合成路线1
该中间体在本合成路线中的序号:
(I) Orcinol (I) is first derivatized to (III) by reaction with sulfonyl chloride (II) in a mixture of aqueous NaHCO3 (sat) and Et2O. Monosulfonate (III) undergoes Mitsunobu reaction with monobenzylated diol (IV) in the presence of PPh3 and DEAD in dichloromethane to yield derivative (V), which is then debenzylated by hydrogenolysis over Pd/C in MeOH, or in THF/HCl/dioxane, to afford (VI). Alcohol (VI) is oxidized with SO3·pyr complex in DMSO/dichloromethane in the presence of DIEA to provide aldehyde (VIII), which finally reacts with aminoguanidine nitrate in EtOH in the presence of HCl/dioxane.
【1】
Soll, R.M.; Lu, T.; Tomczuk, B.; et al.; Amidinohydrazones as guanidine bioisosteres: Application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors. Bioorg Med Chem Lett 2000, 10, 1, 1.
|
【2】
Soll, R.M.; Lu, T.; Fedde, C.L.; Tomczuk, B.E.; Illig, C. (3-Dimensional Pharmaceuticals, Inc.); Amidinohydrazones as protease inhibitors. EP 0906091; JP 2000507588; US 5891909; WO 9736580 .
|
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) |
27257 |
5-Methyl-1,3-benzenediol; Orcinol
|
505-15-4 |
C7H8O2 |
详情 | 详情
|
(II) |
30817 |
2-chlorobenzenesulfonyl chloride
|
2905-23-9 |
C6H4Cl2O2S |
详情 | 详情
|
(III) |
30818 |
3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C13H11ClO4S |
详情 |
详情
|
(IV) |
14687 |
3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol
|
4799-68-2 |
C10H14O2 |
详情 | 详情
|
(V) |
30819 |
3-[3-(benzyloxy)propoxy]-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C23H23ClO5S |
详情 |
详情
|
(VI) |
30820 |
3-(3-hydroxypropoxy)-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C16H17ClO5S |
详情 |
详情
|
(VII) |
30821 |
3-methyl-5-(3-oxopropoxy)phenyl 2-chlorobenzenesulfonate
|
|
C16H15ClO5S |
详情 |
详情
|
(VIII) |
10015 |
1-Hydrazinecarboximidamide; Hydrazinecarboximidamide
|
79-17-4 |
CH6N4 |
详情 | 详情
|
合成路线2
该中间体在本合成路线中的序号:
(I) Orcinol (I) was acetylated with Ac2O in pyridine to give diacetate (II), which was submitted to a Fries rearrangement in the presence of AlCl3 in chlorobenzene at 90 C to afford acetophenone (III). Subsequent condensation of (III) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (IV) was effected either in the presence of CdCO3 in boiling toluene or K2CO3 and tributyl benzylammonium chloride in CH2Cl2 at r.t. The resulting (glucopyranosyloxy)acetophenone (V) was condensed with 5-formylbenzofuran (VI) in the presence of KOH to give chalcone (VII). Hydrogenation of (VII) over Pt/C then yielded the (benzofuranyl)propiophenone (VIII). After protection of the 6'-hydroxyl group of (VIII) as the allyl ether (X) with allyl bromide (IX) and K2CO3, the primary alcohol of (X) was acylated with ClCOOMe to furnish carbonate ester (XI). Finally, the O-allyl group of (XI) was cleaved with palladium catalyst and ammonium formate.
【1】
Doggrell, S.A.; Castañer, J.; T-1095. Drugs Fut 2001, 26, 8, 750.
|
【2】
Tsujihara, K.; et al.; Na+-glucose contransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring. J Med Chem 1999, 42, 26, 5311.
|
【3】
Hongu, M.; Matsumoto, M.; Oku, A.; Saito, K.; Tsujihara, K. (Tanabe Seiyaku Co., Ltd.); Propiophenone derivs. and process for preparing the same. EP 0850948; JP 1998237089; US 6048842 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
16993 |
methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate |
79-22-1 |
C2H3ClO2 |
详情 | 详情
|
(I) |
27257 |
5-Methyl-1,3-benzenediol; Orcinol
|
505-15-4 |
C7H8O2 |
详情 | 详情
|
(II) |
27258 |
3-(acetoxy)-5-methylphenyl acetate
|
|
C11H12O4 |
详情 |
详情
|
(III) |
27259 |
1-(2,6-dihydroxy-4-methylphenyl)-1-ethanone
|
|
C9H10O3 |
详情 |
详情
|
(IV) |
27260 |
(2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate
|
572-09-8 |
C14H19BrO9 |
详情 | 详情
|
(V) |
27261 |
(2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxy-5-methylphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate
|
|
C23H28O12 |
详情 |
详情
|
(VI) |
27262 |
1-benzofuran-5-carbaldehyde
|
|
C9H6O2 |
详情 |
详情
|
(VII) |
27263 |
(E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one
|
|
C24H24O9 |
详情 |
详情
|
(VIII) |
27264 |
3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-1-propanone
|
|
C24H26O9 |
详情 |
详情
|
(IX) |
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(X) |
27265 |
1-(2-(allyloxy)-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-3-(1-benzofuran-5-yl)-1-propanone
|
|
C27H30O9 |
详情 |
详情
|
(XI) |
27266 |
((2R,3S,4S,5R,6S)-6-[3-(allyloxy)-2-[3-(1-benzofuran-5-yl)propanoyl]-5-methylphenoxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl methyl carbonate
|
|
C29H32O11 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(I) Orcinol (I) is acetylated with Ac2O in pyridine giving the diacetate (II), which is submitted to a Fries rearrangement with AlCl3 in hot chlorobenzene yielding acetophenone (III). Subsequent condensation of (III) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (IV) by means of CdCO3 in refluxing toluene (or K2CO3 and tributylbenzylammonium chloride in dichloromethane) affords the glycosylated acetophenone (V), which is condensed with benzofuran-5-carbaldehyde (VI) by means of KOH in ethanol affording deacetylated chalcone (VII). Finally, this compound is hydrogenated with H2 over Pt/C in ethanol.
【1】
Tsujihara, K.; et al.; Na+-glucose contransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring. J Med Chem 1999, 42, 26, 5311.
|
【2】
Hongu, M.; Matsumoto, M.; Oku, A.; Saito, K.; Tsujihara, K. (Tanabe Seiyaku Co., Ltd.); Propiophenone derivs. and process for preparing the same. EP 0850948; JP 1998237089; US 6048842 .
|
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) |
27257 |
5-Methyl-1,3-benzenediol; Orcinol
|
505-15-4 |
C7H8O2 |
详情 | 详情
|
(II) |
27258 |
3-(acetoxy)-5-methylphenyl acetate
|
|
C11H12O4 |
详情 |
详情
|
(III) |
27259 |
1-(2,6-dihydroxy-4-methylphenyl)-1-ethanone
|
|
C9H10O3 |
详情 |
详情
|
(IV) |
27260 |
(2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate
|
572-09-8 |
C14H19BrO9 |
详情 | 详情
|
(V) |
27261 |
(2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxy-5-methylphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate
|
|
C23H28O12 |
详情 |
详情
|
(VI) |
27262 |
1-benzofuran-5-carbaldehyde
|
|
C9H6O2 |
详情 |
详情
|
(VII) |
27263 |
(E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one
|
|
C24H24O9 |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(I) The monosulfonation of orcinol (I) with 2-chlorobenzenesulfonyl chloride (II) in ethyl ether/aqueous NaHCO3 gives the monosulfonate (III), which is condensed with 4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (IV) by means of NaH in DMF to yield the aryl ether (V). The deprotection of (V) with 4N HCl in dioxane affords the piperidine (VI), which is finally treated with amidinosulfonic acid (VII) and TEA in DMF.
The 4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (IV) has been obtained as follows: The reaction of piperidine-4-carboxylic acid (VIII) with Boc2O and NaHCO3 in dioxane/water gives the protected piperidine (IX), which is reduced at the carboxyl group by means of BH3/THF yielding the carbinol (X). Finally, this compound is mesylated with MsCl and TEA in dichloromethane to afford the target intermediate.
【1】
Soll, R.M.; Spurlino, J.; Murphy, L.; Lu, T.; Salemme, F.R.; Bone, R.; Illig, C.R.; Tomczuk, B.E.; Structure-activity and crystallographic analysis of a new class of non-amide-based thrombin inhibitor. Bioorg Med Chem Lett 2000, 10, 1, 79.
|
【2】
Zetter, B.R.; Smith, R. (Children's Medical Center Corp.); Treatment of human prostate cancer with spermine. WO 9711691 .
|
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) |
27257 |
5-Methyl-1,3-benzenediol; Orcinol
|
505-15-4 |
C7H8O2 |
详情 | 详情
|
(II) |
30817 |
2-chlorobenzenesulfonyl chloride
|
2905-23-9 |
C6H4Cl2O2S |
详情 | 详情
|
(III) |
30818 |
3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C13H11ClO4S |
详情 |
详情
|
(IV) |
40396 |
tert-butyl 4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1-piperidinecarboxylate
|
|
C14H27NO3S |
详情 |
详情
|
(V) |
40397 |
tert-butyl 4-[(3-[[(2-chlorophenyl)sulfonyl]oxy]-5-methylphenoxy)methyl]-1-piperidinecarboxylate
|
|
C24H30ClNO6S |
详情 |
详情
|
(VI) |
40398 |
3-methyl-5-(4-piperidinylmethoxy)phenyl 2-chlorobenzenesulfonate
|
|
C19H22ClNO4S |
详情 |
详情
|
(VII) |
15984 |
amino(imino)methanesulfonic acid
|
|
CH4N2O3S |
详情 |
详情
|
(VIII) |
17402 |
4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid |
498-94-2 |
C6H11NO2 |
详情 | 详情
|
(IX) |
17404 |
1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid
|
84358-13-4 |
C11H19NO4 |
详情 | 详情
|
(X) |
40399 |
tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate
|
|
C11H21NO3 |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(I) Alternatively, the monosulfonate (III) can also be obtained as follows: The benzylation of orcinol (I) with benzyl bromide (IX) and NaH in DMF gives the monoether (X), which is sulfonated with 2-chlorobenzenesulfonyl chloride (II) and DIPEA in CH2Cl2 affording the protected sulfonate (XI). Finally, this compound is deprotected by hydro-genation with H2 over Pd/C in THF to furnish the target monosulfonate (III).
【1】
Zetter, B.R.; Smith, R. (Children's Medical Center Corp.); Treatment of human prostate cancer with spermine. WO 9711691 .
|
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) |
27257 |
5-Methyl-1,3-benzenediol; Orcinol
|
505-15-4 |
C7H8O2 |
详情 | 详情
|
(II) |
30817 |
2-chlorobenzenesulfonyl chloride
|
2905-23-9 |
C6H4Cl2O2S |
详情 | 详情
|
(III) |
30818 |
3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C13H11ClO4S |
详情 |
详情
|
(IX) |
12912 |
1-(Bromomethyl)benzene; Alpha-bromotoluene
|
100-39-0 |
C7H7Br |
详情 | 详情
|
(X) |
40400 |
3-(benzyloxy)-5-methylphenol
|
|
C14H14O2 |
详情 |
详情
|
(XI) |
40401 |
3-(benzyloxy)-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C20H17ClO4S |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(II) 2-Chlorobenzenesulfonyl chloride (I) was coupled to orcinol (II) to give sulfonate (III). Subsequent condensation of (III) with 3-benzyloxypropanol (IV) under Mitsunobu conditions afforded ether (V). After hydrogenolytic deprotection of the benzyl group, Swern oxidation of the resulting alcohol (VI) with DMSO and SO3-pyridine complex provided aldehyde (VII). The title amidinohydrazone was then obtained by treatment of (VII) with aminoguanidine nitrate (VIII).
【1】
Soll, R.M.; Lu, T.; Fedde, C.L.; Tomczuk, B.E.; Illig, C. (3-Dimensional Pharmaceuticals, Inc.); Amidinohydrazones as protease inhibitors. EP 0906091; JP 2000507588; US 5891909; WO 9736580 .
|
【2】
Tomczuk, B.E.; Stagnaro, T.P.; Fedde, C.L.; Lu, T.; Markotan, T.P.; Illig, C.R.; Soll, R.M. (3-Dimensional Pharmaceuticals, Inc.); Aminoguanidines and alkoxyguanidines as protease inhibitors. EP 0944590; WO 9823565 .
|
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) |
30817 |
2-chlorobenzenesulfonyl chloride
|
2905-23-9 |
C6H4Cl2O2S |
详情 | 详情
|
(II) |
27257 |
5-Methyl-1,3-benzenediol; Orcinol
|
505-15-4 |
C7H8O2 |
详情 | 详情
|
(III) |
30818 |
3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C13H11ClO4S |
详情 |
详情
|
(IV) |
14687 |
3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol
|
4799-68-2 |
C10H14O2 |
详情 | 详情
|
(V) |
30819 |
3-[3-(benzyloxy)propoxy]-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C23H23ClO5S |
详情 |
详情
|
(VI) |
30820 |
3-(3-hydroxypropoxy)-5-methylphenyl 2-chlorobenzenesulfonate
|
|
C16H17ClO5S |
详情 |
详情
|
(VII) |
30821 |
3-methyl-5-(3-oxopropoxy)phenyl 2-chlorobenzenesulfonate
|
|
C16H15ClO5S |
详情 |
详情
|
(VIII) |
10015 |
1-Hydrazinecarboximidamide; Hydrazinecarboximidamide
|
79-17-4 |
CH6N4 |
详情 | 详情
|
合成路线7
该中间体在本合成路线中的序号:
(I) Vilsmeier formylation of orcinol (I) by means of POCl3 and DMF afforded 2,4-dihydroxy-6-methylbenzaldehyde (II). Coumarin (V) was then prepared by Wittig condensation of (II) with carbethoxymethylene triphenylphosphorane (III) followed by intramolecular cyclization in refluxing xylene. Alkylation of (V) with 3-chloro-3-methyl-1-butyne (VI) in the presence of K2CO3 and KI produced the corresponding alpha,alpha-dimethylpropargyl ether (VII), and subsequent thermal cyclization in refluxing N,N-diethylaniline gave rise to the tricyclic system (VIII). Osmium-catalyzed asymmetric dihydroxylation of (VIII) in the presence of the enantioselective ligand hydroquinone 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2-PYR] produced the required (R,R)-(+)-cis-diol (IX). This was finally acylated with (S)-(-)-camphanic chloride (X) in the presence of pyridine to produce the target dicamphanoyl ester.
【1】
Takeuchi, Y.; Xie, L.; Lee, K.-H.; Cosentino, L.M.; Anti-AIDS agents. 37.(1) synthesis and structure-activity relationships of (3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents. J Med Chem 1999, 42, 14, 2662.
|
【2】
Xie, L.; Takeuchi, Y.; Cosentino, L.M.; Lee, K.-H.; Anti-AIDS agent 33. Synthesis and anti-HIV activity of mono-methyl substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogues. Bioorg Med Chem Lett 1998, 8, 16, 2151.
|
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) |
27257 |
5-Methyl-1,3-benzenediol; Orcinol
|
505-15-4 |
C7H8O2 |
详情 | 详情
|
(II) |
34435 |
2,4-dihydroxy-6-methylbenzaldehyde
|
|
C8H8O3 |
详情 |
详情
|
(III) |
14182 |
ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane
|
1099-45-2 |
C22H21O2P |
详情 | 详情
|
(IV) |
34436 |
ethyl (E)-3-(2,4-dihydroxy-6-methylphenyl)-2-propenoate
|
|
C12H14O4 |
详情 |
详情
|
(V) |
34437 |
7-hydroxy-5-methyl-2H-chromen-2-one
|
|
C10H8O3 |
详情 |
详情
|
(VI) |
22416 |
3-chloro-3-methyl-1-butyne
|
1111-97-3 |
C5H7Cl |
详情 | 详情
|
(VII) |
34438 |
7-[(1,1-dimethyl-2-propynyl)oxy]-5-methyl-2H-chromen-2-one
|
|
C15H14O3 |
详情 |
详情
|
(VIII) |
34439 |
5,8,8-trimethyl-2H,8H-pyrano[2,3-f]chromen-2-one
|
|
C15H14O3 |
详情 |
详情
|
(IX) |
34440 |
(9R,10R)-9,10-dihydroxy-5,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one
|
|
C15H16O5 |
详情 |
详情
|
(X) |
16583 |
(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride
|
39637-74-6 |
C10H13ClO3 |
详情 | 详情
|