[4-(benzyloxy)benzyl]-2,2-dimethyl-4,10-dioxo-7-thioxo-3-oxa-5,8,11-triazatridecan-13-oate C32H37N3O6S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IX)

Sharpless epoxidation of 3-methyl-2-buten-1-ol (I) using L-(+)-diisopropyl tartrate provided the (2S)-epoxide (II). Treatment of (II) with methyl isocyanate gave the corresponding carbamate (III). Subsequent base-catalyzed epoxide opening generated oxazolidinone (IV), which smoothly rearranged to the more stable isomer (V) under the reaction conditions. Protection of the primary alcohol of (V) as the tetrahydropyranyl ether (VII) was followed by hydrolysis of the carbamate group with KOH in aqueous ethylene glycol at 150 C. The resulting amine (VIII) was coupled with Boc-glycyl-sarcosine (IX) using EDC and HOAt to furnish amide (X). Acid-catalyzed removal of the tetrahydropyranyl group of (X) gave alcohol (XI), which was oxidized to carboxylic acid (XII) by means of RuO2-NaIO4. Exchange of the Boc protecting group for a Fmoc group in (XII) was effected by acid cleavage of the tert-butyl carbamate, followed by treatment with Fmoc-chloride. Esterification of the the resulting acid (XIII) with the functionalized dipeptide (XIV) was achieved with DCC-DMAP to produce (XV).

参考文献 中间体
合成目标
【1】 Ledeboer, M.W.; Jin, Q.; Kume, M.; Searcey, M.; Boger, D.L.; Total synthesis and comparative evaluation of luzopeptin A - C and quinoxapeptin A - C. J Am Chem Soc 1999, 121, 49, 11375.
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) 37754 3-methyl-2-buten-1-ol 556-82-1 C5H10O 详情 详情
(II) 37755 [(2S)-3,3-dimethyloxiranyl]methanol C5H10O2 详情 详情
(III) 37756 [(2S)-3,3-dimethyloxiranyl]methyl methylcarbamate C7H13NO3 详情 详情
(IV) 37757 (4R)-4-(1-hydroxy-1-methylethyl)-3-methyl-1,3-oxazolidin-2-one C7H13NO3 详情 详情
(V) 37758 (4R)-4-(hydroxymethyl)-3,5,5-trimethyl-1,3-oxazolidin-2-one C7H13NO3 详情 详情
(VI) 13684 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran 110-87-2 C5H8O 详情 详情
(VII) 37759 (4R)-3,5,5-trimethyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-oxazolidin-2-one C12H21NO4 详情 详情
(VIII) 37760 (3R)-2-methyl-3-(methylamino)-4-(tetrahydro-2H-pyran-2-yloxy)-2-butanol C11H23NO3 详情 详情
(IX) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(X) 37761 tert-butyl 2-[[2-[[(1R)-2-hydroxy-2-methyl-1-[(tetrahydro-2H-pyran-2-yloxy)methyl]propyl](methyl)amino]-2-oxoethyl](methyl)amino]-2-oxoethylcarbamate C21H39N3O7 详情 详情
(XI) 37762 tert-butyl 2-[[2-[[(1R)-2-hydroxy-1-(hydroxymethyl)-2-methylpropyl](methyl)amino]-2-oxoethyl](methyl)amino]-2-oxoethylcarbamate C16H31N3O6 详情 详情
(XII) 37763 (12S)-12-(1-hydroxy-1-methylethyl)-2,2,8,11-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C16H29N3O7 详情 详情
(XIII) 37764 (11S)-1-(9H-fluoren-9-yl)-11-(1-hydroxy-1-methylethyl)-7,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oic acid C26H31N3O7 详情 详情
(XIV) 37765 tert-butyl (5R)-3-[(1S,2S)-1-[(benzyloxy)carbonyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(1,3-dioxan-2-yl)propyl]-5-(hydroxymethyl)-10,10-dimethyl-4,7,7-trioxo-7lambda(6)-thia-2,3,6-triaza-10-silaundecan-1-oate C34H61N3O11SSi2 详情 详情
(XV) 37766 tert-butyl (5R,9S)-3-[(1S,2S)-1-[(benzyloxy)carbonyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(1,3-dioxan-2-yl)propyl]-19-(9H-fluoren-9-yl)-9-(1-hydroxy-1-methylethyl)-10,13-dimethyl-4,8,11,14,17-pentaoxo-5-([[2-(trimethylsilyl)ethyl]sulfonyl]amino)-7,18-dioxa-2,3,10,13,16-pentaazanonadecan-1-oate C60H90N6O17SSi2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XVI)

Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in HOAc, followed by the introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH(XVI), Boc-Hyp-OH(XVIII) and Boc-Pro-OH(XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28946801b).

参考文献 中间体
合成目标
【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185.
【2】 Amblard, M.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX),(X) 43248 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C21H22N2O5S 详情 详情
(XI) 43249 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C16H20N2O5S 详情 详情
(XII) 28112 (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid C15H21NO5 详情 详情
(XIII) 42350 ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate C9H17NO3 详情 详情
(XIV) 43251 (2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoic acid C16H21NO4 详情 详情
(XV) 43252 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C37H42N4O8S 详情 详情
(XVI) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XVII) 43253 2-[(3S)-3-[[(2R,5R)-2-[(benzyloxy)methyl]-5-(2,3-dihydro-1H-inden-2-yl)-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C39H45N5O9S 详情 详情
(XVIII) 19043 (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid C10H17NO5 详情 详情
(XIX) 43254 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl]amino)acetyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic aci C44H52N6O11S 详情 详情
(XX) 19061 (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline C10H17NO4 详情 详情
(XXI) 43255 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben C49H59N7O12S 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XVI)

Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH (XVI), Boc-Hyp-OH (XVIII) and Boc-Pro-OH (XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28947001b).

参考文献 中间体
合成目标
【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185.
【2】 Amblard, M.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX),(X) 43248 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C21H22N2O5S 详情 详情
(XI) 43249 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C16H20N2O5S 详情 详情
(XII) 28112 (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid C15H21NO5 详情 详情
(XIII) 42350 ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate C9H17NO3 详情 详情
(XIV) 43251 (2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoic acid C16H21NO4 详情 详情
(XV) 43252 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C37H42N4O8S 详情 详情
(XVI) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XVII) 43253 2-[(3S)-3-[[(2R,5R)-2-[(benzyloxy)methyl]-5-(2,3-dihydro-1H-inden-2-yl)-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C39H45N5O9S 详情 详情
(XVIII) 19043 (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid C10H17NO5 详情 详情
(XIX) 43254 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl]amino)acetyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic aci C44H52N6O11S 详情 详情
(XX) 19061 (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline C10H17NO4 详情 详情
(XXI) 43255 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben C49H59N7O12S 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

Coupling of AZT (I) with Boc-Gly-OH (II) by means of dicyclohexyl carbodiimide (DCC) in the presence of dimethylaminopyridine (DMAP) in DMF followed by Boc removal by treatment with HCl/dioxane yields AZT ester (III). On the other hand, KNI-727 (IV) is condensed with glutaric anhydride (V) in THF-ether in the presence of dicyclohexylamine (DCHA) to yield the half ester of KNI-727 (VI), which is then condensed with derivative (III) by means of EDC.HCl in DMF in the presence of HOBt to furnish the target compound.

参考文献 中间体
合成目标
【1】 Sano, K.; Kimura, T.; Hamawaki, T.; Matsumoto, H.; Ota, H.; Hayashi, Y.; Kiso, Y.; Goto, T.; "Double-drugs" - a new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker. Bioorg Med Chem Lett 2000, 10, 11, 1227.
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) 45465 1-[(4S,5S)-4-azido-5-(hydroxymethyl)isoxazolidinyl]-5-methyl-2,4(1H,3H)-pyrimidinedione C9H12N6O4 详情 详情
(II) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(III) 45466 [(4S,5S)-4-azido-2-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]isoxazolidinyl]methyl 2-aminoacetate C11H15N7O5 详情 详情
(IV) 45467 (4R)-N-(tert-butyl)-3-((2S,3S)-3-[[2-(2,6-dimethylphenoxy)acetyl]amino]-2-hydroxy-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C30H41N3O5S 详情 详情
(V) 15512 Glutaric Anhydride; dihydro-2H-pyran-2,6(3H)-dione 108-55-4 C5H6O3 详情 详情
(VI) 45468 5-[((1S,2S)-1-([(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]carbonyl)-2-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-phenylpropyl)oxy]-5-oxopentanoic acid C35H47N3O8S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

Reaction of 4-(trifluoromethyl)benzyl alcohol (I) with DSC followed by coupling with partially protected lysine (II) affords carbamate (III), which is converted into derivative (V) first by Boc removal with HCl/dioxane in dichloromethane followed by coupling with Boc-Gly-OH (IV) by means of EDCl and DIEA. Boc removal of compound (V) with HCl/dioxane in dichloromethane, followed by condensation with isophthaloyl dichloride (VI) by means of DIEA in DMF, gives compound (VII), which is finally subjected to methyl ester saponification with LiOH in THF/MeOH to provide the desired product.

参考文献 中间体
合成目标
【1】 Boger, D.L.; et al.; Identification of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibiting the binding and localization of proteinase MMP2 to integrin alphavbeta3. J Am Chem Soc 2001, 123, 7, 1280.
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) 47327 [4-(trifluoromethyl)phenyl]methanol 349-95-1 C8H7F3O 详情 详情
(II) 47328 methyl (2S)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoate C12H24N2O4 详情 详情
(III) 47329 methyl (2S)-6-[(tert-butoxycarbonyl)amino]-2-[([[4-(trifluoromethyl)benzyl]oxy]carbonyl)amino]hexanoate C21H29F3N2O6 详情 详情
(IV) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(V) 47330 methyl (2S)-6-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-2-[([[4-(trifluoromethyl)benzyl]oxy]carbonyl)amino]hexanoate C23H32F3N3O7 详情 详情
(VI) 12501 Isophthaloyl dichloride 99-63-8 C8H4Cl2O2 详情 详情
(VII) 47331 methyl (2S)-6-([2-[(3-[(10S)-10-(methoxycarbonyl)-4,12-dioxo-14-[4-(trifluoromethyl)phenyl]-13-oxa-2,5,11-triazatetradec-1-anoyl]benzoyl)amino]acetyl]amino)-2-[([[4-(trifluoromethyl)benzyl]oxy]carbonyl)amino]hexanoate C44H50F6N6O12 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

Coupling between ethyl 3-aminopropionate (I) and N-Boc-glycine (II) by means of EDC and HOBt affords the protected dipeptide (III). After acidic Boc group cleavage in (III), the N-deprotected dipeptide (IV) is acylated by 3,3,3-triphenylpropionic acid (V) to produce amide (VI). Saponification of the ethyl ester group of (VI) yields acid (VII). This is coupled with (R)-1-Boc-3-(aminomethyl)piperidine (VIII) to afford amide (IX), which is further subjected to acidic N-Boc group cleavage. The resultant piperidine derivative (X) is then reductively condensed with cyclohexanecarboxaldehyde (XI) in the presence of NaBH(OAc)3 to furnish the title compound.

参考文献 中间体
合成目标
【1】 Kimura, T.; Noguchi, K.; Otake, N.; Uchiyama, M.; Naya, A.; Sagara, Y.; Numazawa, T.; Fujikawa, T. (Banyu Pharmaceutical Co., Ltd.); Novel amide derivs.. EP 1213281; WO 0107406 .
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) 17639 beta-Alanine, ethyl ester; ethyl 3-aminopropanoate 924-73-2 C5H11NO2 详情 详情
(II) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(III) 57638 ethyl 3-({2-[(tert-butoxycarbonyl)amino]acetyl}amino)propanoate C12H22N2O5 详情 详情
(IV) 57639 ethyl 3-[(2-aminoacetyl)amino]propanoate C7H14N2O3 详情 详情
(V) 57640 3,3,3-Triphenylpropionic acid; Tritylacetic acid 900-91-4 C21H18O2 详情 详情
(VI) 57641 ethyl 3-({2-[(3,3,3-triphenylpropanoyl)amino]acetyl}amino)propanoate C28H30N2O4 详情 详情
(VII) 57642 N-{2-[(3,3,3-triphenylpropanoyl)amino]acetyl}-beta-alanine C26H26N2O4 详情 详情
(VIII) 57643 tert-butyl (3R)-3-(aminomethyl)-1-piperidinecarboxylate C11H22N2O2 详情 详情
(IX) 57644 tert-butyl (3R)-3-({[3-({2-[(3,3,3-triphenylpropanoyl)amino]acetyl}amino)propanoyl]amino}methyl)-1-piperidinecarboxylate C37H46N4O5 详情 详情
(X) 57645 N-{2-oxo-2-[(3-oxo-3-{[(3S)piperidinylmethyl]amino}propyl)amino]ethyl}-3,3,3-triphenylpropanamide C32H38N4O3 详情 详情
(XI) 33694 cyclohexanecarbaldehyde 2043-61-0 C7H12O 详情 详情

合成路线21

该中间体在本合成路线中的序号：(IV)

The 3-aryl-3-aminopropionic acid (II) was prepared by Knoevenagel condensation of 4-(1-naphthyl)benzaldehyde (I) with malonic acid in the presence of ammonium acetate. Subsequent esterification of (II) by means of thionyl chloride and methanol afforded the methyl ester (III). Coupling of amino ester (III) with N-Boc-glycine (IV) by means of TBTU and HOBt furnished amide (V). After acidic Boc group cleavage, the resultant dipeptide ester (VI) was acylated with 4-(4-methylpyridin-2-ylamino)butyric acid (VII), yielding tripeptide ester (VIII). The methyl ester group of (VIII) was finally hydrolyzed by NaOH in aqueous dioxan.

参考文献 中间体
合成目标
【1】 Goodman, S.L.; Holzemann, G.; Kessler, H.; Sulyok, G.A.G.; Nanomolar small molecule inhibitors for alphavbeta6, alphavbeta5, and +alphavbeta3 integrins. J Med Chem 2002, 45, 5, 1045.
【2】 Holzemann, G.; Jonczyk, A.; Goodman, S.; Stahle, W. (Merck Patent GmbH); beta-Alanine derivs.. WO 0048996 .
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) 54764 4-(1-naphthyl)benzaldehyde C17H12O 详情 详情
(II) 54765 3-[4-(1-naphthyl)phenyl]-beta-alanine C19H17NO2 详情 详情
(III) 54766 methyl 3-amino-3-[4-(1-naphthyl)phenyl]propanoate C20H19NO2 详情 详情
(IV) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(V) 54767 methyl 3-({2-[(tert-butoxycarbonyl)amino]acetyl}amino)-3-[4-(1-naphthyl)phenyl]propanoate C27H30N2O5 详情 详情
(VI) 54768 methyl 3-[(2-aminoacetyl)amino]-3-[4-(1-naphthyl)phenyl]propanoate C22H22N2O3 详情 详情
(VII) 54769 4-[(4-methyl-2-pyridinyl)amino]butanoic acid C10H14N2O2 详情 详情
(VIII) 54770 methyl 3-{[2-({4-[(4-methyl-2-pyridinyl)amino]butanoyl}amino)acetyl]amino}-3-[4-(1-naphthyl)phenyl]propanoate C32H34N4O4 详情 详情
Extended Information