合成路线1
该中间体在本合成路线中的序号:
(IV) The two enantiomers of amlodipine have been obtained as follows:
The reaction of 2-azidoethanol (I) with chloroacetic acid (II) by means of NaH in THF gives 2-(2-azidoethoxy)acetic acid (III), which is condensed with Meldrum's acid (IV) and 3-hydroxypropionitrile (V) in dichloromethane to yield the 2-cyanoethyl acetoacetate (VI). The cyclization of (VI) with 2-chlorobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing ethanol affords the dihydropyridine (IX), which is selectively hydrolyzed at the 2-cyanoethylester with NaOH to give the dihydropyridine monocarboxylic acid (X). The esterification of (X) with (S)-2-methoxy-2-phenylethanol (XI) by means of CDI in dichloromethane provides the ester (XII) as a diastereomeric mixture, which is separated by chromatography to furnish diastereomers (XXI A) and (XII B). The selective ethanolysis of (XII A) and (XII B) with sodium ethoxide in refluxing ethanol/diglyme gives enantiomers (+)-(XIII) and (-)-(XIII), which are finally reduced with H2 over Pd/CaCO3 in ethanol to afford the (-)- and (+)-isomers, respectively, of the target compound.
【1】
Arrowsmith, J.E.; et al.; Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J Med Chem 1986, 29, 9, 1696.
|
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) |
24111 |
2-azido-1-ethanol
|
|
C2H5N3O |
详情 |
详情
|
(II) |
11847 |
2-Chloroacetic acid; Chloroacetic Acid
|
79-11-8 |
C2H3ClO2 |
详情 | 详情
|
(III) |
48263 |
2-(2-azidoethoxy)acetic acid
|
|
C4H7N3O3 |
详情 |
详情
|
(IV) |
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) |
14029 |
Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile
|
109-78-4 |
C3H5NO |
详情 | 详情
|
(VI) |
48264 |
2-cyanoethyl 4-(2-azidoethoxy)-3-oxobutanoate
|
|
C9H12N4O4 |
详情 |
详情
|
(VII) |
24114 |
2-chlorobenzaldehyde
|
89-98-5 |
C7H5ClO |
详情 | 详情
|
(VIII) |
11372 |
Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate
|
|
C5H9NO2 |
详情 |
详情
|
(IX) |
48265 |
3-(2-cyanoethyl) 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate
|
|
C21H22ClN5O5 |
详情 |
详情
|
(X) |
48266 |
2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-3-pyridinecarboxylic acid
|
|
C18H19ClN4O5 |
详情 |
详情
|
(XI) |
48267 |
(2S)-2-methoxy-2-phenyl-1-ethanol
|
66051-01-2 |
C9H12O2 |
详情 | 详情
|
(XII) |
48268 |
3-[(2S)-2-methoxy-2-phenylethyl] 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate
|
|
C27H29ClN4O6 |
详情 |
详情
|
(XIII) |
24115 |
3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate
|
|
C20H23ClN4O5 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(VII) By cyclocondensation of 3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde (I), isopropyl 3-aminocrotonate (II) and methyl 4-fluoroacetylacetate (III) by heating at 110 C.
The starting products are prepared as follows:
Aldehyde (I) is obtained by reaction of 1-chloro-4-fluoro-3-(trifluoromethyl)benzene (IV) with N-methyl-N-phenylformamide (V) by means of butyllithium in TNF.
Aminocrotonate (II) is obtained by reaction of isopropyl acetoacetate (VI) with dry ammonia in methanol. Finally, the acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione (VII) with fluoroacetyl chloride (VIII) by means of pyridine in dichloromethane gives 5-(fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (IX), which is then treated with refluxing methanol to give 4-fluoroacetylacetate (III).
【1】
Baxter, A.J.G.; Dixon, J.; Gould, K.J.; McInally, T.; Tinker, A.C. (Celltech Group plc); Pharmaceutically active dihydropyridines. EP 0125803 .
|
【2】
Baxter, A.J.G.; Dixon, J.; Gould, K.J.; Tinker, A.C. (Celltech Group plc); Dihydropyridine derivs.. EP 0174131; ES 8800154; ES 8801632; JP 1986065867 .
|
【3】
Prous, J.; Castaner, J.; FPL-62129XX. Drugs Fut 1989, 14, 2, 121.
|
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) |
20356 |
3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde
|
|
C8H3ClF4O |
详情 |
详情
|
(II) |
13331 |
isopropyl (E)-3-amino-2-butenoate
|
143093-33-8 |
C7H13NO2 |
详情 | 详情
|
(III) |
20358 |
methyl 4-fluoro-3-oxobutanoate
|
|
C5H7FO3 |
详情 |
详情
|
(IV) |
20359 |
1-chloro-4-fluoro-2-(trifluoromethyl)benzene
|
|
C7H3ClF4 |
详情 |
详情
|
(V) |
20360 |
methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline |
93-61-8 |
C8H9NO |
详情 | 详情
|
(VI) |
13332 |
isopropyl 3-oxobutanoate; Isopropyl acetoacetate
|
542-08-5 |
C7H12O3 |
详情 | 详情
|
(VII) |
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
|
(VIII) |
20363 |
2-fluoroacetyl chloride
|
359-06-8 |
C2H2ClFO |
详情 | 详情
|
(IX) |
20364 |
5-(2-fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
|
|
C8H9FO5 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(X) A synthesis of S-12968 has been published:
The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows:
The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.
【1】
Dolle, F.; et al.; Highly efficient synthesis of [11C]S12968 and [11C]S12967, for the in vivo imaging of the cardiac calcium channels using PET. J Label Compd Radiopharm 2001, 44, 7, 481.
|
【2】
Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749. |
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) |
14743 |
ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate
|
|
C18H21NO7 |
详情 |
详情
|
(II) |
14744 |
2-cyanoethyl (Z)-2-acetyl-3-(2,3-dichlorophenyl)-2-propenoate
|
|
C14H11Cl2NO3 |
详情 |
详情
|
(III) |
14745 |
5-(2-cyanoethyl) 3-ethyl 4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate
|
|
C32H31Cl2N3O8 |
详情 |
详情
|
(IV) |
14746 |
5-(2-cyanoethyl) 3-ethyl (4S)-4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate
|
|
C32H31Cl2N3O8 |
详情 |
详情
|
(V) |
14747 |
(4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid
|
|
C21H26Cl2N2O6 |
详情 |
详情
|
(X) |
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
|
(XIII) |
12273 |
5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione
|
|
C8H10O5 |
详情 |
详情
|
(XIV) |
14029 |
Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile
|
109-78-4 |
C3H5NO |
详情 | 详情
|
(XV) |
13993 |
2-cyanoethyl 3-oxobutanoate
|
|
C7H9NO3 |
详情 |
详情
|
(XVI) |
14742 |
2,3-dichlorobenzaldehyde
|
6334-18-5 |
C7H4Cl2O |
详情 | 详情
|
合成路线4
该中间体在本合成路线中的序号:
(X) The starting compound phthalimido derivative (I) could be obtained as follows:
The condensation of 2-[2-(2-chloroethoxy)ethoxy]ethanol (VI) with potassium phthalimide (VII) in refluxing DMF gives the expected phthalimido derivative (VIII), which is oxidized with the Jones reagent in acetone yielding 2-[2-(2-phthalimidoethoxy)ethoxy]acetic acid (IX). The condensation of (IX) with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (X) by means of carbonyldiimidazole (CDI) and pyridine in dichloromethane affords 2,2-dimethyl-5-[2-[2-(2-phthalimidoethoxy)ethoxy]acetyl]-1,3-dioxane-4,6-dione (XI), which is finally treated with refluxing ethanol to obtain the phthalimido derivative (I) used as starting material.
【1】
Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749. |
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) |
14743 |
ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate
|
|
C18H21NO7 |
详情 |
详情
|
(VI) |
14748 |
2-[2-(2-Chloroethoxy)ethoxy]-1-ethanol; 2-(2-(2-Chloroethoxy)ethoxy)ethanol
|
5197-62-6 |
C6H13ClO3 |
详情 | 详情
|
(VII) |
10926 |
(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium
|
|
C8H4KNO2 |
详情 |
详情
|
(VIII) |
14750 |
2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethyl]-1H-isoindole-1,3(2H)-dione
|
|
C14H17NO5 |
详情 |
详情
|
(IX) |
14751 |
2-[2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]acetic acid
|
|
C14H15NO6 |
详情 |
详情
|
(X) |
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
|
(XI) |
14752 |
2-(2-[2-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxoethoxy]ethoxy]ethyl)-1H-isoindole-1,3(2H)-dione
|
|
C20H21NO9 |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(V) 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.
【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6
该中间体在本合成路线中的序号:
(V) 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.
【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7
该中间体在本合成路线中的序号:
(V) 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.
【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8
该中间体在本合成路线中的序号:
(V) 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.
【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9
该中间体在本合成路线中的序号:
(II) The condensation of 6-chloro-5-methoxy-1H-indole (I) with Meldrum's acid (II) and acetaldehyde (III) catalyzed by L-proline in acetonitrile gives the adduct (IV), which is treated with Cu and ethanol in refluxing pyridine to yield 3-(6-chloro-5-methoxy-1H-indol-3-yl)butyric acid ethyl ester (V). The reaction of (V) with hydrazine at 140 C affords the hydrazide (VI), which is treated with NaNO2 and Ac-OH to provide the corresponding azide that, without isolation, is thermolyzed and rearranged in toluene at 80?C to give 7-chloro-6-methoxy-4-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (VII). The cleavage of the lactam ring of (VII) with KOH in refluxing ethanol/water yields 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (VIII). The decarboxylation of (VIII) by means of refluxing aq. 3M HCl affords 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole (IX), which is finally acylated with acetic anhydride and pyridine in toluene to provide the target 6-chloromelatonin as a racemic compound.
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) |
56744 |
6-chloro-1H-indol-5-yl methyl ether; 6-chloro-5-methoxy-1H-indole
|
|
C9H8ClNO |
详情 |
详情
|
(II) |
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
|
(III) |
11974 |
Acetaldehyde
|
75-07-0 |
C2H4O |
详情 | 详情
|
(IV) |
56745 |
5-[1-(6-chloro-5-methoxy-1H-indol-3-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione
|
|
C17H18ClNO5 |
详情 |
详情
|
(V) |
56746 |
ethyl 3-(6-chloro-5-methoxy-1H-indol-3-yl)butanoate
|
|
C15H18ClNO3 |
详情 |
详情
|
(VI) |
56747 |
3-(6-chloro-5-methoxy-1H-indol-3-yl)butanohydrazide
|
|
C13H16ClN3O2 |
详情 |
详情
|
(VII) |
56748 |
7-chloro-6-methoxy-4-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-one
|
|
C13H13ClN2O2 |
详情 |
详情
|
(VIII) |
56749 |
3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid
|
|
C13H15ClN2O3 |
详情 |
详情
|
(IX) |
56750 |
2-(6-chloro-5-methoxy-1H-indol-3-yl)-1-propanamine; 2-(6-chloro-5-methoxy-1H-indol-3-yl)propylamine
|
|
C12H15ClN2O |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(I) Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Propyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and butyraldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
【1】
Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186.
|
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) |
21391 |
D-aspartic acid; (2R)-2-aminobutanedioic acid
|
1783-96-6 |
C4H7NO4 |
详情 | 详情
|
(I) |
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
|
(II) |
15967 |
propanoyl chloride; propionyl chloride
|
79-03-8 |
C3H5ClO |
详情 | 详情
|
(III) |
23689 |
2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione
|
|
C9H12O5 |
详情 |
详情
|
(IV) |
23712 |
1-ethanethiol; ethylhydrosulfide
|
75-08-1 |
C2H6S |
详情 | 详情
|
(V) |
23696 |
S-ethyl 3-oxopentanethioate
|
|
C7H12O2S |
详情 |
详情
|
(VI) |
23692 |
propyl 3-oxo-3-phenylpropanoate
|
|
C12H14O3 |
详情 |
详情
|
(VII) |
23693 |
propyl (E)-3-amino-3-phenyl-2-propenoate
|
|
C12H15NO2 |
详情 |
详情
|
(VIII) |
23694 |
butyraldehyde
|
123-72-8 |
C4H8O |
详情 | 详情
|
(IX) |
23695 |
propyl 6-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-4-propyl-1,4-dihydro-3-pyridinecarboxylate
|
|
C23H31NO3S |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(I) Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
【1】
Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186.
|
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) |
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
|
(II) |
15967 |
propanoyl chloride; propionyl chloride
|
79-03-8 |
C3H5ClO |
详情 | 详情
|
(III) |
23689 |
2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione
|
|
C9H12O5 |
详情 |
详情
|
(IV) |
23712 |
1-ethanethiol; ethylhydrosulfide
|
75-08-1 |
C2H6S |
详情 | 详情
|
(V) |
23696 |
S-ethyl 3-oxopentanethioate
|
|
C7H12O2S |
详情 |
详情
|
(VI) |
23692 |
propyl 3-oxo-3-phenylpropanoate
|
|
C12H14O3 |
详情 |
详情
|
(VII) |
23693 |
propyl (E)-3-amino-3-phenyl-2-propenoate
|
|
C12H15NO2 |
详情 |
详情
|
(VIII) |
15966 |
propionaldehyde
|
123-38-6 |
C3H6O |
详情 | 详情
|
(IX) |
23699 |
ethyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-1,4-dihydro-3-pyridinecarboxylate
|
|
C21H27NO3S |
详情 |
详情
|
(X) |
21891 |
2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil
|
118-75-2 |
C6Cl4O2 |
详情 | 详情
|
合成路线12
该中间体在本合成路线中的序号:
(I) Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with propanethiol (IV), followed by decarboxylation provided S-propyl 3-oxothiovalerate (V). Propyl 3-amino-3-(m-chlorophenyl)-2-propenoate (VII) was prepared by reaction of (3-chlorobenzoyl)acetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
【1】
Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186.
|
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) |
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
|
(II) |
15967 |
propanoyl chloride; propionyl chloride
|
79-03-8 |
C3H5ClO |
详情 | 详情
|
(III) |
23689 |
2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione
|
|
C9H12O5 |
详情 |
详情
|
(IV) |
23703 |
propylhydrosulfide; 1-propanethiol
|
107-03-9 |
C3H8S |
详情 | 详情
|
(V) |
23704 |
S-propyl 3-oxopentanethioate
|
|
C8H14O2S |
详情 |
详情
|
(VI) |
23705 |
propyl 3-(3-chlorophenyl)-3-oxopropanoate
|
|
C12H13ClO3 |
详情 |
详情
|
(VII) |
23706 |
propyl (E)-3-amino-3-(3-chlorophenyl)-2-propenoate
|
|
C12H14ClNO2 |
详情 |
详情
|
(VIII) |
15966 |
propionaldehyde
|
123-38-6 |
C3H6O |
详情 | 详情
|
(IX) |
23708 |
propyl 2-(3-chlorophenyl)-4,6-diethyl-5-[(propylsulfanyl)carbonyl]-1,4-dihydro-3-pyridinecarboxylate
|
|
C23H30ClNO3S |
详情 |
详情
|
(X) |
21891 |
2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil
|
118-75-2 |
C6Cl4O2 |
详情 | 详情
|
合成路线13
该中间体在本合成路线中的序号:
(I) Acylation of Meldrum's acid (I) with butyryl chloride (II) in the presence of pyridine gave butyryl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiocaproate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), b-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
【1】
Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186.
|
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) |
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
|
(II) |
10792 |
Butanoyl chloride; Butyryl chloride
|
141-75-3 |
C4H7ClO |
详情 | 详情
|
(III) |
23711 |
5-butyryl-2,2-dimethyl-1,3-dioxane-4,6-dione
|
|
C10H14O5 |
详情 |
详情
|
(IV) |
23712 |
1-ethanethiol; ethylhydrosulfide
|
75-08-1 |
C2H6S |
详情 | 详情
|
(V) |
23713 |
S-ethyl 3-oxohexanethioate
|
|
C8H14O2S |
详情 |
详情
|
(VI) |
10004 |
Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester
|
94-02-0 |
C11H12O3 |
详情 | 详情
|
(VII) |
23715 |
ethyl (E)-3-amino-3-phenyl-2-propenoate
|
|
C11H13NO2 |
详情 |
详情
|
(VIII) |
15966 |
propionaldehyde
|
123-38-6 |
C3H6O |
详情 | 详情
|
(IX) |
23716 |
ethyl 4-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-6-propyl-1,4-dihydro-3-pyridinecarboxylate
|
|
C22H29NO3S |
详情 |
详情
|
(X) |
21891 |
2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil
|
118-75-2 |
C6Cl4O2 |
详情 | 详情
|
合成路线14
该中间体在本合成路线中的序号:
(LII) A synthetic route based on the asymmetric reduction of oxo diesters has been reported. Meldrum's acid (LII) was acylated by methyl adipoyl chloride (LI) in the presence of pyridine to produce the intermediate (LIII) which, upon alcoholysis with isobutanol, led to oxo diester (LIV). Enantioselective reduction of (LIV) by means of baker's yeast furnished the (S)-hydroxy diester (LV). Alternatively, the analogous oxo diester (LVI) was prepared by acylation of methyl acetoacetate with methyl adipoyl chloride (LI), followed by deacetylation in the presence of ammonium hydroxide. Then, asymmetric chemical reduction of (LVI) by hydrogenation in the presence of the chiral catalyst Ru2Cl4[(S)-BINAP]2 provided the (S)-hydroxy diester (LVII). Regioselective reduction of either diester (LV) or (LVII) by means of NaBH4 in refluxing THF furnished dihydroxy ester (XLVIII). After conversion of (XLVIII) to the dimesylate (XLIX), displacement with potassium thioacetate afforded the bis(acetylthio) derivative (LVIII), which was further hydrolyzed with KOH to provide dihydrolipoic acid (LIX). In a related procedure, dihydrolipoic acid (LIX) was prepared by reaction of dimesylate (XLIX) with sodium disulfide, followed by reductive treatment with NaBH4 and NaOH. The title cyclic disulfide was then obtained by oxidation of the dithiol (LIX) using oxygen in the presence of FeCl3.
【1】
Bringmann, G.; et al.; A short and productive synthesis of (R)-alpha-lipoic acid. Z Naturforsch B - J Chem Sci 1999, 54, 5, 655.
|
【2】
Laban, G.; Gewald, R. (Asta Medica AG); Process for the preparation of enantiomerically pure diesters of 3-hydroxyoctandioic acid by asymmetric catalytic hydrogenation. DE 19709069; EP 0863125; US 6013833 .
|
【3】
Paust, J.; Klatt, M.J.; Niebel, M. (BASF AG); Method for producing lipoic acid and dihydrolipoic acid. WO 0210151 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XLVIII) |
57977 |
methyl (6S)-6,8-dihydroxyoctanoate
|
|
C9H18O4 |
详情 |
详情
|
(XLIX) |
57975 |
methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate
|
|
C11H22O8S2 |
详情 |
详情
|
(LI) |
49228 |
methyl 6-chloro-6-oxohexanoate
|
|
C7H11ClO3 |
详情 |
详情
|
(LII) |
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
|
(LIII) |
57978 |
methyl 6-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-6-hydroxyhexanoate
|
|
C13H18O7 |
详情 |
详情
|
(LIV) |
57979 |
1-isobutyl 8-methyl 3-oxooctanedioate
|
|
C13H22O5 |
详情 |
详情
|
(LV) |
57980 |
1-isobutyl 8-methyl (3S)-3-hydroxyoctanedioate
|
|
C13H24O5 |
详情 |
详情
|
(LVI) |
57981 |
dimethyl 3-oxooctanedioate
|
|
C10H16O5 |
详情 |
详情
|
(LVII) |
57982 |
dimethyl (3S)-3-hydroxyoctanedioate
|
|
C10H18O5 |
详情 |
详情
|
(LVIII) |
57983 |
methyl (6R)-6,8-bis(acetylsulfanyl)octanoate
|
|
C13H22O4S2 |
详情 |
详情
|
(LIX) |
57984 |
(6R)-6,8-disulfanyloctanoic acid
|
|
C8H16O2S2 |
详情 |
详情
|
合成路线15
该中间体在本合成路线中的序号:
(I) Acylation of Meldrum's acid (I) with 3-tryphenylmethylsulfanyl)propionic acid (II) by means of DCC produces the intermediate adduct (III), which is subsequently reduced to the tritylsulfanyl derivative (IV) by using NaBH4/AcOH. Alkylation of (IV) with methyl 3-bromopropionate (V) in the presence of NaOMe provides the 5,5-disubstituted dioxanedione (VI). Basic hydrolysis of (VI) gives rise to the tricarboxylic acid (VII), which is further decarboxylated to (VIII) in hot DMSO. Finally the S-trityl protecting gropu is removed by treatment with trifluoroacetic acid and triisopropylsilane.
【1】
Jackson, P.F.; Slusher, B.S.; Majer, P.; Maclin, K.M.; Wang, E.; Lapidus, R.S. (Guilford Pharmaceuticals Inc.); NAALADase inhibitors useful as pharmaceutical cpds. and compsns.. JP 2002519408; US 6395718; WO 0001668 .
|
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) |
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
|
(II) |
63154 |
3-[(triphenylmethyl)sulfanyl]propanoic acid
|
|
C22H20O2S |
详情 |
详情
|
(III) |
63155 |
5-{1-hydroxy-3-[(triphenylmethyl)sulfanyl]propylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione
|
|
C28H26O5S |
详情 |
详情
|
(IV) |
63156 |
2,2-dimethyl-5-{3-[(triphenylmethyl)sulfanyl]propyl}-1,3-dioxane-4,6-dione
|
|
C28H28O4S |
详情 |
详情
|
(V) |
50285 |
3-Bromopropionic acid methyl ester; Methyl 3-bromopropionate
|
3395-91-3 |
C4H7BrO2 |
详情 | 详情
|
(VI) |
63157 |
methyl 3-(2,2-dimethyl-4,6-dioxo-5-{3-[(triphenylmethyl)sulfanyl]propyl}-1,3-dioxan-5-yl)propanoate
|
|
C32H34O6S |
详情 |
详情
|
(VII) |
63158 |
6-[(triphenylmethyl)sulfanyl]-1,3,3-hexanetricarboxylic acid
|
|
C28H28O6S |
详情 |
详情
|
(VIII) |
63159 |
2-{3-[(triphenylmethyl)sulfanyl]propyl}pentanedioic acid
|
|
C27H28O4S |
详情 |
详情
|
合成路线16
该中间体在本合成路线中的序号:
(III) Decarboxylation of methyl 3-aminothiophene-2-carboxylate (I) in 2 N NaOH leads to 3-aminothiophene (II). Meldrum's acid (III) is condensed with triethyl orthoformate to produce the ethoxymethylene derivative (IV). Subsequent reaction of enol ether (IV) with 3-aminothiophene (II) gives rise to enamine (V), which is further cyclized to thienopyridinone (VI) upon heating in dowtherm A at 260 C. This is then chlorinated by means of oxalyl chloride to furnish 4-chlorothieno[3,2-b]pyridine (VII). Metalation of (VII) with butyllithium in cold THF, followed by treatment with I2 affords the aryl iodide (VIII). Palladium-catalyzed coupling of (VIII) with the lithiated derivative of 1-methylimidazole (IX) yields (X). Finally, displacement of the chloride group of (X) with 5-amino-2-methylindole (XI) provides the title compound.
【1】
Munchhof, M.J.; Adams, M.A.; Atherton, J.A.; et al.; Development of thienopyridines as VEGFR-2 kinase inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 129.
|
【2】
Sobolov-Jaynes, S.B.; Munchhof, M.J. (Pfizer Products Inc.); Thienopyrimidine and thienopyridine derivs. useful as anticancer agents. EP 1028964; JP 2001522853; WO 9924440 .
|
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) |
27686 |
3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate
|
22288-78-4 |
C6H7NO2S |
详情 | 详情
|
(II) |
63448 |
3-thiophenylamine; 3-thiophenamine
|
|
C4H5NS |
详情 |
详情
|
(III) |
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
|
(IV) |
63449 |
5-[(ethyloxy)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione
|
|
C9H12O5 |
详情 |
详情
|
(V) |
63450 |
2,2-dimethyl-5-[(3-thiophenylamino)methylidene]-1,3-dioxane-4,6-dione
|
|
C11H11NO4S |
详情 |
详情
|
(VI) |
63451 |
thieno[3,2-b]pyridin-7(4H)-one
|
|
C7H5NOS |
详情 |
详情
|
(VII) |
63452 |
7-chlorothieno[3,2-b]pyridine
|
|
C7H4ClNS |
详情 |
详情
|
(VIII) |
63453 |
7-chloro-2-iodothieno[3,2-b]pyridine
|
|
C7H3ClINS |
详情 |
详情
|
(IX) |
38630 |
1-methyl-1H-imidazole
|
616-47-7 |
C4H6N2 |
详情 | 详情
|
(X) |
63454 |
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine
|
|
C11H8ClN3S |
详情 |
详情
|
(XI) |
63455 |
2-methyl-1H-indol-5-ylamine; 2-methyl-1H-indol-5-amine
|
|
C9H10N2 |
详情 |
详情
|
合成路线17
该中间体在本合成路线中的序号:
(VII)
【1】
Wenslow RM, Armstrong JD, Chen AM, et al. 2005. Novel crystal forms of a dihydrogen phosphate salt of a trizolopyrazine dipeptidyl peptidase IV inhibitor. W0 2005020920 |
【2】
Xiao Y, Armstrong JD, Krska SW, et aL. 2004. Process for the preparation of chiral β-amino acid derivatives by asymmetric hydrogenation of enamino esters and amides using trasition-metal complexed chiral ferrocenyldiphasphines. W0 2004085378 |
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) |
27344 |
hydrazine
|
302-01-2 |
H4N2 |
详情 | 详情
|
(II) |
66702 |
N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide |
|
C4H4ClF3N2O2 |
详情 | 详情
|
(III) |
66703 |
2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole |
723286-98-4 |
C4H2ClF3N2O |
详情 | 详情
|
(IV) |
66704 |
(Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene)acetohydrazide |
763105-70-0 |
C6H9F3N4O |
详情 | 详情
|
(V) |
66705 |
3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride |
486460-21-3 |
C6H7F3N4.HCl |
详情 | 详情
|
(VI) |
66706 |
2-(2,4,5-trifluorophenyl)acetic acid |
209995-38-0 |
C8H5F3O2 |
详情 | 详情
|
(VII) |
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
|
(VIII) |
66707 |
5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione |
|
C14H11F3O5 |
详情 | 详情
|
(IX) |
66708 |
1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione |
764667-65-4 |
C16H12F6N4O2 |
详情 | 详情
|
(X) |
66709 |
(Z)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one |
767340-03-4 |
C16H13F6N5O |
详情 | 详情
|
合成路线18
该中间体在本合成路线中的序号:
(VII)
【1】
Dreher SD. Ikemoto N, Njolito E et aL. 2004. Process for preparation of chiral β-anuno acid derivatives. W0 2004085661 |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VI) |
66706 |
2-(2,4,5-trifluorophenyl)acetic acid |
209995-38-0 |
C8H5F3O2 |
详情 | 详情
|
(I) |
27344 |
hydrazine
|
302-01-2 |
H4N2 |
详情 | 详情
|
(II) |
66702 |
N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide |
|
C4H4ClF3N2O2 |
详情 | 详情
|
(III) |
66703 |
2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole |
723286-98-4 |
C4H2ClF3N2O |
详情 | 详情
|
(IV) |
66704 |
(Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene)acetohydrazide |
763105-70-0 |
C6H9F3N4O |
详情 | 详情
|
(V) |
66705 |
3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride |
486460-21-3 |
C6H7F3N4.HCl |
详情 | 详情
|
(VII) |
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
|
(VIII) |
66707 |
5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione |
|
C14H11F3O5 |
详情 | 详情
|
(IX) |
66708 |
1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione |
764667-65-4 |
C16H12F6N4O2 |
详情 | 详情
|
(X) |
66710 |
(R)-2-amino-2-phenylacetamide |
|
C8H10N2O |
详情 | 详情
|
(XI) |
66711 |
(R,Z)-2-((4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-en-2-yl)amino)-2-phenylacetamide |
|
C24H20F6N6O2 |
详情 | 详情
|
(XII) |
66712 |
(2R)-2-((4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)amino)-2-phenylacetamide |
|
C24H22F6N6O2 |
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 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .
【1】
Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350. |
【2】
Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355. |
【3】
Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637. |
【4】
Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889. |
【5】
Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519. |
【6】
Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979. |
【7】
Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640. |
【8】
Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127. |
【9】
Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976. |
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) |
18619 |
(2-aminophenyl)methanol; 2-Amino-benzenemethanol;2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol |
5344-90-1 |
C7H9NO |
详情 | 详情
|
(II) |
36334 |
[2-(isopropylamino)phenyl]methanol;2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol |
|
C10H15NO |
详情 |
详情
|
(III) |
36335 |
2-(isopropylamino)benzaldehyde
|
|
C10H13NO |
详情 |
详情
|
(IV) |
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) |
36333 |
1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid
|
|
C13H13NO3 |
详情 |
详情
|
(VI) |
68799 |
(1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate |
|
C12H22N2O2 |
详情 |
详情
|
(VII) |
68803 |
(1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate |
|
C25H33N3O4 |
详情 |
详情
|
(VIII) |
68804 |
N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate |
|
C20H25N3O2.C2HF3O2 |
详情 |
详情
|
(IX) |
68807 |
1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate |
|
C9H18ClNO3 |
详情 |
详情
|
(X) |
13917 |
(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin |
67843-74-7 |
C3H5ClO |
详情 | 详情
|
(XI) |
68808 |
(S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol |
|
C11H16ClNO |
详情 |
详情
|
(XII) |
68805 |
tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate |
|
C29H42N4O5 |
详情 |
详情
|
(XIII) |
68806 |
N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate |
|
C24H34N4O3.C2HF3O2 |
详情 |
详情
|
(XIV) |
13467 |
Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride |
124-63-0 |
CH3ClO2S |
详情 | 详情
|
(XV) |
68802 |
N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide |
|
C5H11NO3S |
详情 |
详情
|
(XVI) |
67859 |
N-methylmethanesulfonamide |
1184-85-6 |
C2H7NO2S |
详情 | 详情
|
(XVII) |
13917 |
(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin |
67843-74-7 |
C3H5ClO |
详情 | 详情
|
(XVIII) |
12132 |
2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether
|
696-59-3 |
C6H12O3 |
详情 | 详情
|
(XIX) |
15530 |
1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid;3-oxoglutaric acid |
542-05-2 |
C5H6O5 |
详情 | 详情
|
(XX) |
68801 |
(1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one |
|
C14H17NO |
详情 |
详情
|
(XXI) |
68800 |
N-Boc-8-azabicyclo[3.2.1]octan-3-one |
|
C12H19NO3 |
详情 |
详情
|