Dendritic polyethylene glycol derivative, and preparation method and application thereof
11053185 · 2021-07-06
Assignee
Inventors
Cpc classification
C07C43/11
CHEMISTRY; METALLURGY
A61K47/14
HUMAN NECESSITIES
C07C217/08
CHEMISTRY; METALLURGY
A61K47/60
HUMAN NECESSITIES
International classification
C07C43/11
CHEMISTRY; METALLURGY
C07C233/56
CHEMISTRY; METALLURGY
A61K47/60
HUMAN NECESSITIES
Abstract
The disclosure discloses a dendritic polyethylene glycol derivative and a preparation method and an application thereof. The dendritic polyethylene glycol derivative has a structure of formula (I), has multiple end functional groups, has a stronger water solubility in comparison with linear-chain polyethylene glycol, and can solve a problem of insufficient water solubility due to the increase of load when modifying an insoluble drug by the polyethylene glycol. The preparation method of the dendritic polyethylene glycol derivative provided by the disclosure has mild reaction conditions, is green and environmentally friendly, is low in cost, and is easy to implement industrialization. ##STR00001##
Claims
1. A dendritic polyethylene glycol derivative having a structure of formula (I): ##STR00049## wherein, A.sub.1, A.sub.2, D.sub.1 and D.sub.2 are Y-X-structures, which are the same or different, or ##STR00050## structures, which are the same or different; J and K are Y-X-structures, which are the same or different; R.sub.a1, R.sub.a2, R.sub.a3, R.sub.a4, R.sub.b1, R.sub.b2, R.sub.d1, R.sub.d2, R.sub.d3 and R.sub.d4, as well as R.sub.j and R.sub.k are linking groups independently selected from one or a combination of several of (CH.sub.2).sub.r, (CR.sub.1R.sub.2).sub.r, (CH.sub.2).sub.rNH, NHCO(CH.sub.2).sub.r, (CH.sub.2).sub.rCONH and CO(CH.sub.2).sub.r, and r is an integer of 0 to 30, R.sub.1 and R.sub.2 are independently selected from one or a combination of several of H, C1C6 alkyl, OR, NHR, N(R).sub.2, CN, F, Cl, Br, I, COR, COOR, OCOR, CONHR and CON(R).sub.2, R is selected from H, C1C6 alkyl, F, Cl, Br and I, and B is selected from one of OH, NH.sub.2, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, SH, CH.sub.2CH.sub.2CHO and CH.sub.2CH.sub.2CH.sub.2CHO; X is a linking group selected from one or a combination of more than two of (CH.sub.2).sub.i, (CH.sub.2).sub.iNH, CO(CH.sub.2).sub.i, (CH.sub.2).sub.iOCOO, (CH.sub.2).sub.iOCONH, (CH.sub.2).sub.iNHCONH, OC(CH.sub.2).sub.iCOO, (CH.sub.2).sub.iCOO and (CH.sub.2).sub.iCONH, and i is an integer of 0 to 10; Y is an end group selected from one of C1C6 alkyl, C1C6 alkoxy, H, hydroxyl, amino, aminomethyl, maleimide group, carboxyl, ester, sulfhydryl, succinimidyl carbonate, succinimidyl acetate, succinimidyl propionate, succinimidyl succinate, succinimidyl, dithiopyridyl, propionic acid, aldehyde group, thioester group, acrylic group, acryloxy, azido, glutaric group, hydrazide, alkynyl, p-nitrophenyl carbonate, isocyanato, silane, carboxymethyl, vinyl sulfone group and vitamin H residue; E.sub.1-7, E.sub.j and E.sub.k are polyethylene glycol groups (OCH.sub.2CH.sub.2).sub.m, which are the same or different, and m is an integer of 0 to 100; L.sub.1-3 and L.sub.n are branching points independently selected from one or a combination of more than two of structures of formulae (II) to (VIII): ##STR00051## Z is selected from one of O, S, NH, NHCO, CO, COO, OC(O) and (CH.sub.2).sub.s, and s is an integer of 0 to 10; p is an integer of 0 to 10; W is O or S; and V is O or NH.
2. The derivative of claim 1, wherein the Z is selected from one of O, NH, NHCO and (CH.sub.2).sub.s; and/or, the R.sub.a1, the R.sub.a2, the R.sub.a3, the R.sub.a4, the R.sub.b1, the R.sub.b2, the R.sub.d1, the R.sub.d2, the R.sub.d3, the R.sub.d4, the R.sub.j and the R.sub.k are (CH.sub.2).sub.r, which are the same or different, and r is selected from an integer of 0 to 10.
3. The derivative of claim 1, wherein the L.sub.1-3 and the L.sub.n are independently selected from ##STR00052##
4. The derivative of claim 1, wherein the X is (CH.sub.2).sub.i, CO(CH.sub.2).sub.i, (CH.sub.2).sub.iNH or (CH.sub.2).sub.iCONH, and/or the i is 0, 1, 2, 3 or 4; and/or, the Y is selected from one of methyl, methoxy, hydroxyl, amino, azido, sulfydryl, carboxyl, ester, aldehyde group, acrylic group and maleimide group.
5. The derivative of claim 1, wherein the A1, the A2, the D1 and the D2 are independently selected from one of H, CH.sub.3, OCH.sub.3, OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NH.sub.2, N.sub.3, CH.sub.2N.sub.3, CH.sub.2CH.sub.2N.sub.3, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, SH, CH.sub.2CH.sub.2CHO and CH.sub.2CH.sub.2CH.sub.2CHO.
6. The derivative of claim 1, wherein m in the polyethylene glycol group (OCH.sub.2CH.sub.2).sub.m is an integer of 0 to 20.
7. The derivative of claim 1, wherein the dendritic polyethylene glycol derivative is selected from structures of following formulae (IX) to (IX): ##STR00053##
8. The derivative of claim 1, wherein the dendritic polyethylene glycol derivative is selected from structures of following formulae (XIII) to (XVI): ##STR00054## m1-6 is independently selected from an integer of 0 to 20; and/or, in the A.sub.1, the A.sub.2, the D.sub.1, the D.sub.2 and the B, the X is selected from one or a combination of several of (CH.sub.2).sub.i, CO(CH.sub.2).sub.i, (CH.sub.2).sub.iNH and (CH.sub.2).sub.iCONH; and/or, in the A.sub.1, the A.sub.2, the D.sub.1, the D.sub.2 and the B, the Y is selected from one of methoxy, hydroxyl, amino, azido, sulfydryl, carboxyl, ester, aldehyde group, acrylic group and maleimide group; and/or, the R.sub.a1, the R.sub.b1 and the R.sub.d1 are (CH.sub.2).sub.r, which are the same or different, and r is selected from an integer of 0 to 10; and/or, the Z is O or NHCO.
9. The derivative of claim 8, wherein the dendritic polyethylene glycol derivative has structures of following formulae: ##STR00055## ##STR00056##
10. A covalent conjugate, comprising the dendritic polyethylene glycol derivative of claim 1 and a drug molecule, which are linked by a covalent bond.
11. The derivative of claim 6, wherein m in the polyethylene glycol group (OCH.sub.2CH.sub.2).sub.m is an integer of 0 to 12.
12. The derivative of claim 11, wherein m in the polyethylene glycol group (OCH.sub.2CH.sub.2).sub.m is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
13. The derivative of claim 8, wherein m1-6 is independently selected from an integer of 0 to 12.
14. The derivative of claim 8, wherein m1-6 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.
Description
BRIEF DESCRIPTION OF DRAWINGS
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
DETAILED DESCRIPTION OF THE EMBODIMENTS
(11) Unless otherwise defined, all the technical and scientific terms used in the disclosure have the same meaning as commonly understood by those skilled in the art to which the disclosure belongs. For example, alkyl refers to linear-chain or branched-chain hydrocarbon chain radical without unsaturated bonds, and C1-C6 alkyl refers to alkyl containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, or the like; alkoxy refers to a substituent formed after hydrogen in hydroxyl is substituted by alkyl, and C1-C6 alkoxy refers to alkoxy containing 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, or the like. In addition, some groups involved in the disclosure and chemical structures thereof correspond to the followings: hydroxyl, OH; amino, NH.sub.2; aminomethyl-CH.sub.2NH.sub.2; maleimide group,
(12) ##STR00024##
carboxyl,
(13) ##STR00025##
ester,
(14) ##STR00026##
(wherein Q.sub.1 may be an alkyl, an aryl or a heterocyclyl, such as a methyl, an ethyl, an n-propyl, a t-butyl,
(15) ##STR00027##
etc.); sulfydryl, SH; succinimidyl carbonate group,
(16) ##STR00028##
succinimidyl acetate group,
(17) ##STR00029##
succinimidyl propionate group,
(18) ##STR00030##
a succinimidyl succinate group,
(19) ##STR00031##
succinimidyl,
(20) ##STR00032##
dithiopyridyl, such as 2-pyridyldithio
(21) ##STR00033##
and 4-pyridyldithio,
(22) ##STR00034##
propionic acid,
(23) ##STR00035##
aldehyde group, CHO; thioester
(24) ##STR00036##
(wherein Q.sub.2 may be alkyl, such as methyl, ethyl, n-propyl, tert-butyl, etc.); acrylic group,
(25) ##STR00037##
acryloxy
(26) ##STR00038##
azido,
(27) ##STR00039##
glutaric group, such as
(28) ##STR00040##
hydrazide,
(29) ##STR00041##
alkynyl,
(30) ##STR00042##
p-nitrophenyl carbonate,
(31) ##STR00043##
isocyanato,
(32) ##STR00044##
silane group,
(33) ##STR00045##
(wherein Q.sub.3 may be alkyl or alkoxy, which may be the same or different, such as methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, or the like; and preferably, all the Q.sub.3 are methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, etc.); carboxymethyl,
(34) ##STR00046##
vinylsulphone group,
(35) ##STR00047##
and vitamin H residue,
(36) ##STR00048##
(37) The convergent synthesis method described in the disclosure refers to starting from an edge part of a dendrimer molecule to be synthesized, and proceeding inwards gradually. First, a part of a dendritic macromolecule, i.e., a wedge-shaped structure, is synthesized by using a divergent method, and then the synthesized part of the dendritic macromolecule is linked with a core to finally form the dendrimer (as described in 19(3): 6-9 of Fine and Specialty Chemicals, Synthesis and Application of Dendrimer [J], 2011, written by Wang Hetong).
(38) The following clearly and completely describes the technical solutions of the disclosure with reference to the examples of the disclosure. Apparently, the described examples are merely some but not all of the examples of the disclosure. Based on the examples in the disclosure, all other examples obtained by those of ordinary skills in the art without going through any creative work shall fall within the scope of protection of the disclosure.
Example 1 Synthesis of Raw Materials
I. Synthesis of Raw Material (mEG.SUB.3.).SUB.2.NC.SUB.3.H.SUB.6.OH(1)
(39) A synthetic route of the (mEG.sub.3).sub.2NC.sub.3H.sub.6OH(1) is as shown in
1. Synthesis of mEG.SUB.3.-OMs
(40) TEA (32 mL, 230 mmol) and 150 mL of DCM were added to mEG.sub.3-OH (32 mL, 200 mmol) and placed in a reaction flask in an ice-water bath. MsCl (17.5 mL, 220 mmol) was dissolved with DCM (50 mL) and added dropwise to the reaction flask in the ice-water bath after the MsCl was completely dissolved. The mixture was reacted at room temperature for 3 hours. The reaction was detected to be complete by a thin layer chromatography (TLC). The resulting product was washed with water (150 mL) three times. An organic phase was dried with anhydrous sodium sulfate and filtered to remove sodium sulfate. The remaining was concentrated to obtain about 52 g of product.
2. Synthesis of (mEG.SUB.3.).SUB.2.NC.SUB.3.H.SUB.6.OH
(41) The mEG.sub.3-OMs (21.6 g, 89.3 mmol) prepared in the step 1 above and THF (150 mL) were added to aminopropanol (3.1 g, 41.3 mmol). After heating and refluxing overnight, a supernatant was poured out and evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (250 g of silica gel, a MeOH/DCM system being a mobile phase, MeOH/DCM=3-7%) to obtain 2.5 g of product with a yield of 16%.
(42) NMR(CDCl.sub.3) : 3.5-3.8 (m, 22H, OCH.sub.2), 3.37 (s, 6H, CH.sub.3O), 2.7-2.8 (m, 6H, N(CH.sub.2).sub.3), 1.6-1.7 (m, 2H, NCH.sub.2CH.sub.2CH.sub.2OH); ESI-MS: 368.3 (M+H).sup.+, 390.2 (M+Na).sup.+.
II. Synthesis of Raw Material (mEG.SUB.3.).SUB.2.-OH
(43) A synthetic route of the (mEG.sub.3).sub.2-OH is as shown in
1. Synthesis of mEG.SUB.3.-OMs
(44) TEA (32 mL, 230 mmol) and DCM (150 mL) were added to mEG.sub.3-OH (32 mL, 200 mmol) and placed in a reaction flask in an ice-water bath. MsCl (17.5 mL, 220 mmol) was dissolved with DCM (50 mL) and added dropwise to the reaction flask in the ice-water bath after the MsCl was completely dissolved. The mixture was reacted at room temperature for 3 hours. The reaction was detected to be complete by a thin layer chromatography (TLC). The remaining was washed with water (150 mL) three times. An organic phase was dried with anhydrous sodium sulfate and filtered to remove sodium sulfate. The remaining was concentrated to obtain about 52 g of product.
2. Synthesis of (mEG.SUB.3.).SUB.2.-O-Allyl
(45) Toluene (75 mL) was added to 3-propenyloxy-1,2-propanediol (3.01 mL), then NaH (60%, 2.05 g) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (80 mL) containing mEG.sub.3-OMs was added dropwise, and reacted at 60 C. overnight; then HPLC detection was carried out, and the toluene was evaporated to dryness; the remaining was added with DCM and water and washed once respectively, and then the DCM was evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (1% MeOH/DCM being a mobile phase) to obtain 8.8 g of product (with a yield of 85%).
3. Synthesis of (mEG.SUB.3.).SUB.2.-OH
(46) Pd/C (0.8 g) and TsOH (1.6 g) were added to the product (8 g) of the step 2 above, then methanol (80 mL)/water (16 mL) was added and refluxed for 24 hours. It was found by HPLC that the reaction was complete. Pd/C was recovered by filtration and then concentrated to obtain a crude product. The crude product was subjected to column purification (3% MeOH/DCM) to obtain 5.8 g of product (with a yield of 80.2%).
(47) NMR(CDCl.sub.3) : 3.89-3.50 (m, 29H), 3.38 (s, 6H); ESI-MS: 385.4 (M+H).sup.+, 407.2 (M+Na).sup.+.
III. Synthesis of Raw Material (tBuOC-EG.SUB.4.).SUB.2.NC.SUB.3.H.SUB.6.OH (2)
(48) A synthetic route of the (tBuOC-EG.sub.4).sub.2NC.sub.3H.sub.6OH (2) is as shown in
1. Synthesis of MsO-EG.SUB.4.-OtBu
(49) DCM (350 mL) and TEA (22.7 mL, 0.159 mol, 1.3 eq) were added to HO-EG.sub.4-tBu (39.4 g, 0.122 mol). A DCM (150 mL) solution of MsCl (11.4 mL, 0.146 mol, 1.2 eq) were added under an ice-water bath, and reacted at room temperature overnight. The remaining was washed with water (200 mL) three times in turn, dried by over anhydrous sodium sulfate, filtered, and then a solvent was removed by evaporation to obtain a product.
2. Synthesis of (tBuO-EG.SUB.4.).SUB.2.NC.SUB.3.H.SUB.6.OH
(50) Aminopropanol (1.9 mL, 25 mmol) and DMF (200 mL) were added to the MsO-EG.sub.4-OtBu (20 g, 50 mmol) prepared in the step 1 above, and stirred at 70 C. overnight. The remaining was concentrated to obtain a crude product. The crude product was subjected to column purification (MeOH/DCM=0-10%) to obtain 2.3 g of product with a yield of 12.0%.
(51) NMR(CDCl.sub.3) : 3.5-3.8 (m, 34H, OCH.sub.2); 3.3 (m, 6H, N(CH.sub.2).sub.3); 2.5- (t, 2H, CH.sub.2COO); 1.7-1.8 (m, 2H, NCH.sub.2CH.sub.2CH.sub.2OH); 1.4 (s, 18H, (CH.sub.3).sub.3); ESI-MS: 706.3 (M+Na).sup.+.
IV. Synthesis of Raw Material (N.SUB.3.-EG.SUB.4.).SUB.2.-EG.SUB.4.-OH (3)
(52) A synthetic route of the (N.sub.3-EG.sub.4).sub.2-EG.sub.4-OH (3) is as shown in
(53) 1. Synthesis of TrO-EG.sub.4-OH
(54) Toluene was added to EG.sub.4 (245 g), pyridine (30 mL) was added after water was removed by azeotropy, stirred for 5 minutes, and then then triphenylchloromethane (69.7 g) was added, and stayed at room temperature overnight. The remaining was washed with water three times to obtain 87 g of product (with a yield of 80%).
2. Synthesis of TrO-EG.SUB.4.-OMs
(55) DCM (500 mL) and TEA (33 mL) were added to TrO-EG.sub.4-OH (87 g), a DCM solution (200 mL) containing methanesulfonyl chloride (17 mL) was added dropwise under an ice-water bath, and reacted at room temperature overnight. The remaining was washed with water twice, evaporated to dryness, and then concentrated to obtain a product (with a yield of about 100%).
3. Synthesis of (N.SUB.3.-EG.SUB.4.).SUB.2.-O-Allyl
(56) Toluene (40 mL) was added to 3-propenyloxy-1,2-propanediol (1.22 mL), then NaH (60%, 0.79 g) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (80 mL) containing N.sub.3-EG.sub.4-OMs (6.1 g) was added dropwise, and reacted at 60 C. overnight; then HPLC detection was carried out, and the toluene was evaporated to dryness; the remaining was added with DCM and water and washed once respectively, and then the DCM was evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (1% MeOH/DCM being a mobile phase) to obtain 4.3 g of product (with a yield of 85%).
4. Synthesis of (N.SUB.3.-EG.SUB.4.).SUB.2.-OH
(57) Pd/C (0.4 g) and TsOH (0.8 g) were added to the product (4 g) of the step above, then methanol (40 mL)/water (8 mL) was added and refluxed for 24 hours. It was found by HPLC that the reaction was complete. Pd/C was recovered by filtration and then concentrated to obtain a crude product. The crude product was subjected to column purification (3% MeOH/DCM being a mobile phase) to obtain 3.0 g of product (with a yield of 82%).
5. Synthesis of (N.SUB.3.-EG.SUB.4.).SUB.2.-EG.SUB.4.-OTr
(58) Toluene (20 mL) was added to the product (1.5 g) of the step above, then NaH (60%, 128 mg) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (10 mL) of TrO-EG.sub.4-OMs (1.88 g) was added dropwise to the reaction solution, and reacted at 70 C. overnight; then the toluene was evaporated to dryness; the remaining was added with DCM and water and washed once. The DCM was evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (3% MeOH/DCM being a mobile phase) to obtain 2.08 g of product (with a yield of 75.4%).
6. Synthesis of (N.SUB.3.-EG.SUB.4.).SUB.2.-EG.SUB.4.-OH(3)
(59) DCM (15 mL) and TFA (5 mL) were added to the product (1.5 g) of the step above, and reacted at room temperature overnight. A solvent was evaporated to dryness and saturated brine was added, the mixture was washed with ethyl ether until no color appears on a water-liquid plate, then extracted with DCM, and an organic phase was evaporated to dryness to obtain 0.69 g of product (with a yield of 62.3%).
(60) NMR(CDCl.sub.3) : 3.1 (m, 4H, N.sub.3CH.sub.2); 3.5-3.8 (m, 50H, other hydrogen); ESI-MS: 693.2 (M+Na).sup.+.
Example 2 Synthesis of Dendritic Molecule ((mEG.SUB.3.).SUB.2.-NC.SUB.3.H.SUB.6.).SUB.2.NC.SUB.3.H.SUB.6.OH
(61) A synthetic route of the ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH is as shown in
1. Synthesis of (mEG.SUB.3.).SUB.2.-NC.SUB.3.H.SUB.6.-OMs
(62) TEA (1.4 mL) and 30 mL of DCM were added to (mEG.sub.3).sub.2-NC.sub.3H.sub.6OH((1), prepared in Example 1, 3.1 g), and placed in a reaction flask in an ice-water bath. MsCl (0.72 mL) was dissolved with DCM (5 mL) and added dropwise to the reaction flask in the ice-water bath after the MsCl was completely dissolved. The mixture was reacted at room temperature for 3 hours. The remaining was washed with water (30 mL) once. An organic phase was dried with anhydrous sodium sulfate and filtered to remove sodium sulfate. The remaining was concentrated to obtain about 3 g of product (with a yield of 79.8%).
2. Synthesis of Dendritic Molecule ((mEG.SUB.3.).SUB.2.-NC.SUB.3.H.SUB.6.).SUB.2.NC.SUB.3.H.SUB.6.OH
(63) The (mEG.sub.3).sub.2-N-C3H6-OMs (2.5 g) prepared in the step above and THF (30 mL) were added to aminopropanol (0.18 g). After heating and refluxing overnight, a supernatant was poured out and evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (a MeOH/DCM system being a mobile phase, MeOH/DCM=3-7%) to obtain 0.4 g of product (with a yield of 20%).
(64) NMR(CDCl.sub.3) : 3.5-3.8 (m, 42H, OCH.sub.2), 3.37 (s, 12H, CH.sub.3O), 2.7-2.8 (m, 18H, N(CH.sub.2).sub.3), 1.6-1.7 (m, 6H, NCH.sub.2CH.sub.2CH.sub.2); ESI-MS: 796.5 (M+Na).sup.+.
Example 3 Synthesis of Dendritic Molecule ((mEG.SUB.3.).SUB.2.-NC.SUB.3.H.SUB.6.).SUB.2.OH
(65) A synthetic route of the ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2OH is as shown in
(66) Toluene (20 mL) was added to 3-propenyloxy-1,2-propanediol (0.52 g, 4 mmol), then NaH (60%, 0.5 g) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (20 mL) containing (mEG.sub.3).sub.2-NC.sub.3H.sub.6-OMs (a synthesis method was referred to Example 2, 4.5 g) was added dropwise, and reacted at 60 C. overnight; then HPLC detection was carried out, and the toluene was evaporated to dryness; the remaining was added with DCM and water and washed once respectively, and then the DCM was evaporated to dryness to obtain a crude product.
(67) Pd/C (0.5 g) and TsOH (0.1 g) were added to the crude reaction product (5 g) of the step above, then methanol (50 mL)/water (10 mL) was added and refluxed for 24 hours. Pd/C was recovered by filtration and then concentrated to obtain a crude product. The crude product was subjected to column purification (2-7% MeOH/DCM) to obtain 1.1 g of product (with a yield of 35%).
(68) NMR(CDCl.sub.3) : 3.4-3.8 (m, 48H, OCH.sub.2), 3.37 (s, 12H, CH.sub.3O), 3.25 (m, 1H, OCH), 2.5-2.7 (m, 12H, NCH.sub.2), 1.6-1.7 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2); ESI-MS: 791.3 (M+H)+.
Example 4 Synthesis of Dendritic Molecule ((mEG.SUB.3.).SUB.2.-EG.SUB.4.).SUB.2.-OH
(69) A synthetic route of the ((mEG.sub.3).sub.2-EG.sub.4).sub.2-OH is as shown in
1. Synthesis of ((mEG.SUB.3.).SUB.2.-EG.SUB.4.)-OH
(70) Toluene (70 mL) was added to the (mEG.sub.3).sub.2-OH (synthesized in Example 1, 7.7 g), then NaH (60%, 1.0 g) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (90 mL) of TrO-EG.sub.4-OMs (synthesized in Example 1, 12.3 g) was added dropwise to the reaction solution, and reacted at 70 C. overnight; then the toluene was evaporated to dryness; the remaining was added with DCM and water and washed once. The DCM was evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (3% MeOH/DCM being a mobile phase) to obtain 11 g of intermediate (with a yield of 69%).
(71) DCM (100 mL) and TFA (30 mL) were added to the product (10 g) of the step above, and reacted at room temperature overnight. A solvent was evaporated to dryness and saturated brine was added, the mixture was washed with ethyl ether until no color appears on a water-liquid plate, then extracted with DCM, and an organic phase was evaporated to dryness to obtain 8.2 g of product (with a yield of 78%).
(72) NMR(CDCl.sub.3) : 3.89-3.50 (m, 45H), 3.38 (s, 6H); ESI-MS: 583.6 (M+Na).
2. Synthesis of ((mEG.SUB.3.).SUB.2.-EG.SUB.4.).SUB.2.-OMs
(73) TEA (1.6 g) and 60 mL of DCM were added to the reaction product (7.5 g) of the above step and placed in a reaction flask in an ice-water bath. MsCl (1.76 g) was dissolved with DCM (15 mL) and added dropwise to the reaction flask in the ice-water bath after the MsCl was completely dissolved. The mixture was reacted at room temperature for 3 hours. The remaining was washed with water once. An organic phase was dried with anhydrous sodium sulfate and filtered to remove sodium sulfate. The remaining was concentrated to obtain about 8.1 g of product (with a yield of about 95%).
3. Synthesis of ((mEG.SUB.3.).SUB.2.-EG.SUB.4.).SUB.2.-OH
(74) Toluene (40 mL) was added to 3-propenyloxy-1,2-propanediol (0.63 g), then NaH (60%, 0.59 g) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (40 mL) containing ((mEG.sub.3).sub.2-EG.sub.4).sub.2-OMs (a synthesis method was referred to Example 2, 7.5 g) was added dropwise, and reacted at 60 C. overnight; then HPLC detection was carried out, and the toluene was evaporated to dryness; the remaining was added with DCM and water and washed once respectively, and then the DCM was evaporated to dryness to obtain a crude product.
(75) Pd/C (0.8 g) and TsOH (1.6 g) were added to the crude reaction product (8 g) of the step above, then methanol (80 mL)/water (16 mL) was added and refluxed for 24 hours. Pd/C was recovered by filtration and then concentrated to obtain a crude product. The crude product was subjected to column purification (0-3% MeOH/DCM) to obtain 3.7 g of product (with a yield of 67%).
(76) NMR(CDCl.sub.3) : 3.89-3.50 (m, 96H), 3.35 (s, 12H); ESI-MS: 1199.2 (M+Na).sup.+.
Example 5 Synthesis of Dendritic Molecule ((NH.SUB.2.-EG.SUB.4.).SUB.2.-EG.SUB.4.).SUB.2.-NC.SUB.3.H.SUB.6.OH
(77) A synthetic route of the ((NH.sub.2-EG.sub.4).sub.2-EG.sub.4).sub.2-NC.sub.3H.sub.6OH is as shown in
1. Synthesis of (N.SUB.3.-EG.SUB.4.).SUB.2.-EG.SUB.4.-OMs
(78) TEA (1.24 mL) and 40 mL of DCM were added to (N.sub.3-EG.sub.4).sub.2-EG.sub.4-OH ((3), prepared in Example 1, 5 g), and placed in a reaction flask in an ice-water bath. MsCl (0.63 mL) was dissolved with DCM (5 mL), and added dropwise to the reaction flask in the ice-water bath after the MsCl was completely dissolved. The mixture was reacted at room temperature for 3 hours. The remaining was washed with water (30 mL) once. An organic phase was dried with anhydrous sodium sulfate and filtered to remove sodium sulfate. The remaining was concentrated to obtain about 5.2 g of product (with a yield of 93%).
2. Synthesis of ((N.SUB.3.-EG.SUB.4.).SUB.2.-EG.SUB.4.).SUB.2.-NC.SUB.3.H.SUB.6.OH
(79) (N.sub.3-EG.sub.4).sub.2-EG.sub.4-OMs (4.5 g) prepared in the step 1 above and THF (50 mL) were added to aminopropanol (0.19 g). After heating and refluxing overnight, a supernatant was poured out and evaporated to dryness to obtain a crude product. The crude product was recrystallized by ice diethyl ether twice to obtain 0.8 g of product (with a yield of 23%).
3. Synthesis of ((NH.SUB.2.-EG.SUB.4.).SUB.2.-EG.SUB.4.).SUB.2.-NC.SUB.3.H.SUB.6.OH
(80) DMF (20 mL) and triphenylphosphine (425 mg) were added to ((N.sub.3-EG.sub.4).sub.2-EG.sub.4).sub.2-NC.sub.3H.sub.6OH (400 mg) prepared in the step 2 above, reacted at room temperature overnight, then added with water (0.1 mL) and reacted overnight. The DMF was evaporated to dryness, then water (50 mL) was added, and the mixture was washed with ethyl acetate (40 mL) twice and DCM (30 mL) twice in sequence, then water was evaporated to dryness, and the remaining was recrystallized with ice ethyl ether twice to obtain 315 mg of product with a yield of 85%.
(81) NMR(CDCl.sub.3) : 1.6-1.7 (m, 2H, NCH.sub.2CH.sub.2CH.sub.2), 2.7-2.8 (m, 14H, N(CH.sub.2).sub.3&NH.sub.2CH.sub.2), 3.5-3.8 (m, 96H, other hydrogen excluding reactive hydrogen); ESI-MS: 1299.7 (M+Na).sup.+.
Example 6 Synthesis of Dendritic Molecule ((HOOC-EG.SUB.4.).SUB.2.NC.SUB.3.H.SUB.6.).SUB.2.OH
(82) A synthetic route of the ((HOOC-EG.sub.4).sub.2NC.sub.3H.sub.6).sub.2OH is as shown in
1. Synthesis of (tBuO-EG.SUB.4.).SUB.2.NC.SUB.3.H.SUB.6.-OMs
(83) TEA (0.54 mL) and 30 mL of DCM were added to (tBuO-EG.sub.4).sub.2NC.sub.3H.sub.6OH ((2), prepared in Example 1, 2.2 g), and placed in a reaction flask in an ice-water bath. MsCl (0.27 mL) was dissolved with DCM (5 mL), and added dropwise to the reaction flask in the ice-water bath after the MsCl was completely dissolved. The mixture was reacted at room temperature for 3 hours. The remaining was washed with water (30 mL) once. An organic phase was dried with anhydrous sodium sulfate and filtered to remove sodium sulfate. The remaining was concentrated to obtain about 1.7 g of product (with a yield of 69%).
2. Synthesis of ((tBuO-EG.SUB.4.).SUB.2.NC.SUB.3.H.SUB.6.).SUB.2.-OAlly
(84) Toluene (20 mL) was added to 3-propenyloxy-1,2-propanediol (68 mg), then NaH (60%, 72 mg) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (10 mL) (tBuO-EG.sub.4).sub.2NC.sub.3H.sub.6-OMs (1.5 g) was added dropwise, and reacted at 60 C. overnight; then HPLC detection was carried out, and the toluene was evaporated to dryness; the remaining was recrystallized by ice diethyl ether twice to obtain 0.15 g of product (with a yield of 20%).
3. Synthesis of ((HOOC-EG.SUB.4.).SUB.2.NC.SUB.3.H.SUB.6.).SUB.2.OH
(85) Pd/C (0.08 g) and TsOH (0.16 g) were added to the product (0.8 g) of the step above, then methanol (10 mL)/water (2 mL) was added and refluxed for 24 hours. It was found by HPLC that the reaction was complete. Pd/C was recovered by filtration, concentrated and then recrystallized by ice diethyl ether twice to obtain 0.56 g of product (with a yield of 86%).
(86) NMR(CDCl.sub.3) : 1.6-1.7 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2), 2.5-2.8 (m, 20H, N(CH.sub.2).sub.3&CH.sub.2COOH), 3.5-3.8 (m, 73H, other hydrogen excluding reactive hydrogen); ESI-MS: 1221.2 (M+Na).sup.+.
Example 7 Synthesis of Dendritic Molecule ((NH.SUB.2.-EG.SUB.4.).SUB.2.-EG.SUB.4.).SUB.2.-NHCOC.SUB.2.H.SUB.4.COOH
(87) A synthetic route of the ((NH.sub.2-EG.sub.4).sub.2-EG.sub.4).sub.2-NHCOC.sub.2H.sub.4COOH is as shown in
1. Synthesis of ((N.SUB.3.-EG.SUB.4.).SUB.2.-EG.SUB.4.).SUB.2.-NH-tBoc
(88) Toluene (60 mL) was added to 3-Boc-NH-1,2-propanediol (0.78 g), then NaH (60%, 0.36 g) was added under an ice-water bath and reacted at room temperature for 2 hours; a toluene solution (30 mL) containing (N.sub.3-EG.sub.4).sub.2-EG.sub.4-OH ((3), prepared in Example 1, 7.3 g) was added dropwise, and reacted at 60 C. overnight; then HPLC detection was carried out, and the toluene was evaporated to dryness; the remaining was added with DCM and water and washed once respectively, and then the DCM was evaporated to dryness to obtain a crude product. The crude product was recrystallized by ice diethyl ether twice to obtain 4.5 g of product (with a yield of 73%).
2. Synthesis of ((N.SUB.3.-EG.SUB.4.).SUB.2.-EG.SUB.4.).SUB.2.-NHCOC.SUB.2.H.SUB.4.COOH
(89) TFA (13 mL) and methylene chloride (27 mL) were added to ((N.sub.3-EG.sub.4).sub.2-EG.sub.4).sub.2-NH-tBoc (4 g) and stirred at room temperature overnight; a solvent was evaporated to dryness, then the remaining was recrystallized by ice diethyl ether twice to obtain an intermediate. Then methylene chloride (35 mL) and triethylamine (0.5 mL) were added a and stirred evenly; then succinic anhydride (400 mg) was added, and reacted at room temperature overnight; then the remaining was washed with saturated brine (pH=5) once and recrystallized by ice diethyl ether twice to obtain 3 g of product (with a yield of 76%).
3. Synthesis of ((NH.SUB.2.-EG.SUB.4.).SUB.2.-EG.SUB.4.).SUB.2.-NHCOC.SUB.2.H.SUB.4.COOH
(90) DMF (20 mL) and triphenylphosphine (1.96 g) were added to ((N.sub.3-EG.sub.4).sub.2-EG.sub.4).sub.2-NHCOC.sub.2H.sub.4COOH (2 mg) prepared in the step 2 above, reacted at room temperature overnight, then added with water (0.1 mL) and reacted overnight. The DMF was evaporated to dryness, then water (50 mL) was added, and the mixture was washed with ethyl acetate (40 mL) twice and DCM (30 mL) twice in sequence, then water was evaporated to dryness to obtain 1.4 g of product with a yield of 75%.
(91) NMR(CDCl.sub.3) : 2.4-2.6 (m, 4H, CH.sub.2COOH), 2.8 (m, 8H, NH.sub.2CH.sub.2), 3.5-3.8 (m, 103H, other hydrogen excluding reactive hydrogen; ESI-MS: 1415.1 (M+Na).sup.+.
Example 8 Synthesis of Three Derivatives of Dendritic Molecule Derivative ((mEG.SUB.3.).SUB.2.-NC.SUB.3.H.SUB.6.).SUB.2.NC.SUB.3.H.SUB.6.OH
(92) Cholesterol, hexadecanol and menthol derivatives of the ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH were prepared respectively.
(93) 1. DCM (5 mL) and TEA (0.11 mL) were added to ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH (0.4 g) prepared in Example 2, then cholesteryl chloroformate (0.3 g) was dissolved in DCM (5 mL), and added dropwise to a reaction flask. The mixture was stirred at room temperature overnight. The remaining was washed with water once, and then evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (a MeOH/DCM system being a mobile phase, MeOH/DCM=0-7%) to obtain 190 mg of product (with a yield of 31%).
(94) NMR(CDCl.sub.3) : 5.55-5.45 (m, 1H), 4.65-4.50 (m, 1H), 4.1-4.0 (m, 2H), 3.5-3.8 (m, 40H), 3.37 (s, 12H), 2.7-2.8 (m, 12H), 2.50-0.80 (m, 46H), 0.65-0.60 (m, 3H).
(95) 2. DCM (5 mL) and TEA (0.11 mL) were added to ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH (0.4 g) prepared in Example 2, then hexadecanol chloroformate (0.23 g) was dissolved in DCM (5 mL), and added dropwise to a reaction flask. The mixture was stirred at room temperature overnight. The reaction was detected to be complete through TLC, then the remaining was washed with water once, and evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (6% MeOH/DCM) to obtain 150 mg of hexadecanol derivative (with a yield of 28%).
(96) NMR(CDCl.sub.3) R: 4.1-4.2 (m, 4H), 3.5-3.8 (m, 40H), 3.37 (s, 12H), 2.7-2.8 (m, 18H), 1.6-1.7 (m, 8H), 1.2-1.3 (m, 26H), 0.88 (t, 3H).
(97) 3. DCM (5 mL) and pyridine (0.11 mL) were added to ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH (0.4 g) prepared in Example 2, then menthol chloroformate (0.17 g) was dissolved in DCM (5 mL), and added dropwise to a reaction flask. The mixture was stirred at room temperature overnight. The reaction was detected to be complete through TLC, then the remaining was washed with water once, and evaporated to dryness to obtain a crude product. The crude product was subjected to column purification (2% MeOH/DCM) to obtain 155 mg of menthol derivative (with a yield of 31%).
(98) NMR(CDCl.sub.3) R: 4.4 (m, 1H), 4.0-4.2 (m, 2H), 3.5-3.8 (m, 40H, OCH2), 3.37 (s, 12H, CH3O), 2.7-2.8 (m, 18H, N(CH2).sub.3), 2.0 (m, 1H), 1.82 (m, 1H), 1.6-1.7 (m, 9H), 1.4 (m, 4H), 1.0 (m, 9H).
Example 9 Synthesis of Three Derivatives of Linear-Chain Molecule Derivative mEG.SUB.7.-OH
(99) Three derivatives of the mEG.sub.7-OH were prepared using commercially available mEG.sub.7-OH under the same conditions as in Example 8.
(100) Cholesterol derivative: NMR(CDCl.sub.3) : 5.45-5.55 (m, 1H), 4.50-4.65 (m, 1H), 4.0-4.1 (m, 2H), 3.5-3.8 (m, 26H), 3.37 (s, 3H), 0.80-2.50 (m, 40H), 0.60-0.65 (m, 3H).
(101) Hexadecanol derivative: NMR(CDCl.sub.3) : 4.27 (t, 2H), 4.12 (t, 2H), 3.5-3.8 (m, 26H), 3.38 (s, 3H), 1.65 (m, 2H), 1.25 (m, 26H), 0.88 (t, 3H).
(102) Menthol derivative: NMR(CDCl.sub.3) : 4.4-4.6 (m, 1H), 4.2-4.3 (m, 2H), 3.5-3.8 (m, 26H), 3.38 (s, 3H), 1.9-2.1 (m, 2H), 1.0-1.7 (m, 7H), 0.7-0.9 (m, 9H).
Example 10 Comparison of Solubility of Two Cholesterol Derivatives in Water
(103) 50.0 mg of the cholesterol derivative of the ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH prepared in Example 8 was dispersed in 50 mL of water, and 5 mL of the mixture was taken out and added with 1.5 mL of water. Then the solution was shaken vigorously every 5 minutes for 30 seconds. After 30 minutes, the solution was turbid. Another 1.5 mL of water was added and the solution was shaken vigorously every 5 minutes for 30 seconds, and the solution became clear until 9 mL of water was totally added.
(104) 24.2 mg of the cholesterol derivative of the mEG.sub.7-OH prepared in Example 9 was dispersed in 50 mL of water, and 5 mL of the mixture was taken out and added with 1.5 mL of water. Then the solution was shaken vigorously every 5 minutes for 30 seconds. After 30 minutes, the solution became turbid. Another 5 mL of water was added and the solution was shaken vigorously every 5 minutes for 30 seconds until 25 mL of water was totally added. 5 mL of the solution was taken out from the diluted solution and operated similarly, and the solution became clear until 10 mL of water was added.
(105) Results are shown in Table 1. Analysis of the results shows that the solubility of the cholesterol derivative of the dendritic molecule ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH is 35.7 mg/100 g H.sub.2O, which is 13.3 times the solubility (2.69 mg/100 g H.sub.2O) of the cholesterol derivative of the mEG.sub.7-OH, and 178 times the solubility of cholesterol (less than 0.2 mg/100 g H.sub.2O).
Example 11 Comparison Test of Solubility of Two Hexadecanol Derivatives in Water
(106) 111.0 mg of the hexadecanol derivative of the ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH prepared in Example 8 was dispersed in 50 L of water, and shaken vigorously every 5 minutes for 30 seconds. After 30 minutes, the solution became clear. Another 50 L of water was added and the solution was shaken vigorously every 5 minutes for 30 seconds, and the solution was still clear until 1.025 mL of water was added.
(107) 112.9 mg of the hexadecanol derivative of the mEG.sub.7-OH prepared in Example 9 was dispersed in 50 L of water, and shaken vigorously every 5 minutes for 30 seconds. After 30 minutes, the solution was turbid. Another 50 L of water was added and the solution was shaken vigorously every 5 minutes for 30 seconds, and the solution became clear until 250 L of water was added.
(108) Results are shown in Table 1. Analysis of the results shows that the solubility of the hexadecanol derivative of the dendritic molecule ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH can be miscible with water in any ratio at room temperature, while the solubility of the hexadecanol derivative of the mEG.sub.7-OH is 45.2 g/100 g H.sub.2O, and the solubility of hexadecanol is less than 1 mg/100 g H.sub.2O.
Example 12 Comparison of Solubility of Two Menthol Derivatives in Water
(109) 106.7 mg of the menthol derivative of the ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH prepared in Example 8 was dispersed in 50 L of water, and shaken vigorously every 5 minutes for 30 seconds. After 30 minutes, the solution was clear. Another 50 L of water was added and the solution was shaken vigorously every 5 minutes for 30 seconds, and the solution was still clear until 1.025 mL of water was added.
(110) 101.3 mg of the menthol derivative of the mEG.sub.7-OH prepared in Example 9 was dispersed in 50 L of water, and shaken vigorously every 5 minutes for 30 seconds. After 30 minutes, the solution was turbid. Another 50 L of water was added and the solution was shaken vigorously every 5 minutes for 30 seconds. After 30 minutes, the solution became clear.
(111) Results are shown in Table 1. Analysis of the results shows that the solubility of the menthol derivative of the dendritic molecule ((mEG.sub.3).sub.2-NC.sub.3H.sub.6).sub.2NC.sub.3H.sub.6OH can be miscible with water in any ratio at room temperature, while the solubility of the menthol derivative of the mEG.sub.7-OH is 67.5 g/100 g H.sub.2O, and the solubility of menthol is less than 100 mg/100 g H.sub.2O.
(112) TABLE-US-00001 TABLE 1 Solubility of three derivatives Modifier Cholesterol Hexadecanol Menthol None Less than 0.2 mg/ Less than 1 mg/ Less than 100 mg/ 100 g H.sub.2O 100 g H.sub.2O 100 g H.sub.2O mEG.sub.7-OH 2.69 mg/ 45.2 g/ 67.5 g/ 100 g H.sub.2O 100 g H.sub.2O 100 g H.sub.2O Dendritic 35.7 mg/ Miscible with Miscible with molecule 100 g H.sub.2O water in any ratio water in any ratio (prepared in Example 2)
(113) Those described above are merely preferred examples of the disclosure, but are not intended to limit the disclosure. Any modifications and equivalent substitutions made without departing from the principle of the disclosure shall all fall within the scope of protection of the disclosure.