CN114105922B - 一种羟丙基四氢吡喃三醇的合成方法 - Google Patents
一种羟丙基四氢吡喃三醇的合成方法 Download PDFInfo
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- CN114105922B CN114105922B CN202111467236.2A CN202111467236A CN114105922B CN 114105922 B CN114105922 B CN 114105922B CN 202111467236 A CN202111467236 A CN 202111467236A CN 114105922 B CN114105922 B CN 114105922B
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- 238000001308 synthesis method Methods 0.000 title description 3
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- 229910052723 transition metal Inorganic materials 0.000 claims description 14
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 13
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
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- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供一种羟丙基四氢吡喃三醇的合成方法，其通过偶联反应得到产品。本发明的合成方法相较于其他路线，具有产品产率更高、质量更好、反应历程更简单、后处理容易等优点，适于合工业化生产羟丙基四氢吡喃三醇。另外，本发明还提供用于合成羟丙基四氢吡喃三醇的新原料。
Description
技术领域
本发明属于化学合成领域，具体涉及一种羟丙基四氢吡喃三醇的合成方法。
背景技术
羟丙基四氢吡喃三醇(CAS号439685-79-7，又称玻色因)，是一种生物活性物质，具有对抗皮肤老化，脱水等功效，被广泛应用于食品，生物，医药，化妆品等诸多领域。羟丙基四氢吡喃三醇用于化妆品中的机制如下：通过信息传递，刺激粘多糖(GASs)和蛋白多糖(Proteoglycan)的生成，吸收水分，提高细胞外基质间/ECM的水分含量，使基质呈凝胶状，从而充分地填充ECM间隙，增加细胞及皮肤的紧致度。使皮肤的皱纹减少，进而显得更加细腻，同时增强皮肤防御能力。同时，可以在表皮-真皮连接部(DEJ/dermal epidermaljunction)处发挥作用，促进整合素，层粘蛋白-5，胶原蛋白VII，胶原蛋白IV的合成，使表皮和真皮连接的更紧密，让整个皮肤重现饱满，紧致和弹性的效果。
目前涉及到羟丙基四氢吡喃三醇的合成和提纯的文献及专利较少，主要合成方法有以下几种：
一、WO2002051828A2、Bioorganic&Medicinal Chemistry Letters 19(2009)845-849、CN102040575A、CN111559998A等报道，木糖与乙酰丙酮反应后，在木糖上引入支链羰基，再经硼类还原剂(硼氢化钠、硼氢化锂、铝锂氢、硼烷等)还原，或金属催化还原得到玻色因：
二、CN110467591A报道，以木糖和乙酰乙酸乙酯为原料，稀土金属配合物首先促进了木糖和乙酰乙酸乙酯的糖苷化反应，并催化酯基的水解脱羧，再进一步地促进羰基被异丙醇还原，从而制得玻色因：
三、CN111876452A报道，用生物酶一锅法制备玻色因，以木糖和异丙醇作为底物，以筛选得到的异丙醇脱氢酶、玻色因合成酶、羰基还原酶作为催化剂，反应制备得到玻色因：
然而，上述方法均存在操作复杂、产率/产量不高、纯化麻烦的问题。
发明内容
针对现有工艺中存在的问题，本发明提供了一种合成羟丙基四氢吡喃三醇的新工艺方案，其具有操作简便、产率高等优点。
具体地，本发明提供一种合成羟丙基四氢吡喃三醇的方法，包括：
化合物I和化合物II在过渡金属催化剂、配体、碱的存在下，通过偶联反应得到羟丙基四氢吡喃三醇；
其中，R1、R2表示OH、-OC1～C6的烷基，或者BR1R2表示
在一些实施方案中，R1、R2表示甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基。
在一些实施方案中，所述化合物II选自
((2-羟基丙基)硼酸)、
((2-羟基丙基)硼酸二甲酯)或
(1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)丙-2-醇)。
在一些实施方案中，化合物I和化合物II的摩尔比为1：1～1.5，优选1：1.05～1.2，更优选1：1.1～1.15。
在一些实施方案中，所述过渡金属催化剂选自钯过渡金属催化剂、铑过渡金属催化剂、钌过渡金属催化剂中的至少一种。
优选的，所述过渡金属催化剂选自二氯化钯、醋酸钯、三氟乙酸钯、三氯化铑、三氯化钌中的至少一种。
在一些实施方案中，所述配体选自Mor-DalPhos、Me-DalPhos、三苯基膦、三二亚苄基丙酮、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(antphos)、2-二环己基磷-2',4',6'-三异丙基联苯(xphos)中的至少一种。
其中，Mor-DalPhos和Me-DalPhos的结构如下：
在一些实施方案中，过渡金属催化剂的用量为化合物I摩尔量的0.1～3％，优选0.5～2％，更优选1～1.5％。
在一些实施方案中，过渡金属催化剂和配体的摩尔比为1：0.9～1.5，优选1：1～1.3，更优选1：1～1.2。
在一些实施方案中，所述碱选自无机碱，比如碳酸盐、碳酸氢盐或磷酸盐，诸如碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、磷酸钠、磷酸钾等。
在一些实施方案中，化合物I和碱的摩尔比为1：1.5～10，优选1：2～5，更优选1：2～3。
在一些实施方案中，所述反应在溶剂中进行。所述溶剂选自水、丙酮、甲醇、乙醇、异丙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、乙腈中的一种或两种的混合溶剂。优选的，所述溶剂选自水与丙酮、甲醇、乙醇、异丙醇、叔丁醇、正丁醇、四氢呋喃、乙腈之一的混合溶剂。优选的，水与丙酮、甲醇、乙醇、异丙醇、叔丁醇、正丁醇、四氢呋喃或乙腈的质量为1：1～10，优选1：1.5～6，更优选1：2～4。
在一些实施方案中，所述反应的温度为-10～150℃，优选30～80℃，更优选50～70℃；所述反应的时间为1～24h，优选4～12h。
在本发明的另一方面，本发明还提供用于合成羟丙基四氢吡喃三醇的原料硼酸或硼酯类化合物，其结构如以下化合物II所示：
其中，R1、R2表示OH、C1～C6的烷基，或者BR1R2表示
在一些实施方案中，所述化合物II选自
((2-羟基丙基)硼酸)、
((2-羟基丙基)硼酸二甲酯)或
(1-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)丙-2-醇)。
所述硼酸或硼酯类的化合物II可以按照本领域中合成硼酸或硼酯类化合物的常规方法获得。
在本发明的另一方面，本发明还提供化合物II的合成方法，其是以2-羟基-3-溴丙烷为原料，经硼酸酯化或硼酸化反应得到。
在一些实施方案中，化合物II可以通过如下方案合成：以2-羟基-3-溴丙烷作原料，先将羟基保护，通过格氏交换反应制得格氏试剂，该格氏试剂与联硼酸频哪醇酯或硼酸酯反应、脱保护即可得到(2-羟基丙基)硼酸酯类化合物；可选的，(2-羟基丙基)硼酸酯类化合物再经过水解得到(2-羟基丙基)硼酸。
羟基保护可以采用本领域常规的羟基保护剂。在一些实施方案中，所述羟基保护剂可选自硅烷类保护剂；所述硅烷类保护剂选自三甲基氯硅烷、三乙基氯硅烷、异丙基二甲基氯硅烷、叔丁基二甲基氯硅烷、叔丁基二苯基氯硅烷、甲基二异丙基氯硅烷中的至少一种。
脱保护可以采用本领域常规的脱保护剂。在一些实施方案中，在羟基保护剂选自硅烷类保护剂的情况下，所述脱保护剂可以选自氟化物，诸如TBAF(四丁基氟化铵)等。
优选的，所述水解是指用碱水解。所述碱选自碳酸盐、碳酸氢盐或磷酸盐，诸如碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、磷酸钠、磷酸钾等。
发明的有益效果
本发明提供一种合成羟丙基四氢吡喃三醇的新工艺，以及用于合成羟丙基四氢吡喃三醇的硼酸或硼酯类化合物新原料。本发明的合成方法操作简单，收率高、后处理十分简单，相较于其他路线，本发明的合成方法具有产品产率更高、质量更好、反应历程更简单等优点，适于合工业化生产羟丙基四氢吡喃三醇。
附图说明
图1显示了实施例2中产品羟丙基四氢吡喃三醇的核磁碳谱。
图2显示了实施例2中产品羟丙基四氢吡喃三醇的HPLC谱图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。
实施例1：化合物II的制备
向玻璃反应器中加入13.9g 1-溴-2-羟基丙烷，8.2g咪唑和200ml的二氯甲烷作溶剂，在氮气保护下开启电子搅拌，然后分批加入18.1gTBSCl(叔丁基二甲基氯硅烷)。加料结束后室温搅拌过夜，TLC检测反应结束后用饱和食盐水洗涤，浓缩后即可得到21.1g的无色油状物(1-溴-异丙基)叔丁基二甲基硅醚。
向玻璃反应器中加入10.1g(1-溴-异丙基)叔丁基二甲基硅醚，50ml无水四氢呋喃，氮气保护下降温至-40℃，滴加22ml 2M的异丙基氯化镁的四氢呋喃溶液至体系中。-40℃下搅拌2小时，将5g硼酸三甲酯滴加至体系中，搅拌反应至结束。用饱和氯化铵溶液淬灭反应后静置分层，水相再用100ml乙酸乙酯萃取后合并有机相，饱和食盐水洗涤两次干燥浓缩即可得到(2-叔丁基二甲基硅氧基丙基)硼酸二甲酯。将其溶解在100ml的无水四氢呋喃中，加入20.8g TBAF(四丁基氟化铵)，室温搅拌过夜，用100ml水淬灭反应，乙酸乙酯萃取干燥浓缩后得到粗品，经过硅胶柱分离纯化后得到(2-羟基丙基)硼酸二甲酯，然后经碳酸钠溶液水解得到2.7g的(2-羟基丙基)硼酸产品，收率为65％。
多次重复获得(2-羟基丙基)硼酸产品，待用。
实施例2：羟丙基四氢吡喃三醇的制备
向玻璃反应器中加入10.0g(46.9mmol)化合物I，5.3g(51.6mmol)化合物II((2-羟基丙基)硼酸)，10.0g水和20.0g四氢呋喃。用氩气将反应体系惰化，并用微气流保护。在氩气保护下加入二氯化钯0.08g(0.47mmol)和碳酸钾12.9g(93.8mmol)，0.2g(0.47mmol)Mor-DalPhos作为配体，55-60℃反应6小时后结束。体系用活性炭脱色后脱溶即可得到羟丙基四氢吡喃三醇7.4g无色糖浆状产品，收率为82％。
根据图1的核磁碳谱和图2的HPLC谱图，能够确定所述产品为目标产物羟丙基四氢吡喃三醇，即玻色因。
实施例3：羟丙基四氢吡喃三醇的制备
向玻璃反应器中加入15.0g(70.4mmol)化合物I，8.0g(77.4mmol)化合物II((2-羟基丙基)硼酸)，15.0g水和30.0g异丙醇。用氩气将反应体系惰化，并用微气流保护。在氩气保护下加入二氯化钯0.12g(0.7mmol)和碳酸钠14.9g(140.8mmol)，0.29g(0.7mmol)Me-DalPhos作为配体，60-65℃反应8小时后结束。体系用活性炭脱色后脱溶即可得到羟丙基四氢吡喃三醇11.5g无色糖浆状产品，收率为85％。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解，根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (5)
1.一种合成羟丙基四氢吡喃三醇的方法，包括：
化合物I和化合物II在过渡金属催化剂、配体、碱的存在下，通过偶联反应得到羟丙基四氢吡喃三醇；
其中，R1、R2表示OH，或者BR1R2表示
所述过渡金属催化剂选自二氯化钯、醋酸钯、三氟乙酸钯中的至少一种，所述配体选自Mor-DalPhos、Me-DalPhos，Mor-DalPhos和Me-DalPhos的结构如下：
所述碱选自碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾。
2.根据权利要求1所述的方法，其特征在于，所述化合物I和化合物II的摩尔比为1：1～1.5。
3.根据权利要求1所述的方法，其特征在于，过渡金属催化剂的用量为化合物I摩尔量的0.1～3％；过渡金属催化剂和配体的摩尔比为1：0.9～1.5。
4.根据权利要求3所述的方法，其特征在于，过渡金属催化剂和配体的摩尔比为1：1～1.3。
5.根据权利要求3所述的方法，其特征在于，过渡金属催化剂和配体的摩尔比为1：1～1.2。
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