WO2018176884A1 - 一种全绿色封闭循环工艺生产光学纯l-/d-丙交酯的方法 - Google Patents

一种全绿色封闭循环工艺生产光学纯l-/d-丙交酯的方法 Download PDF

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WO2018176884A1
WO2018176884A1 PCT/CN2017/113588 CN2017113588W WO2018176884A1 WO 2018176884 A1 WO2018176884 A1 WO 2018176884A1 CN 2017113588 W CN2017113588 W CN 2017113588W WO 2018176884 A1 WO2018176884 A1 WO 2018176884A1
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dla
lla
plla
pdla
product
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李弘�
张全兴
王子羽
何文文
黄伟
江伟
李爱民
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南京大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • the invention belongs to the field of bio-based degradable material synthesis, and particularly relates to a method for producing optically pure L-/D-lactide by an all-green closed-loop process.
  • Bio-based degradable materials have been recognized as the best alternative to petroleum-based plastics, and their use helps to address the increasingly serious global "white pollution” problem at the source.
  • Polylactic acid (PLA) is considered to be the most promising class of biobased degradable materials.
  • Such materials have been widely used in the fields of film, fiber, packaging materials, etc., in addition to the important applications in the field of biomedicine, such as hard tissue repair materials, surgical sutures, targeted and controlled release drug carriers.
  • PLA's global production scale is much lower than that of traditional petroleum-based plastics, which is mainly due to its high monomer production costs.
  • commercial PLA is mostly produced by a ring-opening polymerization process, and the monomer used is a L-/D-lactic acid (LLa/DLa) cyclic dimer, L-/D-lactide (LLA/DLA).
  • LLA/DLA production process LLA/DLa is first dehydrated and oligomerized to obtain oligomeric lactic acid (o-PLLA/o-PDLA), the latter in Sn II (SnCl 2 , SnOct 2 ) or Sb III (Sb 2 O 3 Catalytic depolymerization and cyclization in the presence of a catalyst to obtain LLA/DLA.
  • the process has the following problems:
  • reaction energy consumption is high, and the reaction temperature is usually higher than 240 °C.
  • optical pure LLA/DLA synthesis mainly obtains o-PLLA/o-PDLA by LLA/DLa dehydration oligomerization, and the latter undergoes anti-biting chain transfer reaction under the action of a catalyst, and cyclization generates LLA/DLA.
  • o-PLLA/o-PDLA inevitably undergoes a polycondensation reaction under the action of a catalyst to form r-PLLA/r-PDLA.
  • the object of the present invention is to solve the problem that the by-product polymer residue in the above-mentioned existing optical pure LLA/DLA large-scale industrial production cannot be recycled, and the crude LLA/DLA has low optical purity, complicated purification process and high energy consumption.
  • the method for producing optically pure L-/D-lactide (LLA/DLA) by the all-green closed-loop process provided by the invention is a raw material 1: fresh L-/D-lactic acid (LLa/DLa) aqueous solution and raw material 2: A mixture of L-/D-lactide synthesis by-product polymer residue (r-PLLA/r-PDLA) is used as a raw material, and first dehydration oligomerization is carried out to obtain LLa/DLa oligomer (o-PLLA/o-PDLA).
  • LLA/DLA optically pure L-/D-propanium Ester
  • r-PLLA/r-PDLA which is a by-product of the lactide synthesis process
  • r-PLLA/r-PDLA which is a by-product of the lactide synthesis process
  • the LLa/DLa aqueous solution as a raw material to carry out lactide synthesis, thereby recycling the by-product polymer residue.
  • the raw material is the raw material 1 when the dehydration oligomerization step is first performed, and the o-PLLA/o-PDLA obtained by dehydration oligomerization enters the lactide synthesis step, and the optical pure LLA/DLA product is obtained in this process.
  • the whole process includes a dehydration oligomerization process and a lactide synthesis process.
  • Dehydration and oligomerization step adding raw materials to the dehydration oligomerization kettle, first controlling the temperature of the kettle at 120-150 ° C, the pressure at 300-200 torr, and reacting for 1-2 h; then maintaining the temperature of the kettle unchanged, controlling the pressure of the reactor at 30-10 torr continued the reaction for 2.0-4.0 h to obtain o-PLLA/o-PDLA having a weight average molecular weight M w of 0.5-3.0 ⁇ 10 3 .
  • This process uses a mixture of LLa/DLa aqueous solution and r-PLLA/r-PDLA as a raw material to react to form a monodisperse oligomer o-PLLA/o-PDLA, although the specific cause of this process is not clear.
  • the commercially available LLa/DLa is usually 85-90% aqueous solution, and the water contained in r-PLLA/r-PDLA and LLa/DLa aqueous solution is catalyzed by the catalyst while dehydration oligomerization is carried out.
  • the hydrolysis reaction occurs under the action, and finally monodisperse o-PLLA/o-PDLA is formed, and the M w can satisfy the requirements of the further lactide synthesis process.
  • Lactide synthesis step o-PLLA/o-PDLA synthesized by the dehydration oligomerization step is injected into a lactide synthesis reactor equipped with a rectification section, and a ternary composite catalyst system is added, and the temperature of the kettle is controlled at 165.
  • the rectification section temperature is 85-90 ° C
  • the pressure is 5.0-0.1 torr
  • the reaction is 1.0-3.0 h
  • the product optically pure LLA/DLA is distilled from the top of the rectification section
  • the by-product polymer residue r-PLLA/ r-PDLA returns to the dehydration oligomerization process
  • the lactide synthesis process product LLA/DLA, without any purification operation process its optical purity is 100% ee;
  • r-PLLA/r-PDLA When the lactide synthesis process by-product r-PLLA/r-PDLA is returned to the dehydration oligomerization process from the lactide synthesis step, it can be directly injected through a pipe, or granulated, or pulverized as a liquid or solid. Dehydration oligomerization reactor. Thereafter, r-PLLA/r-PDLA is mixed with fresh LLa/DLa, and the dehydration oligomerization process is continued to realize the recycling of r-PLLA/r-PDLA.
  • the mass ratio of the fresh LLA/DLa to the r-PLLA/r-PDLA was controlled by the LLA/DLa metering tank and the lactide synthesis bottom mass flow meter (1-3):1.
  • the ternary composite catalytic system consists of a main catalyst bioorganism, a biguanide and a cocatalyst non-toxic metal salt or oxide.
  • the bioorganic hydrazine is specifically one of creatinine, creatine, thioglycolic acid or guanine.
  • the biguanide is specifically one of metformin, morpholine biguanide or phenformin.
  • the cocatalyst is specifically one of Fe 2 O 3 , K 2 CO 3 , MgO, Mg(OOCCH 3 ) 2 , ZnO or Zn(OOCCH 3 ) 2 .
  • the initial feed amount of bioorganic germanium is 0.004-0.006% of the LKa/DLa feed quality.
  • the initial charge of the double crucible is 0.004-0.006% of the LKa/DLa feed quality.
  • the initial charge of the cocatalyst is from 0.002 to 0.004% of the LKa/DLa charge quality.
  • the ternary composite catalytic system of the present invention is a prerequisite for realizing the production of optically pure LLA/DLA by this all-green closed cycle process.
  • the monomer L-/D-lactic acid utilization rate is high (95-97%), achieving atomic economy;
  • the ternary composite catalyst has high catalytic activity and can be used repeatedly; the stereospecificity and selectivity are high, and the product L-/D-lactide is optically pure, eliminating the traditional high number of plates and multi-tower Distilling and purifying the process, simplifying the purification process and reducing energy consumption;
  • the reaction temperature of the lactide synthesis process is lower than that of the conventional process, and the production energy consumption is lowered.
  • Figure 1 is a process flow diagram of the method of the present invention.
  • Chiral HPLC systems include: LC-20AB pump, SPD-M20A UV detector (254nm), CTO–10ASvp column oven, DGU–20A3 degasser, Baseline chiral separation column (150 ⁇ 4.6mm) .
  • Test conditions 5 mmol/L CuSO 4 aqueous solution was used as the mobile phase, the flow rate was 1.0 mL/min, and the column temperature was 25 °C.
  • optical purity analysis results of the raw materials LLa and DLa used in the examples of the present invention are as follows.
  • DLa 90% aqueous solution DLa content ⁇ 99.0%.
  • the chiral gas chromatography system mainly includes: flame ionization detector (FID), Agilent CP-cyclodextrin- ⁇ -236M-19 capillary column (50m ⁇ 0.25mm i.d., wall thickness 0.25 ⁇ m). Test conditions: The column temperature was ramped up to 250 °C at a rate of 15 °C/min from 7 °C. The injector and FID detector temperatures were maintained at 250 ° C and 270 ° C, respectively. Nitrogen was used as the carrier gas.
  • the first dehydrated oligomerization kettle bottom discharge material is continuously injected into the second dehydration oligomerization reactor through a pipeline, the temperature of the kettle is controlled at 120-150 ° C, the pressure is 30-10 torr, the reaction time is 2.0-4.0 h, and the dehydration is carried out.
  • the oligomerization step product o-PLLA/o-PDLA is discharged from the bottom of the tank and enters the lactide synthesis step.
  • the dehydration oligomerization step product o-PLLA/o-PDLA has a weight average molecular weight M w of 0.5-3.0 ⁇ 10 3 .
  • the dehydration oligomerization step product o-PLLA/o-PDLA is continuously injected from the bottom of the second dehydration oligomerization reactor through a pipeline with a rectification column (0.5 mm ⁇ 1.0 mm glass spring packing, theoretical plate number 5-15 pieces).
  • the lactide synthesis kettle is continuously added to the ternary composite catalytic system, the temperature of the control kettle is 165-190 ° C, the temperature of the rectification section is 85-90 ° C, the pressure is 5.0-0.1 torr, and the reaction time is 1.0-3.0 h.
  • the product optically pure LLA/DLA is distilled from the top of the rectifying section.
  • the by-product polymer residue r-PLLA/r-PDLA is discharged from the bottom of the tank and enters the dehydration oligomerization process.
  • the resulting LLA/DLA product was optically pure (100% e.e.) by chiral gas chromatography.
  • the obtained LLA/DLA product contains a trace amount of meso-lactide (m-LA), which is mainly composed of enantiomer impurities contained in the LLa/DLa raw material ( Usually this enantiomeric impurity is difficult to remove completely).
  • m-LA meso-lactide
  • the polyreactor is charged; the bottom of the first dehydrated oligomerization kettle is continuously injected into the second dehydration oligomerization reactor through a pipeline, and the temperature of the kettle is controlled at 120 ° C, the pressure is 30 torr, the reaction time is 2.0 h, and the product of the dehydration oligomerization process o-PLLA is discharged from the bottom of the bottom of the tank and enters the lactide synthesis process.
  • the dehydration oligomerization step product o-PLLA continuously injects a lactide synthesis reactor equipped with a rectification column (theoretical number of 15 plates) from the bottom of the second dehydration oligomerization reactor, and continuously adds creatinine (initial LLA mass) 0.004%), metformin (0.004% of initial LBa mass), ZnO (0.004% of initial LSa mass), controlled kettle temperature of 165 ° C, rectification section temperature of 85 ° C, pressure of 5.0 torr, and residence time of 1.0 h.
  • the product optically pure LLA is distilled from the top of the rectifying section.
  • the by-product polymer residue is discharged from the bottom of the kettle and enters a dehydration oligomerization process.
  • the raw material 1 metering tank and lactide synthesis bottom material 2 mass flow meter, control the fresh LLA and r-PLLA mixed mass ratio is 1:1.
  • the second dehydrated oligomerization bottom sampling port was used to determine the O-PLLA M w of the dehydration oligomerization step product; the LLA obtained from the top product collection tank of the lactide synthesis tank rectification section was analyzed. The results are shown in Table 1.
  • the polyreactor is charged; the bottom of the first dehydrated oligomerization kettle is continuously injected into the second dehydration oligomerization reactor through a pipeline, and the temperature of the kettle is controlled at 120 ° C, the pressure is 30 torr, the reaction time is 2.0 h, and the product of the dehydration oligomerization process o-PLLA is discharged from the bottom of the bottom of the tank and enters the lactide synthesis process.
  • the dehydration oligomerization step product o-PLLA continuously injects a lactide synthesis reactor equipped with a rectification column (theoretical number of plates 15) from the bottom of the second dehydration oligomerization reactor, and continuously adds creatine (initial LLA mass) 0.004%), morpholine biguanide (0.005% of initial LLa mass), Fe 2 O 3 (0.004% of initial LLa mass), controlled kettle temperature at 165 ° C, rectification section temperature at 85 ° C, pressure at 5.0 torr, The reaction time was 1.0 h.
  • the product optically pure LLA is distilled from the top of the rectifying section.
  • the by-product polymer residue is discharged from the bottom of the kettle and enters a dehydration oligomerization process.
  • the raw material 1 metering tank and lactide synthesis bottom material 2 mass flow meter, control the fresh LLA and r-PLLA mixed mass ratio is 1:1.
  • the second dehydrated oligomerization bottom sampling port was used to determine the O-PLLA M w of the dehydration oligomerization step product; the LLA obtained from the top product collection tank of the lactide synthesis tank rectification section was analyzed. The results are shown in Table 1.
  • the polyreactor is charged; the bottom of the first dehydrated oligomerization kettle is continuously injected into the second dehydration oligomerization reactor through a pipeline, and the temperature of the kettle is controlled at 135 ° C, the pressure is 20 torr, the reaction time is 3.0 h, and the product of the dehydration oligomerization process o-PLLA is discharged from the bottom of the bottom of the tank and enters the lactide synthesis process.
  • the dehydration oligomerization step product o-PLLA continuously injects a lactide synthesis reactor equipped with a rectification column (the number of theoretical plates of 10 pieces) from the bottom of the second dehydration oligomerization reactor, and continuously adds thioglycolic acid (initial LLa) 0.005% by mass), phenformin (0.006% of initial LLa mass), K 2 CO 3 (0.002% of initial LBa mass), controlled kettle temperature at 178 ° C, rectification temperature at 88 ° C, pressure at 2.5 torr , the reaction time was 2.0 h.
  • the product optically pure LLA is distilled from the top of the rectifying section.
  • the by-product polymer residue is discharged from the bottom of the kettle and enters a dehydration oligomerization process.
  • the mass ratio of the raw material 1 metering tank and the lactide synthesis bottom material 2 is controlled, and the mass ratio of the fresh LLA to the r-PLLA is controlled to be 2:1.
  • the second dehydrated oligomerization bottom sampling port was used to determine the O-PLLA M w of the dehydration oligomerization step product; the LLA obtained from the top product collection tank of the lactide synthesis tank rectification section was analyzed. The results are shown in Table 1.
  • the fresh DLa 1000 is continuously injected into the first dehydration oligomerization tank through the raw material 1 measuring tank.
  • Kg the control kettle temperature is 135 ° C
  • the pressure is 250 torr
  • the reaction time is 2.0 h
  • the material is discharged from the bottom of the kettle into the second dehydration oligomerization reactor;
  • the first dehydrated oligomerization kettle bottom discharge material is continuously injected into the material through the pipeline
  • the second dehydration oligomerization reactor is controlled at a temperature of 135 ° C, a pressure of 20 torr, and a reaction time of 3.0 h.
  • the product o-PDLA of the dehydration oligomerization step is discharged from the bottom of the tank and enters the lactide synthesis step.
  • the dehydration oligomerization step product o-PDLA continuously injects a lactide synthesis reactor equipped with a rectification column (the number of theoretical plates of 10 pieces) from the bottom of the second dehydration oligomerization reactor, and continuously adds guanine (initial DLa quality) 0.005%), metformin (0.004% of initial DLa mass), MgO (0.002% of initial DLa mass), controlled kettle temperature of 178 ° C, rectification section temperature of 88 ° C, pressure of 2.5 torr, and residence time of 2.0 h .
  • the product optically pure DLA is distilled from the top of the rectifying section.
  • the by-product polymer residue is discharged from the bottom of the kettle and enters a dehydration oligomerization process.
  • the raw material 1 metering tank and lactide synthesis bottom material 2 mass flow meter control the mixing ratio of fresh DLa and r-PDLA when the mass ratio is 2:1.
  • fresh DLa 1000Kg was continuously injected into the first dehydration oligomerization tank through the raw material 1 measuring tank, the temperature of the kettle was controlled at 150 ° C, the pressure was at 200 torr, and the reaction time was 2.0 h.
  • the material was discharged from the bottom of the tank into the second dehydrated oligo.
  • the polyreactor is charged; the bottom of the first dehydrated oligomerization kettle is continuously injected into the second dehydration oligomerization reactor through a pipeline, and the temperature of the kettle is controlled at 150 ° C, the pressure is 10 torr, the reaction time is 4.0 h, and the dehydration oligomerization process is carried out.
  • o-PDLA is discharged from the bottom of the bottom of the tank and enters the lactide synthesis process.
  • the dehydration oligomerization step product o-PDLA continuously injects a lactide synthesis reactor equipped with a rectification column (theoretical number of plates) from the bottom of the second dehydration oligomerization reactor, and continuously adds creatinine (initial DLa mass) 0.006%), morpholine biguanide (0.005% of initial DLa mass), Mg(OOCCH 3 ) 2 (0.003% of initial DLa mass), controlled kettle temperature at 190 ° C, rectification section temperature at 90 ° C, pressure at 1.0 torr , the reaction time was 3.0h.
  • the product optically pure DLA is distilled from the top of the rectifying section.
  • the by-product polymer residue is discharged from the bottom of the kettle and enters a dehydration oligomerization process.
  • the mass ratio of the raw material 1 metering tank and the lactide synthesis bottom material is 2, and the mass ratio of the fresh DLa to the r-PDLA is 3:1.
  • fresh DLa 1000Kg was continuously injected into the first dehydration oligomerization tank through the raw material 1 measuring tank, the temperature of the kettle was controlled at 150 ° C, the pressure was at 200 torr, and the reaction time was 2.0 h.
  • the material was discharged from the bottom of the tank into the second dehydrated oligo.
  • the polyreactor is charged; the bottom of the first dehydrated oligomerization kettle is continuously injected into the second dehydration oligomerization reactor through a pipeline, and the temperature of the kettle is controlled at 150 ° C, the pressure is 10 torr, the reaction time is 4.0 h, and the dehydration oligomerization process is carried out.
  • o-PDLA is discharged from the bottom of the bottom of the tank and enters the lactide synthesis process.
  • the dehydration oligomerization step product o-PDLA continuously injects a lactide synthesis reactor equipped with a rectification column (theoretical number of plates) from the bottom of the second dehydration oligomerization reactor, and continuously adds creatine (initial DLa mass) 0.006%), phenformin (0.006% of initial DLa mass), Zn(OOCCH 3 ) 2 (0.003% of initial DLa mass), controlled kettle temperature at 190 ° C, rectification temperature at 90 ° C, pressure at 1.0 Torr, the reaction time was 3.0 h.
  • the product optically pure DLA is distilled from the top of the rectifying section.
  • the by-product polymer residue is discharged from the bottom of the kettle and enters a dehydration oligomerization process.
  • the mass ratio of the raw material 1 metering tank and the lactide synthesis bottom material is 2, and the mass ratio of the fresh DLa to the r-PDLA is 3:1.

Abstract

一种全绿色封闭循环工艺生产光学纯L-/D-丙交酯的方法，是以L-/D-乳酸水溶液与副产聚乳酸为原料首先进行脱水寡聚反应得到L-/D-乳酸寡聚物，然后在三元复合催化体系的催化作用下合成L-/D-丙交酯，所合成产品无需进一步提纯即达到光学纯；副产的聚乳酸直接与L-/D-乳酸水溶液混合再次进行脱水寡聚反应，从而实现循环利用。优点：单体L-/D-乳酸利用率高(95-97％)；三元复合催化剂催化活性高，并可重复使用，立构专一性及选择性高；避免采用高塔板数、多塔精馏提纯工艺；丙交酯合成工序反应温度较传统工艺低，生产能耗降低。

Description

一种全绿色封闭循环工艺生产光学纯L-/D-丙交酯的方法 技术领域
本发明属于生物基可降解材料合成领域，特别涉及一种全绿色封闭循环工艺生产光学纯L-/D-丙交酯的方法。
背景技术
生物基可降解材料已被公认为是石油基塑料最好的替代品，其应用有助于从源头上解决日益严峻的全球性“白色污染”问题。聚乳酸(PLA)则被认为是最具发展前景的一类生物基可降解材料。该类材料已广泛应用于薄膜、纤维、包装材料等领域，除此之外在生物医药领域也取得重要的应用，如硬组织修复材料、手术缝合线、靶向及控释药物载体等。
迄今为止PLA在全球范围内的生产规模远低于传统石油基塑料，这主要是受制于其高昂的单体生产成本。目前，商品化PLA多采用开环聚合工艺生产，所用单体为L-/D-乳酸(LLa/DLa)的环状二聚体——L-/D-丙交酯(LLA/DLA)。商品化LLA/DLA生产工艺：LLa/DLa先经脱水寡聚得到寡聚乳酸(o-PLLA/o-PDLA)，后者在SnII(SnCl2、SnOct2)或SbIII(Sb2O3)催化剂存在下催化解聚环化得到LLA/DLA。该工艺存在以下几方面的问题：
(1)反应能耗高，通常反应温度高于240℃。
(2)提纯工艺复杂，通常采用高塔板数、多级精馏塔提纯。
目前现有LLA/DLA合成工艺中，一方面，主要采用重金属SnII或SbIII催化剂，此类催化剂容易造成LLA/DLA与r-PLLA/r-PDLA发生消旋化；另一方面，反应温度通常高于240℃，容易使酸性物质的挥发，造成产品LLA/DLA酸含量偏高，无法作为开环聚合反应的单体使用。因此，通过现有工艺合成的LLA/DLA产品需要经过高塔板数、多级精馏塔的进一步提纯，此举不但导致工艺复杂同样也增加了能耗以及生产成本。
(3)催化剂立构选择性差导致LLA/DLA合成工序副产聚合物残渣(r-PLLA/r-PDLA)消旋化，不能用于LLA/DLA合成，通常作为固废处理。这些含有已失效的毒性金属催化剂(SnII、SbIII等)的聚合物残渣会成为污染源。
目前商品化光学纯LLA/DLA合成主要通过LLa/DLa脱水寡聚得到o-PLLA/o-PDLA，后者在催化剂的作用下发生反咬链转移反应，环化生成LLA/DLA。同 时，在此过程中o-PLLA/o-PDLA在催化剂的作用下不可避免的会发生缩聚反应，生成r-PLLA/r-PDLA。这部分副产的r-PLLA/r-PDLA，首先由于消旋化、色泽加深等问题难以再次应用于光学纯LLA/DLA的合成，但其分子量、性能却远无法满足实际应用的要求，因此通常只能作为固体废弃物处理，其中所含的重金属SnII、SbIII催化剂往往成为污染源；其次将这部分已消旋化的聚合物残渣通过降解生成LLa/DLa通常需要较长的反应时间，同时生成的LLa/DLa中也含有部分消旋化的对映异构体，同样无法用于光学纯LLA/DLA的合成。因此，由此问题造成的原料LLa/DLa利用率低是造成商品化LLA/DLA生产成本居高不下的主要原因之一，也是商品化LLA/DLA生产过程中难以解决的问题。
上述现有工艺中存在的问题导致商品化光学纯LLA/DLA生产成本居高不下，成为制约PLA(PLLA、PDLA)等生物基可降解材料发展的主要影响因素之一。因此，研发新型高效、高立构专一性/选择性绿色催化剂以提高原料LLa/DLa的利用率，解决副产聚合物残渣的循环利用问题，降低能耗和生产成本，已成为光学纯LLA/DLA规模化工业生产中亟待解决的问题。
发明内容
本发明的目的是解决上述现有光学纯LLA/DLA规模化工业生产中副产聚合物残渣无法循环使用，粗品LLA/DLA光学纯度低、提纯工艺复杂，能耗高的问题。
本发明提供的全绿色封闭循环工艺生产光学纯L-/D-丙交酯(LLA/DLA)的方法，是以原料1：新鲜L-/D-乳酸(LLa/DLa)水溶液与原料2：L-/D-丙交酯合成副产的聚合物残渣(r-PLLA/r-PDLA)的混合物为原料，首先进行脱水寡聚反应得到LLa/DLa寡聚物(o-PLLA/o-PDLA)，然后在生物有机胍和双胍为主催化剂、无毒金属盐或氧化物为助催化剂组成的三元复合催化体系的催化作用下，采用全绿色封闭循环合成光学纯L-/D-丙交酯(LLA/DLA)。所合成的LLA/DLA产品无需进一步的提纯其光学纯度即达到100％e.e.。其中，原料1与原料2混合时的质量比控制在(1-3)：1。
丙交酯合成工序副产的r-PLLA/r-PDLA作为原料之一与LLa/DLa水溶液混合再次进行丙交酯合成，从而实现副产聚合物残渣的循环利用。采用该方法合成光学纯LLA/DLA时，原料LLa/DLa利用率可达95-97％。
本发明所述新方法的工艺流程图如图1所示。
本发明所述新方法中，初次进行脱水寡聚工序时原料为原料1，经脱水寡聚得到的o-PLLA/o-PDLA进入丙交酯合成工序，此工序得到光学纯LLA/DLA产品，并副产 r-PLLA/r-PDLA；在接下来的全绿色封闭循环工艺中，前一次循环产生的r-PLLA/r-PDLA直接返回脱水寡聚工序与LLa/DLa水溶液混合后作为后一次循环的起始原料。
全工艺流程具体包括脱水寡聚工序和丙交酯合成工序。
(1)脱水寡聚工序：向脱水寡聚釜中加入原料，首先控制釜温度在120-150℃，压力在300-200torr，反应1-2h；然后保持釜温度不变，控制反应釜压力在30-10torr继续反应2.0-4.0h，即得到重均分子量Mw 0.5-3.0×103的o-PLLA/o-PDLA。
该工序以LLa/DLa水溶液与r-PLLA/r-PDLA的混合物为原料，反应生成单分散性的寡聚物o-PLLA/o-PDLA，尽管这一过程的具体原因尚不明确，一种可能的解释是：通常商品化LLa/DLa为85-90％的水溶液，r-PLLA/r-PDLA与LLa/DLa水溶液中所含的水，在脱水寡聚反应进行的同时，在催化剂的催化作用下发生了水解反应，最终生成了单分散性的o-PLLA/o-PDLA，其Mw可以满足进一步丙交酯合成工序的要求。
(2)丙交酯合成工序：将脱水寡聚工序合成得到的o-PLLA/o-PDLA注入配置有精馏段的丙交酯合成釜，并加入三元复合催化体系，控制釜温度在165-190℃，精馏段温度在85-90℃，压力在5.0-0.1torr，反应1.0-3.0h，产品光学纯LLA/DLA从精馏段顶部馏出，副产聚合物残渣r-PLLA/r-PDLA返回脱水寡聚工序；丙交酯合成工序产物LLA/DLA，不经任何提纯操作工序，其光学纯度即达到100％e.e.；
丙交酯合成工序副产的r-PLLA/r-PDLA从丙交酯合成工序返回脱水寡聚工序时，可直接通过管道、或经造粒、或经粉粹后以液体或固体的形式注入脱水寡聚反应釜。此后，r-PLLA/r-PDLA与新鲜的LLa/DLa混合，继续进行脱水寡聚工序，从而实现r-PLLA/r-PDLA的循环利用。通过LLa/DLa计量罐与丙交酯合成釜底质量流量计，控制新鲜LLa/DLa与r-PLLA/r-PDLA混合时质量比为(1-3)：1。
本发明所述的新方法中，三元复合催化体系由主催化剂生物有机胍、双胍和助催化剂无毒金属盐或氧化物组成。
生物有机胍具体为肌酐、肌酸、胍基乙酸或鸟嘌呤之一。
双胍具体为二甲双胍、吗啉双胍或苯乙双胍之一。
助催化剂具体为Fe2O3、K2CO3、MgO、Mg(OOCCH3)2、ZnO或Zn(OOCCH3)2之一。
生物有机胍的初始投料量为LLa/DLa投料质量的0.004-0.006％。
双胍的初始投料量为LLa/DLa投料质量的0.004-0.006％。
助催化剂的初始投料量为LLa/DLa投料质量的0.002-0.004％。
本发明所述的三元复合催化体系是实现这一全绿色封闭循环工艺生产光学纯LLA/DLA的前提。
本发明的优点和有益效果：
1.单体L-/D-乳酸利用率高(95-97％)，实现原子经济化；
2.三元复合催化剂催化活性高，可重复多次使用；立构专一性及选择性高，产品L-/D-丙交酯为光学纯，省去传统高塔板数、多塔精馏提纯工序，简化提纯工艺，降低能耗；
3.丙交酯合成工序反应温度较传统工艺低，生产能耗降低。
附图说明
图1是本发明所述方法的工艺流程图。
具体实施方式
1.原料LLa/DLa光学纯度的分析方法：
采用装配手性色谱分离柱的高效液相色谱仪测定。手性高效液相色谱系统包括：LC-20AB泵，SPD-M20A紫外检测器(254nm)，CTO–10ASvp柱温箱，DGU–20A3脱气机，Baseline手性分离色谱柱(150×4.6mm)。测试条件：5mmol/L CuSO4水溶液为流动相，流速1.0mL/min，柱温25℃。
本发明实施例所使用的原料LLa、DLa光学纯度分析结果如下。
LLa 90％水溶液：LLa含量≥99.5％；
DLa 90％水溶液：DLa含量≥99.0％。
2、产品LLA/DLA光学纯度的分析方法：
采用装配有手性气相色谱分离柱的Agilent 7890B型气相色谱仪进行。手性气相色谱系统主要包括：火焰离子检测器(FID)，Agilent CP-cyclodextrin-β-236M-19型毛细管色谱柱(50m×0.25mm i.d.，壁厚0.25μm)。测试条件：柱温采取程序升温模式由7℃以15℃/min的速率升至250℃。进样器与FID检测器温度分别维持在250℃与270℃。以氮气作为载气。
3、全绿色封闭循环合成光学纯LLA/DLA新方法的具体实施方式
本发明所述的新方法按照以下反应式合成：
Figure PCTCN2017113588-appb-000001
需要指出的是，该新方法同样适用于乙交酯GA的合成。
本发明所述的新方法，具体实施方式如下：
(1)脱水寡聚工序：
I.向第一脱水寡聚釜中连续注入原料，控制釜温在120-150℃，压力在300-200torr，停留反应时间1.0-2.0h，物料从釜底排出进入第二脱水寡聚反应釜；
II.第一脱水寡聚釜釜底排出物料通过管道将物料连续注入第二脱水寡聚反应釜，控制釜温在120-150℃，压力在30-10torr，停留反应时间2.0-4.0h，脱水寡聚工序产物o-PLLA/o-PDLA从釜底排出，进入丙交酯合成工序。脱水寡聚工序产物o-PLLA/o-PDLA重均分子量Mw 0.5-3.0×103。
(2)丙交酯合成工序：
脱水寡聚工序产物o-PLLA/o-PDLA从第二脱水寡聚反应釜底通过管道连续注入配置有精馏塔(0.5mm×1.0mm玻璃弹簧填料，理论塔板数5-15块)的丙交酯合成釜，并连续加入三元复合催化体系，控制釜温度在165-190℃，精馏段温度在85-90℃，压力在5.0-0.1torr，停留反应时间1.0-3.0h。产品光学纯LLA/DLA从精馏段顶部馏出。副产聚合物残渣r-PLLA/r-PDLA从釜底部排出，进入脱水寡聚工序。
所得到的LLA/DLA产品经手性气相色谱检测即为光学纯(100％e.e.)。
需要指出的是，在部分实施例中，所得到的LLA/DLA产品中含微量meso-丙交酯(m-LA)，这主要是由LLa/DLa原料中含有的对映异构体杂质(通常这种对映异构体杂质难以完全去除)所造成。
下面通过实施例来说明本发明所述新技术的具体实施方式，但并不用来限定本发明的范围。
实施例1
初次投料时，通过原料1计量罐向第一脱水寡聚釜中连续注入新鲜LLa 1000Kg，控制釜温在120℃，压力在300torr，停留反应时间1.0h，物料从釜底排出进入第二脱水寡聚反应釜；第一脱水寡聚釜釜底排出物料通过管道将物料连续注入第二脱水寡聚反应釜，控制釜温在120℃，压力在30torr，停留反应时间2.0h，脱水寡聚工序产物o-PLLA从釜底排出，进入丙交酯合成工序。
脱水寡聚工序产物o-PLLA从第二脱水寡聚反应釜底通过管道连续注入配置有精馏塔(理论塔板数15块)的丙交酯合成釜，并连续加入肌酐(初始LLa质量的0.004％)、二甲双胍(初始LLa质量的0.004％)、ZnO(初始LLa质量的0.004％)，控制釜温度在165℃，精馏段温度在85℃，压力在5.0torr，停留反应时间1.0h。产品光学纯LLA从精馏段顶部馏出。副产聚合物残渣从釜底部排出，进入脱水寡聚工序。
循环利用时，通过原料1计量罐与丙交酯合成釜底原料2质量流量计，控制新鲜LLa与r-PLLA混合时质量比为1：1。
待设备运行稳运行24h后通过第二脱水寡聚釜底取样口，测定脱水寡聚工序产物O-PLLA Mw；取丙交酯合成釜精馏段顶部产品收集罐所得到的LLA进行分析，其结果列于表1。
对比例1
本对比实施例的实施方案与工艺参数与实施例1相同，唯一的区别在于所采用的为传统的SnOct2为催化剂，其结果列于表1。
其结果可以看出，由于传统SnII催化剂的使用导致r-PLLA在循化使用中不断消旋化，导致所得到的LLA产品光学纯度较低，完全无法满足开环聚合反应的要求。
实施例2
初次投料时，通过原料1计量罐向第一脱水寡聚釜中连续注入新鲜LLa 1000Kg，控制釜温在120℃，压力在300torr，停留反应时间1.0h，物料从釜底排出进入第二脱水寡聚反应釜；第一脱水寡聚釜釜底排出物料通过管道将物料连续注入第二脱水寡聚反应釜，控制釜温在120℃，压力在30torr，停留反应时间2.0h，脱水寡聚工序产物o-PLLA从釜底排出，进入丙交酯合成工序。
脱水寡聚工序产物o-PLLA从第二脱水寡聚反应釜底通过管道连续注入配置有精馏塔(理论塔板数15块)的丙交酯合成釜，并连续加入肌酸(初始LLa质量的0.004％)、吗啉双胍(初始LLa质量的0.005％)、Fe2O3(初始LLa质量的0.004％)，控制釜温度在165℃，精馏段温度在85℃，压力在5.0torr，停留反应时间1.0h。产品光学纯LLA从精馏段顶部馏出。副产聚合物残渣从釜底部排出，进入脱水寡聚工序。
循环利用时，通过原料1计量罐与丙交酯合成釜底原料2质量流量计，控制新鲜LLa与r-PLLA混合时质量比为1：1。
待设备运行稳运行24h后通过第二脱水寡聚釜底取样口，测定脱水寡聚工序产物O-PLLA Mw；取丙交酯合成釜精馏段顶部产品收集罐所得到的LLA进行分析，其结果列于表1。
实施例3
初次投料时，通过原料1计量罐向第一脱水寡聚釜中连续注入新鲜LLa 1000Kg，控制釜温在135℃，压力在250torr，停留反应时间1.0h，物料从釜底排出进入第二脱水寡聚反应釜；第一脱水寡聚釜釜底排出物料通过管道将物料连续注入第二脱水寡聚反应釜，控制釜温在135℃，压力在20torr，停留反应时间3.0h，脱水寡聚工序产物o-PLLA从釜底排出，进入丙交酯合成工序。
脱水寡聚工序产物o-PLLA从第二脱水寡聚反应釜底通过管道连续注入配置有精馏塔(理论塔板数10块)的丙交酯合成釜，并连续加入胍基乙酸(初始LLa质量的0.005％)、苯乙双胍(初始LLa质量的0.006％)、K2CO3(初始LLa质量的0.002％)，控制釜温度在178℃，精馏段温度在88℃，压力在2.5torr，停留反应时间2.0h。产品光学纯LLA从精馏段顶部馏出。副产聚合物残渣从釜底部排出，进入脱水寡聚工序。
循环利用时，通过原料1计量罐与丙交酯合成釜底原料2质量流量计，控制新鲜LLa与r-PLLA混合时质量比为2：1。
待设备运行稳运行24h后通过第二脱水寡聚釜底取样口，测定脱水寡聚工序产物O-PLLA Mw；取丙交酯合成釜精馏段顶部产品收集罐所得到的LLA进行分析，其结果列于表1。
实施例4
初次投料时，通过原料1计量罐向第一脱水寡聚釜中连续注入新鲜DLa 1000 Kg，控制釜温在135℃，压力在250torr，停留反应时间2.0h，物料从釜底排出进入第二脱水寡聚反应釜；第一脱水寡聚釜釜底排出物料通过管道将物料连续注入第二脱水寡聚反应釜，控制釜温在135℃，压力在20torr，停留反应时间3.0h，脱水寡聚工序产物o-PDLA从釜底排出，进入丙交酯合成工序。
脱水寡聚工序产物o-PDLA从第二脱水寡聚反应釜底通过管道连续注入配置有精馏塔(理论塔板数10块)的丙交酯合成釜，并连续加入鸟嘌呤(初始DLa质量的0.005％)、二甲双胍(初始DLa质量的0.004％)、MgO(初始DLa质量的0.002％)，控制釜温度在178℃，精馏段温度在88℃，压力在2.5torr，停留反应时间2.0h。产品光学纯DLA从精馏段顶部馏出。副产聚合物残渣从釜底部排出，进入脱水寡聚工序。
循环利用时，通过原料1计量罐与丙交酯合成釜底原料2质量流量计，控制新鲜DLa与r-PDLA混合时质量比为2：1。
待设备运行稳运行24h后通过第二脱水寡聚釜底取样口，测定脱水寡聚工序产物O-PDLA Mw；取丙交酯合成釜精馏段顶部产品收集罐所得到的DLA进行分析，其结果列于表1。
实施例5
初次投料时，通过原料1计量罐向第一脱水寡聚釜中连续注入新鲜DLa 1000Kg，控制釜温在150℃，压力在200torr，停留反应时间2.0h，物料从釜底排出进入第二脱水寡聚反应釜；第一脱水寡聚釜釜底排出物料通过管道将物料连续注入第二脱水寡聚反应釜，控制釜温在150℃，压力在10torr，停留反应时间4.0h，脱水寡聚工序产物o-PDLA从釜底排出，进入丙交酯合成工序。
脱水寡聚工序产物o-PDLA从第二脱水寡聚反应釜底通过管道连续注入配置有精馏塔(理论塔板数5块)的丙交酯合成釜，并连续加入肌酐(初始DLa质量的0.006％)、吗啉双胍(初始DLa质量的0.005％)、Mg(OOCCH3)2(初始DLa质量的0.003％)，控制釜温度在190℃，精馏段温度在90℃，压力在1.0torr，停留反应时间3.0h。产品光学纯DLA从精馏段顶部馏出。副产聚合物残渣从釜底部排出，进入脱水寡聚工序。
循环利用时，通过原料1计量罐与丙交酯合成釜底原料2质量流量计，控制新鲜DLa与r-PDLA混合时质量比为3：1。
待设备运行稳运行24h后通过第二脱水寡聚釜底取样口，测定脱水寡聚工序产物O-PDLA Mw；取丙交酯合成釜精馏段顶部产品收集罐所得到的DLA进行分析，其结果 列于表1。
实施例6
初次投料时，通过原料1计量罐向第一脱水寡聚釜中连续注入新鲜DLa 1000Kg，控制釜温在150℃，压力在200torr，停留反应时间2.0h，物料从釜底排出进入第二脱水寡聚反应釜；第一脱水寡聚釜釜底排出物料通过管道将物料连续注入第二脱水寡聚反应釜，控制釜温在150℃，压力在10torr，停留反应时间4.0h，脱水寡聚工序产物o-PDLA从釜底排出，进入丙交酯合成工序。
脱水寡聚工序产物o-PDLA从第二脱水寡聚反应釜底通过管道连续注入配置有精馏塔(理论塔板数5块)的丙交酯合成釜，并连续加入肌酸(初始DLa质量的0.006％)、苯乙双胍(初始DLa质量的0.006％)、Zn(OOCCH3)2(初始DLa质量的0.003％)，控制釜温度在190℃，精馏段温度在90℃，压力在1.0torr，停留反应时间3.0h。产品光学纯DLA从精馏段顶部馏出。副产聚合物残渣从釜底部排出，进入脱水寡聚工序。
循环利用时，通过原料1计量罐与丙交酯合成釜底原料2质量流量计，控制新鲜DLa与r-PDLA混合时质量比为3：1。
待设备稳运行24h后通过第二脱水寡聚釜底取样口，测定脱水寡聚工序产物O-PDLA Mw；取丙交酯合成釜精馏段顶部产品收集罐所得到的DLA进行分析，其结果列于表1。
表1实施例结果
Figure PCTCN2017113588-appb-000002

Claims (6)

  1. 一种封闭循环工艺生产光学纯L-/D-丙交酯(LLA/DLA)的方法，该方法是以原料1：L-/D-乳酸(LLa/DLa)水溶液与原料2：L-/D-丙交酯合成时副产的聚合物残渣r-PLLA/r-PDLA的混合物作为原料，首先进行脱水寡聚反应得到LLa/DLa寡聚物o-PLLA/o-PDLA，再在由生物有机胍和双胍为主催化剂、无毒金属盐或氧化物为助催化剂组成的三元复合催化体系的催化作用下，采用全绿色封闭循环工艺合成光学纯LLA/DLA，所合成的LLA/DLA产品无需进一步的提纯光学纯度即达到100％e.e.；其中，原料1与原料2混合时的质量比控制在(1-3)：1。
  2. 根据权利要求1所述的方法，其主要特征在于：
    初次进行脱水寡聚工序时原料为原料1，经脱水寡聚得到的低聚乳酸o-PLLA/o-PDLA进入丙交酯合成工序，此工序得到光学纯LLA/DLA产品，并副产残渣聚合物r-PLLA/r-PDLA；在接下来的全绿色封闭循环工艺中，前一次循环产生的r-PLLA/r-PDLA直接返回脱水寡聚工序与LLa/DLa水溶液混合后作为后一次循环的起始原料。
  3. 根据权利要求2所述的方法，其特征在于：全工艺流程具体包括脱水寡聚工序和丙交酯合成工序；
    脱水寡聚工序：向脱水寡聚釜中加入原料，首先控制釜温度在120-150℃，压力在300-200torr，反应1-2h；然后保持釜温度不变，控制反应釜压力在30-10torr继续反应2.0-4.0h，即得到重均分子量Mw 0.5-3.0×103的o-PLLA/o-PDLA；
    丙交酯合成工序：将脱水寡聚工序合成得到的o-PLLA/o-PDLA注入配置有精馏段的丙交酯合成釜，并加入三元复合催化体系，控制釜温度在165-190℃，精馏段温度在85-90℃，压力在5.0-0.1torr，反应1.0-3.0h，产品光学纯LLA/DLA从精馏段顶部馏出，副产聚合物残渣r-PLLA/r-PDLA返回脱水寡聚工序；丙交酯合成工序产物LLA/DLA，不经任何提纯操作工序，其光学纯度即达到100％e.e.；
    单体LLa/DLa总有效利用率达95-97％。
  4. 根据权利要求1所述的方法，其特征在于：
    所述的生物有机胍具体为肌酐、肌酸、胍基乙酸或鸟嘌呤之一；
    双胍具体为二甲双胍、吗啉双胍或苯乙双胍之一；
    助催化剂具体为Fe2O3、K2CO3、MgO、Mg(OOCCH3)2、ZnO或Zn(OOCCH3)2之一；
    生物有机胍的初始投料量为LLa/DLa投料质量的0.004-0.006％；
    双胍的初始投料量为LLa/DLa投料质量的0.004-0.006％；
    助催化剂的初始投料量为LLa/DLa投料质量的0.002-0.004％。
  5. 根据权利要求2所述的方法，其特征在于：
    所述的生物有机胍具体为肌酐、肌酸、胍基乙酸或鸟嘌呤之一；
    双胍具体为二甲双胍、吗啉双胍或苯乙双胍之一；
    助催化剂具体为Fe2O3、K2CO3、MgO、Mg(OOCCH3)2、ZnO或Zn(OOCCH3)2之一；
    生物有机胍的初始投料量为LLa/DLa投料质量的0.004-0.006％；
    双胍的初始投料量为LLa/DLa投料质量的0.004-0.006％；
    助催化剂的初始投料量为LLa/DLa投料质量的0.002-0.004％。
  6. 根据权利要求3所述的方法，其特征在于：
    所述的生物有机胍具体为肌酐、肌酸、胍基乙酸或鸟嘌呤之一；
    双胍具体为二甲双胍、吗啉双胍或苯乙双胍之一；
    助催化剂具体为Fe2O3、K2CO3、MgO、Mg(OOCCH3)2、ZnO或Zn(OOCCH3)2之一；
    生物有机胍的初始投料量为LLa/DLa投料质量的0.004-0.006％；
    双胍的初始投料量为LLa/DLa投料质量的0.004-0.006％；
    助催化剂的初始投料量为LLa/DLa投料质量的0.002-0.004％。
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