CN111215054A - 一种顺丙烯膦酸的制备方法 - Google Patents
一种顺丙烯膦酸的制备方法 Download PDFInfo
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Abstract
本发明涉及一种顺丙烯膦酸的制备方法,具体的说是以丙二烯膦酸为原料,乙醇为溶剂,丙二烯膦酸质量分数为40%,采用高聚物基含氮活性炭担载钯或钯钌贵金属颗粒状催化剂,固定床反应模式,在温度50~80℃、氢气压力0.2~0.4MPa的反应条件下,连续催化加氢反应得到顺丙烯膦酸,液时空速1h‑1,反应转化率优于99%,选择性优于92%,催化剂连续反应1300小时无明显性能衰减。本发明提供了一种清洁高效的顺丙烯膦酸制备方法,可实现连续生产,提高生产效率,减少能耗,降低劳动强度,降低磷霉素生产成本。
Description
技术领域
本发明属于医药精细化工领域,具体涉及一种连续高效制备顺丙烯膦酸的方法。
背景技术
磷霉素(phosphomycin,fosfomycin,FOM),化学名:(-)-(1R,2S)-1,2-环氧丙基膦酸,是一种广谱、低毒抗菌药,不易致敏、不易产生耐药性,与大多数抗菌素具有协同作用的经典抗菌素,对大部分的链球菌、绿脓杆菌、奇异变形杆菌以及部分肺炎杆菌和吲哚变形菌均有抑制作用。磷霉素最早在1966年由Hendlin等人从西班牙土壤中分离出的弗式链霉菌经培养产生的代谢物,1969年Christensen对其做了结构确证,并合成了该化合物。磷霉素抗菌效果比青霉素类和头孢菌素类更广泛高效,毒副作用小,目前仍在在日本和欧美国家广泛使用,且近些年用量有较大幅增长。
顺丙烯膦酸(cis-Propenylphosphonic acid,缩写CPPA),分子式C3H7PO3,是合成磷霉素的重要中间体。关于顺丙烯膦酸的制备,国内外工作者做了大量研究报道。最早是1969年Christensen等人在文献[Science,1969,166(1),123-125]中报道的1-丙炔基膦酸二正丁酯在Lindlar催化剂的作用下氢化得到顺丙烯膦酸二正丁酯,然后水解得到顺丙烯膦酸。专利文献GB1237232报道了另一种合成方法,以苯作溶剂,5%Pd/C为催化剂,丙二烯膦酸二叔丁酯催化加氢得到顺丙烯膦酸二叔丁酯,使用极性小的苯选择性达96%,再在浓盐酸下水解得顺丙烯膦酸。专利文献CN102850394B、US3597451和US3849482中也都用该方法制备顺丙烯膦酸。默克公司的专利文献US3733356阐述了两种顺丙烯膦酸的合成方法:一种是丙二烯二膦酰氯用5%Pd/C催化制备顺丙烯二膦酰氯,水解得到顺丙烯膦酸;另一种是丙二烯膦酸用氢氧化钠转化成钠盐,异构化得1-丙炔膦酸二钠盐,用Pd/C催化氢化得到顺丙烯膦酸二钠盐,最后用离子交换法得顺丙烯膦酸。
上述方法经过酯化、氢化、水解三步工艺得到顺丙烯膦酸,酯加氢反应过程催化剂流失损耗较少,但是工艺步骤多,生产效率较低,目前工业生产中都采用丙二烯膦酸直接氢化法生产顺丙烯膦酸,使用4%~5%Pd/C催化剂,搅拌反应釜间歇生产方式,因为反应体系酸性强,催化剂活性组分酸蚀流失较严重、机械搅拌作用下催化剂物理损耗也是导致催化剂性能降低的重要因素。以丙二烯膦酸为原料催化加氢制备顺丙烯膦酸的方法,也有诸多文献报道,主要集中在催化剂的开发方面。郑州大学苏运来等人在文献[化工科技,2005,13(5),34-38]中报道用浸渍法制备了一系列活性组分、质量分数不同的催化剂对丙二烯膦酸加氢的影响,研究了不同载体活性炭、MCM-41、γ-Al2O3和HZSM-5制备的催化剂性能,并且比较了钯和钌两种活性组分催化剂活性。研究结果表明,5%Pd/C催化剂性能最好,催化反应转化率50.45%。随后,他们[郑州大学学报(理学版),2006,38(2),87-100]研究了催化剂的制备方法,对催化剂制备过程中的一些影响因素进行考察,得到催化剂的最佳制备方法,制备的催化剂用于丙二烯膦酸加氢反应,最高转化率52.58%。冯晓玲等人在[浙江工业大学学报,2010,38(1),15-19]中报道了Lindlar催化剂作用下丙二烯膦酸选择加氢新工艺,丙二烯膦酸的转化率大于99%,顺丙烯膦酸的选择性达95%,反应选择性明显优于Pd/C催化工艺。该作者使用Lindlar催化剂取得了还不错的初步反应结果,但众所周知,Lindlar催化剂是Pb部分毒化的碳酸钙载钯催化剂,载体碳酸钙在反应强酸性环境中很快就会分解消失,使用其作为载体是不合适的,而且该催化剂含铅,铅是对人体健康有害的重金属元素,在酸性加氢反应体系中铅易被溶解进入反应料液,极难从物料中脱除,因此该Lindlar催化剂不适合用于生物医药中间体顺丙烯磷酸合成工艺。
现有技术制备顺丙烯膦酸的方法均采用间歇式釜式加氢,丙二烯膦酸中含有两个双键,二者反应活化能差别较小,为防止过度氢化,反应只能在低温低压条件下进行,反应速度慢、效率低,粉末催化剂机械磨耗较大,催化剂与反应料液分离困难,近些年虽然催化剂有所改进,但是仍避免不了生产效率低、能耗物耗高、劳动强度大等问题,存在较大的性能提升空间。
活性炭是一类性能优异的催化剂载体,耐酸耐碱耐热性能好,孔隙结构发达、比表面积大,满足活性组分高分散需求,对于贵金属而言,非常重要的特点废旧催化剂中贵金属回收方便,湿法火法回收效率都很高,环境污染小。炭载催化剂存在的不足主要是活性组分与活性炭之间作用力较弱,与氧化物载体相比活性组分在反应环境中流失比较严重。如何提高活性炭载体与活性组分之间的结合强度,提高催化剂的使用寿命是炭载催化剂研制开发的热点课题。最新的研究结果表明,含氮类活性炭材料中N-C键合结构可保持纳米颗粒稳定,大幅减少贵金属组分在反应中的流失率,提高催化剂使用寿命。
人工合成高分子材料组成明确,杂质含量低、结构可控,加工成型方便,部分高分子材料在高温、绝氧条件下可以碳化为多孔炭材料。使用含氮类高分子如聚苯胺、聚吡咯、聚酰胺或聚苯丙噁嗪树脂等预先成型为颗粒状,然后碳化为相应形状规格的多孔炭材料,该类炭材料可望作为催化剂载体应用于化学反应过程。
综上所述,顺丙烯膦酸的制备可以通过丙二烯膦酸酯化、加氢然后水解方式或者丙二烯膦酸直接氢化反应方式得到,前者反应体系为中性,不存在贵金属催化剂活性组分酸蚀问题,催化剂寿命长,但是工艺步骤多,总体效率较低,该工艺在磷霉素工业生产中已基本被淘汰,取而代之的是丙二烯膦酸直接浆态床间歇氢化工艺,-200目粉末状4%Pd/C为氢化催化剂,存在贵金属催化剂损耗大、生产效率偏低、劳动强度大等问题,因此该工艺也存在较大的改进提升空间,譬如开发耐酸性能更好、更稳定的贵金属催化剂,开发固定床工艺减少催化剂机械磨耗等,提高顺丙烯膦酸制备效率,降低能耗,减少贵金属消耗,提高产品竞争力。
发明内容
针对目前丙二烯膦酸催化氢化生产顺丙烯膦酸工艺中存在的问题,本发明公开了一种丙二烯膦酸连续制备方法,以丙二烯膦酸为原料,乙醇为溶剂,丙二烯膦酸质量分数为40%,采用颗粒状高聚物基含氮活性炭担载钯或钯钌贵金属加氢催化剂,固定床工艺连续氢化制备顺丙烯膦酸。
选用合成高分子基含氮活性炭为载体,钯或者钯和钌复合金属作为活性组分,其质量分数为4%-10%,优选4%-6%,当催化剂的活性组分为钯和钌复合金属时,钯和钌的物质的量之比为3:1。
活性炭孔隙发达、比表面积巨大,贵金属催化剂载体的理想选择。生产活性炭之起始原料多为生物质或矿物质等天然原料,常用的有椰壳活性炭、木质活性炭、煤质活性炭等。由于生物体生长区域差异、生长年份不同,使用天然原料生产的活性炭材料微观结构、组成等各不相同,批次一致性较差,给催化剂制备质量控制和用户使用带来困扰。常规活性炭载体与活性组分金属纳米颗粒之间结合力较弱,使用过程中活性金属流失现象较为严重,酸性反应体系中尤其如此,催化剂套用寿命较短,贵金属单耗高。近年来大量文献报道含氮活性炭材料中存在N-C结构,可大幅提高金属纳米粒子稳定性。
本发明选用高分子基含氮活性炭作为催化剂载体,规格为直径3mm左右的球形颗粒,颗粒压碎强度大于50N。催化剂载体的比表面积为500~800m2/g,总孔容0.8~1.2mL/g,其中中孔孔容0.4~0.6mL/g。
本发明活性炭载体来源于聚酰胺树脂(尼龙),首先加工成型为3-4mm左右的球形颗粒,经绝氧、高温炭化,然后水蒸气活化制成所需的载体颗粒。聚酰胺树脂成型、炭化、水汽活化工艺条件对于高分子基活性炭行业从业技术人员来说是熟知技能,本发明不做详细说明。
本发明贵金属活性组分采用高温喷雾沉积方法,配制等体积浸渍[将载体浸入水中,然后过滤抽除颗粒间液体,称量载体的重量增量对应水的体积即为该载体等体积浸渍所需溶液体积]所需量的合适浓度氯化钯溶液或者依照比例要求配制氯化钯、三氯化钌混合溶液。首先将待浸载体在干燥箱内加热至200-250℃,将含贵金属料液雾化喷洒至载体颗粒上,翻动载体颗粒,保证喷洒液均匀分散至载体表面。高度雾化分散的浸渍液喷到炽热载体,其中水份快速蒸发,贵金属组分沉积于载体颗粒上。抽除干燥箱内水汽,降温至120℃左右继续干燥,然后将物料转入气氛炉内惰性气体保护焙烧,氢气还原,钝化处理得到所述催化剂。催化剂中贵金属活性组分纳米颗粒尺寸5~8nm,活性组分分布于载体颗粒外表层~300μm深度范围内。
本发明顺丙烯膦酸方法为:
将丙二烯膦酸质量分数为40%的乙醇溶液自下而上通过装有氢化催化剂的不锈钢固定床反应器,液时空速为1h-1,反应温度为50~80℃、氢气压力为0.2~0.4MPa,反应转化率优于99%,选择性优于92%,催化剂连续反应工作1300小时性能无明显衰减。
本发明的有益效果为:
1、高分子聚合物组成明确,杂质低,聚合物基活性炭无灰分,批次重复性好;聚酰胺基活性炭富含N-C结构,可保持贵金属活性组分稳定,减少流失,催化剂寿命长。
2、采用固定床反应模式,反应料液以平推流方式通过催化床,料液反混少,反应在较高的温度压力条件下进行仍可以获得理想的顺丙烯膦酸收率,大幅提高了生产效率。
3、该工艺可大幅降低反应能耗,简化操作工序,降低劳动强度,适于推广应用于工业规模生产。
附图说明
图1是催化剂寿命实验考察实验图。
下面通过具体实施例对本发明进行详细说明,但这些实施例并不对本发明的内容构成限制。
具体实施方式
实施例1
催化剂4.2%Pd/C的制备:将直径3mm左右的球形高分子基含氮活性炭在干燥箱内加热至200-250℃,以金属负载量4.2%计,将一定量含金属钯5%的氯化钯的盐酸溶液(盐酸质量浓度10%)雾化喷洒至载体颗粒上,同时翻动载体颗粒,抽除干燥箱内水汽,降温至120℃左右继续干燥2h,然后将物料转入气氛炉内惰性气体(氮气)保护300℃焙烧2h,200℃氢气还原1h,钝化处理得到所述催化剂,记为催化剂A。
实施例2
催化剂3.1%Pd-1.3%Ru/C的制备:将直径3mm左右的球形高分子基含氮活性炭在干燥箱内加热至200-250℃,以金属总负载量5.4%计,将一定量含金属钯5%的氯化钯的盐酸溶液(盐酸质量浓度10%)和一定量含金属钌5%的三氯化钌溶液混合后(钯钌摩尔比为3:1),雾化喷洒至载体颗粒上,同时翻动载体颗粒,抽除干燥箱内水汽,降温至120℃左右继续干燥2h,然后将物料转入气氛炉内惰性气体保护400℃焙烧2h,300℃氢气还原2h,钝化处理得到所述催化剂,记为催化剂B。
对比例1
催化剂4.2%Pd/C(椰壳活性炭)的制备:将直径3mm左右椰壳活性炭在干燥箱内加热至200-250℃,以金属负载量4.2%计,将一定量含金属钯5%的氯化钯的盐酸溶液(盐酸质量浓度10%)雾化喷洒至载体颗粒上,同时翻动载体颗粒,抽除干燥箱内水汽,降温至120℃左右继续干燥2h,然后将物料转入气氛炉内惰性气体保护300℃焙烧2h,200℃氢气还原1h,钝化处理得到所述催化剂,记为催化剂C。
对比例2
催化剂3.1%Pd-1.3%Ru/C(椰壳活性炭)的制备:将直径3mm左右椰壳活性炭在干燥箱内加热至200-250℃,以金属总负载量5.4%计,将一定量含金属钯5%的氯化钯的盐酸溶液(盐酸质量浓度10%)和一定量含金属钌5%的三氯化钌溶液混合后(钯钌摩尔比为3:1),雾化喷洒至载体颗粒上,同时翻动载体颗粒,抽除干燥箱内水汽,降温至120℃左右继续干燥2h,然后将物料转入气氛炉内惰性气体保护400℃焙烧2h,300℃氢气还原2h,钝化处理得到所述催化剂,记为催化剂D。
实施例3
向50mL的高压釜中加入10.0g 20wt.%丙二烯膦酸的乙醇溶液,0.1g催化剂氮气置换3次,充入氢气至0.1MPa,于50℃反应至体系压力不再变化,液相色谱分析反应物的转化率和产物选择性。反应完成后,过滤分离催化剂,分离后的催化剂在同样的反应条件下继续反应,以此考察催化剂的寿命,不同催化剂的反应结果见表1。
表1不同催化剂催化加氢性能
催化剂 | 转化率 | 选择性 | 套用次数 |
A | 98.2% | 91% | 129 |
B | 98% | 95% | 187 |
C | 95.5% | 90% | 38 |
D | 93.4% | 92% | 46 |
。
催化剂A、B、C、D在反应初期均能有效催化剂顺丙烯膦酸的氢化到丙二烯膦酸,但催化剂套用实验中,各催化剂表现出不同效果,从表1结果看出,催化剂A和B分别使用129、187次仍保持较高活性,而催化剂C和D分别使用38、46次后,活性下降明显,说明高分子基含氮活性炭作载体制备的催化剂不仅具有良好的活性和选择性,且催化剂的使用寿命更长,优于普通椰壳炭制备的催化剂。
实施例4
在内径10mm、长度100mm的SUS316制反应管中填充制备的催化剂B 5.0g。升温至50℃、氢气压力0.2MPa的条件下通入40wt.%丙二烯膦酸的乙醇溶液,丙二烯膦酸的乙醇溶液的流速为0.17mL/min、氢气的流速为20mL/min,进行反应,考察催化剂寿命。实验结果见附图。
Claims (7)
1.一种顺丙烯膦酸的制备方法,其特征在于:丙二烯膦酸乙醇溶液固定床连续催化氢化制备顺丙烯膦酸,所述加氢催化剂载体为高分子基含氮活性炭,活性组分为质量分数4%-10%的金属钯或钯钌复合金属。
2.根据权利要求1所述的方法,其特征在于:所述催化剂的活性组分为钯或者钯和钌复合金属,催化剂中活性组分的质量分数为4%-10%,优选4%-6%。
3.根据权利要求1、2所述的方法,其特征在于:所述催化剂的活性组分钯和钌复合金属时,钯和钌的物质的量之比为3:1。
4.根据权利要求1所述的方法,其特征在于:所述负载型催化剂的载体为聚酰胺基高分子材料炭化制成的含氮活性炭,规格为直径3-4mm的球形颗粒,颗粒压碎强度大于50N。
5.根据权利要求1或4所述的方法,其特征在于:催化剂载体的比表面积为500~800m2/g,总孔容0.8~1.2mL/g,其中中孔孔容0.4~0.6mL/g。
6.根据权利要求1所述的方法,其特征在于:所述贵金属负载方法采用高温喷雾沉积方法,负载型催化剂中贵金属活性组分纳米颗粒尺寸5~8nm,活性组分分布于载体颗粒外表层~300μm深度(载体表面向载体内部的深度)范围内。
7.根据权利要求1所述的方法,其特征在于:乙醇溶液中丙二烯膦酸质量分数为40%,反应温度为50~80℃、氢气压力为0.2~0.4MPa,液时空速为1h-1。
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CN112321636B (zh) * | 2020-12-03 | 2022-05-27 | 无锡德方生物科技有限公司 | 一种抗生素中间体的制备方法 |
CN112375098A (zh) * | 2020-12-07 | 2021-02-19 | 商河探荣新技术开发中心 | 一种碳酸盐-硼烷催化剂在制备抗生素中间体中的用途 |
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