WO2015153217A1 - Cellulose ethers having 1,2,3-triazolyl substituents - Google Patents
Cellulose ethers having 1,2,3-triazolyl substituents Download PDFInfo
- Publication number
- WO2015153217A1 WO2015153217A1 PCT/US2015/022415 US2015022415W WO2015153217A1 WO 2015153217 A1 WO2015153217 A1 WO 2015153217A1 US 2015022415 W US2015022415 W US 2015022415W WO 2015153217 A1 WO2015153217 A1 WO 2015153217A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- pentynyl
- cellulose
- average
- alkyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B11/00—Preparation of cellulose ethers
- C08B11/193—Mixed ethers, i.e. ethers with two or more different etherifying groups
Definitions
- This invention relates to new cellulose ethers having 1,2,3-triazolyl substituents and methods for preparing and using them.
- the present invention provides a compound which is a cellulose ether having an average of 1.0 to 2.5 Ci-C 6 alkyl ether groups per glucopyranosyl unit and an average of 0.01 to 1 triazole-containing substituents per glucopyranosyl unit.
- the present invention is further directed to a process for preparing a cellulose ether comprising 1,2,3-triazole rings; said process comprising contacting a cellulose ether having an average of 1.0 to 2.5 Ci-C 6 alkyl ether groups per glucopyranosyl unit and an average of 0.01 to 1 pentynyl ether groups per glucopyranosyl unit with a compound having an azido group.
- alkyl groups are a saturated, substituted or unsubstituted hydrocarbyl group having from one to twenty-two carbon atoms in a linear or branched arrangement. Substitution on alkyl groups of one or more hydroxy, carboxylic acid or salts thereof (attached to alkyl via carbon, e.g., carboxymethyl cellulose), halo or alkoxy groups is permitted. Preferably, alkyl groups are substituted by hydroxyl or unsubstituted.
- alkenyl is an alkyl group having at least one carbon-carbon double bond, preferably one carbon-carbon double bond.
- An "aryl” group is a substituent derived from an aromatic hydrocarbon compound. An aryl group has a total of from six to twenty ring atoms, unless otherwise specified, and has one or more rings which are separate or fused. Substitution on aryl groups of one or more alkyl or alkoxy groups is permitted.
- An “aralkyl” group is an "alkyl” group substituted by an "aryl” group.
- the alkyl ether groups are C1-C4 alkyl; preferably C1-C3 alkyl; preferably methyl, ethyl, 2-hydroxyethyl or 2-hydroxypropyl;
- Ci or C3 alkyl preferably methyl or 2-hydroxypropyl. More than one type of alkyl group may be present on a cellulose ether.
- cellulose ethers include, e.g., methylcellulose (MC), ethylcellulose (EC), ethyl methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl methyl cellulose (HPMC) and carboxymethyl cellulose (CMC).
- HPMC and MC are preferred cellulose-based polymers. Specific examples of preferred cellulose based polymers include METHOCEL polymers commercially available from Dow.Chemical Company.
- the cellulose ether has no more than 2.3 alkyl ether groups per glucopyranosyl unit, preferably no more than 2.1.
- the number of alkyl ether groups per glucopyranosyl units is determined by analysis of the weight % of the substituents. For example, for METHOCEL polymers the determination of the % methoxyl and %
- hydroxypropoxyl in hydroxypropyl methylcellulose is carried out according to the United States Pharmacopeia (USP 32). The values obtained are % methoxyl and %
- the pentynyl ether is a 4-pentynyl ether, i.e., a substituent HC ⁇ C(CH2)3- is attached to a hydroxyl oxygen.
- the cellulose ether has at least 0.03 pentynyl ether groups per glucopyranosyl unit, preferably at least 0.05, preferably at least 0.08, preferably at least 0.11, preferably at least 0.13; preferably no more than 0.8, preferably no more than 0.6, preferably no more than 0.5, preferably no more than 0.45, preferably no more than 0.4.
- the average number of pentynyl ether groups per glucopyranosyl unit also known as the degree of substitution (DS) is measured by DS-GC.
- the compound of this invention is derived from a cellulose ether having an average of 1.0 to 2.5 Ci-C 6 alkyl ether groups per glucopyranosyl unit has a viscosity, measured from a 2 wt solution in water at 20 °C, of 2.4 to 100,000 mPa-s, preferably 5 to 60,000, preferably 15 to 10,000, preferably 50 to 8,000, preferably 100 to 6,000.
- Viscosities were measured for cellulose ethers having a viscosity of less than 600 mPa- s by preparing 2% by weight cellulose ether solutions in water according to United States Pharmacopeia (USP 35, "Hypromellose", pages 3467-3469) followed by an Ubbelohde viscosity measurement according to DIN 51562-1:1999-01 (January 1999). Viscosities were measured for cellulose ethers having a viscosity higher than 600 mPa-s by preparing 2% by weight cellulose ether solutions in water according to United States Pharmacopeia (USP 35, "Hypromellose", pages 3467-3469) followed by viscosity measurement with a rotational rheometer (e.g.
- Cellulose polymers contain repeat units having a l,4'- -glucopyranosyl structure, also known as anhydroglucose.
- the cellulose ether is of formula (I)
- R 1 , R 2 and R 3 are independently selected from: hydrogen and alkyl; wherein alkyl groups may comprise from one to six carbon atoms which may be unsubstituted or substituted with hydroxyl, carboxylic acid or salts thereof (attached to alkyl via carbon, e.g., carboxymethyl cellulose), halo or CrC 4 alkoxy; and n is from 25 to 7,500.
- alkyl groups are unsubstituted or substituted only with hydroxyl.
- n is from 50 to 5,000, preferably 100 to 2,500.
- alkyl groups have from one to four carbon atoms, preferably from one to three.
- the cellulose ether has been modified by replacing on average 0.01 to 1 hydroxyl groups (R 1 , R 2 or R 3 substituent is H) with a pentynyl ether group.
- the pentynyl alkylcellulose compounds may be prepared by applying alkylation methods known in the art, e.g., alkylation of a carbohydrate hydroxyl group with an alkynyl halide in the presence of base.
- alkylation methods known in the art, e.g., alkylation of a carbohydrate hydroxyl group with an alkynyl halide in the presence of base.
- a compound of this invention may be prepared according to the following example reaction scheme (I), Base
- R 1 is hydrogen and the halo group is chloro.
- the symbol attached to the 1,4 oxygen atoms indicates the presence of neighboring glucopyranosyl units.
- Solvents which may be useful include, e.g., polar aprotic solvents, especially DMSO.
- Suitable bases include, e.g., metal (especially alkali metal) hydroxides or alkoxides and organolithium compounds.
- the reaction is carried out at a temperature from 0°C to 50°C, preferably from 10°C to 30°C.
- the cellulose ethers may also be prepared by reaction of cellulose with a base (e.g., alkali metal hydroxide), pentynyl halide and an alkylating agent (e.g., ethylene oxide, propylene oxide methyl chloride, ethyl chloride).
- a base e.g., alkali metal hydroxide
- pentynyl halide e.g., ethylene oxide, propylene oxide methyl chloride, ethyl chloride
- an alkylating agent e.g., ethylene oxide, propylene oxide methyl chloride, ethyl chloride
- the compounds of this invention may be formed by the conversion of a pentynyl alkylcellulose polymer to a triazole by the Huisgen 1,3-dipolar cycloaddition of azides and alkynes to 1,2,3-triazole products.
- This reaction is regioselective with respect to the azide orientation in the [2+3] cycloaddition and is reported to give high yields under mild conditions, to have high tolerance of other functionalities and to require minimal work-up and purification.
- This reaction has been described in many publications, e.g., W.H.Binder et al., Macromol. Rapid Commun. , 2007, 28, 15-54; H.C.
- the reaction scheme (II) is shown below with Cu(I) as the catalyst.
- the pentynyl alkylcelluloses serve as the alkyne starting material.
- the Cu(I) catalysis may be provided by reduction of CuS0 4 hydrate, e.g., with sodium ascorbate in situ or by Cu(I) salts prepared by other means, e.g., Cu(I) complexes with triarylphosphines, Cu(I) bromide or iodide, or by reduction of Cu(II) acetate.
- Other useful catalysts for this reaction include, e.g., Ru, Pd(II), Pt(II) and Ni(II).
- R represents the remainder of a pentynyl alkylcellulose.
- the R 4 substituent can be any organic substituent, i.e., one in which carbon, hydrogen, oxygen, sulfur and nitrogen atoms comprise at least 85% of its weight, preferably at least 90% preferably at least 95%, preferably at least 98%.
- the organic substituent has a molecular weight no greater than 500,000, preferably no greater than 100,000, preferably no greater than 25,000, preferably no greater than 15,000.
- Mn number- average molecular weight
- addition polymers are formed in solution.
- the organic substituent has from one to thirty carbon atoms; preferably no more than twenty-two carbon atoms, preferably no more than fifteen carbon atoms, preferably no more than ten carbon atoms.
- additional azide groups these may react with molecules of pentynyl alkylcellulose to form a polymer or network structure.
- the organic substituent does not contain any additional azide groups.
- the compounds of this invention are cellulose ethers having an average of 1.0 to 2.5 Ci-C 6 alkyl ether groups per glucopyranosyl unit and 0.01 to 1 substituents of formula (II) per glucopyranosyl unit, attached to an oxygen atom, i.e., the substituent of formula (II) is R 1 , R 2 or R 3 in formula (I).
- R 4 is a biomolecule, e.g., protein, carbohydrate (e.g., cyclodextrin, saccharide), lipid (e.g., steroid, glycolipid, phospholipid, prostaglandin, leukotriene), nucleoside, nucleotide.
- biomolecule e.g., protein, carbohydrate (e.g., cyclodextrin, saccharide), lipid (e.g., steroid, glycolipid, phospholipid, prostaglandin, leukotriene), nucleoside, nucleotide.
- Pentynylmethylcellulose Process to create Pentynylmethylcellulose.
- the procedure listed below is a lab based procedure.
- This product could also be obtained via a pressurized synthesis where the methyl cellulose (or cellulose) is alkalized with NaOH and then etherified with pentynyl halide (bromide, chloride or iodide) (or as well methyl chloride / EO / PO) at elevated temperature and pressure.
- pentynyl halide bromide, chloride or iodide
- a methylcellulose with a degree of substitution (DS) of 1.8 methyl groups per glucopyranosyl unit and a methylcellulose with a DS of 1.19 methyl groups per glucopyranosyl unit were used.
- Methylcellulose was filled in a nitrogen flushed flask and dried at high vacuum. As solvent 50 mL DMSO (dry) was added under nitrogen and stirred overnight. The base "Li-dimsyl" was freshly prepared as followed. A flask filled with DMSO (dry) was briefly evacuated in high vacuum and the equal volume of methyl lithium (1.6 molar in diethyl ether) was added drop-wise under nitrogen. The mixture was flushed for 1 h (with needles in a septum) under stirring to remove ether and methane.
- Pentynyl-DS There are multiple ways to analyze the Pentynyl-DS. No method is generally accepted. For the purposes of this invention, the DS-GC values are used to determine the degree of substitution (DS).
- glucosidic linkages were cleaved by methanolysis to gain the monomer units as methyl glucoside derivatives.
- Methanolic hydrochloric acid (MeOH/HCl) was prepared from dry methanol and acetyl chloride under ice cooling. Around 1-2 mg of PyMC was weighted in a V-Vial, covered with 1.5 M MeOH/HCl, mixed well, and treated for 2 h at 90 °C. After cooling to room temperature (r.t.) solvent was removed in a stream of nitrogen. Subsequently, the residue was co- distilled repeatedly with some drops of methanol.
- TMS trimethylsilylation
- the column used was Phenomenex Zebron ZB-5MS, film thickness 0.25 ⁇ , length 25.0 m, inner diameter 0.25 mm ID. Injection was splitless, temperature 250 °C, carrier gas H2, pressure 56.1 kPa, linear velocity mode 45 cm/sec.
- a 3-O-pentynyl glucose can be combined with 2-0-, 6-0-, and 2,6-di-O-methyl or no further substitution, resulting in up to 8 compounds.
- MRFmonomer ECN2,3,6-TMS / ECNmonomer
- GLC monomer analysis was accomplished after methanolysis and trimethylsilylation. Methanolysis was carried out as follows: (1) two samples of 1-2 mg polymer PyMC65A-carboxy in 1 mL 1.5 M MeOH/HCl were heated for 120 min. at 90 °C. Since they were not completely dissolved, they were additionally heated for 120 min. at 120 °C. (2) Full dissolution was achieved when heating with 3.0 M MeOH/HCl for 120 min. at 90 °C. Further treatment was performed as described above.
Abstract
A compound which is a cellulose ether having an average of 1.0 to 2.5 C1-C6 alkyl ether groups per glucopyranosyl unit and an average of 0.01 to 1 triazole-containing substituents per glucopyranosyl unit.
Description
CELLULOSE ETHERS HAVING 1,2,3-TRIAZOLYL SUBSTITUENTS
This invention relates to new cellulose ethers having 1,2,3-triazolyl substituents and methods for preparing and using them.
Some pentynyl- and 1,2,3-triazolyl-alkyl-substituted carbohydrate polymers are known. For example, M.N. Tahir et al., Macromol. Chem. Phys. , vol. 211 (2010) 1648-1662 discloses pentynyl ethers of dextrans and dextrans having 1,2,3-triazolyl-alkyl substituents. However, this reference does not disclose the compounds claimed herein. STATEMENT OF INVENTION
The present invention provides a compound which is a cellulose ether having an average of 1.0 to 2.5 Ci-C6 alkyl ether groups per glucopyranosyl unit and an average of 0.01 to 1 triazole-containing substituents per glucopyranosyl unit.
The present invention is further directed to a process for preparing a cellulose ether comprising 1,2,3-triazole rings; said process comprising contacting a cellulose ether having an average of 1.0 to 2.5 Ci-C6 alkyl ether groups per glucopyranosyl unit and an average of 0.01 to 1 pentynyl ether groups per glucopyranosyl unit with a compound having an azido group.
DETAILED DESCRIPTION
Percentages are weight percentages (wt ) and temperatures are in °C, unless specified otherwise. Operations were performed at room temperature (20-25 °C), unless specified otherwise. An "alkyl" group is a saturated, substituted or unsubstituted hydrocarbyl group having from one to twenty-two carbon atoms in a linear or branched arrangement. Substitution on alkyl groups of one or more hydroxy, carboxylic acid or salts thereof (attached to alkyl via carbon, e.g., carboxymethyl cellulose), halo or alkoxy groups is permitted. Preferably, alkyl groups are substituted by hydroxyl or unsubstituted. An "alkenyl" group is an alkyl group having at least one carbon-carbon double bond, preferably one carbon-carbon double bond. An "aryl" group is a substituent derived from an aromatic hydrocarbon compound. An aryl group has a total of from six to twenty ring atoms, unless otherwise specified, and has one or more rings which are separate or fused. Substitution on aryl groups of one or more alkyl or alkoxy groups is permitted. An "aralkyl" group is an "alkyl" group substituted by an "aryl" group.
In the compound of this invention, preferably the alkyl ether groups are C1-C4 alkyl; preferably C1-C3 alkyl; preferably methyl, ethyl, 2-hydroxyethyl or 2-hydroxypropyl;
preferably Ci or C3 alkyl; preferably methyl or 2-hydroxypropyl. More than one type of alkyl group may be present on a cellulose ether. Especially preferred cellulose ethers include, e.g., methylcellulose (MC), ethylcellulose (EC), ethyl methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl methyl cellulose (HPMC) and carboxymethyl cellulose (CMC). HPMC and MC are preferred cellulose-based polymers. Specific examples of preferred cellulose based polymers include METHOCEL polymers commercially available from Dow.Chemical Company. Preferably, the cellulose ether has no more than 2.3 alkyl ether groups per glucopyranosyl unit, preferably no more than 2.1. The number of alkyl ether groups per glucopyranosyl units is determined by analysis of the weight % of the substituents. For example, for METHOCEL polymers the determination of the % methoxyl and %
hydroxypropoxyl in hydroxypropyl methylcellulose is carried out according to the United States Pharmacopeia (USP 32). The values obtained are % methoxyl and %
hydroxypropoxyl. These are subsequently converted into degree of substitution (DS) for methyl substituents and molar substitution (MS) for hydroxypropyl substituents. Residual amounts of salt have been taken into account in the conversion.
Preferably, the pentynyl ether is a 4-pentynyl ether, i.e., a substituent HC≡C(CH2)3- is attached to a hydroxyl oxygen. Preferably, the cellulose ether has at least 0.03 pentynyl ether groups per glucopyranosyl unit, preferably at least 0.05, preferably at least 0.08, preferably at least 0.11, preferably at least 0.13; preferably no more than 0.8, preferably no more than 0.6, preferably no more than 0.5, preferably no more than 0.45, preferably no more than 0.4. The average number of pentynyl ether groups per glucopyranosyl unit, also known as the degree of substitution (DS) is measured by DS-GC.
Preferably, the compound of this invention is derived from a cellulose ether having an average of 1.0 to 2.5 Ci-C6 alkyl ether groups per glucopyranosyl unit has a viscosity, measured from a 2 wt solution in water at 20 °C, of 2.4 to 100,000 mPa-s, preferably 5 to 60,000, preferably 15 to 10,000, preferably 50 to 8,000, preferably 100 to 6,000. Viscosities were measured for cellulose ethers having a viscosity of less than 600 mPa- s by preparing 2% by weight cellulose ether solutions in water according to United States Pharmacopeia (USP 35, "Hypromellose", pages 3467-3469) followed by an Ubbelohde viscosity measurement according to DIN 51562-1:1999-01 (January 1999). Viscosities were measured for cellulose ethers having a viscosity higher than 600 mPa-s by preparing 2% by weight
cellulose ether solutions in water according to United States Pharmacopeia (USP 35, "Hypromellose", pages 3467-3469) followed by viscosity measurement with a rotational rheometer (e.g. Haake RS600) with cone & plate geometry at 20 °C at a steady shear rate = 10 s"1. Viscosities of cellulose ethers have been correlated with molecular weights, and accordingly, one skilled in the art would understand the meaning of either measurement. See CM. Keary, Carbohydrate Polymers, vol. 45 (2001), pages 293-303. For the compounds of this invention, one would make an adjustment to account for the degree of substitution on the original cellulose ether and the molecular weight of the substituents and would thus arrive at an average molecular weight.
Cellulose polymers contain repeat units having a l,4'- -glucopyranosyl structure, also known as anhydroglucose. Preferably, the cellulose ether is of formula (I)
wherein R1, R2 and R3 are independently selected from: hydrogen and alkyl; wherein alkyl groups may comprise from one to six carbon atoms which may be unsubstituted or substituted with hydroxyl, carboxylic acid or salts thereof (attached to alkyl via carbon, e.g., carboxymethyl cellulose), halo or CrC4 alkoxy; and n is from 25 to 7,500. Preferably, alkyl groups are unsubstituted or substituted only with hydroxyl. Preferably, n is from 50 to 5,000, preferably 100 to 2,500. Preferably, alkyl groups have from one to four carbon atoms, preferably from one to three. In the cellulose ether used in this invention, the cellulose ether has been modified by replacing on average 0.01 to 1 hydroxyl groups (R1, R2 or R3 substituent is H) with a pentynyl ether group.
The pentynyl alkylcellulose compounds may be prepared by applying alkylation methods known in the art, e.g., alkylation of a carbohydrate hydroxyl group with an alkynyl halide in the presence of base. For example, a compound of this invention may be prepared according to the following example reaction scheme (I),
Base
wherein R2 and R3 are as defined previously, R1 is hydrogen and the halo group is chloro. The symbol attached to the 1,4 oxygen atoms indicates the presence of neighboring glucopyranosyl units. Solvents which may be useful include, e.g., polar aprotic solvents, especially DMSO. Suitable bases include, e.g., metal (especially alkali metal) hydroxides or alkoxides and organolithium compounds. Preferably, the reaction is carried out at a temperature from 0°C to 50°C, preferably from 10°C to 30°C. A similar reaction would be expected on glucopyranosyl units in which R2 or R3 were hydrogen instead of R1 being hydrogen, and multiple alkylations are possible as well, but would be expected to occur less frequently given the low degree of substitution of alkynyl groups claimed herein. There also may be some glucopyranosyl units having three alkyl ether groups which would be unreactive to the pentynyl halide.
The cellulose ethers may also be prepared by reaction of cellulose with a base (e.g., alkali metal hydroxide), pentynyl halide and an alkylating agent (e.g., ethylene oxide, propylene oxide methyl chloride, ethyl chloride). This results in direct formation of pentynyl alkylcellulose from cellulose. Preferably this reaction is carried out at higher than atmospheric pressure (500 to 3,500 kPa) and at a temperature from 40 to 120 °C.
The compounds of this invention may be formed by the conversion of a pentynyl alkylcellulose polymer to a triazole by the Huisgen 1,3-dipolar cycloaddition of azides and alkynes to 1,2,3-triazole products. This reaction is regioselective with respect to the azide orientation in the [2+3] cycloaddition and is reported to give high yields under mild conditions, to have high tolerance of other functionalities and to require minimal work-up and purification. This reaction has been described in many publications, e.g., W.H.Binder et al., Macromol. Rapid Commun. , 2007, 28, 15-54; H.C. Kolb et al., Drug Discovery Today, 2003, 8, 1128-1137. The reaction scheme (II) is shown below with Cu(I) as the catalyst. The pentynyl alkylcelluloses serve as the alkyne starting material. The Cu(I) catalysis may be provided by reduction of CuS04 hydrate, e.g., with sodium ascorbate in situ or by Cu(I) salts prepared by other means, e.g., Cu(I) complexes with triarylphosphines, Cu(I) bromide or
iodide, or by reduction of Cu(II) acetate. Other useful catalysts for this reaction include, e.g., Ru, Pd(II), Pt(II) and Ni(II).
R represents the remainder of a pentynyl alkylcellulose.
The R4 substituent can be any organic substituent, i.e., one in which carbon, hydrogen, oxygen, sulfur and nitrogen atoms comprise at least 85% of its weight, preferably at least 90% preferably at least 95%, preferably at least 98%. Preferably, the organic substituent has a molecular weight no greater than 500,000, preferably no greater than 100,000, preferably no greater than 25,000, preferably no greater than 15,000. When the organic substituent is a polymer having a molecular weight distribution, the molecular weight is measured as the number- average molecular weight (Mn). Preferably addition polymers are formed in solution. In one preferred embodiment, the organic substituent has from one to thirty carbon atoms; preferably no more than twenty-two carbon atoms, preferably no more than fifteen carbon atoms, preferably no more than ten carbon atoms. When the organic substituent contains additional azide groups, these may react with molecules of pentynyl alkylcellulose to form a polymer or network structure. In one preferred embodiment of the invention the organic substituent does not contain any additional azide groups.
The formation of a compound of this invention is illustrated below in reaction scheme
(III) for a specific case as a continuation of reaction scheme (I)
The compounds of this invention are cellulose ethers having an average of 1.0 to 2.5 Ci-C6 alkyl ether groups per glucopyranosyl unit and 0.01 to 1 substituents of formula (II) per
glucopyranosyl unit, attached to an oxygen atom, i.e., the substituent of formula (II) is R1, R2 or R3 in formula (I).
In a preferred embodiment of the invention R4 is a biomolecule, e.g., protein, carbohydrate (e.g., cyclodextrin, saccharide), lipid (e.g., steroid, glycolipid, phospholipid, prostaglandin, leukotriene), nucleoside, nucleotide.
EXAMPLES
Process to create Pentynylmethylcellulose. The procedure listed below is a lab based procedure. This product could also be obtained via a pressurized synthesis where the methyl cellulose (or cellulose) is alkalized with NaOH and then etherified with pentynyl halide (bromide, chloride or iodide) (or as well methyl chloride / EO / PO) at elevated temperature and pressure.
As starting material a methylcellulose with a degree of substitution (DS) of 1.8 methyl groups per glucopyranosyl unit and a methylcellulose with a DS of 1.19 methyl groups per glucopyranosyl unit were used.
General procedure
Methylcellulose was filled in a nitrogen flushed flask and dried at high vacuum. As solvent 50 mL DMSO (dry) was added under nitrogen and stirred overnight. The base "Li-dimsyl" was freshly prepared as followed. A flask filled with DMSO (dry) was briefly evacuated in high vacuum and the equal volume of methyl lithium (1.6 molar in diethyl ether) was added drop-wise under nitrogen. The mixture was flushed for 1 h (with needles in a septum) under stirring to remove ether and methane. After the volume corresponds again to the DMSO employed, the calculated amount of "Li- dimsyl" was transferred into the flask with MC in DMSO under nitrogen and stirred at room temperature for 30 min. Under cooling, the calculated amount of pentynyl chloride was added drop-wise. The reaction mixture was stirred for 2 days while its color turns from pale yellow to dark orange. For purification the reaction mixture was dialyzed against tap and finally distilled water (MWCO 14000 g/mol). Afterwards the charge of the dialysis tube was freeze dried. In Table 0-1 amounts of reagents, starting material and raw products are summarized.
Table 0-1: Preparation parameters of pentynyl methylcelluloses (PyMC) from MC
Sample PyMC29A PyMC29B PyMC65A PyMC65B
1 2 3 4
DS (methyl) starting
1.8 1.8 1.19 1.19 material
methylcellulose (mg) 493 506 500* 495* eq. Li-dimsyl/OH 1.10 1.60 1.10 1.60
Li-dimsyl (mL) 2.18 3.25 3.50 5.04 eq. 5-chloro-l-pentyne/OH 1.60 2.10 1.60 2.10
5-chloro-l-pentyne (mL) 0.54 0.72 0.86 1.12
Raw product PyMC (mg) 480 520 525 515 after drying at high vacuum
Table 0-2: Properties of pentynyl methylcelluloses (PyMC)
Sample 1 2 3 4
DS-GCpentynyl 0.22 0.24 0.32 0.32
Yield % 20.0 15.0 29.1 20.0
Note: Yield is calculated based on the ratio of DS-GC pentynyl and eq. Li-dimsyl/OH
There are multiple ways to analyze the Pentynyl-DS. No method is generally accepted. For the purposes of this invention, the DS-GC values are used to determine the degree of substitution (DS).
The analysis of the substitution patterns of methyl- and pentynyl-groups was performed by GLC and GLC-MS. Each sample was analyzed in duplicate.
In the first step, glucosidic linkages were cleaved by methanolysis to gain the monomer units as methyl glucoside derivatives. Methanolic hydrochloric acid (MeOH/HCl) was prepared from dry methanol and acetyl chloride under ice cooling. Around 1-2 mg of PyMC was weighted in a V-Vial, covered with 1.5 M MeOH/HCl, mixed well, and treated for 2 h at 90 °C. After cooling to room temperature (r.t.)
solvent was removed in a stream of nitrogen. Subsequently, the residue was co- distilled repeatedly with some drops of methanol.
The second step, trimethylsilylation (TMS) of remaining free OH groups was performed by adding 10 μL· pyridine, 50 μL· dichloromethane and 50 μL· N,0- Bis(trimethylsilyl)trifluoroacetamide (BSTFA) to the methanolysed and dried sample, and heating for 1 h at 100 °C. After cooling to r.t. 1 mL dichloromethane was added and an appropriate dilution of this sample solution was used for GLC analysis. GLC- MS was recorded for one of the samples. For the GLC, we used the following temperature program:
Rate Temperature Hold time
60 °C 1 min
20 °C/min 130 °C 0 min
4 °C/min 290 °C 10 min
20 °C/min 310 °C 10 min
The column used was Phenomenex Zebron ZB-5MS, film thickness 0.25 μιη, length 25.0 m, inner diameter 0.25 mm ID. Injection was splitless, temperature 250 °C, carrier gas H2, pressure 56.1 kPa, linear velocity mode 45 cm/sec.
Peaks of the methyl 0-alkynyl-0-methyl-0-TMS-a, -glucosides (i.e. two peaks/pattern) were assigned by interpretation of their mass spectra. With three different substituents in positions 2, 3, and 6, -H, -CH3, -(CH2)3C≡CH, 33 = 27 combinations are possible, and thus up to 54 peaks are expected (27 pairs of α,β- glucosides). For example, a 3-O-pentynyl glucose can be combined with 2-0-, 6-0-, and 2,6-di-O-methyl or no further substitution, resulting in up to 8 compounds. We could assign 18 α,β-glucoside pairs, beside the 8 pairs of pure MC additional 10 pairs containing pentynyl at any position, and detect even more, but not assign and quantify all tiny and overlapping peaks. Therefore the pentynyl-DS is probably slightly underestimated. Quantitative monomer composition data are obtained from the peak areas measured by GLC with FID detection. Molar responses of the monomers are calculated in line with the effective carbon number (ECN) concept but modified as described in the table below. The effective carbon number (ECN) concept has been described by Ackman (R.G. Ackman, J. Gas Chromatogr., 2 (1964) 173-179 and R.F. Addison, R.G. Ackman, J. Gas Chromatogr., 6 (1968) 135-138) and applied to the
quantitative analysis of partially alkylated alditol acetates by Sweet et. al (D.P. Sweet, R.H. Shapiro, P. Albersheim, Carbohyd. Res., 40 (1975) 217-225).
ECN increments used for ECN calculations:
In order to correct for the different molar responses of the monomers, the peak areas are multiplied by molar response factors MRFmonomer which are defined as the response relative to the 2,3,6-TMS monomer, which represents the unsubstituted monomer in the pentynyl derivative prior to the sample preparation for the GC DS determination. MRFmonomer = ECN2,3,6-TMS / ECNmonomer
Conversion of Pentynylmethylcellulose into a Triazole Product.
Three different azides have been used for the reaction:
The first reaction was carried out with aminoethylazide and PyMC29A. Secondly, thiolpropylazide was reacted with PyMC29B, and finally carboxypropylazide was submitted to the cycloaddition with PyMC65A.
Reaction of pentynyl methylcellulose with aminoethylazide (-» PyMC29A-amino)
For the reaction with pentynyl methylcellulose PyMC29A, 101 mg (0.14 mmol alkynyl, Mw (AGU) = 209.8 g/mol, DSMe = 2.0, DSPy = 0.3 assumed) of the polymer was filled in a flask and 50 μΕ (43 mg, 0.5 mmol, 3.45 eq. per alkynyl) of 2- aminoethylazide was added. Then 8 mL of DMSO and 2 mL of water were added,
and the yellowish solution was stirred overnight. As catalyst 180 μL· (0.18 mmol) of a sodium ascorbate solution (1 M stock solution: 990.5 mg sodium 1-ascorbate in 5 mL dist. water) and subsequently 12 mg (0.045 mmol) of CuS04 · 5 H20 dissolved in 0.17 mL water were added. The reaction was stirred for 4 days at room temperature. The product was isolated by dialysis against dist. water (dialysis tube MWCO 14000). After freeze drying 116 mg raw product PyMC29A-amino was obtained. GLC monomer analysis after methanolysis and trimethylsilylation was accomplished as described above.
Success of cycloadditions was obvious from the disappearance or strong reduction of alkynyl-related absorption bands in the IR spectra. ATR FTIR spectra of the product have been generated. All IR spectra are normalized with respect to the most intense absorption band at 1053 cm"1. The C≡C-H valence vibration at 3280 cm"1 of the pentynyl derivatives has disappeared after the cycloaddition reaction.
Reaction of pentynyl methylcellulose with thiolpropylazide (-> PyMC29B-thiol)
Reaction of pentynyl methylcellulose PyMC29B with 3 -thiolpropylazide was carried out in the same manner. 70 mg (0.1 mmol alkynyl,
Mw (AGU) = 209.8 g/mol, DSMe = 2.0, DSPy = 0.3 assumed) polymer, 40 mg (0.345 mmol, 3.45 eq. per alkynyl) azide, 8 mL DMSO, 2 mL water, 123 (0.123 mmol) sodium ascorbate stock solution (1 M) and 7.9 mg (0.03 mmol) CuS04 · 5 H20 in 0.12 mL water were applied. After dialysis and lyophilisation 133 mg raw product of PyMC29B-thiol was obtained. GLC monomer analysis was performed as described above, but by a slightly modified procedure. Since the PyMC-thiol did not fully dissolve, methanolysis was extended for 120 min. at 120 °C additionally. A second entry with successful dissolving was carried out with 3 M MeOH/HCl for 120 min. at 90 °C and additionally for 60 min. at 120 °C.
Success of cycloadditions was obvious from the disappearance or strong reduction of alkynyl-related absorption bands in the IR spectra. ATR FTIR spectra of the product have been generated. All IR spectra are normalized with respect to the most intense absorption band at 1053 cm"1. The C≡C-H valence vibration at 3280 cm"1 of the pentynyl derivatives has disappeared after the cycloaddition reaction.
Reaction of pentynyl methylcellulose with carboxypropylazide (-» PyMC65A-carboxy)
60 mg (0.116 mmol alkynyl, Mw (AGU) = 206.6 g/mol, DSMe = 1.3, DSPy = 0.4 assumed) polymer PyMC65A, 40 μL· (38 mg, 0.29 mmol, 2.5 eq. per alkynyl) carboxypropylazide, 8 mL DMSO, 2 mL water, 106 (0.106 mmol) sodium ascorbate stock solution (1 M) and 6.7 mg (0.027 mmol) CuS04 · 5 H20 in 0.1 mL water solution were applied. Ca. 56 mg of PyMC65A-carboxy raw product was obtained after dialysis and lyophilisation. GLC monomer analysis was accomplished after methanolysis and trimethylsilylation. Methanolysis was carried out as follows: (1) two samples of 1-2 mg polymer PyMC65A-carboxy in 1 mL 1.5 M MeOH/HCl were heated for 120 min. at 90 °C. Since they were not completely dissolved, they were additionally heated for 120 min. at 120 °C. (2) Full dissolution was achieved when heating with 3.0 M MeOH/HCl for 120 min. at 90 °C. Further treatment was performed as described above.
Success of cycloadditions was obvious from the disappearance or strong reduction of alkynyl-related absorption bands in the IR spectra. ATR FTIR spectra of the product have been generated. All IR spectra are normalized with respect to the most intense absorption band at 1053 cm"1. The C≡C-H valence vibration at 3280 cm"1 of the pentynyl derivatives has disappeared after the cycloaddition reaction.
Claims
1. A compound which is a cellulose ether having an average of 1.0 to 2.5 Ci-C6 alkyl ether groups per glucopyranosyl unit and an average of 0.01 to 1 triazole-containing substituents per glucopyranosyl unit.
2. The compound of claim 1 having a viscosity, measured from a 2 wt solution in water at 20 °C, of 50 mPa- s to 60,000 mPa- s.
3. The compound of claim 2 in which the alkyl ether groups have from one to three carbon atoms.
4. The compound of claim 1 having an average of 0.1 to 0.5 triazole-containing substituents per glucopyranosyl unit.
5. The compound of claim 4 in which the alkyl ether groups have from one to three carbon atoms.
6. The compound of claim 5 in which the alkyl ether groups are unsubstituted or substituted only by a single hydroxyl group.
7. The compound of claim 1 in which the compound has an average of 50 to 5000 glucopyranosyl units.
8. The compound of claim 7 in which the alkyl ether groups have from one to three carbon atoms.
9. The compound of claim 8 having an average of 0.1 to 0.5 triazole-containing substituents per glucopyranosyl unit.
10. The compound of claim 9 in which the alkyl ether groups are unsubstituted or substituted only by a single hydroxyl group.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461974141P | 2014-04-02 | 2014-04-02 | |
US61/974,141 | 2014-04-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015153217A1 true WO2015153217A1 (en) | 2015-10-08 |
Family
ID=52811270
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/022415 WO2015153217A1 (en) | 2014-04-02 | 2015-03-25 | Cellulose ethers having 1,2,3-triazolyl substituents |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2015153217A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3214098A1 (en) * | 2016-03-03 | 2017-09-06 | SE Tylose GmbH & Co.KG | Cellulose ethers substituted with hydroxyalkyl and omega-alkinyl groups and cellulose ethers substituted with hydroxyalkyl, omega-alkinyl and azido groups and their use as water-insoluble adhesives |
US20220109162A1 (en) * | 2018-08-20 | 2022-04-07 | Hyundai Motor Company | Electrode including metal nanoparticles having conductive polymer shell and conductive film and method for manufacturing the same |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101812140A (en) * | 2010-01-21 | 2010-08-25 | 清华大学 | Cyclodextrin-bonded comb-shaped copolymer and preparation method thereof |
CN102827293A (en) * | 2012-08-29 | 2012-12-19 | 中科院广州化学有限公司 | Alkynyl hydroxypropyl cellulose and preparation method and application of temperature-sensitive hydrogel of alkynyl hydroxypropyl cellulose |
WO2013124654A1 (en) * | 2012-02-20 | 2013-08-29 | Cambridge Enterprise Limited | Cucurbituril-based hydrogels |
EP2712873A1 (en) * | 2012-09-28 | 2014-04-02 | SE Tylose GmbH & Co.KG | Cellulose ethers with a reactive anchor group, modified cellulose ethers that can be obtained therefrom and method for the production thereof |
-
2015
- 2015-03-25 WO PCT/US2015/022415 patent/WO2015153217A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101812140A (en) * | 2010-01-21 | 2010-08-25 | 清华大学 | Cyclodextrin-bonded comb-shaped copolymer and preparation method thereof |
WO2013124654A1 (en) * | 2012-02-20 | 2013-08-29 | Cambridge Enterprise Limited | Cucurbituril-based hydrogels |
CN102827293A (en) * | 2012-08-29 | 2012-12-19 | 中科院广州化学有限公司 | Alkynyl hydroxypropyl cellulose and preparation method and application of temperature-sensitive hydrogel of alkynyl hydroxypropyl cellulose |
EP2712873A1 (en) * | 2012-09-28 | 2014-04-02 | SE Tylose GmbH & Co.KG | Cellulose ethers with a reactive anchor group, modified cellulose ethers that can be obtained therefrom and method for the production thereof |
Non-Patent Citations (11)
Title |
---|
"Hypromellose", USP 35, pages 3467 - 3469 |
ANDREAS KOSCHELLA ET AL: "A click-chemistry approach to cellulose-based hydrogels", CARBOHYDRATE POLYMERS, APPLIED SCIENCE PUBLISHERS, LTD. BARKING, GB, vol. 86, no. 1, 12 April 2011 (2011-04-12), pages 154 - 161, XP028378205, ISSN: 0144-8617, [retrieved on 20110421], DOI: 10.1016/J.CARBPOL.2011.04.031 * |
C.M. KEARY, CARBOHYDRATE POLYMERS, vol. 45, 2001, pages 293 - 303 |
CHRISTIAN BORK: "Alkinylether von Glucanen als Intermediate für Glycostrukturen", INTERNET CITATION, 25 October 2013 (2013-10-25), XP002740289, Retrieved from the Internet <URL:http://digisrv-1.biblio.etc.tu-bs.de:8080/docportal/servlets/MCRFileNodeServlet/DocPortal_derivate_00034144/Dissertation_ChristianBork.pdf> [retrieved on 20150529] * |
D.P. SWEET; R.H. SHAPIRO; P. ALBERSHEIM, CARBOHYD. RES., vol. 40, 1975, pages 217 - 225 |
H.C. KOLB ET AL., DRUG DISCOVERY TODAY, vol. 8, 2003, pages 1128 - 1137 |
M.N. TAHIR ET AL., MACROMOL. CHEM. PHYS., vol. 211, 2010, pages 1648 - 1662 |
POHL M ET AL: "Studies on the molecular flexibility of novel dendronized carboxymethyl cellulose derivatives", EUROPEAN POLYMER JOURNAL, PERGAMON PRESS LTD. OXFORD, GB, vol. 45, no. 4, April 2009 (2009-04-01), pages 1098 - 1110, XP026006504, ISSN: 0014-3057, [retrieved on 20090118], DOI: 10.1016/J.EURPOLYMJ.2009.01.009 * |
R.F. ADDISON; R.G. ACKMAN, J. GAS CHROMATOGR., vol. 6, 1968, pages 135 - 138 |
R.G. ACKMAN, J. GAS CHROMATOGR., vol. 2, 1964, pages 173 - 179 |
W.H.BINDER ET AL., MACROMOL. RAPID COMMUN., vol. 28, 2007, pages 15 - 54 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3214098A1 (en) * | 2016-03-03 | 2017-09-06 | SE Tylose GmbH & Co.KG | Cellulose ethers substituted with hydroxyalkyl and omega-alkinyl groups and cellulose ethers substituted with hydroxyalkyl, omega-alkinyl and azido groups and their use as water-insoluble adhesives |
JP2017193701A (en) * | 2016-03-03 | 2017-10-26 | エスエー、テュローゼ、ゲゼルシャフト、ミット、ベシュレンクテル、ハフツング、ウント、コンパニー、コマンディートゲゼルシャフトSe Tylose Gmbh & Co.Kg | Cellulose ether substituted with hydroxyl and alkyne groups, as well as cellulose ether substituted with hydroxyalkyl, alkyne and azido groups, furthermore the use thereof as water-insoluble adhesive |
US10800858B2 (en) | 2016-03-03 | 2020-10-13 | Se Tylose Gmbh & Co. Kg | Cellulose ethers substituted with hydroxyl and alkyne groups and with hydroxyalkyl, alkyne and azide groups, and use thereof as water-insoluble adhesives |
US20220109162A1 (en) * | 2018-08-20 | 2022-04-07 | Hyundai Motor Company | Electrode including metal nanoparticles having conductive polymer shell and conductive film and method for manufacturing the same |
US11631864B2 (en) * | 2018-08-20 | 2023-04-18 | Hyundai Motor Company | Electrode including metal nanoparticles having conductive polymer shell and conductive film and method for manufacturing the same |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5902697B2 (en) | Novel cellulose ethers and their use | |
Casaburi et al. | Carboxymethyl cellulose with tailored degree of substitution obtained from bacterial cellulose | |
JP6389470B2 (en) | Preparation of poly α-1,3-glucan ether | |
US9062128B2 (en) | Hydroxyalkyl methylcellulose having solubility and thermoreversible gelation properties improved | |
JP4452776B2 (en) | Method for preparing alkyl hydroxyalkyl cellulose | |
KR100769423B1 (en) | A Process for Preparing Alkylhydroxyalkyl Cellulose | |
Koschella et al. | Regioselectively functionalized cellulose derivatives: a mini review | |
KR102077869B1 (en) | Cellulose ethers having a reactive anchor group, modified cellulose ethers obtainable therefrom and methods for the preparation thereof | |
EP3868790B1 (en) | Cyclic oligosaccharide and method for producing same | |
EP3353215A1 (en) | Process for preparing an ester of a cellulose ether in the presence of acetic acid and a reaction catalyst | |
WO2015153217A1 (en) | Cellulose ethers having 1,2,3-triazolyl substituents | |
Zheng et al. | Cellulose levulinate: a protecting group for cellulose that can be selectively removed in the presence of other ester groups | |
Ren et al. | Etherification of hemicelluloses from sugarcane bagasse | |
Gräbner et al. | Synthesis of novel adamantoyl cellulose using differently activated carboxylic acid derivatives | |
WO2015153216A1 (en) | Pentynyl cellulose ethers | |
Huijbrechts et al. | 1‐Allyloxy‐2‐hydroxy‐propyl‐starch: Synthesis and characterization | |
Kadokawa et al. | Synthesis of Linear and Hyperbranched Stereoregular Aminopolysaccharides by Oxazoline Glycosylation | |
Jun-Li et al. | Preparation and characterization of sugarcane bagasse hemicellulosic derivatives containing quaternary ammonium groups in various media | |
Heinze et al. | Functionalization pattern of tert-butyldimethyl-silyl cellulose evaluated by NMR spectroscopy | |
EP3529281A1 (en) | Efficient process of preparing an esterified cellulose ether | |
KR20160075234A (en) | Method of preparing acetylated cellulose ether | |
JP6295380B2 (en) | Process for preparing esterified cellulose ethers in the presence of aliphatic carboxylic acids | |
CN117529522A (en) | Methylcellulose with high powder dissolution temperature | |
Thompson et al. | Regioselective and controlled-density branching in amylose esters |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15714382 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase | ||
122 | Ep: pct application non-entry in european phase |
Ref document number: 15714382 Country of ref document: EP Kind code of ref document: A1 |