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【结 构 式】 
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【分子编号】14628 【品名】5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione 【CA登记号】 |
【 分 子 式 】C10H18N4O2 【 分 子 量 】226.27868 【元素组成】C 53.08% H 8.02% N 24.76% O 14.14% |
合成路线1
该中间体在本合成路线中的序号：(III)CPX has been obtained by two related ways: 1) Nitrosation of 6-amino-1,3-dipropyluracil (I) with NaNO2 in acetic acid gives the 5-nitrosouracil derivative (II), which is reduced with H2 over Pd/C in ethanol to yield 5,6-diamino-1,3-dipropyluracil (III). Acylation of (III) with cyclopentanecarboxylic acid (IV) by heating up to the mixture's melting point or by treatment with diisopropylcarbodiimide (DIC) gives the amide (V), which is finally cyclized by means of NaOH in refluxing water or refluxing methanol/water. 2) Acylation of the 5-nitrosouracil (II) with cyclopentanecarbonyl chloride (VI) by means of lithium hexamethyldisilazane (LHMDS) in THF gives the amide (VII), which is submitted to a reductive cyclization with Sn(OAc)2 in the same solvent.
| 【1】 Castaner, J.; Martin, L.; Sorbera, L.A.; CPX. Drugs Fut 2000, 25, 10, 1011. |
| 【2】 Hiner, R.N.; Rzeszotarski, W.J.; Hicks, R.P.; Costello, D.G.; Feeney, S.W.; Blake, P.R.; Erickson, R.H.; Abreu, M.E.; 1,3,8-Trisubstituted xanthines. Effects of substitution pattern upon adenosine receptor A1/A2 affinity. J Med Chem 1991, 34, 4, 1431. |
| 【3】 Schow, S.R.; Lum, R.T.; Melville, C.R.; Nelson, M.G.; Moore, A.G.; Convenient one-pot synthesis of xanthines from 6-amino-5-nitrosouracils. Synthesis 1999, 7, 1123. |
| 【4】 Hong, O.; Ukena, D.; Padgett, W.L.; Daly, J.W.; Shamim, M.T.; 8-Aryl- and 8-cycloalkyl-1,3-dipropylxanthines: Further potent and selective antagonists for A1-adenosine receptors. J Med Chem 1988, 31, 3, 613. |
| 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) | 41030 | 6-amino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | 41862-14-0 | C10H17N3O2 | 详情 | 详情 |
| (II) | 41031 | 6-amino-5-nitroso-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H16N4O3 | 详情 | 详情 | |
| (III) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (IV) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |
| (V) | 41034 | N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)cyclopentanecarboxamide | C16H26N4O3 | 详情 | 详情 | |
| (VI) | 41032 | cyclopentanecarbonyl chloride | 4524-93-0 | C6H9ClO | 详情 | 详情 |
| (VII) | 41033 | N-(5-nitroso-2,6-dioxo-1,3-dipropyl-1,2,3,6-tetrahydro-4-pyrimidinyl)cyclopentanecarboxamide | C16H24N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)a) A synthetic method is presented: Acylation of 1,3-dipropyl-5,6-diaminouracil (I) with a 3-noradamantane carboxylic acid (II) gave (III). Treatment of (III) with aqueous NaOH afforded the cyclized product KW-3902.
| 【1】 Suzuki, F.; Shimada, J.; Kubo, K.; Ohno, T.; Karasawa, A.; Ishii, A.; Hiromi, N. (Kyowa Hakko Kogyo Co., Ltd.); Xanthine derivs. EP 0386675; JP 1991173888; US 5068236 . |
| 【2】 Ohno, T.; Nonaka, H.; Karasawa, A.; Kubo, K.; Suzuki, F.; Mizumoto, H.; Shimada, J.; Ishii, A.; 8-(Dicyclopropylmethyl)-1,3-dipropylxanthine: A potent and selective adenosine A1 antagonist with renal protective and diuretic activities. J Med Chem 1991, 34, 1, 466-9. |
| 【3】 Suzuki, F.; KW-3902. Drugs Fut 1992, 17, 10, 876. |
| 【4】 Ohno, T.; Ishii, A.; Suzuki, F.; Karasawa, A.; Nonaka, H.; Kubo, K.; Shimada, J.; Mizumoto, H.; 8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors. J Med Chem 1992, 35, 5, 924. |
| 【5】 Karasawa, A.; Nonaka, H.; Suzuki, F.; Ishii, A.; Mizumoto, H.; Shimada, J.; Kubo, K.; A. Structure-activity relationships on diuretic activities and protective effects against acute renal failure. J Med Chem 1992, 35, 16, 3066. |
| 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) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (II) | 14629 | tricyclo[3.3.1.0(3,7)]nonane-3-carboxylic acid; 3-Noradamantanecarboxylic acid | 16200-53-6 | C10H14O2 | 详情 | 详情 |
| (III) | 14630 | N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)tricyclo[3.3.1.0(3,7)]nonane-3-carboxamide | C20H30N4O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The oxidation of tricyclo[3.3.1.03,7]nonane-3-carboxylic acid methyl ester (I) with CrO3 in acetic anhydride/acetic acid gives a mixture of the 9-oxo and 6-oxo isomers (II), which is condensed with 5,6-diamino-1,3-dipropylpyrimidine-2,4(1H,3H)-dione (III) by means of LiOH, and after HPLC separation yields the 9-oxo isomer (IV) of the condensation product. The cyclization of (IV) by means of Ca(OH)2 affords the 1,3-dipropylxanthine derivative (V), which is finally reduced with LiBH4 to a mixture of isomers that is separated by HPLC yielding finally metabolite M1.
| 【1】 Shimada, J.; Eguchi, T.; Yasuzawa, T.; Nakamura, A.; Horiguchi, A.; Mochida, K.; Suzuki, F.; Synthesis of rat metabolites of a adenosine A1 antagonist, KW-3902. Symp Med Chem 1996, Abst 1-P-24. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 20541 | methyl 9-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxylate | C11H14O3 | 详情 | 详情 | |
| (IIb) | 20542 | methyl 6-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxylate | C11H14O3 | 详情 | 详情 | |
| M1 | 63837 | 8-(9-hydroxytricyclo[3.3.1.0~3,7~]non-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione | C20H28N4O3 | 详情 | 详情 | |
| (I) | 20540 | methyl tricyclo[3.3.1.0(3,7)]nonane-3-carboxylate | C11H16O2 | 详情 | 详情 | |
| (III) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (IV) | 20544 | N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)-9-oxotricyclo[3.3.1.0(3,7)]nonane-3-carboxamide | C20H28N4O4 | 详情 | 详情 | |
| (V) | 20545 | 8-(9-oxotricyclo[3.3.1.0(3,7)]non-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione | C20H26N4O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The asymmetric Diels-Alder cycloaddition of cyclopentadiene (II) with the acrylic ester (I) of the chiral auxiliary D-pantolactone catalyzed by TiCl4 gives the chiral norbornene (III), which is treated with LiOH or NaOH to eliminate the auxiliary to yield the carboxylic acid (IV). The reaction of (IV) with oxalyl chloride affords the acyl chloride (V), which is condensed with 5,6-diamino-1,3-dipropyluracil (VI) by means of DMAP in pyridine to provide the amide (VII). The cyclization of (VII) by means of NaOH in dioxane gives the 1,3-dipropylxanthine derivative (VIII), which is finally epoxidated by means of magnesium monoperphthalate (MMPP) in aq. isopropanol to furnish the target xanthine derivative.
| 【1】 Pfister, J.R.; et al.; Synthesis and biological evaluation of the enantiomers of the potent and selective A1-adenosine antagonist 1, 3-dipropyl-8-[2-(5,6-epoxynorbonyl)]xanthine. J Med Chem 1997, 40, 12, 1773. |
| 【2】 Belardinelli, L.; Olsson, R.; Baker, S.; Scammells, P.J.; Milner, P.G.; Pfister, J.R.; Schreiner, G.F. (University of Florida); Novel A1 adenosine receptor agonists and antagonists. EP 0725782; JP 1997507052; US 5446046; WO 9511904 . |
| 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) | 54720 | (3R)-2,2-dimethyl-4-oxotetrahydro-3-furanyl acrylate | C9H12O4 | 详情 | 详情 | |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 54721 | (3R)-2,2-dimethyl-4-oxotetrahydro-3-furanyl (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carboxylate | C14H18O4 | 详情 | 详情 | |
| (IV) | 54722 | (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid | C8H10O2 | 详情 | 详情 | |
| (V) | 54723 | (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride | C8H9ClO | 详情 | 详情 | |
| (VI) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (VII) | 54724 | (1S,2S,4S)-N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide | C18H26N4O3 | 详情 | 详情 | |
| (VIII) | 54725 | 8-[(1S,2S,4S)bicyclo[2.2.1]hept-5-en-2-yl]-1,3-dipropyl-3,9-dihydro-1H-purine-2,6-dione | C18H24N4O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Alkylation of 4-hydroxybenzaldehyde (I) with iodoacetic acid in the presence of K2CO3 afforded ether (II). Subsequent condensation of (II) with 5,6-diamino-1,3-dipropyluracil (III) gave imine (IV). Oxidative ring closure by means of FeCl3 in boiling EtOH, with concomitant esterification, furnished xanthine (V). The ethyl ester of (V) was then displaced by hydrazine to yield hydrazide (VI). Finally, condensation of (VI) with dimethylmaleic anhydride (VII) gave rise to the corresponding maleimide.
| 【1】 Jacobson, K.A.; et al.; Functionalized congeners of 1,3-dialkylxanthines: preparation of analogues with high affinity for adenosine receptors. J Med Chem 1985, 28, 9, 1334-40. |
| 【2】 Karton, Y.; Melman, N.; Ji, X.-D.; Jacobson, K.A.; Linden, J.; Kim, Y.-C.; Acyl-hydrazide derivatives of a xanthine carboxylic congener (XCC) as selective antagonists at human A2B adenosine receptors. Drug Dev Res 1999, 47, 4, 178. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40086 | 2-iodoacetic acid | 64-69-7 | C2H3IO2 | 详情 | 详情 | |
| (I) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 25513 | 2-(4-Formylphenoxy)acetic acid; 4-Formyl phenoxy acetic acid | 22042-71-3 | C9H8O4 | 详情 | 详情 |
| (III) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (IV) | 35608 | 2-(4-[[(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)imino]methyl]phenoxy)acetic acid | C19H24N4O5 | 详情 | 详情 | |
| (V) | 35609 | ethyl 2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)phenoxy]acetate | C21H26N4O5 | 详情 | 详情 | |
| (VI) | 35610 | 2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)phenoxy]acetohydrazide | C19H24N6O4 | 详情 | 详情 | |
| (VII) | 35611 | 3,4-dimethyl-2,5-furandione | 766-39-2 | C6H6O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)Alkylation of 4-hydroxybenzaldehyde (I) with iodoacetic acid afforded 4-formylphenoxyacetic acid (II). This was condensed with 5,6-diamino-1,3-dipropyluracil (III) to produce imine (IV), which was oxidatively cyclized to xanthine (V) in the presence of ferric chloride. After activation of (V) as the corresponding acid chloride (VI), coupling with 4-aminobenzonitrile (VII) furnished the title amide.
| 【1】 Jacobson, K.A.; et al.; Functionalized congeners of 1,3-dialkylxanthines: preparation of analogues with high affinity for adenosine receptors. J Med Chem 1985, 28, 9, 1334-40. |
| 【2】 Ji, X.; Kim, Y.-C.; Linden, J.; Jacobson, K.A.; Melman, N.; Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A2B adenosine receptors. J Med Chem 2000, 43, 6, 1165. |
| 【3】 Kim, Y.-C.; Linden, J.M.; Jocobson, K.A. (University of Virginia); Substd. 8-phenylxanthines useful as antagonists of A2B adenosine receptors. WO 0073307 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40086 | 2-iodoacetic acid | 64-69-7 | C2H3IO2 | 详情 | 详情 | |
| (I) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 25513 | 2-(4-Formylphenoxy)acetic acid; 4-Formyl phenoxy acetic acid | 22042-71-3 | C9H8O4 | 详情 | 详情 |
| (III) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (IV) | 35608 | 2-(4-[[(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)imino]methyl]phenoxy)acetic acid | C19H24N4O5 | 详情 | 详情 | |
| (V) | 44758 | 2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)phenoxy]acetic acid | C19H22N4O5 | 详情 | 详情 | |
| (VI) | 44759 | 2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)phenoxy]acetyl chloride | C19H21ClN4O4 | 详情 | 详情 | |
| (VII) | 15361 | 4-Aminobenzonitrile | 873-74-5 | C7H6N2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The cyclization of 5,6-diamino-1,3-dipropylpyrimidine-2,4(1H,3H)-dione (I) with bicyclo[2,2,2]octane-1,4-dicarboxylic acid monoethyl ester (II) by means of HATU and TEA in acetonitrile gives the dipropylxanthine derivative (III), which is esterified with MeOH and sulfuric acid, yielding the methyl ester (IV). The reduction of the ester group of (IV) by means of LiBH4 in refluxing THF affords the hydroxymethyl derivative (V), which is oxidized with DMP in dichloromethane to provide the carbaldehyde (VI). The condensation of aldehyde (VI) with phosphonate (VII) by means of KHMDS in toluene leads to the acrylic acid methyl ester (VIII), which is hydrolyzed with LiOH in methanol/water to give the free acid (IX). Finally the double bond of the acrylic moiety is hydrogenated with H2 over Pd/C in methanol to yield the target xanthine derivative.
| 【1】 Ensinger, C.L.; Kumaravel, G.; Petter, R.C.; Dowling, J.E.; Kiesman, W.F.; Chang, H.X.; Lin, K.C. (Biogen, Inc.); Polycycloalkylpurines as adenosine receptor antagonists. EP 1230243; JP 2003513982; WO 0134610 . |
| 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) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (II) | 60200 | 4-[(propyloxy)carbonyl]bicyclo[2.2.2]octane-1-carboxylic acid | C13H20O4 | 详情 | 详情 | |
| (III) | 60201 | 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxylic acid | C20H28N4O4 | 详情 | 详情 | |
| (IV) | 60202 | methyl 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxylate | C21H30N4O4 | 详情 | 详情 | |
| (V) | 60203 | 8-[4-(hydroxymethyl)bicyclo[2.2.2]oct-1-yl]-1,3-dipropyl-3,9-dihydro-1H-purine-2,6-dione | C20H30N4O3 | 详情 | 详情 | |
| (VI) | 60204 | 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-carbaldehyde | C20H28N4O3 | 详情 | 详情 | |
| (VII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (VIII) | 60205 | methyl 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]oct-1-yl]-2-propenoate | C23H32N4O4 | 详情 | 详情 | |
| (IX) | 60206 | 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]oct-1-yl]-2-propenoic acid | C22H30N4O4 | 详情 | 详情 |