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【结 构 式】 
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【分子编号】15983 【品名】1H-pyrazole-1-carboximidamide 【CA登记号】4023-00-1 |
【 分 子 式 】C4H6N4 【 分 子 量 】110.1186 【元素组成】C 43.63% H 5.49% N 50.88% |
合成路线1
该中间体在本合成路线中的序号：(IX)1) The esterification of N-acetylneuraminic acid (I) with methanol/HCl gives the corresponding methyl ester (II), which is acetylated with acetic anhydride, pyridine and dimethylaminopyridine (DMAP) yielding the pentaacetate (III). The reaction of (III) with trimethylsilyl trifluoromethanesulfonate in ethyl acetate affords the 2,3-didehydro derivative (IV), which is treated with trimethylsilyl azide in butanol to give the 4-azido derivative (V). The selective deacetylation of (V) with sodium methoxide in methanol yields N-acetyl-4-azido-2,4-dideoxy-2,3-didehydroneuraminic acid methyl ester (VI), which is reduced with H2 over Lindlar catalyst (Pd-Pb) in water and treated with Dowex 8x2 resin to afford the N-acetyl-4-amino-2,4-dideoxy-2,3-didehydroneuraminic acid (VII). The reaction of (VII) with BrCN and sodium acetate in methanol gives the corresponding 4-cyanoamino derivative (VIII), which is converted into the final product by reaction with ammonium formate in aqueous NH4OH. 2) The amino derivative (VII) can be converted directly into the final product by reaction with amidinosulfonic acid (X), NaOH and K2CO3 in water. 3) The amino derivative (VII) can also be converted directly into the final product by reaction with pyrazole-1-carboxamidine (XI) and triethylamine in water.
| 【1】 Chandler, M.; Bamford, M.J.; Conroy, R.; et al.; Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-Ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-gluco-nononic acid. J Chem Soc - Perkins Trans I 1995, 9, 7, 1173-80. |
| 【2】 von Itzstein, M.; Wu, W.-Y.; Jin, B.; The synthesis of 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid: A potent influenza virus sialidase inhibitor. Carbohydr Res 1994, 259, 2, 301-5. |
| 【3】 Fromtling, R.; Castaner, J.; Zanamivir. Drugs Fut 1996, 21, 4, 375. |
| 【4】 Weir, N.G.; Chandler, M.; Bamford, M.J. (Glaxo Wellcome plc); Synthesis of N-acetyl neuraminic acid derivs. WO 9407885 . |
| 【5】 Patel, V. (Glaxo Wellcome plc); Synthesis of N-acetyl neuraminic acid derivs. WO 9407886 . |
| 【6】 Chandler, M.; Weir, N. (Glaxo Wellcome plc); Preparation of N-acetyl neuraminic derivs. WO 9312105 . |
| 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) | 15975 | (2S,4S,5R,6R)-5-(acetamido)-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydro-2H-pyran-2-carboxylic acid | 131-48-6 | C11H19NO9 | 详情 | 详情 |
| (II) | 15976 | methyl (2S,4S,5R,6R)-5-(acetamido)-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydro-2H-pyran-2-carboxylate | 50998-13-5 | C12H21NO9 | 详情 | 详情 |
| (III) | 15977 | methyl (2R,4S,5S,6R)-5-(acetamido)-2,4-bis(acetoxy)-6-[(1S,2R)-1,2,3-tris(acetoxy)propyl]tetrahydro-2H-pyran-2-carboxylate | C22H31NO14 | 详情 | 详情 | |
| (IV) | 15978 | methyl (3aS,4R,7aR)-2-methyl-4-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate | C18H23NO10 | 详情 | 详情 | |
| (V) | 15979 | methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C18H24N4O10 | 详情 | 详情 | |
| (VI) | 15980 | methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate | C12H18N4O7 | 详情 | 详情 | |
| (VII) | 15981 | (2R,3R,4S)-3-(acetamido)-4-amino-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid | C11H18N2O7 | 详情 | 详情 | |
| (VIII) | 15982 | (2R,3R,4S)-3-(acetamido)-4-(cyanoamino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid | C12H17N3O7 | 详情 | 详情 | |
| (IX) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (X) | 15984 | amino(imino)methanesulfonic acid | CH4N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (I) with di-tert-butyl dicarbonate and triethylamine in dichloromethane gives 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (II), which is condensed with 2-(4-benzyloxyphenyl)-2-chloroacetic acid ethyl ester (III) (obtained by chlorination of 2-(4-benzyloxyphenyl)acetic acid ethyl ester (IV) with PCl5), by means of K2CO3 in refluxing acetonitrile yields the disubstituted acetate (V). The selective debenzylation of (V) with H2 over Pd/C in ethyl acetate affords the phenol (VI), which is alkylated with 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (VII) by means of diethyl azodicarboxylate (AZE) and triphenyl phosphine providing the protected intermediate (VIII). The deprotection of (VIII) with HCl in ethanol gives intermediate (IX) with two free NH groups, which is treated with pyrazole-1-carboxamidine (X) and diisopropylethylamine (DIEA) in DMF yielding the bis amidino derivative (XI), which is finally hydrolyzed with NaOH in ethanol/water.
| 【1】 Kucznierz, R.; Von der Saal, W.; Leinert, H.; Grams, F.; Stegmeier, K. (Roche Diagnostics GmbH); New cyclic guanidines, process for preparing the same and medicaments. DE 19530996; EP 0846115; JP 1999511445; WO 9708165 . |
| 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) | 28634 | 1,2,3,4-tetrahydro-7-isoquinolinol | C9H11NO | 详情 | 详情 | |
| (II) | 28635 | tert-butyl 7-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C14H19NO3 | 详情 | 详情 | |
| (III) | 28636 | ethyl 2-[4-(benzyloxy)phenyl]-2-chloroacetate | C17H17ClO3 | 详情 | 详情 | |
| (IV) | 28637 | Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate | C17H18O3 | 详情 | 详情 | |
| (V) | 28638 | tert-butyl 7-[1-[4-(benzyloxy)phenyl]-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C31H35NO6 | 详情 | 详情 | |
| (VI) | 28639 | tert-butyl 7-[2-ethoxy-1-(4-hydroxyphenyl)-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C24H29NO6 | 详情 | 详情 | |
| (VII) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VIII) | 28640 | tert-butyl 7-[1-(4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]phenyl)-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C34H46N2O8 | 详情 | 详情 | |
| (IX) | 28641 | ethyl 2-[4-(4-piperidinyloxy)phenyl]-2-(1,2,3,4-tetrahydro-7-isoquinolinyloxy)acetate | C24H30N2O4 | 详情 | 详情 | |
| (X) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (XI) | 28642 | ethyl 2-[4-([1-[amino(imino)methyl]-4-piperidinyl]oxy)phenyl]-2-([2-[amino(imino)methyl]-1,2,3,4-tetrahydro-7-isoquinolinyl]oxy)acetate | C26H34N6O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The stereospecific synthesis of BCX-1812(RWJ-270201) has been reported: Ring opening of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA yielding the carbamate (III). Cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) and other isomers. Compound (V) is isolated from the mixture and then hydrogenated with H2 over PtO2 in MeOH and a catalytic amount of HCl to provide amine (VI). Reaction of (VI) with acetic anhydride gives the acetamide (VII), which is Boc-deprotected with ethereal HCl yielding amine (VIII). The guanylation of (VIII) with pyrazolecarboxamidine hydrochloride (IX) and DIEA affords the guanidino derivative (X), which is finally hydrolyzed with NaOH to the desired (1S,2S,3R,4R,1'S)-diastereomer.
| 【1】 Babu, Y.S.; Chad, P.; Bantia, S.; et al.; BCX-1812 (RWJ-270201): Discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J Med Chem 2000, 43, 19, 3482. |
| 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) | 33410 | cis-2-azabicyclo[2.2.1]hept-5-en-3-one | C6H7NO | 详情 | 详情 | |
| (II) | 33412 | methyl cis-4-amino-2-cyclopentene-1-carboxylate | C7H11NO2 | 详情 | 详情 | |
| (III) | 33413 | methyl cis-4-[(tert-butoxycarbonyl)amino]-2-cyclopentene-1-carboxylate | C12H19NO4 | 详情 | 详情 | |
| (IV) | 33414 | 3-(nitromethyl)pentane | C6H13NO2 | 详情 | 详情 | |
| (V) | 33415 | methyl (3aR*,4R*,6S*,6aS*)-4-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-6-carboxylate | C18H30N2O5 | 详情 | 详情 | |
| (VI) | 45760 | methyl (1S,2S,3S,4R)-3-[(1S)-1-amino-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate | C18H34N2O5 | 详情 | 详情 | |
| (VII) | 45761 | methyl (1S,2S,3S,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate | C20H36N2O6 | 详情 | 详情 | |
| (VIII) | 45762 | methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-amino-2-hydroxycyclopentanecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (IX) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (X) | 45763 | methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-[[amino(imino)methyl]amino]-2-hydroxycyclopentanecarboxylate | C16H30N4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Condensation of 2-chloro-5-cyanopyridine (V) with ethylenediamine (VI) yields the N-pyridyl ethylenediamine (VII). Subsequent reaction of amine (VII) with pyrazole-1-carboxyamidine (VIII) in refluxing acetonitrile affords guanidine (IX). Finally, condensation between guanidine (IX) and enaminone (IV) in the presence of NaOEt produces the title pyrimidine derivative
| 【1】 Brown, S.P.; Goff, D.; Ring, D.B.; Harrison, S.D.; Subramanian, S.; Nuss, J.M.; Boyce, R.S.; Johnson, K.; Pfister, K.B.; Ramurthy, S.; Renhowe, P.A.; Seely, L.; Wagman, A.S.; Zhou, X.A. (Chiron Corp.); Inhibitors of glycogen synthase kinase 3. EP 1087963; US 6417185; WO 9965897 . |
| 【2】 Ring, D.B.; Harrison, S.D.; Nuss, J.M.; Boyce, R.S.; Johnson, K.; Pfister, K.B.; Ramurthy, S.; Seely, L.; Wagman, A.S.; Desai, M.; Levine, B.H. (Chiron Corp.); Inhibitors of glycogen synthase kinase 3. WO 0220495 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 60242 | 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(4-methyl-1H-imidazol-2-yl)-2-propen-1-one | C15H15Cl2N3O | 详情 | 详情 | |
| (V) | 57164 | 2-Chloro-5-cyanopyridine; 6-Chloro-3-cyanopyridine; 6-Chloronicotinonitrile | 33252-28-7 | C6H3ClN2 | 详情 | 详情 |
| (VI) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VII) | 54332 | 6-[(2-aminoethyl)amino]nicotinonitrile | n/a | C8H10N4 | 详情 | 详情 |
| (VIII) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (IX) | 60243 | N-{2-[(5-cyano-2-pyridinyl)amino]ethyl}guanidine | C9H12N6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)Treatment of beta-alanine (I) with phthalic anhydride (II) in refluxing toluene provides phthalimidopropionic acid (III), which upon cyclocondensation with 2-aminophenol (IV) in hot polyphosphoric acid provides the benzoxazole derivative (V). Hydrazinolysis of phthalimide (V) affords the primary amine (VI), which is finally condensed with pyrazole-1-carboxamidine hydrochloride (VII) in DMF to produce the target guanidine compound.
| 【1】 López-Tudanca, P.; Labeaga, L.; Innerárity, A.; Alonso-Cires, L.; Tapia, I.; Mosquera, R.; Orjales, A.; Synthesis and pharmacological characterization of a new benzoxazole derivative as a potent 5-HT3 receptor agonist. Bioorg Med Chem 2003, 11, 13, 2709. |
| 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) | 17022 | beta-Alanine; 3-aminopropionic acid | 107-95-9 | C3H7NO2 | 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) | 53389 | 3-Phthalimidopropionic acid; Phthalyl-beta-alanine | 3339-73-9 | C11H9NO4 | 详情 | 详情 |
| (IV) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (V) | 64846 | 2-[2-(1,3-benzoxazol-2-yl)ethyl]-1H-isoindole-1,3(2H)-dione | C17H12N2O3 | 详情 | 详情 | |
| (VI) | 64847 | 2-(1,3-benzoxazol-2-yl)-1-ethanamine; 2-(1,3-benzoxazol-2-yl)ethylamine | C9H10N2O | 详情 | 详情 | |
| (VII) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIV)Condensation of amine (I) with N,N’-di-Boc-thiourea (II) using HgCl2 and Et3N in DMF (1) or with di-Boc-amidinopyrazole (III) in THF gives the protected guanidine derivative (IV), which by deacetylation with methanolic sodium methoxide followed by saponification of the deacylated methyl pyranosoate (V) leads to the carboxylic acid (VI). Alternatively, acid (VI) is prepared by direct hydrolysis of compound (IV) by means of aqueous NaOH or K2CO3 in H2O/MeOH. After conversion of acid (VI) to the corresponding benzhydryl ester (VII) by treatment with diphenyldiazomethane and BF3·Et2O, selective acylation of the primary hydroxyl group with octanoyl chloride (VIII) and Et3N in CH2Cl2 yields the 9-octanoate ester (IX) (1). Finally, compound (IX) is deprotected by removal of N-Boc and O-benzhydryl protecting groups by treatment with trifluoroacetic acid in CH2Cl2, followed by basification of the obtained TFA salt with NaHCO3 (2-8). Scheme 1.
Alternatively, reaction of the 4-amino-5,6-dihydropyran derivative (X) with di-Boc-amidinopyrazole (III) provides the corresponding 4-guanidinodihydropyran, which is hydrolyzed with K2CO3 in MeOH/H2O to give carboxylic acid (VI). In an alternative strategy, carboxylic acid (VI) is prepared by hydrolysis of the 4-amino-5,6-dihydropyrancarboxylate ester (X) with NaOH followed by reaction with the amidinopyrazole derivative (III). Deprotection of di-Boc intermediate (VI) by stirring at 80 °C in MeOH gives laninamivir (XI), which is finally selectively acylated with trimethyl orthooctanoate (XII) in the presence of methanolic HCl. Laninamivir (XI) can also be obtained by hydrolysis of intermediate (X) with NaOH followed by reaction of the resulting free amine (XIII) with pyrazole-1-carboxamidine HCl (XIV) or, alternatively, by treatment of 4-amino-5,6-dihydropyran (X) with pyrazole-1-carboxamidine HCl (XIV), and then hydrolysis of the methyl ester with K2CO3 in MeOH (3). Scheme 1.
| 【1】 Honda, T., Kobayashi, Y., Masuda, T., Yamashita, M., Arai, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. EP 0823428, JP 1998330373, JP 1999279059, JP 199927968. |
| 【2】 Murakami, M., Yamaoka, M., Honda, T., Watanabe, M. (Daiichi Sankyo Co., Ltd.). Hydrates and crystals of a neuraminic acid compound. EP 1277759, US 2003105158, US 6844363, WO 200108131. |
| 【3】 Nakamura, Y., Murakami, M., Yamaoka, M., Wakayama, M., Umeo, K. (Daiichi Sankyo Co., Ltd.). Method for manufacturing neuraminic acid derivatives. EP 2132191, JP 2010523472, WO 2008126943. |
| 【4】 Honda, T., Kubo, S., Masuda, T., Arai, M., Kobayashi, Y., Yamashita, M. Synthesis and in vivo influenza-inhibitory effect of ester prodrug of 4-guanadino-7-O-methyl-Neu5Ac2en. Bioorg Med Chem Lett 2009, 19(11): 2938-40. |
| 【5】 Honda, T., Masuda, T. Synthesis of 4-guanidino-7-modified-neu5Ac2en derivatives and their biological activities as influenza sialidase inhibitors. J Synth Org Chem Jpn 2009, 67(11): 1105. |
| 【6】 Yamashita, M., Kawaoka, Y. (University of Tokyo; Daiichi Sankyo Co., Ltd.). Drug for treatment of influenza. EP 2123271, WO 2008108323. |
| 【7】 Honda, T., Arai, M., Yamashita, M., Masuda, T., Kobayashi, Y. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 6340702. |
| 【8】 Kobayashi, Y., Honda, T., Yamashita, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 2002137791, US 6451766. |
| 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) | 65992 | C17H26N2O9 | 详情 | 详情 | ||
| (II) | 21843 | tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate | 145013-05-4 | C11H20N2O4S | 详情 | 详情 |
| (III) | 29482 | N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate | 152120-54-2 | C14H22N4O4 | 详情 | 详情 |
| (IV) | 65993 | C27H44N4O13 | 详情 | 详情 | ||
| (V) | 65994 | C23H40N4O11 | 详情 | 详情 | ||
| (VI) | 65995 | C22H38N4O11 | 详情 | 详情 | ||
| (VII) | 65996 | C35H48N4O11 | 详情 | 详情 | ||
| (VIII) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (IX) | 65997 | C43H62N4O12 | 详情 | 详情 | ||
| (X) | 65998 | C14H20N2O8 | 详情 | 详情 | ||
| (XI) | 65999 | Laninamivir; (4S,5R,6R)-5-Acetamido-4-guanidino-6-((1R,2R)-2,3-dihydroxy-1-methoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid | 203120-17-6 | C13H22N4O7 | 详情 | 详情 |
| (XII) | 66000 | trimethyl orthooctanoate; 1,1,1-Trimethoxyoctane | 161838-87-5 | C11H24O3 | 详情 | 详情 |
| (XIII) | 66001 | (4S,5R,6R)-5-acetylamino-4-amino-6-[(1R,2R)-2,3-dihydroxy-1-methoxy-propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid | 475483-21-7 | C12H20N2O7 | 详情 | 详情 |
| (XIV) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIV)Intermediates (III) and (XII) are prepared as follows:
Trimethyl orthooctanoate (XII) is prepared by Pinner reaction of octanonitrile (XXXVII) with MeOH in the presence of HCl in MeOAc followed by treatment of the resulting methyl octanimidate hydrochloride (XXXVIII) with MeOH in methylcyclohexane (3). Scheme 5.
Intermediate (III) can be prepared by consecutive N-protection of the amidine nitrogens in pyrazole-1-carboxamidine (XIV), first by treatment with Boc2O by means of DIEA in DMF, and then reaction of the resulting monoprotected intermediate (XXXIX) with Boc2O in the presence of NaH in THF (3). Scheme 5.
| 【3】 Nakamura, Y., Murakami, M., Yamaoka, M., Wakayama, M., Umeo, K. (Daiichi Sankyo Co., Ltd.). Method for manufacturing neuraminic acid derivatives. EP 2132191, JP 2010523472, WO 2008126943. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 52079 | sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate | 627076-29-3 | C6H6NNaO3 | 详情 | 详情 |
| (XII) | 66000 | trimethyl orthooctanoate; 1,1,1-Trimethoxyoctane | 161838-87-5 | C11H24O3 | 详情 | 详情 |
| (XIV) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (XXXVII) | 59081 | octanenitrile | 124-12-9 | C8H15N | 详情 | 详情 |
| (XXXVIII) | 66024 | C9H19NO.HCl | 详情 | 详情 | ||
| (XXXIX) | 66025 | N-(tert-Butoxycarbonyl)-1H-pyrazole-1-carboxamidine; N-Boc-1H-pyrazole-1-carboxamidine | 152120-61-1 | C9H14N4O2 | 详情 | 详情 |