CN116947795B - 一种s-羟丙基四氢吡喃三醇的连续合成方法 - Google Patents
一种s-羟丙基四氢吡喃三醇的连续合成方法 Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 23
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 21
- QDHDQJXBEOUAGE-UHFFFAOYSA-N oxane-2,3,4-triol Chemical compound OC1CCOC(O)C1O QDHDQJXBEOUAGE-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000003197 catalytic effect Effects 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 238000009901 transfer hydrogenation reaction Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 8
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- 238000000926 separation method Methods 0.000 claims description 7
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 7
- 235000019254 sodium formate Nutrition 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- -1 acetonyl tetrahydropyran triol Chemical compound 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000004005 microsphere Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
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- 230000008569 process Effects 0.000 claims description 4
- KOGFZZYPPGQZFZ-QVAPDBTGSA-N (2s,3r,4s,5r)-2-(2-hydroxypropyl)oxane-3,4,5-triol Chemical compound CC(O)C[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O KOGFZZYPPGQZFZ-QVAPDBTGSA-N 0.000 abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 6
- 238000006317 isomerization reaction Methods 0.000 abstract description 4
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- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
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- 238000002425 crystallisation Methods 0.000 description 2
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- 150000003741 xylose derivatives Chemical class 0.000 description 1
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Abstract
本发明属于精细化学品技术领域,具体涉及一种S‑羟丙基四氢吡喃三醇的连续合成方法。本发明的方法通过将丙酮基四氢吡喃三醇溶解于溶剂中作为待加氢溶液,然后将加氢溶液和氢气在微混合器内进行混合后通入填充新型负载型的S‑构型手性钌催化剂的微填充床反应器内进行反应,获得了收率高达90%以上,ee值大于99%的高品质S‑构型羟丙基四氢吡喃三醇。与现有技术相比,本发明方法物料异构化或降解的风险低;催化剂固载后容易与物料分离,后处理成本低,产品重金属残留的风险低;反应器传质传热效率高,体积小,无需高压下进行氢化反应,安全性高;贵金属催化剂使用寿命更长,催化剂用量小,成本更低,可进一步保障产品的光学纯度;可适用于催化加氢和催化转移加氢,应用范围广,均能够实现连续自动化生产,易于工业化应用。
Description
技术领域
本发明属于精细化学品技术领域,具体涉及一种S-羟丙基四氢吡喃三醇的固定床连续加氢的合成方法。
背景技术
玻色因,又名羟丙基四氢吡喃三醇,是一种具有抗衰老活性的木糖衍生物。羟丙基四氢吡喃三醇的立体构型对其活性具有重要影响,研究表明2-位手性碳的两种非对映异构体中S-羟丙基四氢吡喃三醇(CAS号868156-46-1)活性明显高于R-构型(CN100441588C),作为更有效的玻色因成分具有更广阔的应用前景。
目前,现有技术中S-羟丙基四氢吡喃三醇的制备方法主要是对中间体丙酮基四氢吡喃三醇的羰基进行不对称还原。所用的还原剂主要包括硼试剂和钌手性催化剂。
其中采用含硼还原剂(Bioorg.Med.Chem.Lett.2009,19,845)进行羰基不对称还原时,后处理淬灭过程中会产生大量需要处理的硼酸盐废渣,同时由于硼酸极易与多羟基的玻色因铰链,使得产品的分离纯化非常困难,因此后处理成本较高,并且生产的产品中残留硼盐的风险也较高,由于硼酸和硼酸盐属化妆品禁用物质,因此会给消费者带来安全风险。
现有技术CN115093386B中采用传统均相的手性钌催化,间歇式催化加氢还原,由于催化剂溶解在反应溶剂中,无法通过过滤完全去除,因此存在金属钌残留的风险。而且该方法在还原前需要先对丙酮基四氢吡喃三醇的三个羟基进行保护基保护,因此增加了2步反应(上保护和脱保护),原子经济性差,脱保护过程也会产生大量有机废液,如下:
其中,R为保护基。
CN115819387A中采用钌配体催化转移加氢,反应需要强碱参与,反应时间较长,可能导致糖苷衍生物异构化和分解(Lobryde-Bruyn-Van
Erensteins重排),产生难以去除的副产物。而且该方法采用均相催化剂,催化剂用量高,昂贵的催化剂不仅无法回收套用,还可能导致钌金属残
留,带来产品的安全性风险。
WO2023109877A1中采用双膦双铵钌催化剂在加入碱的溶液中进行催化加氢,反应时间长达10小时,同样存在重排产生副产物,催化剂无法回收套用及残留问题,不利于工业化应用。
鉴于现有技术中存在的问题,亟需开发一种路线简单,安全高效,成本低廉,所得产品品质高,适用于大规模工业化生产S-羟丙基四氢吡喃三醇的方法,满足市场对于S构型玻色因的需求。
发明内容
本发明所要解决的技术问题为克服现有技术的不足,提供一种S-羟丙基四氢吡喃三醇的连续合成方法。本发明方法反应停留时间短,物料异构化或降解的风险低;为非均相反应,催化剂固载后容易与物料分离,后处理成本低,产品重金属残留的风险低;固定床微反应器传质传热效率高,体积小,无需高压下进行氢化反应,安全性高;贵金属催化剂固载后可连续使用,使用寿命更长,催化剂用量小,成本更低,并且载体的限域效应可进一步保障产品的光学纯度;可适用于催化加氢和催化转移加氢,应用范围广,均能够实现连续自动化生产,易于工业化应用。
本发明提供一种连续催化加氢制备S-羟丙基四氢吡喃三醇的方法,包括以下步骤:
(1)将丙酮基四氢吡喃三醇溶解于溶剂中作为待加氢溶液;
(2)将步骤(1)所得待加氢溶液和氢气在微混合器内进行混合,混合后所得气液混合物通入填充固体颗粒催化剂的微填充床反应器内进行反应;
(3)将反应结束后得到的气液混合物进行气液分离,液体产物进入后续的分离纯化系统;
其中,固体颗粒催化剂为负载型的S-构型手性钌催化剂S,S-Ru-1,结构如下:
其中●为微球硅胶,粒度50-200um,钌含量为1%。
手性钌催化剂S,S-Ru-1的制备工艺如下:
优选地,步骤(1)中所述的溶剂为甲醇、乙醇,异丙醇,更优选甲醇。
优选地,步骤(1)中所述待加氢溶液中丙酮基四氢吡喃三醇的质量浓度为5%-20%(设置为范围),更优选为10%。
优选地,步骤(2)中所述的微混合器为微筛孔混合器。
优选地,步骤(2)中所述气液混合物中丙酮基四氢吡喃三醇与氢气的摩尔比为1:3-10;更优选为1:5。
优选地,步骤(2)中反应器内反应温度为100~140℃,压力2-3MPa;更优选反应器内反应温度为120℃,压力2.5MPa。
优选地,步骤(2)中所述气液混合物在微填充床中的停留时间为60-100s,更优选为70s。
本发明还提供一种连续催化转移加氢制备S-羟丙基四氢吡喃三醇的方法,包括以下步骤:
(1)将丙酮基四氢吡喃三醇溶解于含甲酸钠的溶剂中作为待加氢溶液;
(2)将步骤(1)所得待加氢溶液通入填充固体颗粒催化剂的微填充床反应器内进行反应;
(3)反应结束后得到的液体产物进入后续的分离纯化系统;
其中,固体颗粒催化剂为负载型的S-构型手性钌催化剂S,S-Ru-2,结构如下:
其中●为微球硅胶,粒度50-200um,钌含量为1%。
手性钌催化剂S,S-Ru-2的制备工艺如下:
优选地,步骤(1)中所述的溶剂为水。
优选地,步骤(1)中所述待加氢溶液中丙酮基四氢吡喃三醇的质量浓度为5%-20%,更优选为10%。
优选地,步骤(1)中所述的待加氢溶液中甲酸钠与丙酮基四氢吡喃三醇的摩尔比为8-15:1,更优选为10:1。
优选地,步骤(2)中反应器内反应温度为80-120℃,压力0.1-1MPa;更优选反应器内反应温度为100℃,压力0.2MPa。
优选地,步骤(2)中所述气液混合物在微填充床中的停留时间为80-120s,更优选为100s。
与现有技术相比,本发明的方法能够实现连续自动化催化加氢或催化转移加氢,应用范围广,易于工业化应用,同时具有以下优势:
(1)本发明方法无需进行基团保护,一步加氢获得,工艺的原子经济性更好,步骤更短,后处理简单,无大量废液废渣产生。
(2)本发明方法无需加碱,反应停留时间短,物料异构化或降解的风险低,无副产物产生。
(3)本发明方法为非均相反应,催化剂固载后容易与物料分离,后处理成本低,产品重金属残留的风险低。
(4)本发明使用固定床微反应器传质传热效率高,体积小,无需高压下进行氢化反应,安全性高。
(5)本发明采用催化剂共价负载在微球硅胶上,固定化后固载在固定床中连续加氢,能够避免搅拌碰撞和剪切,催化剂结构不容易被破坏,稳定性更好。贵金属催化剂固载后可连续使用,使用寿命更长(连续运行500h以上),单位产品催化剂用量更少(见下表),成本更低。
催化剂用量比较
由上表可知,本发明使用的手性钌催化剂,经过修饰共价固载后,装填到微填床中,连续催化加氢,催化效率提高6-300倍。
(6)现有技术中采用的传统的釜式反应,反应时间长达10小时以上,产能低。本发明方法最长仅需120秒,极大缩短了反应时间,同时全连续生产减少了人员的操作,实现了生产的自动化,极大提高了产能。
(7)本发明方法转化率高达100%,产品收率高达90以上,获得的S-构型羟丙基四氢吡喃三醇品质高,ee值大于99%。
附图说明
图1:连续催化加氢反应的流程示意图,其中1为微筛孔微混合器,2为微填充床,3为气液分离器。
图2:连续催化转移加氢的流程示意图,其中1为混合罐,2为微填充床,3为离子交换柱。
图3:实施例2样品HPLC检测图谱
图4:实施例3样品HPLC检测图谱
具体实施方式
下面结合具体实施例对本发明作进一步的说明,但本发明的保护范围并不局限于此。本发明中所用木糖、乙酰丙酮及其他试剂和溶剂均可直接从市场上采购获得。
实施例1:还原反应的原料丙酮基羟丙基四氢吡喃三醇的制备(连续流工艺)
将D-木糖和水配置成25%(w/w)的A溶液,将氢氧化钠和水配置成20%
(w/w)的B溶液,打开微通道反应器,温度设置到80℃。反应开始,将A以流速33ml/min,B以流速13ml/min和乙酰丙酮以流速6.5ml/min,同时通入单元1,停留时间90秒。流出液经过离子交换柱除盐后,浓缩蒸干,加入异丙醇结晶得丙酮基羟丙基四氢吡喃三醇固体。
实施例2:S-羟丙基四氢吡喃三醇的制备
将丙酮基四氢吡喃三醇加入甲醇中,配置成10%溶液(w/w),控制氢气与丙酮基四氢吡喃三醇的摩尔比为5:1,溶液与氢气在入口微筛孔微混合器中混合,形成的气液混合物经过装填有S,S-Ru-1催化剂900g(催化剂尺寸100微米左右)的微反应器,设置反应温度为120℃,反应压力为2.5MPa,流速300ml/min,停留时间为70秒,在微反应器出口处收集反应产物,检测显示丙酮基四氢吡喃三醇的转化率100%。收集500h的反应液,减压浓缩蒸干,加入异丙醇结晶得白色固体,ee值99.9%,收率90%,钌未检出(ICP-
MS),HPLC图谱见图3。
实施例3:S-羟丙基四氢吡喃三醇的制备
将丙酮基四氢吡喃三醇和甲酸钠加入水中,配置成10%溶液(w/w),甲酸钠与丙酮基四氢吡喃三醇的摩尔比为10:1,溶液经过装填有S,S-Ru-2催化剂900g(催化剂尺寸100微米左右)的微反应器,设置反应温度为100
度,反应压力为0.2MPa,流速200ml/min,停留时间为100秒,在微反应器出口处收集反应产物,检测显示丙酮基四氢吡喃三醇的转化率100%,收集500h的反应液,树脂除盐,减压浓缩蒸干,加入异丙醇结晶得白色固体,
ee值99%,收率90%,钌未检出(ICP-MS),HPLC图谱见图4。
Claims (6)
1.一种连续催化加氢制备S-羟丙基四氢吡喃三醇的方法,其特征在于,包括如下步骤:
(1)将丙酮基四氢吡喃三醇溶解于溶剂中作为待加氢溶液;
(2)将步骤(1)所得待加氢溶液和氢气在微混合器内进行混合,混合后所得气液混合物通入填充固体颗粒催化剂的微填充床反应器内进行反应;
所述的固体颗粒催化剂为负载型的S-构型手性钌催化剂S,S-Ru-1,结构如下:
其中为微球硅胶,粒度50-200um;
所述负载型的S-构型手性钌催化剂S,S-Ru-1中钌含量为1%;
(3)将反应结束后得到的气液混合物进行气液分离,液体产物进入后续的分离纯化系统;
其中,步骤(1)中所述的溶剂为甲醇、乙醇、异丙醇,所述待加氢溶液中丙酮基四氢吡喃三醇的质量浓度为5%-20%;
步骤(2)中所述的微混合器为微筛孔混合器;所述气液混合物中丙酮基四氢吡喃三醇与氢气的摩尔比为1:3~10;反应器内反应温度为100~140℃,压力2-3MPa;所述气液混合物在微填充床中的停留时间为60~100s。
2.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述的溶剂为甲醇,所述待加氢溶液中丙酮基四氢吡喃三醇的质量浓度为10%。
3.根据权利要求1所述的制备方法,其特征在于,步骤(2)中所述的微混合器为微筛孔混合器;所述气液混合物中丙酮基四氢吡喃三醇与氢气的摩尔比为1:5;反应器内反应温度为120℃,压力2.5MPa;所述气液混合物在微填充床中的停留时间为70s。
4.一种连续催化转移加氢制备S-羟丙基四氢吡喃三醇的方法,其特征在于,包括如下步骤:
(1)将丙酮基四氢吡喃三醇溶解于含甲酸钠的溶剂中作为待加氢溶液;
(2)将步骤(1)所得待加氢溶液通入填充固体颗粒催化剂的微填充床反应器内进行反应;
所述的固体颗粒催化剂为负载型的S-构型手性钌催化剂S,S-Ru-2,结构如下:
其中为微球硅胶,粒度50-200um;
所述负载型的S-构型手性钌催化剂S,S-Ru-2中钌含量为1%;
(3)反应结束后得到的液体产物进入后续的分离纯化系统
其中,步骤(1)中所述的溶剂为水,所述待加氢溶液中丙酮基四氢吡喃三醇的质量浓度为5%-20%,甲酸钠与丙酮基四氢吡喃三醇的摩尔比为8~15:1;
步骤(2)中反应温度为80-120℃,压力0.1-1MPa;所述待加氢溶液在微填充床中的停留时间为80-120s。
5.根据权利要求4所述的制备方法,其特征在于,步骤(1)中所述的溶剂为水,所述待加氢溶液中丙酮基四氢吡喃三醇的质量浓度为10%,甲酸钠与丙酮基四氢吡喃三醇的摩尔比为10:1。
6.根据权利要求4所述的制备方法,其特征在于,步骤(2)中反应温度为100℃,压力0.2MPa;所述待加氢溶液在微填充床中的停留时间为100s。
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