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【结 构 式】 
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【分子编号】28928 【品名】4-methylmorpholine 【CA登记号】109-02-4 |
【 分 子 式 】C5H11NO 【 分 子 量 】101.14848 【元素组成】C 59.37% H 10.96% N 13.85% O 15.82% |
合成路线1
该中间体在本合成路线中的序号：(B)N2-tert-Butyloxycarbonyl-N5-benzyloxycarbonyl-L-arginine (I) is cyclized by treatment with isobutyloxycarbonyl chloride and N-methylmorpholine to the lactam (II). The tert-butyloxycarbonyl group is removed by hydrochloric acid to give the aminolactam (III), which is coupled with N-benzyloxycarbonyl-D-phenylalanyl-L-proline (IV) using, as in the first step, the mixed anhydride method. The resulting tripeptide lactam (V) is reduced with LiAlH4 to an aldehyde, present as the cyclic alpha-aminoalcohol (VI). Deblocking by hydrogenolysis gives RGH-2958. In solution the aldehyde group is either in the cyclic alpha-aminoalcohol form or is hydrated.
| 【1】 Rabloczky, Gy.; Bagdy, D.; Bajusz, S.; RGH-2958. Drugs Fut 1985, 10, 10, 829. |
| 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) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (B) | 28928 | 4-methylmorpholine | 109-02-4 | C5H11NO | 详情 | 详情 |
| (I) | 29740 | N(5)-[[[(benzyloxy)carbonyl]amino](imino)methyl]-N(2)-(tert-butoxycarbonyl)ornithine | 51219-18-2 | C19H28N4O6 | 详情 | 详情 |
| (II) | 28933 | tert-butyl 1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinylcarbamate | C19H26N4O5 | 详情 | 详情 | |
| (III) | 28929 | benzyl (E)-amino(3-amino-2-oxo-1-piperidinyl)methylidenecarbamate | C14H18N4O3 | 详情 | 详情 | |
| (IV) | 29741 | (2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)-2-pyrrolidinecarboxylic acid | 7669-64-9 | C22H24N2O5 | 详情 | 详情 |
| (V) | 29742 | benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-oxo-1-piperidinyl]methylidenecarbamate | C36H40N6O7 | 详情 | 详情 | |
| (VI) | 29743 | benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-hydroxy-1-piperidinyl]methylidenecarbamate | C36H42N6O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(B)N2-tert-Butoxycarbonyl-N6-benzyloxycarbonyl-L-arginine (I) is converted by treatment with isobutyl oxycarbonyl chloride (A) and N-methylmorpholine (B) to the lactam (II), and the tert-butoxycarbonyl group is cleaved off to give the aminolactam (III), which is coupled with N-tert-butoxycarbonyl-D-phenylalanyl-L-proline (IV) to the tripeptide (V) using the mixed anhydride method as in the first step. The lactam carbonyl is reduced with LiAlH4 to an aldehyde group present as the cyclic a aminoalcohol (VI). Removal of the benzyloxycarbonyl blocking group provides GYKI-14451. In solution the aldehyde group is either in the cyclic alpha-aminoalcohol form or is hydrated.
| 【1】 Voutilainen, S.; Valkonen, V.P.; Venho, B.; et al.; Magy Kem Lapja 1982, 27, 2, 358-365. |
| 【2】 Bajusz, S.; Szell, E.; Barabas, E.; Bagdy, D. (Gedeon Richter Ltd.); D-Phenylalanyl-L-prolyl-L-arginine aldehyde sulfate and process for the preparation thereof. DE 3200812; FR 2497799; GB 2091270; JP 57181046; US 4399065; US 4478745 . |
| 【3】 Nogradi, M.; GYKI-14451. Drugs Fut 1985, 10, 1, 23. |
| 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) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (B) | 28928 | 4-methylmorpholine | 109-02-4 | C5H11NO | 详情 | 详情 |
| (I) | 28927 | tert-butyl 3-[(amino[[(benzyloxy)carbonyl]imino]methyl)amino]propylcarbamate | C17H26N4O4 | 详情 | 详情 | |
| (II) | 28933 | tert-butyl 1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinylcarbamate | C19H26N4O5 | 详情 | 详情 | |
| (III) | 28929 | benzyl (E)-amino(3-amino-2-oxo-1-piperidinyl)methylidenecarbamate | C14H18N4O3 | 详情 | 详情 | |
| (IV) | 28932 | (2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl]-2-pyrrolidinecarboxylic acid | C19H26N2O5 | 详情 | 详情 | |
| (V) | 28930 | tert-butyl (1R)-2-[(2S)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate | C33H42N6O7 | 详情 | 详情 | |
| (VI) | 28931 | tert-butyl (1R)-2-[(2S)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-hydroxy-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate | C33H44N6O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：Hydrogenation of (X) with H2 over Pd/C in acetic acid affords Nalpha-(N-acetylmuramoyl-L-alanyl-D-isoglutaminyl)-L-lysine (XI), which is finally condensed with N-hydroxynorbornene-2,3-dicarboxyimide ester of stearic acid (XII) by means of N-methylmorpholine in DMF.
| 【1】 Shiba, T.; Yamamura, Y.; Nagase, O.; Kotani, S.; Ogawa, H. (Daiichi Seiyaku Co.; Ltd.); Muramyldipeptide derivatives, process for preparing said compounds and pharmaceutical compositions containing said compounds. EP 0021367 . |
| 【2】 Robinson, C.P.; MUROCTASIN. Drugs Fut 1989, 14, 5, 432. |
| 【3】 Shiba, T.; Kusumoto, S.; Tarumi, Y.; Ikenaka, K.; Chemical synthesis of N-acetylmuramyl peptides with partial structures of bacterial cell wall and their analogs in relation to immunoadjuvant activities. 1976, 49(2): 533-9. Bull Chem Soc Jpn 1976, 49, 2, 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 |
|---|---|---|---|---|---|---|
| 28928 | 4-methylmorpholine | 109-02-4 | C5H11NO | 详情 | 详情 | |
| (X) | 20876 | benzyl 2-[[4-([2-[(2-[[3-(acetamido)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoyl]amino]-6-[[(benzyloxy)carbonyl]amino]hexanoate | C47H62N6O14 | 详情 | 详情 | |
| (XI) | 20877 | N(2)-[4-([2-[(2-[[3-(acetamido)-2,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoyl]lysine | C25H44N6O12 | 详情 | 详情 | |
| (XII) | 20878 | 4-(stearoyloxy)-4-azatricyclo[5.2.1.0(2,6)]dec-2(6)-ene-3,5-dione | C27H43NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(B)Compound can be prepared in two different ways: 1) By condensation of ampicilline (aminobenzylpenicilline) (I) with 1-chlorocarbonyl-2-oxo-3-mehylsulfonylimidazolidine (II) by means of NaOH in cool water or triethylamine in THF-water. 2) By condensation of 6-aminopenicillanic acid (III) with D-[(3-methylsulfonyl-2-oxoimidazolidin-1-yl)carbonylamino]phenylacetic acid (IV) by means of tetramethylchloroformamidinium chloride (A) and N-methylmorpholine (B) in methylene chloride - THF. The phenylacetic acid (IV) is obtained by condensation of D-phenylglycine (V) with 1-chlorocarbonyl-2-oxo-3-mehylsulfonylimidazolidine (II) by means of NaOH in dioxane - water. The acid chloride (II) is prepared by reaction of 2-imidazolidone (VI) with methanesulfonyl chloride (VII) in refluxing THF to give N-methylsulfonyl-2-imidazolidone (VIII), which is then condensed with phosgene by means of trimethylchlorosilane and triethylamine in dioxane.
| 【1】 Koenig, H.B.; et al.; Penicillin compounds their production and their medicinal use. DE 2152968; FR 2157909; GB 1392850; JP 48049788; JP 48049911 . |
| 【2】 Koenig, H.B.; et al.; Penicillins their production and their medicinal use. DE 2152967; FR 2157908; GB 1392849; JP 48049787; JP 48049910 . |
| 【3】 Schroeck, W.; et al.; Penicillanic acids their production and their medicinal use. DE 2318955; ES 425197; FR 2225151; GB 1465355; JP 49135990 . |
| 【4】 Playle, A.C.; Castañer, J.; Mezlocillin. Drugs Fut 1977, 2, 9, 600. |
| 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) | 28928 | 4-methylmorpholine | 109-02-4 | C5H11NO | 详情 | 详情 |
| (A) | 40169 | N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride | C5H12Cl2N2 | 详情 | 详情 | |
| (I) | 31107 | (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | 69-53-4 | C16H19N3O4S | 详情 | 详情 |
| (II) | 40167 | 3-(methylsulfonyl)-2-oxo-1-imidazolidinecarbonyl chloride | 41762-76-9 | C5H7ClN2O4S | 详情 | 详情 |
| (III) | 32631 | (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (+)-6-Aminopenicillanic acid; 6-APA | 551-16-6 | C8H12N2O3S | 详情 | 详情 |
| (IV) | 40168 | (2R)-2-([[3-(methylsulfonyl)-2-oxo-1-imidazolidinyl]carbonyl]amino)-2-phenylethanoic acid | C13H15N3O6S | 详情 | 详情 | |
| (V) | 40170 | (2R)-2-amino-2-phenylethanoic acid | C8H9NO2 | 详情 | 详情 | |
| (VI) | 36228 | 2-imidazolidinone | 120-93-4 | C3H6N2O | 详情 | 详情 |
| (VII) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (VIII) | 36229 | 1-(methylsulfonyl)-2-imidazolidinone | 41730-79-4 | C4H8N2O3S | 详情 | 详情 |