CA2100820C - Amino-cyclodextrin and related structures - Google Patents
Amino-cyclodextrin and related structuresInfo
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- CA2100820C CA2100820C CA002100820A CA2100820A CA2100820C CA 2100820 C CA2100820 C CA 2100820C CA 002100820 A CA002100820 A CA 002100820A CA 2100820 A CA2100820 A CA 2100820A CA 2100820 C CA2100820 C CA 2100820C
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- cyclodextrin
- alpha
- carbon atoms
- allyl
- nmr
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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Abstract
There are disclosed novel azidodeoxy cyclodextrins, which have similar or improved properties to known cyclodextrins. The novel compounds are substituted cyclodextrins having substituents such as alkyl or alkenyl. There is also disclosed a process for preparing such compounds by reacting cyclodextrin with a phosphine derivative and carbon tetrabromide.
Description
i~2100~2p AZ IDO-CYCI~ODEXTRIN
This invention relates to methods of synthesis of aminocyclodextrins: Cyclodextrins are widely known as food and drug additives, as catalysts in chemical and industrial processes, and in numerous spectroscopic, analytical and preparative procedures, (see Li and Purdy, Chem..Rev. 1992, 92, 1457-1470. Their inclusion compounds are similarly widely known) see Saenger, Angew. Chem. Int. Ed. Engl.
1980, 19, 433-362.
The present invention primarily relates to processes of preparing substituted cyclodextrins. Specific reagents are utilized to produce specific products. The present invention secondarily provides novel compounds prepared by the process. Although the invention will be described and referred to as it relates to processes of preparation of aminocyclodextrins and novel aminocyclodextrins prepared 2o thereby, it will be understood that the principles of this invention are equally applicable to similar processes and products, . and accordingly it will be understood that the invention is not limited to such processes and products.
BACKGROUND OF THE INVENTION
Cyclodextrins are cyclic alpha-1,4-oligosaccharide starch derivates) Alpha, beta, gamma, and delta cyclodextrins are known, containing six, seven, eight, and nine.glucose units.respectively. Their importance lies in 3o their enzymic properties attributed to their hollow truncated cone structure having primary 6-hydroxyls at the narrower end, and secondary 2- and 3-hydroxyls at the wider end, a relatively hydrophobic interior cavity and a relatively hydrophilic exterior.
The cyclodextrins form inclusion complexes and its is believed that these inclusion complexes and similar compounds modify the chemical and physical environment is i~2100820 affecting chemical reactions to induce chirality in otherwise achiral reactions. The cyclodextrins are themselves inherently chiral being composed of chiral D-glucose units.
Substituted aminodeoxy cyclodextrins are particularly noted for their chiral catalytic effects (Tagaki et al., Tetrahedron Lett., 1990, 31, 3897-3900, Parrot-Lopez et al., Tetrahedron: Asymmetry, 1990, 1,.367-370, Angew. Chem.
Int. Ed. Engl., 1992, 31, 1381-1383.
Azidodeoxy cyclodextrins are suitable precursors for aminodeoxy cyclodextrins.
It is a principal object of the invention to prepare azidodeoxy cyclodextrins.
In accordance with one aspect of one embodiment of the present invention there is provided a compound of formula .FOA'~"~A
P~
'C
ofd wherein C is cyclodextrin, A is azido and n is 0, 1, 2 or 3,R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or azidoalkyl of 1 to 6 carbon atoms, with the proviso when R is azidoalkyl, n is 0.
In another aspect of the present invention; there is provided a process of preparation of a compound of formula Faa nu~A ,I
~1'v ..
C ' r T~:-:
2~0~82~
wherein C is cyclodextrin, A is azido and n is 0, 1, 2 or 3, R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or azidoalkyl of 1 to 6 carbon atoms, with the proviso when R is azidoalkyl, n is 0, comprising when n is 1, 2, or 3 reacting a cyclodextrin of formula FoR nu~.A
G
o~
wherein C is cyclodextrin, R is hydrogen, alkyl of 1 to 6 carbon atoms, or alkenyl of 2 to 6 carbon atoms, with alkali metal azide triphenyl p~hosphine, and carbon tetrabromide, when n is 0 reacting cyclodextrin with alkali metal hydride in a first step, and the product thereof with haloazidoalkane in a second step.
Having thus generally described the invention, reference will now be made to the Examples.
EXPERIMENTAL DATA
Example 1 2-O-Allyl-alpha-cyclodextrin To a solution of dried a-cyclodextrin (2.88 g, 2.96 mmol) in DMSO (30 ml) was added lithium hydride (35 mg; 1.5 eq). The mixture was stirred under Argon until the solution became clear (24 hours). To this solution was added allyl bromide (256 ~C1, 1 eq) and lithium iodide (10 mg). The mixture was allowed to stand at 55°C for 4 hours.
TLC on silica gel (CHjCN/HO2, 8/2) showed 3 products having Rf values of 0.28, 0.20, 0.09, and corresponding respectively to diallyl, monoallyl-a-cyclodextrins, and starting material. a-cyclodextrin and its derivatives were precipitated out by the addition of acetone (500 ml). The 210~~~0 precipitate was filtered and washed with acetone (100 ml) to give 3 g of crude product which was purified by flash chromatography on a silica gel column (4x40 cm) eluting y with CH3CN/HZO, 9/1 (1 liter) then 8/2 (1.5 liters). The ' pure fractions of monoallyl-a-cyclodextrin were combined, then concentrated in vacuo to give a solid (900 mg, 30%).
The proton NMR spectra showed that it was a mixture of 2, and 6-O-allyl-a-cyclodextrins. The latter was present in about 20% (based on the integration of the alkenyl protons). Pure 2-O-monoallyl-a-cyclodextrin was obtained after recrystallization from MeOH/HZO (720 mg, 24%).
ON
- Y O,~-~ ~~~w~-cy.J..tn~.
mp 270°C (dec). Cc (aJp+55° (c 0.1, H20) . y IR (KBr) 3400 (OH) .
~H NMR (DMSO-d6, 300 MHz) ~ :3.20 (dd, 1H, Jz_~ = 3.3, JZ_3 =
9.0, H2") 3.22-3.48 (m, 21II, H2, H4, HzO, 3.50-7.70 (m, 18H, H5, H6) , 3.70-3.82 (m, 5H, H3) , 3.85 (td, 1H, J3_z = Jg_4 9.0, JH3-off - 2.2, I-I3") , 4.16 (dd, 1H, Jd_e = 12.8, Jd_~ = 5.7, Hd)., 4.28 (dd, 1H, Je.d = 12.8, J~-~ = 5.7, He) , 4.38-4.52 (m, 6H, OH6) , 4.79 (s, 5H, H1) , 4.95 (d, 1H, J~_z = 3.3, H1A) , 5. 18 (dd, 1~I, Ja_~ = 10.4, Ja_b = 1.8, Ha) , 5.29 (dd, 1H, Jb_~
- 17.3, Jb_a = 1.8, Hb), 5.40-5.70 (m, 11H, OH2, OH3), 5.80-5.95 (m, 1H, J~_b = 17.3, J~_a = 10.4, J~_d = J~_e = 5.7, Hc) .
'3C NMR (DMSO-d6, 300 MHz) ~: 60.1(C6), 71.9, 72.2 (C2, C5), 72.4 (allyl) , 72.8 (C3") , 73.2, 73.3, 73.4 (C3) , 79.6 (C2") , 82.2, 82.4 (C4), 82.8 (C4A), 82.8 (C4A), 100.2 (C1A), 101.2, 102.0, 102.1, (C1), 117.7 (allyl), 134.8 (allyl).
3 5 FABMS C39H6403o . 10 3 5 ( M+N a ) .
Example 2 (i) 6 Azido-6-deoxy-alpha-cyclodextrin and (ii) 6 6' Diazido-6 6'-dideoxy-alpha-cvclodextrin_ ~.
~3 ~3 ~3 (ii1 a ! a To a solution of dried a-cyclodextrin (2.8 g, 2.88 mmol) in DMF (60 ml) were added lithium azide (1.40 g, 10 eq), triphenylphosphine (1.89 g, 2.5 eq) and carbon tetrabromide (2.39 g, 2.5 eq). The addition of the.latter caused a mildly exothermic reaction and the solution turned yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 major products having Rf values of 0.35, 0.20, 0.09, and corresponding respectively to diazido, monoazido-a-cyclodextrins and starting material. After addition of methanol ~ ( 10 ml ) , the brown solution was concentrated to about half by rotary evaporation under reduced pressure, then poured into acetone (500 ml) to precipitate out a-cyclodextrin and its derivatives. The precipitate was filtered and washed with acetone (100 ml) to give 3 g of crude products which were purified by flash chromatography on a silca gel column (4x40 cm) eluting with CH3CN/HzO, 9/1 (2 liters) then 8/2 (1.5 liters). The pure fractions were combined, then concentrated in vacuo to give 6-azido-6-deoxy-a-cyclodextrin (570 mg, 20%), and 6,6'-diazido- .
6,6'dideoxy-a-cyclodextrin (760 mg, 26%).
6-Azido-6-deoxy-a-cyclodextrin y3 mp -190°C (dec) lit. 217°C (dec), Carbohydr. Res., 1971, 18, 29-37) [a]p + 133 ° (c 0.2, H20) ; (lit. + 128° (c 0.4, H20) , Carbohydr. Res., 1971, 18, 29-37) IR (KBr) 3400 (OH) , 2100 (N3) .
This invention relates to methods of synthesis of aminocyclodextrins: Cyclodextrins are widely known as food and drug additives, as catalysts in chemical and industrial processes, and in numerous spectroscopic, analytical and preparative procedures, (see Li and Purdy, Chem..Rev. 1992, 92, 1457-1470. Their inclusion compounds are similarly widely known) see Saenger, Angew. Chem. Int. Ed. Engl.
1980, 19, 433-362.
The present invention primarily relates to processes of preparing substituted cyclodextrins. Specific reagents are utilized to produce specific products. The present invention secondarily provides novel compounds prepared by the process. Although the invention will be described and referred to as it relates to processes of preparation of aminocyclodextrins and novel aminocyclodextrins prepared 2o thereby, it will be understood that the principles of this invention are equally applicable to similar processes and products, . and accordingly it will be understood that the invention is not limited to such processes and products.
BACKGROUND OF THE INVENTION
Cyclodextrins are cyclic alpha-1,4-oligosaccharide starch derivates) Alpha, beta, gamma, and delta cyclodextrins are known, containing six, seven, eight, and nine.glucose units.respectively. Their importance lies in 3o their enzymic properties attributed to their hollow truncated cone structure having primary 6-hydroxyls at the narrower end, and secondary 2- and 3-hydroxyls at the wider end, a relatively hydrophobic interior cavity and a relatively hydrophilic exterior.
The cyclodextrins form inclusion complexes and its is believed that these inclusion complexes and similar compounds modify the chemical and physical environment is i~2100820 affecting chemical reactions to induce chirality in otherwise achiral reactions. The cyclodextrins are themselves inherently chiral being composed of chiral D-glucose units.
Substituted aminodeoxy cyclodextrins are particularly noted for their chiral catalytic effects (Tagaki et al., Tetrahedron Lett., 1990, 31, 3897-3900, Parrot-Lopez et al., Tetrahedron: Asymmetry, 1990, 1,.367-370, Angew. Chem.
Int. Ed. Engl., 1992, 31, 1381-1383.
Azidodeoxy cyclodextrins are suitable precursors for aminodeoxy cyclodextrins.
It is a principal object of the invention to prepare azidodeoxy cyclodextrins.
In accordance with one aspect of one embodiment of the present invention there is provided a compound of formula .FOA'~"~A
P~
'C
ofd wherein C is cyclodextrin, A is azido and n is 0, 1, 2 or 3,R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or azidoalkyl of 1 to 6 carbon atoms, with the proviso when R is azidoalkyl, n is 0.
In another aspect of the present invention; there is provided a process of preparation of a compound of formula Faa nu~A ,I
~1'v ..
C ' r T~:-:
2~0~82~
wherein C is cyclodextrin, A is azido and n is 0, 1, 2 or 3, R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or azidoalkyl of 1 to 6 carbon atoms, with the proviso when R is azidoalkyl, n is 0, comprising when n is 1, 2, or 3 reacting a cyclodextrin of formula FoR nu~.A
G
o~
wherein C is cyclodextrin, R is hydrogen, alkyl of 1 to 6 carbon atoms, or alkenyl of 2 to 6 carbon atoms, with alkali metal azide triphenyl p~hosphine, and carbon tetrabromide, when n is 0 reacting cyclodextrin with alkali metal hydride in a first step, and the product thereof with haloazidoalkane in a second step.
Having thus generally described the invention, reference will now be made to the Examples.
EXPERIMENTAL DATA
Example 1 2-O-Allyl-alpha-cyclodextrin To a solution of dried a-cyclodextrin (2.88 g, 2.96 mmol) in DMSO (30 ml) was added lithium hydride (35 mg; 1.5 eq). The mixture was stirred under Argon until the solution became clear (24 hours). To this solution was added allyl bromide (256 ~C1, 1 eq) and lithium iodide (10 mg). The mixture was allowed to stand at 55°C for 4 hours.
TLC on silica gel (CHjCN/HO2, 8/2) showed 3 products having Rf values of 0.28, 0.20, 0.09, and corresponding respectively to diallyl, monoallyl-a-cyclodextrins, and starting material. a-cyclodextrin and its derivatives were precipitated out by the addition of acetone (500 ml). The 210~~~0 precipitate was filtered and washed with acetone (100 ml) to give 3 g of crude product which was purified by flash chromatography on a silica gel column (4x40 cm) eluting y with CH3CN/HZO, 9/1 (1 liter) then 8/2 (1.5 liters). The ' pure fractions of monoallyl-a-cyclodextrin were combined, then concentrated in vacuo to give a solid (900 mg, 30%).
The proton NMR spectra showed that it was a mixture of 2, and 6-O-allyl-a-cyclodextrins. The latter was present in about 20% (based on the integration of the alkenyl protons). Pure 2-O-monoallyl-a-cyclodextrin was obtained after recrystallization from MeOH/HZO (720 mg, 24%).
ON
- Y O,~-~ ~~~w~-cy.J..tn~.
mp 270°C (dec). Cc (aJp+55° (c 0.1, H20) . y IR (KBr) 3400 (OH) .
~H NMR (DMSO-d6, 300 MHz) ~ :3.20 (dd, 1H, Jz_~ = 3.3, JZ_3 =
9.0, H2") 3.22-3.48 (m, 21II, H2, H4, HzO, 3.50-7.70 (m, 18H, H5, H6) , 3.70-3.82 (m, 5H, H3) , 3.85 (td, 1H, J3_z = Jg_4 9.0, JH3-off - 2.2, I-I3") , 4.16 (dd, 1H, Jd_e = 12.8, Jd_~ = 5.7, Hd)., 4.28 (dd, 1H, Je.d = 12.8, J~-~ = 5.7, He) , 4.38-4.52 (m, 6H, OH6) , 4.79 (s, 5H, H1) , 4.95 (d, 1H, J~_z = 3.3, H1A) , 5. 18 (dd, 1~I, Ja_~ = 10.4, Ja_b = 1.8, Ha) , 5.29 (dd, 1H, Jb_~
- 17.3, Jb_a = 1.8, Hb), 5.40-5.70 (m, 11H, OH2, OH3), 5.80-5.95 (m, 1H, J~_b = 17.3, J~_a = 10.4, J~_d = J~_e = 5.7, Hc) .
'3C NMR (DMSO-d6, 300 MHz) ~: 60.1(C6), 71.9, 72.2 (C2, C5), 72.4 (allyl) , 72.8 (C3") , 73.2, 73.3, 73.4 (C3) , 79.6 (C2") , 82.2, 82.4 (C4), 82.8 (C4A), 82.8 (C4A), 100.2 (C1A), 101.2, 102.0, 102.1, (C1), 117.7 (allyl), 134.8 (allyl).
3 5 FABMS C39H6403o . 10 3 5 ( M+N a ) .
Example 2 (i) 6 Azido-6-deoxy-alpha-cyclodextrin and (ii) 6 6' Diazido-6 6'-dideoxy-alpha-cvclodextrin_ ~.
~3 ~3 ~3 (ii1 a ! a To a solution of dried a-cyclodextrin (2.8 g, 2.88 mmol) in DMF (60 ml) were added lithium azide (1.40 g, 10 eq), triphenylphosphine (1.89 g, 2.5 eq) and carbon tetrabromide (2.39 g, 2.5 eq). The addition of the.latter caused a mildly exothermic reaction and the solution turned yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 major products having Rf values of 0.35, 0.20, 0.09, and corresponding respectively to diazido, monoazido-a-cyclodextrins and starting material. After addition of methanol ~ ( 10 ml ) , the brown solution was concentrated to about half by rotary evaporation under reduced pressure, then poured into acetone (500 ml) to precipitate out a-cyclodextrin and its derivatives. The precipitate was filtered and washed with acetone (100 ml) to give 3 g of crude products which were purified by flash chromatography on a silca gel column (4x40 cm) eluting with CH3CN/HzO, 9/1 (2 liters) then 8/2 (1.5 liters). The pure fractions were combined, then concentrated in vacuo to give 6-azido-6-deoxy-a-cyclodextrin (570 mg, 20%), and 6,6'-diazido- .
6,6'dideoxy-a-cyclodextrin (760 mg, 26%).
6-Azido-6-deoxy-a-cyclodextrin y3 mp -190°C (dec) lit. 217°C (dec), Carbohydr. Res., 1971, 18, 29-37) [a]p + 133 ° (c 0.2, H20) ; (lit. + 128° (c 0.4, H20) , Carbohydr. Res., 1971, 18, 29-37) IR (KBr) 3400 (OH) , 2100 (N3) .
.. .
~H NMR (DMSO-d6, 300 MHz) . ~: 3.20-3.45 (m, 30H, H2,H4, H20), 3.52-3.70 (m, 18H, H5, H6), 3.71-3.87 (m, 6H, H3), 4.40-4.60 (m, 5H, OH6), 4.72-4.82 (m, 5H, H1), '4.83 (d, 1H, J~-2 =~3.2, H1A), 5.31-5.49 (m, 6H, OH3), 5.49-5.62 (m, 6H, OH2).
~3C NMR (DMSO-d6), 300 MHz) ~: 51.3 (C6A), 60.0-60.3 (C6), 70.4 (C2A), 72.0, 72.2, 72.3, 72.4, 73.0 (C2,C5), 73.2 (C3A) , 73.3 (C3) , 82. l, 82. 2, 82.4 (C4) , 83'. 2 (C4A) , 101.7 (C1A), 102.0, 102.2, 102.3 (C1).
FARMS C36H5o029N3 ~ 1020 (M+Na) .
~H NMR (DMSO-d6, 300 MHz) . ~: 3.20-3.45 (m, 30H, H2,H4, H20), 3.52-3.70 (m, 18H, H5, H6), 3.71-3.87 (m, 6H, H3), 4.40-4.60 (m, 5H, OH6), 4.72-4.82 (m, 5H, H1), '4.83 (d, 1H, J~-2 =~3.2, H1A), 5.31-5.49 (m, 6H, OH3), 5.49-5.62 (m, 6H, OH2).
~3C NMR (DMSO-d6), 300 MHz) ~: 51.3 (C6A), 60.0-60.3 (C6), 70.4 (C2A), 72.0, 72.2, 72.3, 72.4, 73.0 (C2,C5), 73.2 (C3A) , 73.3 (C3) , 82. l, 82. 2, 82.4 (C4) , 83'. 2 (C4A) , 101.7 (C1A), 102.0, 102.2, 102.3 (C1).
FARMS C36H5o029N3 ~ 1020 (M+Na) .
6.6'-Diazido-6,6'-dideoxy-a-cyclodextrin i 5 Analytical reversed HPLC (~.c-Bondapack (T'1Vn C 18 Column, 3 .9x3 00 mm) showed, that it is a mixture of 2 isomers in relative ratios of 75/25 as calculated from the peak areas on HPLC
chromatogram.
i'13 ~I3 , 2 0 -!
a y~ _ d~az;de 2 5 Analytical reversed phase HPLC of the mixture of the 2 isomers of diazido-a-. cyclodextrin. A stepwise gradient elution was applied : 10 % MeOH/H20 for 10 min. , then 50 % Me0HIH20 for 20 min. , column was washed with MeOH
between injections.
Retention times of the peaks 1 and ? are respectively : 19.S0 and 21.9-: min.
36 mg of this~mixture yielded by semi-preparative reversed phase HPLC (Novapak (TM) C18 Column, 7.8x300 mm) 21 mg, 80% of ,~;
..:
r 2~~Q~~~
the major isomer and 6 mg, 70% of the minor one. ' The determination of the structure of the 2 isomers was done by ~3C NMR and Korner's method. The major isomer -is the AD isomer and the minor one is the AC isomer.
M~t70 ~ ~'~°~''~
1 ~ 2 'J 3 a-cyclodextmn i ~.r (Si ~ : !a,.I ~ ~' ~- -r Isomer Determination of Di- and Triazido-a-cyclodextrin by Korners method (J. Am. Chem. Soc. 1986, 108,4509).
The AD isomer V~ y~
a mp 165°C (dec).
[aJp+77 ° (c 0.11, H20) .
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MI-iz) ~ : 3.11-3.48 (m, 36H, H2, H4, HzOI), 3.48-3.70 (m, 18H, H5, H6), 3.70-3.90 (m, 6H, H3), 4.42-4 .68 (m, 5H, OI-16) , 4.7G (d, 2H, J~_z = 3. 6, H1) , 4.78 (d, 2I-i, J~_z = 3 . 3 , H1) , 4 . 84 (d, 2H, J~_2 = 2 . , 4 H1A) , 5. 30-5.72 (m, 12H, OH2, OH3).
~3C NMR (DMSO-d6, 300 MHz) ~ : 51.3 (C6A), 60.0, 60.3 (C6), 70.4 (C2A) , 72.0, (C2) , 72. 1 (C5) , 72.4 ~(C5A) , 73.0, (C3A) , 73.2 (C3), 82.2, 82.4 (C4), 83.2 (C4A), 101.7 (C1A), 102.0, 102.2 (C1) .
FABMS C36H5aO2aN6 . 10 2 3 ( M+H ) Example 3 (i) 6-Azido-6-deoxy-alpha-cvclodextrin and (ii) 6 6'-Diazido-6 6'-dideoxy-alpha-cyclodextrin and ~~oos~o ..
(iii) 6 6' 6" Triazido-6 6' 6"-trideoxy-alpha-cyclodextrin To a solution of dried a-cyclodextrin (2.5 g, 2.61 mmol) in DMF (60 ml) were added lithium azide (1.28 g, 10 eq), triphenylphosphine (2.05 g, 3 eq) and carbon tetrabromide (2.60 g, 3 eq). The addition of the latter caused a mildly exothermic reaction and the solution turned yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/H20, 8/2) showed 4 major products having Rf values of 0.50, 0.35;
0.20, 0.09, and corresponding respectively to triazido, diazido, monoazido-a-cyclodextrin and starting material After addition of methanol (10 ml), the brown solution was concentrated to about half by rotary evaporation under reduced pressure, then poured into acetone (500 ml) to precipitate out a-cyclodextrin and its derivatives. The precipitate was filtered and washed with acetone (100 ml) to give 3 g of crude products which were purified by flash chromatography on a silica gel column (4x40 cm) eluting with CH3CN/HzO, 9/1 (2 liter) then 8/2 (1.5 liter) . The pure fractions were combined, then concentrated in vacuo to give:
6-Azido-6-deoxy-a-cyclodextrin (470 mg, 18%), 6,6'-diazido 6,6'-dideoxy-a-cyclodextrin (mixture of 2 isomers, 670 mg, 25%), and 6,6',6"-triazido-6,6',6"-tridexoy-a-cyclodextrin (270 mg, 10%).
~3 ~3 ~1 ~z ~
l~~ lii~
tiii~
a a a _6 6' 6" Triazido-6 6' 6"-trideoxy-a-cvclodextrin Analytical reversed phase HPLC (~-Bondapak C18 Column, 3.9x300 mm) showed that it is a mixture of 3 isomers in relative ratios of 70/20/10 as calculated from the peak areas on HPLC chromatogram.
chromatogram.
i'13 ~I3 , 2 0 -!
a y~ _ d~az;de 2 5 Analytical reversed phase HPLC of the mixture of the 2 isomers of diazido-a-. cyclodextrin. A stepwise gradient elution was applied : 10 % MeOH/H20 for 10 min. , then 50 % Me0HIH20 for 20 min. , column was washed with MeOH
between injections.
Retention times of the peaks 1 and ? are respectively : 19.S0 and 21.9-: min.
36 mg of this~mixture yielded by semi-preparative reversed phase HPLC (Novapak (TM) C18 Column, 7.8x300 mm) 21 mg, 80% of ,~;
..:
r 2~~Q~~~
the major isomer and 6 mg, 70% of the minor one. ' The determination of the structure of the 2 isomers was done by ~3C NMR and Korner's method. The major isomer -is the AD isomer and the minor one is the AC isomer.
M~t70 ~ ~'~°~''~
1 ~ 2 'J 3 a-cyclodextmn i ~.r (Si ~ : !a,.I ~ ~' ~- -r Isomer Determination of Di- and Triazido-a-cyclodextrin by Korners method (J. Am. Chem. Soc. 1986, 108,4509).
The AD isomer V~ y~
a mp 165°C (dec).
[aJp+77 ° (c 0.11, H20) .
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MI-iz) ~ : 3.11-3.48 (m, 36H, H2, H4, HzOI), 3.48-3.70 (m, 18H, H5, H6), 3.70-3.90 (m, 6H, H3), 4.42-4 .68 (m, 5H, OI-16) , 4.7G (d, 2H, J~_z = 3. 6, H1) , 4.78 (d, 2I-i, J~_z = 3 . 3 , H1) , 4 . 84 (d, 2H, J~_2 = 2 . , 4 H1A) , 5. 30-5.72 (m, 12H, OH2, OH3).
~3C NMR (DMSO-d6, 300 MHz) ~ : 51.3 (C6A), 60.0, 60.3 (C6), 70.4 (C2A) , 72.0, (C2) , 72. 1 (C5) , 72.4 ~(C5A) , 73.0, (C3A) , 73.2 (C3), 82.2, 82.4 (C4), 83.2 (C4A), 101.7 (C1A), 102.0, 102.2 (C1) .
FABMS C36H5aO2aN6 . 10 2 3 ( M+H ) Example 3 (i) 6-Azido-6-deoxy-alpha-cvclodextrin and (ii) 6 6'-Diazido-6 6'-dideoxy-alpha-cyclodextrin and ~~oos~o ..
(iii) 6 6' 6" Triazido-6 6' 6"-trideoxy-alpha-cyclodextrin To a solution of dried a-cyclodextrin (2.5 g, 2.61 mmol) in DMF (60 ml) were added lithium azide (1.28 g, 10 eq), triphenylphosphine (2.05 g, 3 eq) and carbon tetrabromide (2.60 g, 3 eq). The addition of the latter caused a mildly exothermic reaction and the solution turned yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/H20, 8/2) showed 4 major products having Rf values of 0.50, 0.35;
0.20, 0.09, and corresponding respectively to triazido, diazido, monoazido-a-cyclodextrin and starting material After addition of methanol (10 ml), the brown solution was concentrated to about half by rotary evaporation under reduced pressure, then poured into acetone (500 ml) to precipitate out a-cyclodextrin and its derivatives. The precipitate was filtered and washed with acetone (100 ml) to give 3 g of crude products which were purified by flash chromatography on a silica gel column (4x40 cm) eluting with CH3CN/HzO, 9/1 (2 liter) then 8/2 (1.5 liter) . The pure fractions were combined, then concentrated in vacuo to give:
6-Azido-6-deoxy-a-cyclodextrin (470 mg, 18%), 6,6'-diazido 6,6'-dideoxy-a-cyclodextrin (mixture of 2 isomers, 670 mg, 25%), and 6,6',6"-triazido-6,6',6"-tridexoy-a-cyclodextrin (270 mg, 10%).
~3 ~3 ~1 ~z ~
l~~ lii~
tiii~
a a a _6 6' 6" Triazido-6 6' 6"-trideoxy-a-cvclodextrin Analytical reversed phase HPLC (~-Bondapak C18 Column, 3.9x300 mm) showed that it is a mixture of 3 isomers in relative ratios of 70/20/10 as calculated from the peak areas on HPLC chromatogram.
~~o~~
V. 5 ~I : X13 4-( ) I
Analytical reversed phase 1-1PLC of the mixture of the 3 isomers of triazido-a cvclodextrin. A stepwise gradient elution was applied : 10 ~Io ivIeOH/H.''.O
for 10 mina, then ~0 % VIe01-UH?0 for?0 min: , column was washed with MeOH
between injections.
Retention times of the peal, 7. -: (p), and ~ l-1) :u'o respectively :
2'_'.16, '_'=1.03, and ?6.67 min.
100_mg of this mixture yields by semi preparative reversed HPLC. (Novapak C18 Column, 7.8x300 mm) 16 mg, 80%, 50.mg, 70~, and 8 mg, 70% of pure isomers.
The determination of the structure of the 3 isomers was done by ~3C NMR and Korner's method. The isomer 7 on the HPLC chromatogram correspond to the ACE isomer, the isomer 4(5) to the ABD or ABE isomer and the isomer 5(4) to the ABE or ABD isomer.
2 0 ~ R~,d~:~.~.
~./ 'r 1 ' a-cvclodex~=i, w ' 5 ( l ~6 -=t ~(S) 4-isomer Determination of Di- and Triazido-a-cyclodextrin by Korner's method (J. Am. Chem. Soc. 1986, 108,4509).
Example 4 2-O-Allyl-6-azido-6-deoxy-alpha-cyclodextrin and 2 O Ally_1 6 6'- --diazido-6 6'-dideoxy-alpha-cyclodextrin To a solution of dried 2-O-allyl-a-cyclodextrin (872 mg, 0.86 mmol) in DMF (30 ml) were added lithium azide (420 mg, 10 eq), triphenylphosphine (564 mg, 2.5 eq) and carbon tetrabromide (715 mg, 2.5 eq). The addition of the latter caused a mildly exothermic reaction and the solution turned 21~Q~~0 ( .
yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 major products having Rf values of 0.54, 0.40, 0.20, and corresponding respectively to diazido-monoallyl-a-cyclodextrin, monoazido-monoallyl-a-cyclodextrin and starting material. After addition of methanol (5 ml), the brown solution was concentrated to about 3 ml by rotary evaporation under reduced pressure, then applied on a silica gel column (4x40 cm) eluting with CH3CN/HzO, 92/8 (11), 90/10 (1.51), then 85/15 (1.51). The pure fractions were combined, then concentrated in vacuo to give: 2-O-allyl-6-azido-6-deoxy-a-cyclodextrin (320 mg, 36%), and 2-O-allyl-6,6'-diazido-6,6'-dideoxy-a-cyclodextrin (160 mg, 20%) .
2-O-ally~l-6-azido-6-deoxy-a-Cvclodextrin mp = 175°C (dec). a [a]p+153° (c 0.1, H20) .
IR (KBr) 3400 (OH), 2100 (N3). O
~H ~NMR (DMSO-d6, 300 MHz) ~ : 3.15-3.49 (m, 20H, H2, H4, Hz0), 3.49-3.70 (m, 18H, H5, H6), 3.70-3.87 (m, 5H, H3), 3.87-3.90 (m, 1H, H3") , 4. 16 (dd, 1H, Jd_e = 12.8, Jd_~ = 5.7, Hd) , 4.28 (dd, 1H, J~_d = 12.8, Je_~ = 5.7, He) , 4.38-4.65 (m, 5H, OH6), 4.78, 4.84, 4.96, 5.02 (s, 6H, H1, H1"), 5.17 (d, 1H, Je_~ = 10.3, Ha), 5.29 (d, 1H, Jb_~ = 17.3, Hb), 5.37-5.78 (m, 11H, OH2, OH3), 5.78-5.96 (m; 1H, Hc).
~3C NMR (DMSO-d6, 300 MHz) ~: 51.3 (C6"), 60.1, 60.31, 60.33 (C6) , 70.4, 71.7, 71.9, 7.2.0, 72. 1, 72.3, 72.4 (C2, C5) , 72.7 (allyl) , 73.0 (C3") , 73. 1, 73.2, 73.3 (C3) , 79.6 (C2A) , 82.1, 82.2, 82.4, 82.5 (C4), 83.2 (C4a), 101.80 , 101.82 (C1"), 102.00, 102.07, 102.2 (C1), 117.8 (allyl), 134.8 (allyl).
FABMS C39H630z9N3 . 10 6 0 ( M+Na ) .
~~~Q~~O
2 O-allyl-6 6'-diazido-6 6'-dideoxy-a-Cvclodextrin N~ N
mp = 172°C (dec).
[a]o+131° (c 0.1, HZO) .
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MHz) H4, HZO) ~ : 3.20-3.48 (m, H2, , 3.48-3.69 (m, l8Fi, FiS, H6) , 3.69.3.88 H3) 3.88-(m, 5H, , 3.98 (m, 1H, H3A) ( 4. 16 (dd, 1H, = 12.8, = Hd) Jd_e Jd_~ 5.7.,, 4.28 (dd, 1H, Je_d = 12.8, Je_~ = Fie) , 4.50-4.70 5.7, (m, 4H, OH6), 4.77, 4.79, 4.83, 4.95, 5.00(s, 6H, H1A),5.18 H1, (d, 1H, Je_~ = 10.3 Ha), 5.29 (d, Jb_~ _ 17.3,Hb), 5.37-5.78 (m, llH, OH2, 1H, (m, 1H, OH3), 5.78-5.96 Hc).
~3C NMR (DMSO-d6, 300 MHz) ~: 51.3 (C6A), 60.0, 60.4 (C6), 70.4; 71.8, 72.0, 72.1, 72.2, 72.3, 72.4 (C2, C5); 72.7 (allyl), 73.0 (C3A), 73.3, 73.5, 73.6 (C3), 79.4 (C2A), 82.3, 82.5, 83.2, 83.3 (C4), 101.8, 101.9 (C1A), 102.0, 102.2 (C1), 117.7 (allyl), 134.8, 134.9 (allyl).
FABMS C39HszOzsN6 : 1085 (M+Na) . Example 5 2-O-All~l-6-azido-6-deoxy-alpha-cvclodextrin and 2-O-All~l-6 6'-diazido-6 6'-dideoxy-alpha-cyclodextrin and 2-O-A11y1-6 6' 6"-triazido-6 6' 6"-trideoxy-alpha-cyclodextrin To a solution of dried 2-O-allyl-a-cyclodextrin (740 mg, 0.73 mmol) in DMF (30 ml) were added lithium azide (358 mg, 10 eq), triphenylphosphine (574 mg, 3 eq) and carbon tetrabromide (728 mg, 3 eq) . The addition of the latter caused a mildly exothermic reaction and the solution turned yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/H20, 8/2) showed 3 major products having Rf values of 0.68, 0.54, ~1~~8~4 -.
0.40, and corresponding respectively to triazido-monoallyl-a-cyclodextrin, diazido-monoallyl-a-cyclodextrin and monoazido-monoallyl-a-cyclodextrin. After addition of methanol (5 ml), the brown solution was concentrated to about 3 mol by rotary evaporation under reduced pressure, then applied on a silica gel column (4x40 cm) eluting with CH3CN/HZO, 92/8 (11), 90/10 (1.51), then 85/15 (1.51). The pure fractions were combined, then concentrated in vacuo to give: 2-O-allyl-6-azido-6-deoxy-a-cyclodextrin (200 mg, 26%), 2-O-allyl-6,6'-diazido-6,6'-dideoxy-a-cyclodextrin (260 fig, 330) and 2-O-allyl-6,6',6"-triazido-6,6'-6"-tridexoy-a-cyclodextrin (214 mg, 27%).
2 O a11L1-6 6' 6"-triazido-6 6' 6"-tridexoy-a-CVClodextrin:
1~3 1V 3 a mp = 168°C (dec).
[a]p+110° (c 0.11, MeOH) .
IR (KBr) 3400 (OI-i) , 2100 (N3) .
~H NMR (DMSO-d6, 300 MHz) ~ : 3. 18-3.42 (m, H2, H4, Hz0) , 3.45-3.64 (m, 18H, H5, H6), 3.64-3.82 (m, 5H, H3), 3.82-3.95 (m, 1H, H3") , 4.12 (dd, 1H, Jd_e = 12.8, Jd_~ = 5.7, Hd) , 4.25 (dd, 1H, Je_d = 12.8, Je_~ = 5.7, He),, 4.50-4.70 (m, 3H, OH6), 4.72, 4.80, 4.90, 4.98 (s, 6H, H1, H1"),.5.11 (d, 1H, Je_~ = 10.3, Ha) , 5. 25 (d, 1H, Jb_~ = 17. 3, Hb) , 5.35-5.70 (m, 11H, OH2, OH3) , 5.75-5.95 (m, 1H, IIc) .
~3C NMR (DMSO-d6, 300 MHz) ~: 51.2, 51.3 (C6°') , 60.3 (C6) , 70.3, 71.7, 71.8, 72.0, 72.1, 72.3 (C2, C5), 72.7 (allyl), 73.0, 73.1, 73.2 (C3), 79.2, 79.3 (C2~), 82.6, 82.8, 83.1, 83.3 (C4), 101.6, 101.7, 101.8 (C1A), 102.00, 102.03, 102.1 (C1), 117.6, 117.7 (allyl), 134.7, 134.8 (allyl).
z~ o~g~o FABMS C39H6~ 027N9 ~ 1110 ( M+Na ) Example 6 Alphahalo-omega-azidohaloalkane 1-Iodo-n-azidoalkanes Preparation of chloroazidoalkanes:
To a solution of 1-bromo-n-chloroalkane (50 mmol) in DMSO (50 ml) was added sodium azide (3.25 g, 1 eq) . The solution was stirred at room temperature for 20 hours, then diluted with water (100 ml), and extracted with ether (2x100 ml). The organic layers were combined, then dried over anhydrous sodium sulfate. The residue obtained after removal of the solvent was used without further purification.
1-Chloro-3-azidopropane Yield 80%
~H NMR (CDC13, 300 MHz) . 2.00 (quint, 2H, J = 6.2), 3.48 (t, 2H, J = 6.4), 3.62 (t, 2H, J = 6.2).
1-Chloro-4-azidobutane Yield 86%
~H NMR (CDC13, 300 MHz) . 1.60-2.00 (m, 4H), 3.31 (t, 2H, J = 6.2), 3.54 (t, 2H, J = 6.2).
1-Chloro-5-azidopentane Yield 90%
~H NMR (CDC13, 300 MHz) . 1.47-1.68 (m, 4H), 1.80 (quint, 2H, J = 7.3), 3.29 (t, 2H, J = 6.4), 3.54 (t, 2H, J = 6.5) Preparation of iodoazidoalkanes:
A solution of chloroazidoalkane (50 mmol) and sodium iodide (7.5 g, 2 eq) in acetone was heated at reflux for 20 hours. After removal of the solvent in vacuo, the residue was diluted with water (30 ml), then extracted with ether (2x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate. The residue obtained after removal of the solvent was purified by distillation.
~2oosza 1-Iodo-3-azidopropane Yield 710 Ebo_~ 20-25°C
~H NMR (CDC13, 300 MHz) ~: 2.04 (quint, 2H, J = 7.3), 3.25 (t, 2H, J = 6.7), 3.43 (t, 2ii, J = 6.6).
1-Iodo-4-azidobutane Yield 75%
Ebo.~ 60°C
~H NrIR (CDC13, 300 MHz) ~5: 1.65-1.76 (m, 2H), 1.85-1.97 (m, 2H), 3.20 (t, 2H, J = 6.7), 3.31 (t, 2H, J = 6.6).
1-Iodo-5-azidopentane Yield 80%
EB0.1 70°C
1H NMR (CD13, 300 MHz) ~: 1.42-1.5,6 (m, 2H), 1.56-1.68 (m, 2H), 1.78-1.90 (quint, 2H, J = 7.3), 3.19 (t, 2H, J = 6.8), 3.29 (t, 2H, J = 6.6).
Example 7 2-O-Azidoalkyl-beta-cyclodextrin To a solution of dried f3-cyclodextrin (2.4 g, 2.11 mmol) in DMSO (15 ml) was added lithium hydride (26 mg, 1.5 eq). The mixture was stirred under Argon until the solution became clear (24 hours). To this solution was added 1-iodo-n-azidoalkane (1.5 eq). The mixture was allowed to stand at 60°C for 10 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 products corresponding to dialkyl, monoalkyl-f3-cyclodextrin, and starting material. After evaporation of DMSO in vacuo, the residue was dissolved in water (5 ml), then applied on a silica gel column (4x40 cm). Elution with CH3CN/HzO, 9/1 removed the dialkyl, monoalkyl derivatives, and starting material were eluted with CFi3CN/HZO, 8/2. The pure fractions of monoalkyl-f3 cyclodextrin were combined, the concentrated in vacuo to give a solid.
21p4~~0 ....
a i~~ ~, 2-O-Az idopropyl-fi-cy-clodextrin Yield 250 mp 210°C (dec).
[a]p+141.3° (c 0.22, MeOH). Q
IR (KBr) 3400 (OII) , 2100 (N3) .
~H NMR (DMSO-d6, 300 MHz) ~ : 1.68-1.85 (m, 2H (propyl)( 3.00-3.48 (m, 30H, fI2, H4, (propyl), Hz0), 3.49-3.90 (m, 30II, H3, H5, H6, (propyl) , 4.40-4..60 (m, 7Hi, OH6) , 4.78-4 .90 (m, 6I-I, H1.) , 4 . 95-5. 05 (m, 1H, H1A) , 5. 60-6. 10 (m, 13H, OH2, OH3).
'3C NMR (DMSO-d6, 300 MHz) ~ : 28.9, 47. 6 (propyl) , 60.0 (C6), 68.9 (propyl), 71.9, 72.1, 72.3, 72.5 (C2, C5), 72.7 (C3A), 73.1 (C3), 80.8 (C2A), 81.6, 81.7 (C4), 82.2 (C4A)r 100.2 (Cl"), 101.9, 102.0 (Cl).
FABMS C45H~SO35N3 . 1240 (M+Na) .
2-O-Az idobut~l-f3-cyclodextrin Yield 25%
mp 210°C (dec), [a]p+127.1° (c 0.22, Hz0) . Q
IR (KBr) 3400 (OH), 2100 (N3).
'H NMR (DMSO-d6, 300 MHz) ~ : 1.50-1.65 (m, 4H (butyl) ) , 3.22 (dd, 1H, Jz_~ - 3.3; Jz_3 = 10.0, H2A) , 3.22-3.48 (m, 30H, H1, H4, (butyl) , Hz0) , 3.48-3.82 (m, 30H, H2, H5, H6, (butyl)), 4.45 (t, 7H, JH6-OH = 5~2, OH6), 4.78-4.86 (m, 6H, H1) , 4.96 (d, 1H, J~_Z = 3.5, H1A) , 5. 55-6. 00 (m, 13H, OH2, OH3).
~3C NMR (DMSO-d6, 300 MHz) . 24.8, 26.5, 50.5 (butyl), 60.0 (C6), 71.3 (butyl), 71.8, 71.9, 72.1 72.3, 72.,5 (C2, C5) , 72.8 (C3A) , 73. 1, 73.2 (C3) , 80.7 (C2A) , 81.6, 81.8, 81.9 (C4), 82.3 (C4A), 100.4 (C1A), 101.9, 102.0 (C1).
FABMS C46H7~035N3 ~ 12 54 ( M+Na ) .
2-O-Az idopentyl-f3-c~clodextrin Yield 300 mp 230°C (dec).
[a]p+115.5° (c 0.20, MeOH).
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MHz) . 1.28-1.40 (m, 2H (pentyl), 1.47-1.60 (m, 4H (pentyl) ) , 3.21 (dd, 1H, JZ_~ = 3.3, J2_3 =
9.7, H2A), 3.21-3.48 (m, 30H, H2, H4, (pentyl), H20), 3.48-3.82 (m, 30H, H3, H5, H6, (pentyl) ) ) , 4.47 (t, 7H, JH6-OH
5.3, OH6) , 4.78-4.87 (m, 6H, H1) , 4.96 (d, 1H, J~_Z = 3.3, H1A), 5.55-6.00 (m, 13H, OH2, OH3).
~3C NMR (DMSO-d6, 300 MHz) . 22.5, 28.0, 50.6 (pentyl), 60.0 (C6), 71.7 (pentyl), 71.8, 72.1 , 72.3, 72.5 (C2, C5), 72.8 (C3A), 73.1 (C3), 80.7 (C2A), 81.6, 81.8 (C4), 82.3 (C4A), 100.4 (ClA), 101.9, 102.0 (C1).
FABMS C4~H79035N3 ~ 12 6 8 ( M+Na ) .
Example 8 2-O-Azidoalkyl-alpha-cyclodextrin and 3-O-Azidoalkyl-alpha-cyclodextrin ~~a~82~
To a solution of dried a-cyclodextrin (2.4 g, 2.46 mmol) in DMSO (15 ml) was added lithium hydride (30 mg, 1.5 eq). The mixture was stirred under Argon until the .
solution became clear (24 hours). To this solution was added 1-iodo-n-azidoal)cane (1.5 eq). The mixture was allowed to stand at 60°C for 10 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 products corresponding to dialkyl, monoalkyl-a-cyclodextrin, and starting material. After evaporation of DMSO in vacuo, the residence was dissolved in water (5 ml), then applied on a silica gel column (4x40 cm) . Elution with CIi3CN/HZO, 9/1 removed the dialkyl, monoalkyl derivatives, and starting material were eluted with CH3CN/H20, 8/2. The pure fractions of monoalkyl-a-cyclodextrin were combined, then concentrated in vacuo to give a solid. The '3C NMR spectra showed that the alkylation had occurred at C-2 and'C-3 positions at almost the same ratio.
N~
N~~ N3 N. I, ~3 a a /~ O
O
2- -O-Azidopro~~yl-a-cyclodextrin and 3-O-Azidopropyl-a-cyclodextrin a Yield 300 a.(3) O~N3 mp 165°C (dec).
[a]p+136.4° (c 0.22, MeOII) .
IR (I<Br) 3400 (OI3) , 2100 (N3) .
~H NMR (DMSO-d6, 3200 MHz) ~ : 1.68-1.82 (m, 2H (propyl), 3.18 (dd, 1H, Jz_~ = 3.3, Jz_3 = 9.4, H2A) , 3.20-3.48 (m, 26H, ~~008~0 H2, H4, (propyl), Hz0), 3.48-3.88 (m, 25H, H3, H5, H6, (propyl) , 3.90 (td, 1H, J3_Z = J3_4 = 8 ~ 9, JH3-OH = 2 ~9, H3A) 5.35-5.75 (m, 11H, OH2, OH3).
On the ~3C NMR spectrum the peaks corresponding to 2-O-Azidopropyl-a-cyclodextrin were assigned as following:
'3C NMR (DMSO-d6, 300 MHz) ~ : 28.9, 47.6 (propyl) , 60.0 (C6), 68.6 (propyl), 71.9, 72.2 (C2, C5), 72.8 (C3A), 73.2, 73.4 (C3) , 80.6 (C2A) , 81.8, 82.2, 82.4 (C4) , '82.7 (C4A) , 100.0 (C1f'), 102.1, 102.2 (C1).
FABMS C39Fi6s03oN3 ~ 1078 (M+Na) 2-O-Azidobutyl-a-cyclodextrin, and 3-O-Azidobutyl-a-cyclo-dextrin a 2 o z ( 3) Oi~~ N3 Yield 36%
mp 220°C (dec).
[a]o+123.5° (C 0.37, MeOH).
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MHz) ~ : 1.45-1.65 (m, 4H, (butyl)), 3. 18 (dd, 1H, JZ_~ = 3.0, Jz_3 = 9.8, H2A) , 3. 22-3.48 (m, 26H, H2, H4, (butyl), Hz0), 3.48-3.82 (m, 23fi, H3, H5, H6), 3.84-3.96 (m, 3H, H3A, (butyl) ) , 4 . 39-4. 60 (m, 6H, OH6) , 4.74-4 .84 (m, 5H, H1) , 4 .95 (d, 1H, Ji_z = 3.1, H1A) , 5.32-5.80 (m, lli-i, OH2, OH3) .
On the '3C NMR spectrum the peaks corresponding to 2-O-Azidobutyl-a-cyclodextrin were assigned as following:
~3C NMR (DMSO-d6, 300 MHz) ~: 24.8-26.6, 50.6 (butyl), 60.0 (C6), 71.0 (butyl), 71.9, 72.2 (C2, C5), 72.8 (C3"), 73.1, 73.2, 73.3, 73.4 (C3), 80.4 (C2A), 81.8, 82.1, 82.4 (C4), 2~~~~~0 82.7 (C4~) , 102. 0, 1.02.1 (C1) .
FABI~IS C4~II6~03oN3 . 1092 (M-i-Na) .
2-O-AzidopPntYl a cyclodextrin and 3-0-Azidopentvl-a-cyclodextrin a.
2(~~ O N3 Yield 300 mp 235°C (dec).
(a]p+108.5° (c 0.37, MeOH) .
IR (KBr) 3400 (OH) , 2100 (N3) .
III NMR (DMSO-d6) , 300 MHz) ~ : 1. 28,-1.40 (m, 2H (pentyl) ) , 1. 42-1. 60 (m, 4H (pentyl) , 3 . 12-3. 19 (m, 1H, H2A) , 3 . 19-3.45 (m, 26f-I, H2, H4, (pentyl) , H20) ) , 3.45-3.82 (m, 23FI, H3, H5, H6), 3.82-3.95 (m, 31i, H3", (pentyl)), 4.4,0-4.58 (m, 6H, OI16) , 4 .74-4.85 (m, 5I-i, I-I1) , 4 .94 (d, lI-i, J~_z = 3 . 1 H1A) , 5.33-5.72 (m, 11H, 0132, Oft3) .
On.the '3C NMR spectrum the peaks corresponding to 2-O-Azidopentyl-a-cyclodextrin were assigned as following:
~3C NMR (DMSO-d6, 300 I~IEIz) ~ . 22.5, 28.0, 28.9, 50.6 (pentyl), 60.0 (C6), 71.4 (pentyl), 71.7, 71.9, 72.2, 72.3 (C2 C5), 72.8 (C3''), 73.2, 73.3, 73.4, 73.6 (C3), 80.4 (C2~') , 81.8, 82. l, 82.4 (C4) , 82.7 (C4~) , 100. 1 (ClA) , 101.9, 102.0, 102.1, 102.2 (C1).
FABMS C4~H69030N3 ~ 1106 (M+Na) .
The novel compounds of this invention have properties similar to those of the known cyclodextrins.
Although embodiments of the invention have been described above, it is not limited thereto and it will be apparent to those s)cilled in the art that numerous modifications form part of the present invention insofar as ~~oo~~o ..
they do not depart from the spirit, nature and scope of the claimed and described invention.
V. 5 ~I : X13 4-( ) I
Analytical reversed phase 1-1PLC of the mixture of the 3 isomers of triazido-a cvclodextrin. A stepwise gradient elution was applied : 10 ~Io ivIeOH/H.''.O
for 10 mina, then ~0 % VIe01-UH?0 for?0 min: , column was washed with MeOH
between injections.
Retention times of the peal, 7. -: (p), and ~ l-1) :u'o respectively :
2'_'.16, '_'=1.03, and ?6.67 min.
100_mg of this mixture yields by semi preparative reversed HPLC. (Novapak C18 Column, 7.8x300 mm) 16 mg, 80%, 50.mg, 70~, and 8 mg, 70% of pure isomers.
The determination of the structure of the 3 isomers was done by ~3C NMR and Korner's method. The isomer 7 on the HPLC chromatogram correspond to the ACE isomer, the isomer 4(5) to the ABD or ABE isomer and the isomer 5(4) to the ABE or ABD isomer.
2 0 ~ R~,d~:~.~.
~./ 'r 1 ' a-cvclodex~=i, w ' 5 ( l ~6 -=t ~(S) 4-isomer Determination of Di- and Triazido-a-cyclodextrin by Korner's method (J. Am. Chem. Soc. 1986, 108,4509).
Example 4 2-O-Allyl-6-azido-6-deoxy-alpha-cyclodextrin and 2 O Ally_1 6 6'- --diazido-6 6'-dideoxy-alpha-cyclodextrin To a solution of dried 2-O-allyl-a-cyclodextrin (872 mg, 0.86 mmol) in DMF (30 ml) were added lithium azide (420 mg, 10 eq), triphenylphosphine (564 mg, 2.5 eq) and carbon tetrabromide (715 mg, 2.5 eq). The addition of the latter caused a mildly exothermic reaction and the solution turned 21~Q~~0 ( .
yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 major products having Rf values of 0.54, 0.40, 0.20, and corresponding respectively to diazido-monoallyl-a-cyclodextrin, monoazido-monoallyl-a-cyclodextrin and starting material. After addition of methanol (5 ml), the brown solution was concentrated to about 3 ml by rotary evaporation under reduced pressure, then applied on a silica gel column (4x40 cm) eluting with CH3CN/HzO, 92/8 (11), 90/10 (1.51), then 85/15 (1.51). The pure fractions were combined, then concentrated in vacuo to give: 2-O-allyl-6-azido-6-deoxy-a-cyclodextrin (320 mg, 36%), and 2-O-allyl-6,6'-diazido-6,6'-dideoxy-a-cyclodextrin (160 mg, 20%) .
2-O-ally~l-6-azido-6-deoxy-a-Cvclodextrin mp = 175°C (dec). a [a]p+153° (c 0.1, H20) .
IR (KBr) 3400 (OH), 2100 (N3). O
~H ~NMR (DMSO-d6, 300 MHz) ~ : 3.15-3.49 (m, 20H, H2, H4, Hz0), 3.49-3.70 (m, 18H, H5, H6), 3.70-3.87 (m, 5H, H3), 3.87-3.90 (m, 1H, H3") , 4. 16 (dd, 1H, Jd_e = 12.8, Jd_~ = 5.7, Hd) , 4.28 (dd, 1H, J~_d = 12.8, Je_~ = 5.7, He) , 4.38-4.65 (m, 5H, OH6), 4.78, 4.84, 4.96, 5.02 (s, 6H, H1, H1"), 5.17 (d, 1H, Je_~ = 10.3, Ha), 5.29 (d, 1H, Jb_~ = 17.3, Hb), 5.37-5.78 (m, 11H, OH2, OH3), 5.78-5.96 (m; 1H, Hc).
~3C NMR (DMSO-d6, 300 MHz) ~: 51.3 (C6"), 60.1, 60.31, 60.33 (C6) , 70.4, 71.7, 71.9, 7.2.0, 72. 1, 72.3, 72.4 (C2, C5) , 72.7 (allyl) , 73.0 (C3") , 73. 1, 73.2, 73.3 (C3) , 79.6 (C2A) , 82.1, 82.2, 82.4, 82.5 (C4), 83.2 (C4a), 101.80 , 101.82 (C1"), 102.00, 102.07, 102.2 (C1), 117.8 (allyl), 134.8 (allyl).
FABMS C39H630z9N3 . 10 6 0 ( M+Na ) .
~~~Q~~O
2 O-allyl-6 6'-diazido-6 6'-dideoxy-a-Cvclodextrin N~ N
mp = 172°C (dec).
[a]o+131° (c 0.1, HZO) .
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MHz) H4, HZO) ~ : 3.20-3.48 (m, H2, , 3.48-3.69 (m, l8Fi, FiS, H6) , 3.69.3.88 H3) 3.88-(m, 5H, , 3.98 (m, 1H, H3A) ( 4. 16 (dd, 1H, = 12.8, = Hd) Jd_e Jd_~ 5.7.,, 4.28 (dd, 1H, Je_d = 12.8, Je_~ = Fie) , 4.50-4.70 5.7, (m, 4H, OH6), 4.77, 4.79, 4.83, 4.95, 5.00(s, 6H, H1A),5.18 H1, (d, 1H, Je_~ = 10.3 Ha), 5.29 (d, Jb_~ _ 17.3,Hb), 5.37-5.78 (m, llH, OH2, 1H, (m, 1H, OH3), 5.78-5.96 Hc).
~3C NMR (DMSO-d6, 300 MHz) ~: 51.3 (C6A), 60.0, 60.4 (C6), 70.4; 71.8, 72.0, 72.1, 72.2, 72.3, 72.4 (C2, C5); 72.7 (allyl), 73.0 (C3A), 73.3, 73.5, 73.6 (C3), 79.4 (C2A), 82.3, 82.5, 83.2, 83.3 (C4), 101.8, 101.9 (C1A), 102.0, 102.2 (C1), 117.7 (allyl), 134.8, 134.9 (allyl).
FABMS C39HszOzsN6 : 1085 (M+Na) . Example 5 2-O-All~l-6-azido-6-deoxy-alpha-cvclodextrin and 2-O-All~l-6 6'-diazido-6 6'-dideoxy-alpha-cyclodextrin and 2-O-A11y1-6 6' 6"-triazido-6 6' 6"-trideoxy-alpha-cyclodextrin To a solution of dried 2-O-allyl-a-cyclodextrin (740 mg, 0.73 mmol) in DMF (30 ml) were added lithium azide (358 mg, 10 eq), triphenylphosphine (574 mg, 3 eq) and carbon tetrabromide (728 mg, 3 eq) . The addition of the latter caused a mildly exothermic reaction and the solution turned yellow. The reaction was stirred under Argon at room temperature for 6 hours. TLC on silica gel (CH3CN/H20, 8/2) showed 3 major products having Rf values of 0.68, 0.54, ~1~~8~4 -.
0.40, and corresponding respectively to triazido-monoallyl-a-cyclodextrin, diazido-monoallyl-a-cyclodextrin and monoazido-monoallyl-a-cyclodextrin. After addition of methanol (5 ml), the brown solution was concentrated to about 3 mol by rotary evaporation under reduced pressure, then applied on a silica gel column (4x40 cm) eluting with CH3CN/HZO, 92/8 (11), 90/10 (1.51), then 85/15 (1.51). The pure fractions were combined, then concentrated in vacuo to give: 2-O-allyl-6-azido-6-deoxy-a-cyclodextrin (200 mg, 26%), 2-O-allyl-6,6'-diazido-6,6'-dideoxy-a-cyclodextrin (260 fig, 330) and 2-O-allyl-6,6',6"-triazido-6,6'-6"-tridexoy-a-cyclodextrin (214 mg, 27%).
2 O a11L1-6 6' 6"-triazido-6 6' 6"-tridexoy-a-CVClodextrin:
1~3 1V 3 a mp = 168°C (dec).
[a]p+110° (c 0.11, MeOH) .
IR (KBr) 3400 (OI-i) , 2100 (N3) .
~H NMR (DMSO-d6, 300 MHz) ~ : 3. 18-3.42 (m, H2, H4, Hz0) , 3.45-3.64 (m, 18H, H5, H6), 3.64-3.82 (m, 5H, H3), 3.82-3.95 (m, 1H, H3") , 4.12 (dd, 1H, Jd_e = 12.8, Jd_~ = 5.7, Hd) , 4.25 (dd, 1H, Je_d = 12.8, Je_~ = 5.7, He),, 4.50-4.70 (m, 3H, OH6), 4.72, 4.80, 4.90, 4.98 (s, 6H, H1, H1"),.5.11 (d, 1H, Je_~ = 10.3, Ha) , 5. 25 (d, 1H, Jb_~ = 17. 3, Hb) , 5.35-5.70 (m, 11H, OH2, OH3) , 5.75-5.95 (m, 1H, IIc) .
~3C NMR (DMSO-d6, 300 MHz) ~: 51.2, 51.3 (C6°') , 60.3 (C6) , 70.3, 71.7, 71.8, 72.0, 72.1, 72.3 (C2, C5), 72.7 (allyl), 73.0, 73.1, 73.2 (C3), 79.2, 79.3 (C2~), 82.6, 82.8, 83.1, 83.3 (C4), 101.6, 101.7, 101.8 (C1A), 102.00, 102.03, 102.1 (C1), 117.6, 117.7 (allyl), 134.7, 134.8 (allyl).
z~ o~g~o FABMS C39H6~ 027N9 ~ 1110 ( M+Na ) Example 6 Alphahalo-omega-azidohaloalkane 1-Iodo-n-azidoalkanes Preparation of chloroazidoalkanes:
To a solution of 1-bromo-n-chloroalkane (50 mmol) in DMSO (50 ml) was added sodium azide (3.25 g, 1 eq) . The solution was stirred at room temperature for 20 hours, then diluted with water (100 ml), and extracted with ether (2x100 ml). The organic layers were combined, then dried over anhydrous sodium sulfate. The residue obtained after removal of the solvent was used without further purification.
1-Chloro-3-azidopropane Yield 80%
~H NMR (CDC13, 300 MHz) . 2.00 (quint, 2H, J = 6.2), 3.48 (t, 2H, J = 6.4), 3.62 (t, 2H, J = 6.2).
1-Chloro-4-azidobutane Yield 86%
~H NMR (CDC13, 300 MHz) . 1.60-2.00 (m, 4H), 3.31 (t, 2H, J = 6.2), 3.54 (t, 2H, J = 6.2).
1-Chloro-5-azidopentane Yield 90%
~H NMR (CDC13, 300 MHz) . 1.47-1.68 (m, 4H), 1.80 (quint, 2H, J = 7.3), 3.29 (t, 2H, J = 6.4), 3.54 (t, 2H, J = 6.5) Preparation of iodoazidoalkanes:
A solution of chloroazidoalkane (50 mmol) and sodium iodide (7.5 g, 2 eq) in acetone was heated at reflux for 20 hours. After removal of the solvent in vacuo, the residue was diluted with water (30 ml), then extracted with ether (2x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate. The residue obtained after removal of the solvent was purified by distillation.
~2oosza 1-Iodo-3-azidopropane Yield 710 Ebo_~ 20-25°C
~H NMR (CDC13, 300 MHz) ~: 2.04 (quint, 2H, J = 7.3), 3.25 (t, 2H, J = 6.7), 3.43 (t, 2ii, J = 6.6).
1-Iodo-4-azidobutane Yield 75%
Ebo.~ 60°C
~H NrIR (CDC13, 300 MHz) ~5: 1.65-1.76 (m, 2H), 1.85-1.97 (m, 2H), 3.20 (t, 2H, J = 6.7), 3.31 (t, 2H, J = 6.6).
1-Iodo-5-azidopentane Yield 80%
EB0.1 70°C
1H NMR (CD13, 300 MHz) ~: 1.42-1.5,6 (m, 2H), 1.56-1.68 (m, 2H), 1.78-1.90 (quint, 2H, J = 7.3), 3.19 (t, 2H, J = 6.8), 3.29 (t, 2H, J = 6.6).
Example 7 2-O-Azidoalkyl-beta-cyclodextrin To a solution of dried f3-cyclodextrin (2.4 g, 2.11 mmol) in DMSO (15 ml) was added lithium hydride (26 mg, 1.5 eq). The mixture was stirred under Argon until the solution became clear (24 hours). To this solution was added 1-iodo-n-azidoalkane (1.5 eq). The mixture was allowed to stand at 60°C for 10 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 products corresponding to dialkyl, monoalkyl-f3-cyclodextrin, and starting material. After evaporation of DMSO in vacuo, the residue was dissolved in water (5 ml), then applied on a silica gel column (4x40 cm). Elution with CH3CN/HzO, 9/1 removed the dialkyl, monoalkyl derivatives, and starting material were eluted with CFi3CN/HZO, 8/2. The pure fractions of monoalkyl-f3 cyclodextrin were combined, the concentrated in vacuo to give a solid.
21p4~~0 ....
a i~~ ~, 2-O-Az idopropyl-fi-cy-clodextrin Yield 250 mp 210°C (dec).
[a]p+141.3° (c 0.22, MeOH). Q
IR (KBr) 3400 (OII) , 2100 (N3) .
~H NMR (DMSO-d6, 300 MHz) ~ : 1.68-1.85 (m, 2H (propyl)( 3.00-3.48 (m, 30H, fI2, H4, (propyl), Hz0), 3.49-3.90 (m, 30II, H3, H5, H6, (propyl) , 4.40-4..60 (m, 7Hi, OH6) , 4.78-4 .90 (m, 6I-I, H1.) , 4 . 95-5. 05 (m, 1H, H1A) , 5. 60-6. 10 (m, 13H, OH2, OH3).
'3C NMR (DMSO-d6, 300 MHz) ~ : 28.9, 47. 6 (propyl) , 60.0 (C6), 68.9 (propyl), 71.9, 72.1, 72.3, 72.5 (C2, C5), 72.7 (C3A), 73.1 (C3), 80.8 (C2A), 81.6, 81.7 (C4), 82.2 (C4A)r 100.2 (Cl"), 101.9, 102.0 (Cl).
FABMS C45H~SO35N3 . 1240 (M+Na) .
2-O-Az idobut~l-f3-cyclodextrin Yield 25%
mp 210°C (dec), [a]p+127.1° (c 0.22, Hz0) . Q
IR (KBr) 3400 (OH), 2100 (N3).
'H NMR (DMSO-d6, 300 MHz) ~ : 1.50-1.65 (m, 4H (butyl) ) , 3.22 (dd, 1H, Jz_~ - 3.3; Jz_3 = 10.0, H2A) , 3.22-3.48 (m, 30H, H1, H4, (butyl) , Hz0) , 3.48-3.82 (m, 30H, H2, H5, H6, (butyl)), 4.45 (t, 7H, JH6-OH = 5~2, OH6), 4.78-4.86 (m, 6H, H1) , 4.96 (d, 1H, J~_Z = 3.5, H1A) , 5. 55-6. 00 (m, 13H, OH2, OH3).
~3C NMR (DMSO-d6, 300 MHz) . 24.8, 26.5, 50.5 (butyl), 60.0 (C6), 71.3 (butyl), 71.8, 71.9, 72.1 72.3, 72.,5 (C2, C5) , 72.8 (C3A) , 73. 1, 73.2 (C3) , 80.7 (C2A) , 81.6, 81.8, 81.9 (C4), 82.3 (C4A), 100.4 (C1A), 101.9, 102.0 (C1).
FABMS C46H7~035N3 ~ 12 54 ( M+Na ) .
2-O-Az idopentyl-f3-c~clodextrin Yield 300 mp 230°C (dec).
[a]p+115.5° (c 0.20, MeOH).
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MHz) . 1.28-1.40 (m, 2H (pentyl), 1.47-1.60 (m, 4H (pentyl) ) , 3.21 (dd, 1H, JZ_~ = 3.3, J2_3 =
9.7, H2A), 3.21-3.48 (m, 30H, H2, H4, (pentyl), H20), 3.48-3.82 (m, 30H, H3, H5, H6, (pentyl) ) ) , 4.47 (t, 7H, JH6-OH
5.3, OH6) , 4.78-4.87 (m, 6H, H1) , 4.96 (d, 1H, J~_Z = 3.3, H1A), 5.55-6.00 (m, 13H, OH2, OH3).
~3C NMR (DMSO-d6, 300 MHz) . 22.5, 28.0, 50.6 (pentyl), 60.0 (C6), 71.7 (pentyl), 71.8, 72.1 , 72.3, 72.5 (C2, C5), 72.8 (C3A), 73.1 (C3), 80.7 (C2A), 81.6, 81.8 (C4), 82.3 (C4A), 100.4 (ClA), 101.9, 102.0 (C1).
FABMS C4~H79035N3 ~ 12 6 8 ( M+Na ) .
Example 8 2-O-Azidoalkyl-alpha-cyclodextrin and 3-O-Azidoalkyl-alpha-cyclodextrin ~~a~82~
To a solution of dried a-cyclodextrin (2.4 g, 2.46 mmol) in DMSO (15 ml) was added lithium hydride (30 mg, 1.5 eq). The mixture was stirred under Argon until the .
solution became clear (24 hours). To this solution was added 1-iodo-n-azidoal)cane (1.5 eq). The mixture was allowed to stand at 60°C for 10 hours. TLC on silica gel (CH3CN/HZO, 8/2) showed 3 products corresponding to dialkyl, monoalkyl-a-cyclodextrin, and starting material. After evaporation of DMSO in vacuo, the residence was dissolved in water (5 ml), then applied on a silica gel column (4x40 cm) . Elution with CIi3CN/HZO, 9/1 removed the dialkyl, monoalkyl derivatives, and starting material were eluted with CH3CN/H20, 8/2. The pure fractions of monoalkyl-a-cyclodextrin were combined, then concentrated in vacuo to give a solid. The '3C NMR spectra showed that the alkylation had occurred at C-2 and'C-3 positions at almost the same ratio.
N~
N~~ N3 N. I, ~3 a a /~ O
O
2- -O-Azidopro~~yl-a-cyclodextrin and 3-O-Azidopropyl-a-cyclodextrin a Yield 300 a.(3) O~N3 mp 165°C (dec).
[a]p+136.4° (c 0.22, MeOII) .
IR (I<Br) 3400 (OI3) , 2100 (N3) .
~H NMR (DMSO-d6, 3200 MHz) ~ : 1.68-1.82 (m, 2H (propyl), 3.18 (dd, 1H, Jz_~ = 3.3, Jz_3 = 9.4, H2A) , 3.20-3.48 (m, 26H, ~~008~0 H2, H4, (propyl), Hz0), 3.48-3.88 (m, 25H, H3, H5, H6, (propyl) , 3.90 (td, 1H, J3_Z = J3_4 = 8 ~ 9, JH3-OH = 2 ~9, H3A) 5.35-5.75 (m, 11H, OH2, OH3).
On the ~3C NMR spectrum the peaks corresponding to 2-O-Azidopropyl-a-cyclodextrin were assigned as following:
'3C NMR (DMSO-d6, 300 MHz) ~ : 28.9, 47.6 (propyl) , 60.0 (C6), 68.6 (propyl), 71.9, 72.2 (C2, C5), 72.8 (C3A), 73.2, 73.4 (C3) , 80.6 (C2A) , 81.8, 82.2, 82.4 (C4) , '82.7 (C4A) , 100.0 (C1f'), 102.1, 102.2 (C1).
FABMS C39Fi6s03oN3 ~ 1078 (M+Na) 2-O-Azidobutyl-a-cyclodextrin, and 3-O-Azidobutyl-a-cyclo-dextrin a 2 o z ( 3) Oi~~ N3 Yield 36%
mp 220°C (dec).
[a]o+123.5° (C 0.37, MeOH).
IR (KBr) 3400 (OH), 2100 (N3).
~H NMR (DMSO-d6, 300 MHz) ~ : 1.45-1.65 (m, 4H, (butyl)), 3. 18 (dd, 1H, JZ_~ = 3.0, Jz_3 = 9.8, H2A) , 3. 22-3.48 (m, 26H, H2, H4, (butyl), Hz0), 3.48-3.82 (m, 23fi, H3, H5, H6), 3.84-3.96 (m, 3H, H3A, (butyl) ) , 4 . 39-4. 60 (m, 6H, OH6) , 4.74-4 .84 (m, 5H, H1) , 4 .95 (d, 1H, Ji_z = 3.1, H1A) , 5.32-5.80 (m, lli-i, OH2, OH3) .
On the '3C NMR spectrum the peaks corresponding to 2-O-Azidobutyl-a-cyclodextrin were assigned as following:
~3C NMR (DMSO-d6, 300 MHz) ~: 24.8-26.6, 50.6 (butyl), 60.0 (C6), 71.0 (butyl), 71.9, 72.2 (C2, C5), 72.8 (C3"), 73.1, 73.2, 73.3, 73.4 (C3), 80.4 (C2A), 81.8, 82.1, 82.4 (C4), 2~~~~~0 82.7 (C4~) , 102. 0, 1.02.1 (C1) .
FABI~IS C4~II6~03oN3 . 1092 (M-i-Na) .
2-O-AzidopPntYl a cyclodextrin and 3-0-Azidopentvl-a-cyclodextrin a.
2(~~ O N3 Yield 300 mp 235°C (dec).
(a]p+108.5° (c 0.37, MeOH) .
IR (KBr) 3400 (OH) , 2100 (N3) .
III NMR (DMSO-d6) , 300 MHz) ~ : 1. 28,-1.40 (m, 2H (pentyl) ) , 1. 42-1. 60 (m, 4H (pentyl) , 3 . 12-3. 19 (m, 1H, H2A) , 3 . 19-3.45 (m, 26f-I, H2, H4, (pentyl) , H20) ) , 3.45-3.82 (m, 23FI, H3, H5, H6), 3.82-3.95 (m, 31i, H3", (pentyl)), 4.4,0-4.58 (m, 6H, OI16) , 4 .74-4.85 (m, 5I-i, I-I1) , 4 .94 (d, lI-i, J~_z = 3 . 1 H1A) , 5.33-5.72 (m, 11H, 0132, Oft3) .
On.the '3C NMR spectrum the peaks corresponding to 2-O-Azidopentyl-a-cyclodextrin were assigned as following:
~3C NMR (DMSO-d6, 300 I~IEIz) ~ . 22.5, 28.0, 28.9, 50.6 (pentyl), 60.0 (C6), 71.4 (pentyl), 71.7, 71.9, 72.2, 72.3 (C2 C5), 72.8 (C3''), 73.2, 73.3, 73.4, 73.6 (C3), 80.4 (C2~') , 81.8, 82. l, 82.4 (C4) , 82.7 (C4~) , 100. 1 (ClA) , 101.9, 102.0, 102.1, 102.2 (C1).
FABMS C4~H69030N3 ~ 1106 (M+Na) .
The novel compounds of this invention have properties similar to those of the known cyclodextrins.
Although embodiments of the invention have been described above, it is not limited thereto and it will be apparent to those s)cilled in the art that numerous modifications form part of the present invention insofar as ~~oo~~o ..
they do not depart from the spirit, nature and scope of the claimed and described invention.
Claims (15)
1. a compound of formula wherein C is cyclodextrin, A is azido and n is 0, 1, 2 or 3, R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or azidoalkyl of 1 to 6 carbon atoms, with the proviso when R is azidoalkyl, n is 0.
2. A compound of claim 1, wherein n is l, 2 or 3, R is alkyl of 1 to 6 carbon atoms, or alkenyl of 2 to 6 carbon atoms.
3. A compound of claim 2 selected from the group consisting of 6,6'-diazido-6,6'-dideoxy-alpha-cyclodextrin, 6,6',6"-triazido-6,6',6"-trideoxy-alpha-cyclodextrin, and 2-0-allyl-6-azido-6-deoxy-alpha-cyclodextrin, 2-0-allyl-6,6'-diazido-6,6'-dideoxy-alpha-cyclodextrin and 2-0-allyl-6,6',6"-triazido-6,6',6"-trideoxy-alpha-cyclodextrin.
4. A compound of claim 3, selected from the group consisting of the 1,3- and 1,4- isomers of 6,6'-diazido-6,6'-dideoxy-alpha-cyclodextrin, and the 1,3,5,-,1,2,4- and 1,2,5- isomers of 6,6',6"-triazido-6,6',6"-trideoxy-alpha-cyclodextrin.
5. A compound of claim 1, wherein n is 0 and R is azidoalkyl.
6. A compound of claim 1, selected from the group consisting of 2-0-azidopropyl-beta-cyclodextrin, 2-0-azidobutyl-beta-cyclodextrin, 2-0-azidopentyl-beta-cyclodextrin, 3-0-azidopropyl-beta-cyclodextrin, 3-0-azidobutyl-beta-cyclodextrin, and 3-0-azidopentyl-beta-cyclodextrin.
7. A process of preparation of a compound of formula wherein C is cyclodextrin, A is azido nad n is 0, 1, 2 or 3, R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or azidoalkyl or 1 to 6 carbon atoms, with the proviso when R is azidoalkyl, n is 0, comprising when n is 1, 2, or 3 reacting a cyclodextrin of formula wherein C is cyclodextrin, R is hydrogen, alkyl of 1 to 6 carbon atoms, or alkenyl of 2 to 6 carbon atoms, with alkali metal azide triphenyl phosphine, and carbon tetrabromide, when n is 0 reacting cyclodextrin with alkali metal hydride in a first step, and the product thereof with haloazidoalkane in a second step.
8. A process of claim 7 wherein n is 1, 2 or 3.
9. A process of claim 8 wherein R is hydrogen, C is alpha-cyclodextrin and the alkali metal azide is lithium azide.
10. A process of claim 8 wherein R is allyl, C is alpha-cyclodextrin and the alkali metal azide is lithium azide.
11. A process of claim 7 wherein n is 0.
12. A process of claim 11 wherein R in the formula II is hydrogen, C is beta-cyclodextrin, the alkali metal hydride is lithium hydride and the haloazidoalkane is iodoazidoalkane.
13. A process of claim 12 wherein the iodoazidoalkane is 1-iodo-3-azidopropane.
14. A process of claim 12 wherein the iodoazidoalkane is 1-iodo-4-azidobutane.
15. A process of claim 12 wherein the iodoazidoalkane is 1-iodo-5-azidopentane.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002100820A CA2100820C (en) | 1993-07-19 | 1993-07-19 | Amino-cyclodextrin and related structures |
| PCT/US1994/008103 WO1995003336A1 (en) | 1993-07-19 | 1994-07-19 | Amino-cyclodextrin syntheses |
| US08/583,097 US5959089A (en) | 1993-07-19 | 1994-07-19 | Amino-cyclodextrin syntheses |
| AU74730/94A AU7473094A (en) | 1993-07-19 | 1994-07-19 | Amino-cyclodextrin syntheses |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002100820A CA2100820C (en) | 1993-07-19 | 1993-07-19 | Amino-cyclodextrin and related structures |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2100820A1 CA2100820A1 (en) | 1995-01-20 |
| CA2100820C true CA2100820C (en) | 1999-11-02 |
Family
ID=4151944
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002100820A Expired - Lifetime CA2100820C (en) | 1993-07-19 | 1993-07-19 | Amino-cyclodextrin and related structures |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7473094A (en) |
| CA (1) | CA2100820C (en) |
| WO (1) | WO1995003336A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2860082B2 (en) * | 1995-07-08 | 1999-02-24 | 株式会社分子バイオホトニクス研究所 | Novel cyclodextrin derivatives with isothiocyanate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3810737A1 (en) * | 1988-03-30 | 1989-10-12 | Macherey Nagel Gmbh & Co Kg | SUBSTITUTED CYCLODEXTRINE |
-
1993
- 1993-07-19 CA CA002100820A patent/CA2100820C/en not_active Expired - Lifetime
-
1994
- 1994-07-19 AU AU74730/94A patent/AU7473094A/en not_active Abandoned
- 1994-07-19 WO PCT/US1994/008103 patent/WO1995003336A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995003336A1 (en) | 1995-02-02 |
| AU7473094A (en) | 1995-02-20 |
| CA2100820A1 (en) | 1995-01-20 |
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