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【结 构 式】

【分子编号】20436

【品名】glycine

【CA登记号】56-40-6

【 分 子 式 】C2H5NO2

【 分 子 量 】75.06724

【元素组成】C 32% H 6.71% N 18.66% O 42.63%
与该中间体有关的原料药合成路线共 16 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1

该中间体在本合成路线中的序号：(XXVI)

The reaction of the dianhydride (II) with benzyl carbazate (E) gives the bis(benzyloxycarbonylhydrazide) compound (XXI), which by an enzymatic treatment with an aminopeptidase from Streptomyces sapporonensis yields the monohydrazide (XXII). The protection of (XXII) with benzyloxycarbonyl chloride (B) affords the protected monohydrazide (XXIII), which is cyclized by treatment with SOCl2 giving the monocarboxy anhydride (XXIV). Hydrolysis of (XXIV) with HCl yields amino acid (XXV), which is condensed with glycine (XXVI) to afford the dipeptide (XXVII). The condensation of (XXVII) with (X) gives the protected FK-156 (XXVIII), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol-acetic acid affording FK-156 still protected with an acetoxy and a hydrazine group (XXIX).

参考文献 中间体
合成目标
【1】 Hemmi, K.; Nakaguchi, O.; Hashimoto, M.; Taleno, H.; Kitaura, Y.; Okada, S.; An efficient method for selective amino acid protection of meso-2,2'-diaminocarboxylic acid: An improved synthesis of FK-156. Tetrahedron Lett 1982, 23, 6, 693-696.
【2】 Imanaka, H.; Nakahaa, K.; Gotoh, T.; Aoki, H.; Iwami, M.; Studies on a new immunoactive peptide, FK-156. I. Taxonomy of the producing strains. J Antibiot 1982, 35, 10, 1280-85.
【3】 Okada, S.; Hemmi, K.; Takano, H.; Hashimoto, M.; Nakaguchi, O.; Kitaura, Y.; Aratani, M.; Miyazaki, Y.; Studies of a new immunoactive peptide, FK-156. IV. Synthesis od FK-156 and its geometric isomer. J Antibiot 1982, 35, 10, 1300-11.
【4】 Gotoh, T.; Imoraka, H.; Nakahara, K.; Tanaka, H.; Uchida, I.; Kawai, Y.; Studies on a new immunoactive peptide, FK-156. III. Structure elucidation. J Antibiot 1982, 35, 10, 1293-99.
【5】 Okahara, M.; Nakahara, K.; Gotoh, T.; Hashimoto, M..; Kino, T.; Aoki, H.; Imanaka, H.; Kohsaka, M.; Nishiura, T.; Kuroda, Y.; Studies on a new immunoactive peptide, FK-156. II. Fermentation, extraction and chemical and biological charaterization. J Antibiot 1982, 35, 10, 1286-92.
【6】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K.; Aratani, M.; Takeno, H.; Okada, S.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New peptides, processes for their preparation and pharmaceutical compsns. containing them. EP 0027260 .
【7】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 .
【8】 Arya, V.P.; Blancafort, P.; Castaner, J.; Serradell, M.N.; FK-156. Drugs Fut 1983, 8, 8, 667.
【9】 Hemmi, K.; Takeno, H.; Okada, S.; Nakaguchi, O.; Kitaura, Y.; Hashimoto, M.; Total synthesis of FK-156 isolated from a Streptomyces as an immunostimulating peptide: Application of a novel copper chelate amino protection. J Am Chem Soc 1981, 103, 7026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(E) 36108 benzyl 1-hydrazinecarboxylate 5331-43-1 C8H10N2O2 详情 详情
(II) 10892 (4R)-4-[3-[(4S)-2,5-Dioxo-1,3-oxazolan-4-yl]propyl]-1,3-oxazolane-2,5-dione C9H10N2O6 详情 详情
(X) 36102 (4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid C20H26N2O8 详情 详情
(XXI) 36109 benzyl 2-((2R,6S)-2,6-diamino-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoyl)-1-hydrazinecarboxylate C23H30N6O6 详情 详情
(XXII) 36110 (2S,6R)-2,6-diamino-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid C15H22N4O5 详情 详情
(XXIII) 36111 (2S,6R)-2,6-bis[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid C31H34N4O9 详情 详情
(XXIV) 36112 benzyl 2-[(2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolidin-4-yl]pentanoyl]-1-hydrazinecarboxylate C24H26N4O8 详情 详情
(XXV) 36113 (2S,6R)-2-amino-6-[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid C23H28N4O7 详情 详情
(XXVI) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(XXVII) 36114 2-[((2S,6R)-2-amino-6-[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoyl)amino]acetic acid C25H31N5O8 详情 详情
(XXVIII) 36115 (4R,7S,10R,15S)-10-[(benzyloxy)carbonyl]-15-((4R)-4-[[(benzyloxy)carbonyl]amino]-5-[2-[(benzyloxy)carbonyl]hydrazino]-5-oxopentyl)-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid C45H55N7O15 详情 详情
(XXIX) 36116 (4R,7S,10R,15S)-15-[(4R)-4-amino-5-hydrazino-5-oxopentyl]-10-carboxy-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid C22H37N7O11 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

The reaction of 5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepin-2-thione (I) with glycine (A) by means of Na2CO3 in refluxing ethanol-water gives 2-carboxymethylamino-7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepine (II), which is cyclized by means of dicyclohexylcarbodiimide in methylene chloride to afford 8-nitro-(2-chlorophenyl)-1,2-dihydro-1H,4H-imidazo[1,2-a][1,4]benzodiazepin-1-one (III). The reaction of (III) with dimethylformamide diethylacetal (B) by means of triethylamine in benzene yields 8-nitro-2-(dimethylaminomethylene)-6-(2-chlorophenyl)-1,2-dihydro-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one (IV), which is treated with N-methylpiperazine (C) in refluxing toluene to produce 8-nitro-(2-chlorophenyl)-2-(N-methylpiperazin-1-ylmethylene)-1,2-dihydro-1H,4H-imidazo [1,2-a][1,4]benzodiazepin-1-one (V). This compound is finally treated with methanesulfonic acid.

参考文献 中间体
合成目标
【1】 Taylor, J.B.; Harrison D.R.; 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones. US 4044142 .
【2】 Ager, J.R.; et al.; Central nervous system activity of a novel class of annelated 1,4-benzodiazwpines, aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-ones. J Med Chem 1977, 20, 8, 1035-41.
【3】 Thorpe, P.J.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RU-31,158. Drugs Fut 1980, 5, 3, 144.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40922 N,N'-dicyclohexylurea 2387-23-7 C13H24N2O 详情 详情
(A) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(B) 31457 N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine 1188-33-6 C7H17NO2 详情 详情
(I) 32632 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-thione C15H10ClN3O2S 详情 详情
(II) 32633 2-[[5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepin-2-yl]amino]acetic acid C17H13ClN4O4 详情 详情
(III) 30373 6-(2-chlorophenyl)-8-nitro-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one C17H11ClN4O3 详情 详情
(IV) 32634 6-(2-chlorophenyl)-2-[(Z)-(dimethylamino)methylidene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one C20H16ClN5O3 详情 详情
(V) 30375 6-(2-chlorophenyl)-2-[(Z)-(4-methyl-1-piperazinyl)methylidene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one C23H21ClN6O3 详情 详情
(C) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 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 3,4-dimethoxybenzaldehyde (I) with glycine (II) by means of KOH in hot methanol gives racemic threo-3-(3,4-dimethoxyphenyl)serine (III), which is acylated with N-(ethoxycarbonyl)phthalimide (IV) by means of Na2CO3 in water yielding the corresponding N-phthaloyl derivative (V). The reaction of (V) with AlCl3 and ethyl mercaptan in dichloromethane affords N-phthaloyl-3-(3,4-dihydroxyphenyl)serine (VI), which is deprotected with hydrazine in refluxing ethanol to racemic threo-3-(3,4-dihydroxyphenyl)serine (VII). The resolution of the racemic form (VII) is performed through its benzyloxy derivative.

参考文献 中间体
合成目标
【1】 Ohashi, N.; Nagata, S.; Ishimuzi, K.; Katsube, J. (Sumitomo Pharmaceuticals Co., Ltd.); Process for the production of optically active thr. EP 0024210; US 4319040 .
【2】 Ohashi, N.; Nagata, S.; Ishizumi, K. (Sumitomo Pharmaceuticals Co., Ltd.); Process for producing 3-(3,4-dihydroxyphenyl)serin. EP 0128684; US 4562263 .
【3】 Castaner, J.; Prous, J.; L-threo-DOPS. Drugs Fut 1987, 12, 5, 433.
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) 18304 3,4-Dimethoxybenzaldehyde; Veratraldehyde 120-14-9 C9H10O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 22983 3-hydroxy-3,4-dimethoxyphenylalanine C11H15NO5 详情 详情
(IV) 10283 ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide 22509-74-6 C11H9NO4 详情 详情
(V) 22985 3-(3,4-dimethoxyphenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxypropionic acid C19H17NO7 详情 详情
(VI) 22986 3-(3,4-dihydroxyphenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxypropionic acid C17H13NO7 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XII)

Several novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), a key intermediate in the synthesis of losartan, have been described: 1) Treatment of glycine methyl ester hydrochloride (I) with NaOH in methanol, followed by reaction with methyl pentanimidate (II), gives 2-butyl-4,5-dihydro-1H-imidazol-5-one (III), which is treated with POCl3 to give the 2-butyl-5-chloro-1H-imidazole (IV). Reaction of (IV) with POCl3 and DMF yields the enamine (V), which is finally hydrolyzed with water to 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), the desired intemediate in the synthesis of losartan. 2) Imidazolinone (III) can also be obtained by cyclization of chloroacetic acid methyl ester (VI), chloroacetyl chloride (VII) or bromoacetyl bromide (VIII) with pentanamidine (IX) by means of NaOH in methanol. 3) Alternatively, imidazolinone (III) can be treated with dimethylformamide dimethylacetal in dichloromethane yielding the enamine (X), which is finally treated with POCl3 and hydrolyzed with water. 4) The reaction of glycine (XI) with methyl pentanimidate (II) in NaOH/MeOH gives amidine (XII), which, without isolation, is treated with POCl3 and DMF at 100 C for 2 h, and then hydrolyzed with water to give the desired 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde. Methyl pentanimidate (II) is obtained treating a solution of valeronitrile in MeOH with HCl gas followed by neutralization with aqueous KOH and extraction with Et2O.

参考文献 中间体
合成目标
【1】 Kohr, J.; Griffiths, G.J.; Imwinkelried, R.; Hauck, M.B.; Roten, C.A.; Stucky, G.C.; Novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde: A key intermediate for the synthesis of the angiotensin II antagonist losartan. J Org Chem 1999, 64, 22, 8084.
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) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(II) 34050 methyl pentanimidoate C6H13NO 详情 详情
(III) 34051 2-butyl-3,5-dihydro-4H-imidazol-4-one C7H12N2O 详情 详情
(IV) 34052 2-butyl-5-chloro-1H-imidazole C7H11ClN2 详情 详情
(V) 34053 N-[(2-butyl-5-chloro-4H-imidazol-4-ylidene)methyl]-N,N-dimethylamine; (2-butyl-5-chloro-4H-imidazol-4-ylidene)-N,N-dimethylmethanamine C10H16ClN3 详情 详情
(VI) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(IX) 14576 pentanimidamide 109-51-3 C5H12N2 详情 详情
(X) 34054 2-butyl-5-[(E)-(dimethylamino)methylidene]-3,5-dihydro-4H-imidazol-4-one C10H17N3O 详情 详情
(XI) 13925 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 83857-96-9 C8H11ClN2O 详情 详情
(XII) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(XIII) 34055 2-(pentanimidoylamino)acetic acid C7H14N2O2 详情 详情
(XIV) 13921 Pentanenitrile; n-Valeronitrile 110-59-8 C5H9N 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VI)

In a different method, N-phthaloylglycine (VII) was obtained by melting a mixture of phthalic anhydride (V) and glycine (VI). Subsequent chlorination of (VII) using SOCl2 provided acid chloride (VIII). Condensation of (VIII) with the sodium derivative of the tricarboxylate compound (IX) gave the keto triester (X). Hydrogenolysis of the benzyl ester groups of (X), followed by decarboxylation in refluxing toluene, gave rise to delta-phthalimidolevulinic acid (XI). This was finally hydrolyzed to the title compound upon refluxing with 7 N HCl.

参考文献 中间体
合成目标
【1】 Neuberger, A.; Scott, J.J.; The synhtesis of delta-succinamidolaevulic acid and related compounds. J Chem Soc 1954, 1820.
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) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(VI) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(VII) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(VIII) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(IX) 59145 tribenzyl 1,1,2-ethanetricarboxylate C26H24O6 详情 详情
(X) 59146 tribenzyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxo-1,2,2-butanetricarboxylate C36H29NO9 详情 详情
(XI) 59147 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid C13H11NO5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

The condensation of the labeled glycine (I) with phthalic anhydride (II) by heating at 160 C gives the labeled phthalimido acetic acid (III), which is treated with refluxing SOCl2 to yield the acyl chloride (IV). The condensation of (IV) with 3-iodopropionic acid ethyl ester (V) by means of the Zn/Cu couple and Pd(PPh3)4 in hot toluene affords the labeled 5-phthalimido-levulinate (VI), which is finally treated with refluxing 6N HCl to provide the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Iida, K.; Kajiwara, M.; Synthesis of 13C and 15N multilabeled 5-aminolevulinic acid. J Label Compd Radiopharm 2002, 45, 2, 139.
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) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(I) 61588 GLYCINE-13C2-15N C2H5NO2 详情 详情
(II) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(III) 61589 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(IV) 61590 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride C10H6ClNO3 详情 详情
(V) 61591 ethyl 3-iodopropanoate C5H9IO2 详情 详情
(VI) 59167 ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate C15H15NO5 详情 详情
(VI) 61592 ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate C15H15NO5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol, affords 4-phthalimidoaetoacetic acid ethyl ester (VI), which is condensed with 1-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
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) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VII) 61597 ethyl 2-bromoacetate C4H7BrO2 详情 详情
(VIII) 61598 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The condensation of phthalic anhydride (I) with 1-13C-labeled glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
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) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(II) 61599 glycine C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(III) 61600 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(IV) 61627 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VI) 61628 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 61629 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 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 condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
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) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VII) 61630 ethyl 2-bromoacetate C4H7BrO2 详情 详情
(VIII) 61631 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情

合成路线10

该中间体在本合成路线中的序号：(II)

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with 2-13C-labeled Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the ester is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
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) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(V) 61632 2,2-dimethyl-1,3-dioxane-4,6-dione C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VI) 61633 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 61634 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Reaction of glycine (II) with phthalic anhydride (I) in a microwave oven gave phthaloylglycine (III). Subsequent condensation with phenylamidoxime (IV) in the presence of DCC in dimethoxyethane afforded the O-acyl intermediate (V), which on heating cyclized to the title oxadiazole.

参考文献 中间体
合成目标
【1】 Antunes, R.; Batista, H.; Srivastava, R.M.; Thomas, G.; Araujo, C.C.; New phthalimide derivatives with potent analgesic activity: II. Bioorg Med Chem Lett 1998, 8, 21, 3071.
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) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 11284 (6aR,9R,10aR)-7-Allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylic acid C18H20N2O2 详情 详情
(IV) 20438 N'-hydroxybenzenecarboximidamide 613-92-3 C7H8N2O 详情 详情
(V) 20439 2-[2-([[(Z)-amino(phenyl)methylidene]amino]oxy)-2-oxoethyl]-1H-isoindole-1,3(2H)-dione C17H13N3O4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(III)

The cyclic peptide precursor (XIV) was prepared by solid-phase synthesis on a preformed HMPB-MBHA resin. Attachment of N-Fmoc-glycine (I) to the resin by means of DCC and DMAP afforded resin (II). The Fmoc protecting group was then removed with piperidine in DMF, yielding the glycine-bound resin (III). Further couplings with the following protected amino acids: N-Fmoc-3-(aminomethyl)-5-nitrobenzoic acid (IV), N-Fmoc-L-tyrosine(O-t-butyl) (VI) and N-Fmoc-glycine (I), followed by Fmoc deprotection cycles, produced in turn the peptide resins (V), (VII) and (VIII). To peptide resin (VIII) was then coupled N-Fmoc-L-aspartic acid gamma-t-butyl ester (IX), yielding resin (X). Peptide (XI) was then liberated from the resin by means of 1% trifluoroacetic acid in CH2Cl2. The Fmoc group was subsequently removed by treatment with diethylamine in acetonitrile, giving (XII).

参考文献 中间体
合成目标
【1】 Park, H.S.; et al.; Protein surface recognition by synthetic receptors: A route to novel submicromolar inhibitors for alpha-chymotrypsin. J Am Chem Soc 1999, 121, 1, 8.
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) 42131 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid 29022-11-5 C17H15NO4 详情 详情
(X),(XI) 47339 2-([3-[(4S,10S)-4-[4-(tert-butoxy)benzyl]-10-[2-(tert-butoxy)-2-oxoethyl]-14-(9H-fluoren-9-yl)-3,6,9,12-tetraoxo-13-oxa-2,5,8,11-tetraazatetradec-1-yl]-5-nitrobenzoyl]amino)acetic acid C48H54N6O13 详情 详情
(III) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(IV) 47335 3-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-5-nitrobenzoic acid C23H18N2O6 详情 详情
(V) 47336 2-[[3-(aminomethyl)-5-nitrobenzoyl]amino]acetic acid C10H11N3O5 详情 详情
(VI) 18858 (2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid C28H29NO5 详情 详情
(VII) 47337 2-([3-[([(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]amino)methyl]-5-nitrobenzoyl]amino)acetic acid C23H28N4O7 详情 详情
(VIII) 47338 2-([3-[([(2S)-2-[(2-aminoacetyl)amino]-3-[4-(tert-butoxy)phenyl]propanoyl]amino)methyl]-5-nitrobenzoyl]amino)acetic acid C25H31N5O8 详情 详情
(IX) 22260 (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid C23H25NO6 详情 详情
(XII) 47340 2-[(3-[(4S,10S)-10-amino-4-[4-(tert-butoxy)benzyl]-14,14-dimethyl-3,6,9,12-tetraoxo-13-oxa-2,5,8-triazapentadec-1-yl]-5-nitrobenzoyl)amino]acetic acid C33H44N6O11 详情 详情

合成路线13

该中间体在本合成路线中的序号：(III)

Reaction of methyl 2,3,4-tri-O-acetyl-beta-D-glucuronyl-3-nitrobenzyl alcohol (I) with N,N'-disuccinimidyl carbonate affords the mixed carbonate ester (II), which is further coupled to glycine (III), producing carbamate (IV). Alcoholysis of (IV) with NaOMe in MeOH yields the deacetylated conjugate (V). This is then activated as the pentafluorophenyl ester (VI) upon treatment with pentafluorophenol and DCC.

参考文献 中间体
合成目标
【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.
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) 65153 methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetyloxy)-6-[4-(hydroxymethyl)-2-nitrophenoxy]tetrahydro-2H-pyran-2-carboxylate C20H23NO13 详情 详情
(II) 65155 methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetyloxy)-6-{4-[({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}oxy)methyl]-2-nitrophenoxy}tetrahydro-2H-pyran-2-carboxylate C25H26N2O17 详情 详情
(III) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(IV) 65156 2-({[(3-nitro-4-{[(2S,3R,4S,5R,6S)-3,4,5-tris(acetyloxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl]oxy}benzyl)oxy]carbonyl}amino)acetic acid C23H26N2O16 详情 详情
(V) 65154 2-({[(3-nitro-4-{[(2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl]oxy}benzyl)oxy]carbonyl}amino)acetic acid C17H20N2O13 详情 详情
(VI) 65157 methyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-nitro-4-{[({[2-oxo-2-(2,3,4,5,6-pentafluorophenoxy)ethyl]amino}carbonyl)oxy]methyl}phenoxy)tetrahydro-2H-pyran-2-carboxylate C23H19F5N2O13 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

Cyclization of 4-phenoxyphthalic acid (I) with glycine (II) at 215 °C gives the phthalimide (III), which by esterification with MeOH and H2SO4 at reflux yields the methyl ester (IV). Subsequent rearrangement of the phthalimidoacetate (IV) by means of Na in BuOH at 97 °C, followed by flash chromatography provides the isoquinoline-2-carboxylate (V). Bromination of compound (V) using POBr3 and NaHCO3 in acetonitrile leads to butyl 8-bromo-3-hydroxy-6-phenoxyisoquinoline-2-carboxylate (VI), which by hydrolysis with NaOH in refluxing H2O/EtOH affords the carboxylic acid (VII). Substitution of bromine in intermediate (VII) using MeI and BuLi in THF at –78 °C, followed by alkylation with PhCH2Br by means of K2CO3 in refluxing acetone yields the 2-methyl isoquinoline (VIII). Ester hydrolysis of compound (VIII) using KOH in MeOH gives the corresponding carboxylic acid (IX), which is then activated with i-BuOCOCl and Et3N in CH2Cl2, followed by condensation with benzyl glycinate hydrochloride (X) to yield the benzyl ester (XI). Finally, compound (XI) is debenzylated with H2 over Pd/C in EtOAc/MeOH .

参考文献 中间体
合成目标
【1】 Arend, M.P., Flippin, L.A., Du, X., Ho, W.-B., Turtle, E.D., Guenzler-Pukall, V. (FibroGen, Inc.). Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin. WO 2004108681.
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) 67865 4-phenoxyphthalic acid 　 C14H10O5 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 67866 2-(1,3-dioxo-5-phenoxyisoindolin-2-yl)acetic acid 　 C16H11NO5 详情 详情
(IV) 67867 methyl 2-(1,3-dioxo-5-phenoxyisoindolin-2-yl)acetate 　 C17H13NO5 详情 详情
(V) 67868 butyl 1,4-dihydroxy-6-phenoxyisoquinoline-3-carboxylate 　 C20H19NO5 详情 详情
(VI) 67869 butyl 1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylate 　 C20H18BrNO4 详情 详情
(VII) 67870 1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid 　 C16H10BrNO4 详情 详情
(VIII) 67871 benzyl 4-(benzyloxy)-1-methyl-6-phenoxyisoquinoline-3-carboxylate 　 C31H25NO4 详情 详情
(IX) 67872 4-(benzyloxy)-1-methyl-6-phenoxyisoquinoline-3-carboxylic acid 　 C21H21NO4 详情 详情
(X) 67873 benzyl 2-aminoacetate hydrochloride 　 C9H11NO2.HCl 详情 详情
(XI) 67874 benzyl 2-(4-(benzyloxy)-1-methyl-6-phenoxyisoquinoline-3-carboxamido)acetate 　 C33H28N2O5 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

Condensation of 5-bromophthalide (XXIII) with phenol (XIII) by means of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (XXIV), which is submitted to lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene to yield 2-(chloro-methyl)-4-phenoxybenzoyl chloride (XXV). Esterification of acid chloride (XXV) with MeOH at 50 °C provides the methyl ester (XXVI), which is then condensed with methyl N-tosylglycinate (XXVII) in the presence of K2CO3 and NaI in DMF at 50 °C to afford the N-substituted amino ester (XXVIII). Cyclization of diester (XXVIII) with NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXIX), which is submitted to Mannich reaction with bis(dimethylamino)methane (XXX) by means of AcOH at 57 °C to provide the 1-(dimethylaminomethyl)isoquinoline derivative (XXXI). Treatment of compound (XXXI) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXXII). Hydrogenolysis of benzylic acetate (XXXII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XX), which is finally condensed with glycine (II) by means of NaOMe in MeOH at 110 °C .

参考文献 中间体
合成目标
【1】 Thompson, M.D., Park, J.M., Arend, M.P. (FibroGen, Inc.). Process for making isoquinoline compounds. CN 103435546; WO 2014014834.
【2】 Witschi, C., Park, J.M., Thompson, M.D., Martinelli, M.J., Yeowell, D.A.,Arend, M.P. (FibroGen, Inc.). Crystalline forms of a prolyl hydroxylase inhibitor. WO 2014014835, US 2014024675.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(XIII) 23540 Phenol 108-95-2 C6H6O 详情 详情
(XX) 67882 methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate 　 C18H15NO4 详情 详情
(XXIII) 33229 5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one 64169-34-2 C8H5BrO2 详情 详情
(XXIV) 67885 5-phenoxyphthalide 57830-14-5 C14H10O3 详情 详情
(XXV) 67886 2-(chloromethyl)-4-phenoxybenzoyl chloride 　 C14H10Cl2O2 详情 详情
(XXVI) 67887 methyl 2-(chloromethyl)-4-phenoxybenzoate 　 C15H13ClO3 详情 详情
(XXVII) 57744 methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate 2645-02-5 C10H13NO4S 详情 详情
(XXVIII) 67888 methyl 2-((N-(2-methoxy-2-oxoethyl)-4-methylphenylsulfonamido)methyl)-4-phenoxybenzoate 　 C25H25NO7S 详情 详情
(XXIX) 67889 methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 　 C17H13NO4 详情 详情
(XXX) 14349 N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine 51-80-9 C5H14N2 详情 详情
(XXXI) 67890 methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 　 C20H20N2O4 详情 详情
(XXXII) 67891 methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 　 C20H17NO6 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

Condensation of 2,5-dichlorobenzoyl chloride (I) with glycine (II) in the presence of NaOH in H2O/THF gives 2-(2,5-dichlorobenzoylamino) acetic acid (III), which then couples with the 1,3,2-benzodioxaborolyl butanamine derivative (IV) by means of TBTU and DIEA in DMF to yield peptide (V). O-Deprotection of 1,3,2-benzodioxaborolane (V) by means of HCl and 2-methylisopropyl boronic acid in methanol/hexane affords boroxin derivative (VI), which is finally esterified with citric acid (VII) in THF or MIBK or acetonitrile or 2-Me-THF or acetone or EtOAc .

参考文献 中间体
合成目标
【1】 Elliott, E.L., Ferdous, A.J., Kaufman, M.J. et al. (Millennium Pharmaceuticals, Inc.). Boronate ester compounds and pharmaceutical compositions thereof. CN 102066386, EP 2318419, JP 2011524902, US 2009325903, WO 2009154737.
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) 68548 2,5-dichlorobenzoyl chloride;2,5-dichloro-benzoyl chlorid 2905-61-5 C7H3Cl3O 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 68549 2-(2,5-dichlorobenzoylamino)acetic acid 　 C9H7Cl2NO3 详情 详情
(IV) 68550 (S)-3-methyl-1-((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butan-1-amine 2,2,2-trifluoroacetate 　 C17H28BNO4.C2HF3O2 详情 详情
(V) 68551 2,5-dichloro-N-(2-(((S)-3-methyl-1-((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-2-oxoethyl)benzamide 　 C24H33BCl2N2O4 详情 详情
(VII) 13856 2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid 77-92-9 C6H8O7 详情 详情
Extended Information