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【结 构 式】 
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【分子编号】26649 【品名】tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate 【CA登记号】 |
【 分 子 式 】C11H22N2O3 【 分 子 量 】230.30736 【元素组成】C 57.37% H 9.63% N 12.16% O 20.84% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of 2,6-dichloropyridine (I) with BuLi and CO2 in THF gives 2,6-dichloropyridine-3-carboxylic acid (II) (1), which by reaction with refluxing SOCl2 yields the acyl chloride (III). The reaction of (III) with malonic ester by means of magnesium ethoxide in ethyl ether affords the nicotinoylacetic ester (IV), which is condensed with thiazol-2-amine (V) and triethylorthoformate by means of acetic anhydride providing the nicotinoyl acrylate (VI). The cyclization of (VI) by means of K2CO3 in hot dioxane gives the 7-chloro-4-oxo-1-(2-thiazolyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (VII), which is condensed with the chiral pyrrolidine (VIII) by means of triethylamine yielding the proteted intermediate (IX). Finally, this compound is deprotected and hydrolyzed with hot aqueous HCl.
| 【1】 Tomita, K.; et al.; Synthesis and antitumor activity of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 249. |
| 【2】 Tomita, K.; Chiba, K.; Kashimoto, S.; Shibamori, K.; Tsuzuki, Y. (Dainippon Pharmaceutical Co., Ltd.); Novel cpd., process for producing the same, and antitumor agent. EP 0787726; US 5817669; WO 9534559 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 | |
| (I) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 26644 | 2,6-dichloronicotinic acid | 38496-18-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (III) | 26645 | 2,6-dichloronicotinoyl chloride | C6H2Cl3NO | 详情 | 详情 | |
| (IV) | 26646 | ethyl 3-(2,6-dichloro-3-pyridinyl)-3-oxopropanoate | C10H9Cl2NO3 | 详情 | 详情 | |
| (V) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (VI) | 26647 | ethyl (Z)-2-[(2,6-dichloro-3-pyridinyl)carbonyl]-3-(1,3-thiazol-2-ylamino)-2-propenoate | C14H11Cl2N3O3S | 详情 | 详情 | |
| (VII) | 26648 | ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C14H10ClN3O3S | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (IX) | 26650 | ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C25H31N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The chiral intermediate, the pyrrolidine (VIII) has been obtained as follows: The optical resolution of (trans)-3-amino-1-benzyl-4-methoxypyrroloidine (rac)-(X) with D-tartaric acid gives the enathiomer (S,S)(XI), which is treated with tert-butoxycarbonyl anhydride in methanol to yield the carbamate (XII). The reduction of (XII) with LiAlH4 in THF followed by reprotection with tert-butoxycarbonyl anhydride in dichloromethane affords (S,S)-1-benzyl-3-[N-(tert-butoxycarbonyl)-N-methylamino]-4-methoxypyrrolidine (XIII), which is finally debenzylated to the target compound (VIII) by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Tomita, K.; Chiba, K.; Kashimoto, S.; Shibamori, K.; Tsuzuki, Y. (Dainippon Pharmaceutical Co., Ltd.); Novel cpd., process for producing the same, and antitumor agent. EP 0787726; US 5817669; WO 9534559 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (X) | 26651 | (3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine | C12H18N2O | 详情 | 详情 | |
| (XI) | 26651 | (3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine | C12H18N2O | 详情 | 详情 | |
| (XII) | 26652 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate | C17H26N2O3 | 详情 | 详情 | |
| (XIII) | 26653 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinyl(methyl)carbamate | C18H28N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Treatment of 2,6-dichloropyridine (I) with butyllithium in THF followed by quenching with CO2 affords 2,6-dichloronicotinic acid (II) . After chlorination with boiling SOCl2, the resulting acid chloride (IIIa) is condensed with diethyl malonate by means of magnesium ethoxide in Et2O to give the nicotinoyl acetate (IV) . Alternatively, activation of 2,6-dichloronicotinic acid (II) with CDI provides imidazolide (IIIb) which, without isolation, is condensed with the potassium salt of diethyl malonate in the presence of MgCl2 and Et3N to yield the keto ester (IV) . Treatment of compound (IV) with triethylorthoformate and acetic anhydride followed by reaction with 2-aminothiazole (V) gives the enamino ester (VI), which is cyclized to the 1,8-naphthyridine derivative (VII) upon heating with K2CO3 in dioxane . Condensation of chloronaphthyridine (VII) with the chiral pyrrolidine (VIII) by means of triethylamine in acetonitrile yields the protected voreloxin (IX), which is finally hydrolyzed with hot aqueous HCl . In a related method, chloronaphthyridine (VII) is coupled with the unprotected pyrrolidine (X) to afford voreloxin ethyl ester (XI), which is finally hydrolyzed with NaOH in H2O/EtOH .
| 【1】 Tomita, K. et al. Synthesis and antitumor activity of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids. 217th ACS Natl Meet (March 21-25, Anaheim) 1999, Abst MEDI 249. |
| 【2】 Tomita, K., Chiba, K., Kashimoto, S., Shibamori, K., Tsuzuki, Y. (Dainippon Sumitomo Pharma Co., Ltd.). Novel compound, process for producing the same, and antitumor agent. EP 0787726, US 5817669, WO 1995034559. |
| 【3】 Tsuzuki, Y., Tomita, K., Shibamori, K.-I., Sato, Y., Kashimoto, S., Chiba, K. Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 2. J Med Chem 2004, 47(8): 2097-109. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 26645 | 2,6-dichloronicotinoyl chloride | C6H2Cl3NO | 详情 | 详情 | |
| (I) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 26644 | 2,6-dichloronicotinic acid | 38496-18-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (IV) | 26646 | ethyl 3-(2,6-dichloro-3-pyridinyl)-3-oxopropanoate | C10H9Cl2NO3 | 详情 | 详情 | |
| (V) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (VI) | 26647 | ethyl (Z)-2-[(2,6-dichloro-3-pyridinyl)carbonyl]-3-(1,3-thiazol-2-ylamino)-2-propenoate | C14H11Cl2N3O3S | 详情 | 详情 | |
| (VII) | 26648 | ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C14H10ClN3O3S | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (IX) | 26650 | ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C25H31N5O6S | 详情 | 详情 | |
| (X) | 69211 | (3S,4S)-4-methoxy-N-methylpyrrolidin-3-amine compound with 1-methyl-4-(methylsulfonyl)benzene (1:2) | C6H14N2O.2C8H10O2S | 详情 | 详情 | |
| (XI) | 69210 | ethyl 7-((3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl)-4-oxo-1-(thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate | C20H23N5O4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Protection of 3-pyrroline (XII) with Boc2O in MeOH followed by oxidation of the resulting N-Boc-pyrroline (XIII) with m-CPBA in CH2Cl2 provides epoxide (XIV), which is also alternatively prepared by reaction of 1-Boc-3-pyrroline (XIII) with NBS in aqueous DMSO and subsequent cyclization of the obtained bromohydrin (XV) in 1 N NaOH. A further method to prepare pyrroline (XIII) is by condensation of cis-1,4-dichloro-2-butene (XVI) with tert-butyl carbamate in the presence of NaH in dry DMF. Ring opening of epoxide (XIV) with NaN3 in dioxane/H2O leads to the trans-azidoalcohol (XVII), which is alkylated with iodomethane and NaH in THF to give the methyl ether (XVIII). After catalytic hydrogenation of azide (XVIII) over Pd/C, the N-Boc protecting group in the resulting amine (XIX) is replaced with a benzyl group by acidic hydrolysis followed by alkylation with benzyl chloride and Et3N to give the protected pyrrolidine (XX) . Optical resolution of racemic trans-3-amino-1-benzyl-4-methoxypyrrolidine (XX) using D-(+)-tartaric acid provides the target (S,S)-enantiomer, which is then protected as the tert-butyl carbamate (XXI) by treatment with Boc2O in MeOH. Subsequent reduction of carbamate (XXI) with LiAlH4 in THF followed by reprotection of the resulting Nmethylamine with Boc2O in CH2Cl2 provides compound (XXII), which is finally debenzylated by catalytic hydrogenation over Pd/C in EtOH to the desired pyrrolidine (VIII) .
Epoxide (XIV) is converted to the aminopyrrolidine (X) by two additional strategies. Ring opening of epoxide (XIV) with aqueous methylamine yields the racemic trans-aminoalcohol (XXIII), which is resolved by acylation with N-Boc-L-phenylalanine and EDC in CH2Cl2 followed by separation of the diastereomers by column chromatography. Hydrolysis of the desired diastereomer (XXIV) with 20% NaOH in EtOH affords the (S,S)-enantiomer of amino alcohol (XXIII), which is protected as the bis-carbamate (XXV) using Boc2O in MeOH. Finally, methylation of alcohol (XXV) with iodomethane and NaH in DMF, followed by removal of both Boc groups with p-TsOH in i-PrOH provides the target (S,S)-3-methoxy-4-(methylamino)pyrrolidine ditosylate (X) .
Alternatively, reaction of epoxide (XIV) with benzylamine provides the racemic amino alcohol (XXVI), which can be resolved by recrystallization of the diastereoisomeric salts with (+)-mandelic acid in acetonitrile/water. Subsequent debenzylation of the target enantiomer with H2 and Pd/C in BuOH provides the (S,S)-amino alcohol (XXVII). Protection of the primary amino group of compound (XXVII) with Boc2O in EtOH gives the bis-carbamate (XXVIII), which is finally submitted to N,O-dialkylation with iodomethane and NaH, followed by Boc group cleavage with p-TsOH in THF/MeOH to yield the key intermediate (X) .
| 【1】 Tomita, K., Chiba, K., Kashimoto, S., Shibamori, K., Tsuzuki, Y. (Dainippon Sumitomo Pharma Co., Ltd.). Novel compound, process for producing the same, and antitumor agent. EP 0787726, US 5817669, WO 1995034559. |
| 【2】 Tsuzuki, Y., Chiba, K., Mizuno, K., Tomita, K., Suzuki, K. Practical synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine. Tetrahedron Asymmetry 2001, 12(21): 2989-97. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （LVIV） | 69218 | (S,S)-tert-butyl 3-hydroxy-4-(methylamino)pyrrolidine-1-carboxylate | C10H20N2O3 | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (X) | 69211 | (3S,4S)-4-methoxy-N-methylpyrrolidin-3-amine compound with 1-methyl-4-(methylsulfonyl)benzene (1:2) | C6H14N2O.2C8H10O2S | 详情 | 详情 | |
| (XII) | 22833 | 2,5-dihydro-1H-pyrrole;3-Pyrroline | 109-96-6 | C4H7N | 详情 | 详情 |
| (XIII) | 22834 | 2,5-Dihydro-1H-pyrrole-1-carboxylic acid 1,1-d;2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester;tert-Butyl 2H-pyrrole-1(5H)-carboxylate;1-tert-Butoxycarbonylpyrroline;tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 73286-70-1 | C9H15NO2 | 详情 | 详情 |
| (XIV) | 22835 | tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C9H15NO3 | 详情 | 详情 | |
| (XV) | 69212 | (3S,4R)-tert-butyl 3-bromo-4-hydroxypyrrolidine-1-carboxylate | C9H16BrNO3 | 详情 | 详情 | |
| (XVI) | 50004 | cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene | 1476-11-5 | C4H6Cl2 | 详情 | 详情 |
| (XVII) | 69213 | (3S,4S)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate | C9H16N4O3 | 详情 | 详情 | |
| (XVIII) | 69214 | (3S,4S)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate | 429673-78-9 | C10H18N4O3 | 详情 | 详情 |
| (XIX) | 69215 | (3S,4S)-tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate | 429673-79-0 | C10H20N2O3 | 详情 | 详情 |
| (XX) | 26651 | (3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine | C12H18N2O | 详情 | 详情 | |
| (XXI) | 26652 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate | C17H26N2O3 | 详情 | 详情 | |
| (XXII) | 26653 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinyl(methyl)carbamate | C18H28N2O3 | 详情 | 详情 | |
| (XXIII) | 69216 | rac-tert-butyl 3-hydroxy-4-(methylamino)pyrrolidine-1-carboxylate | C10H20N2O3 | 详情 | 详情 | |
| (XXIV) | 69217 | (3S,4S)-tert-butyl 3-((S)-2-((tert-butoxycarbonyl)amino)-N-methyl-3-phenylpropanamido)-4-hydroxypyrrolidine-1-carboxylate | C24H37N3O6 | 详情 | 详情 | |
| (XXV) | 69219 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 | |
| (XXVI) | 69220 | (3S,4S)-tert-butyl 3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate | 252574-03-1 | C16H24N2O3 | 详情 | 详情 |
| (XXVII) | 22837 | tert-butyl (3S,4S)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate | 190792-74-6 | C9H18N2O3 | 详情 | 详情 |
| (XXVIII) | 69221 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C14H26N2O5 | 详情 | 详情 |