CN102775591B - Preparation method of tetraamino-terminated glycolide-lactide telechelic copolymer - Google Patents
Preparation method of tetraamino-terminated glycolide-lactide telechelic copolymer Download PDFInfo
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Abstract
The invention discloses a preparation method of tetraamino-terminated glycolide-lactide telechelic copolymer, belonging to the field of organic synthesis. The preparation method comprises the following steps: (1) adding glycolide, lactide, toluene, a catalyst and an initiator to prepare dihydroxyglycolide-lactide copolymer; (2) adding dichloromethane, dihydroxyglycolide-lactide copolymer, N alpha, N epsilon-bis(tert-butoxy carbonyl)-L-lysine, a catalyst and a coupling agent to prepare the glycolide-lactide copolymer with amino-terminated tert-butoxy carbonyl protecting group; and (3) adding dichloromethane, glycolide-lactide copolymer with amino-terminated tert-butoxy carbonyl protecting group and trifluoroacetic acid to prepare the tetraamino-terminated glycolide-lactide telechelic copolymer. The preparation method has the advantages of simple steps; the prepared product has controllable structure and molecular weight, and stable and reliable quality, and contains four amino groups with high activity and high spatial freedom at the chain end; the product can be used for preparing the networked degradable polyester biological elastomer with hydroxyl group on the surface by reacting with the epoxy-terminated polymers.
Description
Technical field
The present invention relates to the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, belong to the organic synthesis field.
Background technology
The degradable biological elastomerics of the advantages such as mechanical property that have snappiness, good snappiness, good biocompatibility and be complementary with the many soft tissues of human body shows huge application potential at biomedical sector.Different from natural materials, the degradable biological elastomerics of synthetic has mechanical property and degradation rate can design in advance and regulate and control; There is good mechanical property, easily build the high porosity three-dimensional rack, and still keep the stability on structural integrity and mechanical property in degradation process; Material is originally as non-immunogenic, and degraded product is the intermediate metabolites of body-internal-circulation, nontoxic, has reliable biological safety.Therefore, in recent years about just being subject to the world, the elastomeric research of synthetic degradable biological pays close attention to widely.The network-type polyester bioelastomer particularly formed through chemically crosslinked, because it has the ester bond structure similar to the linear polyesters biomaterial, and good biocompatibility, snappiness, biological degradability, the designability of structure and the advantages such as controllability of performance, shown wide medical use prospect.
The key for preparing the network-type degradable polyester bioelastomer of synthetic is the large monomer of polyester that the synthetic end group of design contains functional functional group, and as linking agent, by the chemical crosslink reaction with other functional monomer, obtain network-type degradable polyester bioelastomer material.The second lactide copolymer, due to its good biocompatibility, biodegradability and mechanical property, is widely accepted and adopts in fields such as organizational project and controlled drug release.Therefore, research is synthetic a kind of take the second lactide copolymer as main chain, and the distant pawl multipolymer that contains a plurality of functional end amino at molecular chain-end has important theory significance and actual application value concurrently.
Improve the bioactive functionalization that important channel is polyester molecule of degradable poly ester material, at first in polyester molecule, introduce functional functional group, then by the combination of these functional functional groups and bioactive molecules, obtain having the biomaterial of high biological activity.In design with while preparing functionalized polyester, generally must consider three aspects: (1) functional group functional.Functional group should be easy to and bioactive molecules (as peptide, carbohydrate, VITAMIN) combination, and the reaction conditions gentleness.In addition, the side reaction that may occur when bioactive molecules is combined in order to reduce functionalized polyester, preferably only contain a kind of functional group that can be used for biological functional in the functional poly ester molecule.(2) biocompatibility and degradability.Synthetic functionalized polyester have degradability and polyester itself with and degraded product all should be accepted by biomass cells and tissue.(3) operability of synthetic method.Synthetic method is simply easy to implement.In the recent period, the functionalization research of relevant linear polyester has more bibliographical information.Sum up, synthetic method mainly contains two kinds: a kind of is first to prepare the functionalization monomer, and then the polymerization by the functionalization monomer obtains functionalized polyester; Another kind of be that surface modification by the non-functional polyester to synthetic obtains functionalized polyester, as the method by radiation produces free radical in surface of polyester, then cause vinyl monomer in the surface of polyester graft polymerization.Yet two kinds of methods all have deficiency separately, the shortcoming of first method is that the building-up process of functionalization monomer is very complicated and product yield is low; The shortcoming of second method is that reaction conditions is usually very harsh, and the modified techniques such as simultaneously radiation also can cause the generation of the side reaction such as polyester molecule chain rupture, thereby is difficult to control the chemical structure of final product.The existence of these deficiencies has hindered the practical application process of functionalized polyester in biomedical materials field to a certain extent.
Chinese patent (patent No. ZL 200710058430.9) discloses amino star-like poly (glycolide-lactide)/polyethyleneglycol block copolymer of a kind of end and preparation method thereof.At first take stannous octoate as catalyzer, under the poly-hydroxy initiator exists, carry out the tube sealing polymerization of glycollide and rac-Lactide, obtain the star-like poly (glycolide-lactide) of terminal hydroxy group; Then it reacts with Succinic anhydried, obtains holding the star-like poly (glycolide-lactide) of carboxyl; The star-like poly (glycolide-lactide) of rearmost end carboxyl reacts with amino-end peg again, obtains holding amino star-like poly (glycolide-lactide)/polyethyleneglycol block copolymer.Because its first step building-up reactions adopts the tube sealing polymerization, not only operational difficulty, and reaction lack of homogeneity, product structure and molecular weight all are difficult to accurate control.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of the present invention's four ends, step is simply easy to implement, the distant pawl multipolymer of the amino second rac-Lactide of four ends of preparation, product structure and molecular weight are controlled, stable and reliable product quality, and the amino that the multipolymer end of the chain contains four high reactivity high spatial degree of freedom, with the amino distant pawl multipolymer of second rac-Lactide of this four end and epoxy terminated polymer reaction, can prepare the network-type degradable polyester bioelastomer that contains great amount of hydroxy group in surface, there is medical use prospect widely.
The technical solution used in the present invention is: the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add the monomer glycollide, the monomer rac-Lactide, dry toluene, metallic tin salt catalyst and initiator, under agitation condition, in 108～111 ℃ of reactions 8～16 hours, after reaction finishes, evaporate to dryness toluene, adding chloroform to surplus materials in surplus materials no longer dissolves, cross and filter out insolubles, the filtrate obtained is used methanol extraction, by drying precipitate, obtain both-end hydroxyl second lactide copolymer,
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, catalyzer and coupling agent, under agitation condition, in 20～30 ℃ the reaction 24～30 hours after, reactant is filtered, the filtrate obtained is used methanol extraction, by drying precipitate, obtains the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
(3) deaminizating protecting group: in being connected with the reactor of nitrogen; add methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid; under agitation condition; in 0～5 ℃ of reaction 3～6 hours; after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then uses methanol extraction; by drying precipitate, obtain the distant pawl multipolymer of the amino second rac-Lactide of four ends.
Metallic tin salt catalyst described in step (1) is a kind of in stannous iso caprylate, stannous octoate or tin protochloride.
The described initiator of step (1) is BDO.
In step (1), the mol ratio of monomer glycollide and rac-Lactide is 1:1～9; The mol ratio of glycollide and rac-Lactide sum and metallic tin salt catalyst is 1:0.01; The mol ratio of glycollide and rac-Lactide sum and initiator is 1:0.06～0.24; The mol ratio of glycollide and rac-Lactide sum and dry toluene is 1:10～30.
Temperature of reaction in step (1) is 111 ℃, and the reaction times is 12 hours.
Catalyzer described in step (2) is 4-(dimethylamino) pyridine-4-tosylate.
Coupling agent described in step (2) is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, dicyclohexyl carbodiimide or N, a kind of in N '-di-isopropyl carbodiimide.
8, the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends as claimed in claim 1, is characterized in that: both-end hydroxyl second lactide copolymer and N in step (2)
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs is 1:3～8; The mol ratio of both-end hydroxyl second lactide copolymer and catalyzer is 1:1～5; The mol ratio of both-end hydroxyl second lactide copolymer and coupling agent is 1:3～8; The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:10～25.
In step (3), with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end and the mass ratio of methylene dichloride, be 1:10～25; With the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end and the mass ratio of trifluoroacetic acid, be 1:4～15.
4-(dimethylamino) pyridine-4-tosylate is to make with reacting of tosic acid by Dimethylamino pyridine.
The amino second distant pawl multipolymer of rac-Lactide (I) structural formula of four ends prepared by step (3) is:
The structural formula of both-end hydroxyl second lactide copolymer (II) prepared by step (1) is:
The structural formula of the second lactide copolymer (III) with the amino tertbutyloxycarbonyl protecting group of end prepared by step (2) is:
Design of the present invention: at first by changing monomer ratio, catalyst levels, that initiator amount prepares structure is clear and definite, the both-end hydroxyl second lactide copolymer that molecular weight is controlled; Then by the polymer terminal group chemical reaction, the terminal hydroxy group of both-end hydroxyl second lactide copolymer is carried out to functional modification, preparation is with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end; Finally, by simple deprotection reaction, make the above-mentioned second lactide copolymer deprotection with the amino t-butoxycarbonyl protecting group of end, obtain structure clear and definite, the distant pawl multipolymer of the amino second rac-Lactide of four ends that molecular weight is controlled.
The beneficial effect that adopts technique scheme to produce is: the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of the present invention's four ends, step is simply easy to implement, the distant pawl multipolymer of the amino second rac-Lactide of four ends of preparation, product structure and molecular weight are controlled, stable and reliable product quality, and the amino that the multipolymer end of the chain contains four high reactivity high spatial degree of freedom, with the amino distant pawl multipolymer of second rac-Lactide of this four end and epoxy terminated polymer reaction, can prepare the network-type degradable polyester bioelastomer that contains great amount of hydroxy group in surface, thereby make synthetic elastomer material keep good degradability, also have higher biological activity in the time of biocompatibility and mechanical property concurrently, enrich the Design & preparation knowledge with consummating function network-type degradable polyester bioelastomer, actively promote research and the application process of network-type degradable polyester bioelastomer in biomedical materials field.
Embodiment
Embodiment 1
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, stannous octoate and 1, the 4-butyleneglycol, under agitation condition, in 111 ℃ of reactions 8 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:1, glycollide and rac-Lactide integral molar quantity and dry toluene mol ratio are 1:10, the mol ratio of glycollide and rac-Lactide integral molar quantity and stannous octoate is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.06.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, dicyclohexyl carbodiimide, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 20 ℃ of reactions 30 hours, reactant filters, the filtrate obtained is used methanol extraction, and throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:14, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 3:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 1:1, and the mol ratio of both-end hydroxyl second lactide copolymer and dicyclohexyl carbodiimide is 1:3;
N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs are unstable, in application process at first from N
α, N
εseparate and obtain N in-bis-(tertbutyloxycarbonyl)-1B two hexamethylene ammonium salts
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs and then reacted.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 0 ℃ of reaction 6 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:14, and trifluoroacetic acid is 4.6:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 2
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, stannous iso caprylate and 1, the 4-butyleneglycol, under agitation condition, in 111 ℃ of reactions 9 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:2, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:12, the mol ratio of glycollide and rac-Lactide integral molar quantity and stannous iso caprylate is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.06.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, N, N '-di-isopropyl carbodiimide, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 22 ℃ of reactions 24 hours, reactant filtered, and the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:14, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 4:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 1:1, both-end hydroxyl second lactide copolymer and N, the mol ratio of N '-di-isopropyl carbodiimide is 1:4;
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 2 ℃ of reactions 4 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:14, and trifluoroacetic acid is 4.6:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 3
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, tin protochloride and 1, the 4-butyleneglycol, under agitation condition, in 111 ℃ of reactions 9 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:3, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:16, the mol ratio of glycollide and rac-Lactide integral molar quantity and tin protochloride is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.1.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 24 ℃ of reactions 25 hours, reactant filters, the filtrate obtained is used methanol extraction, and throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:14, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 3:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 1:1, and the mol ratio of both-end hydroxyl second lactide copolymer and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 1:4;
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 5 ℃ of reactions 3 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:14, and trifluoroacetic acid is 4.2:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 4
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, stannous octoate and 1, the 4-butyleneglycol, under agitation condition, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, in 111 ℃ of reactions 10 hours, after reaction finishes, evaporate to dryness toluene, adding chloroform to surplus materials in surplus materials no longer dissolves, cross and filter out insolubles, the filtrate obtained is used methanol extraction, by throw out in 40 ℃ of vacuum-dryings 24 hours, obtain both-end hydroxyl second lactide copolymer,
The mol ratio of glycollide and rac-Lactide is 1:4, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:25, the mol ratio of glycollide and rac-Lactide integral molar quantity and stannous octoate is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.14.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, dicyclohexyl carbodiimide, under agitation condition, in 26 ℃ of reactions 25 hours, reactant filters, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:14, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 4:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 1:1, and the mol ratio of both-end hydroxyl second lactide copolymer and dicyclohexyl carbodiimide is 1:5;
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 0 ℃ of reaction 4 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:14, and trifluoroacetic acid is 4.6:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 5
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, stannous iso caprylate and 1, the 4-butyleneglycol, under agitation condition, in 111 ℃ of reactions 12 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:5, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:10, the mol ratio of glycollide and rac-Lactide integral molar quantity and stannous iso caprylate is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.18.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, N, N '-di-isopropyl carbodiimide, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 29 ℃ of reactions 26 hours, reactant filtered, and the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:20, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 3:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 2:1, both-end hydroxyl second lactide copolymer and N, the mol ratio of N '-di-isopropyl carbodiimide is 1:3;
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 1 ℃ of reaction 5 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:20, and trifluoroacetic acid is 5:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 6
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, tin protochloride and 1, the 4-butyleneglycol, under agitation condition, in 111 ℃ of reactions 14 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:6, glycollide and rac-Lactide integral molar quantity and dry toluene mol ratio are 1:20, the mol ratio of glycollide and rac-Lactide integral molar quantity and tin protochloride is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.2.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 25 ℃ of reactions 27 hours, reactant filters, the filtrate obtained is used methanol extraction, and throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:16, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 3:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 3:1, and the mol ratio of both-end hydroxyl second lactide copolymer and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 1:4;
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 0 ℃ of reaction 6 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:20, and trifluoroacetic acid is 10:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 7
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, stannous octoate and 1, the 4-butyleneglycol, under agitation condition, in 111 ℃ of reactions 16 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:9, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:25, the mol ratio of glycollide and rac-Lactide integral molar quantity and stannous octoate is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.24.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, N, N '-di-isopropyl carbodiimide, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 30 ℃ of reactions 24 hours, reactant filtered, and the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:25, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 6:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 2:1, both-end hydroxyl second lactide copolymer and N, the mol ratio of N '-di-isopropyl carbodiimide is 1:6;
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 4 ℃ of reactions 3 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:10, and trifluoroacetic acid is 8:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
The performance test results of the distant pawl multipolymer of the amino second rac-Lactide of four ends of embodiment 1～7 preparation is as following table 1.
Table 1
| Embodiment | １ | ２ | ３ | ４ | ５ | ６ | ７ |
| Matter average molecular weight (M w） | 14842 | 13466 | 12547 | 10864 | 9756 | 9283 | 8962 |
| Number-average molecular weight (M n） | 11874 | 10859 | 10118 | 8832 | 7932 | 7426 | 7113 |
| Molecular weight distribution (M w/M n） | 1.25 | 1.24 | 1.24 | 1.23 | 1.23 | 1.25 | 1.26 |
| Second-order transition temperature (T g) / 0C | 14.3 | 11.5 | 9.8 | 7.7 | 6.5 | 5.0 | 4.4 |
Embodiment 8
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, tin protochloride and 1, the 4-butyleneglycol, under agitation condition, in 108 ℃ of reactions 16 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:1, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:25, the mol ratio of glycollide and rac-Lactide integral molar quantity and tin protochloride is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.2.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 25 ℃ of reactions 27 hours, reactant filters, the filtrate obtained is used methanol extraction, and throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:10, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 8:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 5:1, and the mol ratio of both-end hydroxyl second lactide copolymer and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 1:8.
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 0 ℃ of reaction 6 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:10, and trifluoroacetic acid is 5:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 9
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, tin protochloride and 1, the 4-butyleneglycol, under agitation condition, in 110 ℃ of reactions 12 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:1, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:15, the mol ratio of glycollide and rac-Lactide integral molar quantity and tin protochloride is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.2.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 25 ℃ of reactions 27 hours, reactant filters, the filtrate obtained is used methanol extraction, and throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:25, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 5:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 3:1, and the mol ratio of both-end hydroxyl second lactide copolymer and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 1:8.
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 0 ℃ of reaction 6 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:25, and trifluoroacetic acid is 15:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
Embodiment 10
The preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends, comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add successively monomer glycollide and rac-Lactide, dry toluene, tin protochloride and 1, the 4-butyleneglycol, under agitation condition, in 109 ℃ of reactions 12 hours, after reaction finishes, evaporate to dryness toluene, add chloroform to surplus materials and no longer dissolve in surplus materials, cross and filter out insolubles, the filtrate obtained is used methanol extraction, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to both-end hydroxyl second lactide copolymer;
The mol ratio of glycollide and rac-Lactide is 1:1, the mol ratio of glycollide and rac-Lactide integral molar quantity and dry toluene is 1:25, the mol ratio of glycollide and rac-Lactide integral molar quantity and tin protochloride is 1:0.01, and the mol ratio of glycollide and rac-Lactide integral molar quantity and BDO is 1:0.2.
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add successively methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, 4-(dimethylamino) pyridine-4-tosylate, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, both-end hydroxyl second lactide copolymer is dissolved in methylene dichloride, under agitation condition, in 25 ℃ of reactions 27 hours, reactant filters, the filtrate obtained is used methanol extraction, and throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:16, N
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs and both-end hydroxyl second lactide copolymer is 3:1, the mol ratio of 4-(dimethylamino) pyridine-4-tosylate and both-end hydroxyl second lactide copolymer is 1:1, and the mol ratio of both-end hydroxyl second lactide copolymer and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 1:3.
N
α, N
εthe preparation method of-bis-(tertbutyloxycarbonyl)-1Bs is with embodiment 1.
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add successively methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, to be dissolved in methylene dichloride with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end, under agitation condition, in 0 ℃ of reaction 6 hours, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, filter, throw out, in 40 ℃ of vacuum-dryings 24 hours, is obtained to the distant pawl multipolymer of the amino second rac-Lactide of four ends;
Second lactide copolymer and the mass ratio of methylene dichloride with the amino tertbutyloxycarbonyl protecting group of end are 1:16, and trifluoroacetic acid is 6:1 with the mass ratio of second lactide copolymer with holding amino tertbutyloxycarbonyl protecting group.
The performance test results of the distant pawl multipolymer of the amino second rac-Lactide of four ends of embodiment 8～10 preparations is as following table 2.
Table 2
| Embodiment | 8 | 9 | 10 |
| Matter average molecular weight (M w） | 9367 | 9198 | 9154 |
| Number-average molecular weight (M n） | 7553 | 7477 | 7331 |
| Molecular weight distribution (M w/M n） | 1.24 | 1.23 | 1.25 |
| Second-order transition temperature (T g) / 0C | 5.1 | 4.8 | 5.0 |
Claims (5)
1. the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of an end, it is characterized in that: comprise the following steps: (1) ring-opening polymerization: in being connected with the reactor of nitrogen, add monomer glycollide, monomer rac-Lactide, dry toluene, metallic tin salt catalyst and initiator, under agitation condition, react, after reaction finishes, evaporate to dryness toluene, adding chloroform to surplus materials in surplus materials no longer dissolves, cross and filter out insolubles, the filtrate obtained is used methanol extraction, by drying precipitate, obtain both-end hydroxyl second lactide copolymer;
(2) terminal hydroxy group functionalization: in being connected with the reactor of nitrogen, add methylene dichloride, both-end hydroxyl second lactide copolymer, N
α, N
ε-bis-(tertbutyloxycarbonyl)-1Bs, catalyzer and coupling agent, react under agitation condition, after reaction finishes, reactant is filtered, the filtrate obtained is used methanol extraction, by drying precipitate, obtains the second lactide copolymer with the amino tertbutyloxycarbonyl protecting group of end;
(3) deaminizating protecting group: in being connected with the reactor of nitrogen, add methylene dichloride, with the end amino tertbutyloxycarbonyl protecting group second lactide copolymer, trifluoroacetic acid, under agitation condition, react, after reaction finishes, vacuum is taken off unreacted trifluoroacetic acid, then use methanol extraction, by drying precipitate, obtain the distant pawl multipolymer of the amino second rac-Lactide of four ends;
In step (1), temperature of reaction is 108～111 ℃, and the reaction times is 8～16 hours; In step (2), temperature of reaction is 20～30 ℃, and the reaction times is 24～30 hours; In step (3), temperature of reaction is 0～5 ℃, and the reaction times is 3～6 hours;
In step (1), the mol ratio of monomer glycollide and rac-Lactide is 1:1～9; The mol ratio of glycollide and rac-Lactide sum and metallic tin salt catalyst is 1:0.01; The mol ratio of glycollide and rac-Lactide sum and initiator is 1:0.06～0.24; The mol ratio of glycollide and rac-Lactide sum and dry toluene is 1:10～30;
Coupling agent described in step (2) is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, dicyclohexyl carbodiimide or N, a kind of in N '-di-isopropyl carbodiimide;
Both-end hydroxyl second lactide copolymer and N in step (2)
α, N
εthe mol ratio of-bis-(tertbutyloxycarbonyl)-1Bs is 1:3～8; The mol ratio of both-end hydroxyl second lactide copolymer and catalyzer is 1:1～5; The mol ratio of both-end hydroxyl second lactide copolymer and coupling agent is 1:3～8; The mass ratio of both-end hydroxyl second lactide copolymer and methylene dichloride is 1:10～25;
In step (3), with the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end and the mass ratio of methylene dichloride, be 1:10～25; With the second lactide copolymer of the amino tertbutyloxycarbonyl protecting group of end and the mass ratio of trifluoroacetic acid, be 1:4～15.
2. the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends as claimed in claim 1, it is characterized in that: the temperature of reaction in step (1) is 111 ℃, the reaction times is 12 hours.
3. the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends as claimed in claim 1 is characterized in that: metallic tin salt catalyst described in step (1) is a kind of in stannous iso caprylate, stannous octoate or tin protochloride.
4. the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends as claimed in claim 1, it is characterized in that: the described initiator of step (1) is BDO.
5. the preparation method of the distant pawl multipolymer of the amino second rac-Lactide of a kind of four ends as claimed in claim 1, it is characterized in that: catalyzer described in step (2) is 4-(dimethylamino) pyridine-4-tosylate.
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