CN112573999A - 一种3-氯龙胆醇的制备方法 - Google Patents
一种3-氯龙胆醇的制备方法 Download PDFInfo
- Publication number
- CN112573999A CN112573999A CN201910937928.5A CN201910937928A CN112573999A CN 112573999 A CN112573999 A CN 112573999A CN 201910937928 A CN201910937928 A CN 201910937928A CN 112573999 A CN112573999 A CN 112573999A
- Authority
- CN
- China
- Prior art keywords
- methyl
- chloro
- preparation
- methoxy
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
- C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种3‑氯龙胆醇的制备方法;先以龙胆酸甲酯或2‑羟基‑5‑甲氧基‑苯甲酸甲酯为反应物,分别经过氯化生成中间产物3‑氯龙胆酸甲酯或2‑羟基3‑氯‑5‑甲氧基‑苯甲酸甲酯,进而采用还原剂将中间产物还原为3‑氯龙胆酸。这种制备方法具有原料易于获得、中间产物少、步骤简单和产量高的特点,由于目前3‑氯龙胆醇的各种制备方法,为其生物活性研究和应用奠定了基础。
Description
技术领域:
本发明属于药物化学领域,具体涉及一种3-氯龙胆醇的制备方法。
背景技术:
3-氯-2,5-二羟基苯甲醇(3-chloro-2,5-dihydroxybenzyl alcohol),又名3-氯龙胆醇(3-chlorogentisyl alcohol)具有多种药用生物活性。首先,该化合物具有显著抑制线虫和藤壶幼虫定殖的作用,是一种新型抗生物污损剂(见文献Novel antifouling andantimicrobial compound from a marine-derived fungus sp.Marine Biotechnology(2006),8(6),634-640);其次,该化合物具有通过诱导DNA损伤促进人子宫颈癌细胞凋亡的作用,可应用于抗肿瘤领域(文献3-chloro-2,5-dihydroxybenzyl alcohol activateshuman cervical carcinoma HeLa cell apoptosis by inducingDNAdamage.International Journal of Oncology(2007),31(6),1317-1323)。3-氯龙胆醇的生物活性使其具有广阔的应用前景。为了更好应用该化合物,首先要提升其制备的效率。
目前3-氯龙胆醇的制备方法主要包括从真菌次级代谢产物中分离纯化和化学合成。早在1971年Sequin-Frey和Tamm就从茎点霉属(Phoma)真菌的次级代谢产物中分离得到,随后从加拿大青霉(Penicillium canadense)和叶点霉属(Phyllosticta)真菌中相继分离得到(见文献Gentisyl acetal and chlorgentisyl alcohol,two new metabolitesfrom a Phoma species.Helvetica Chimica Acta(1971),54(3),851-61)。2006年从海洋来源的白粉寄生孢菌(Ampelomyces)属真菌中分离得到该化合物(见文献Novelantifouling and antimicrobial compound from a marine-derived fungusAmpelomyces sp.Marine Biotechnology(2006),8(6),634-640)。2007年又从海洋来源真菌Penicillium terrestre的次级代谢产物中分离得到该化合物(见文献Gentisylalcohol derivatives from the marine-derived fungus Penicilliumterrestre.Journal of Natural Products(2008),71(1),66-70)。目前报道的化学合成方法主要包括从二乙酰龙胆酸开始通过三个中间物才能合成3-氯龙胆醇,其原料需要利用龙胆酸自行制备,并且二乙酰龙胆酸合成产量只有32%。另外还有通过6-氯-邻甲酚或氯代对苯二酚合成的,其产率也只有二分之一(见文献Isolation and synthesis of 3-chlorogentisyl alcohol-a metabolite of Penicillium canadense.Tetrahedron(1972),28(1107-1111))。
综上所述,3-氯龙胆醇早在上世纪70年代就有其制备方法的报道,但是由于其生物活性的研究工作主要从2006年开始,其生物活性没有得到充分的认识,因此其制备方法没有得到应有的重视。由于在真菌次级代谢产物中的3-氯龙胆醇含量少,通常要进行大规模培养,培养周期长,因此基于分离提纯天然产物的制备技术工作量大、步骤繁琐和产率低的特点不利于制备该化合物。鉴于该化合物结构特点,化学合成更适合用来制备该化合物。但是目前化学合成该化合物的方法操作步骤繁琐、原材料不易获取或产率较低,因此为了更好地利用3-氯龙胆醇的药用活性,需建立原料易获取、简便和高效的基于化学合成的制备方法。
发明内容:
本发明涉及一种3-氯龙胆醇的制备方法;制备步骤为先以2,5-二羟基苯甲酸甲酯(龙胆酸甲酯)或2-羟基-5-甲氧基-苯甲酸甲酯为反应物,经过苯环上3位氯化分别生成中间产物3-氯龙胆酸甲酯或2-羟基-3-氯-5-甲氧基-苯甲酸甲酯,进而采用还原剂氢化铝锂(lithium aluminum hydride,LAH)将中间产物还原为3-氯龙胆酸。该方法的原料龙胆酸甲酯是中药的原料药,易于获取,只需经过1个中间物即可得到3-氯龙胆醇,其产率高于目前该化合物报道的制备方法。
具体实施方式:
实施例1:由龙胆酸甲酯或2-羟基-5-甲氧基-苯甲酸甲酯氯化得到中间产物
将龙胆酸甲酯(4.62g,27.5mmol)或2-羟基-5-甲氧基-苯甲酸甲酯(5g,27.5mmol)分别溶于无水二甲基甲酰胺(38mL)中,将N-氯代琥珀酰亚胺(N-Chlorosuccinimide,3.66g,27.5mmol)分别加入溶液中。在氩气或氮气保护下,分别在室温反应2.5h,倒入水中,分别采用乙醚提取,乙醚相用盐水洗,真空旋蒸至干燥,然后用硅胶柱层析(乙酸乙酯∶己烷=1∶10)纯化。
实验结果:分别得到3-氯龙胆酸甲酯(4.11g,74%)或2-羟基-3-氯-5-甲氧基-苯甲酸甲酯(4.38g,74%)两种中间产物。
实施例2:由3-氯龙胆酸甲酯或2-羟基-3-氯-5-甲氧基-苯甲酸甲酯制备3-氯龙胆醇
分别将3-氯龙胆酸甲酯(4g,20mmol)或2-羟基-3-氯-5-甲氧基-苯甲酸甲酯(4.32g,20mmol)溶于100ml四氢呋喃。将混合物冷却到0℃,分别加入氢化铝锂(1ithiumaluminum hydride,LAH)(890mg,22mmol或1.67g,44mmol),从冷水浴中移出后,搅拌反应混合物10分钟,加热回流混合物12小时冷却混合物到0℃。分别缓慢加入25ml饱和硫酸铵溶液,用二氯甲烷提取,二氯甲烷相用盐水洗,真空旋蒸至干燥,加5N的HCl 50ml搅拌过夜后,重复二氯甲烷提取和干燥步骤后,用柱层析纯化残余物。少量产物用DMSO溶解,进行核磁氢谱检测。
实验结果:两种中间产物均可制备得到3-氯龙胆醇(2.8g,80%)。1H NMR(DMSO,400MHz)9.86(s,1H),8.38(s,1H),6.73(d,J=2.8Hz,1H),6.10(d,J=3.2Hz,1H),5.18(t,J=5.6Hz,1H),4.47(d,J=5.6Hz,1H)。其纯度可以>99%,产量高于目前的制备方法。
Claims (3)
1.一种3-氯龙胆醇的制备方法;其特征在于:其制备顺序是首先以龙胆酸甲酯或2-羟基-5-甲氧基-苯甲酸甲酯为原料,分别氯化成中间产物3-氯龙胆酸甲酯或2-羟基-3-氯-5-甲氧基-苯甲酸甲酯,然后采用还原剂分别将中间产物3-氯龙胆酸甲酯或2-羟基-3-氯-5-甲氧基-苯甲酸甲酯还原为3-氯龙胆酸。
2.根据权利要求1中所述的制备方法,其特征在于:龙胆酸甲酯及其衍生物氯化反应中采用N-氯代琥珀酰亚胺。
3.根据权利要求1中所述的制备方法,其特征在于:3-氯龙胆酸甲酯及其衍生物生成3-氯龙胆酸的还原剂是氢化铝锂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910937928.5A CN112573999B (zh) | 2019-09-29 | 2019-09-29 | 一种3-氯龙胆醇的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910937928.5A CN112573999B (zh) | 2019-09-29 | 2019-09-29 | 一种3-氯龙胆醇的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112573999A true CN112573999A (zh) | 2021-03-30 |
CN112573999B CN112573999B (zh) | 2022-09-02 |
Family
ID=75116124
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910937928.5A Active CN112573999B (zh) | 2019-09-29 | 2019-09-29 | 一种3-氯龙胆醇的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112573999B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070292545A1 (en) * | 2005-10-18 | 2007-12-20 | Aaron Monte | Anti-infective agents and methods of use |
WO2010080414A2 (en) * | 2008-12-19 | 2010-07-15 | The University Of North Carolina At Chapel Hill | Substituted fno (2-[furan-2-yl] naphthalen-1-ol) derivatives as anti-cancer agents |
CN106243003A (zh) * | 2015-06-03 | 2016-12-21 | 上海海雁医药科技有限公司 | 环烃基取代的甲磺酰基苯甲酰胺衍生物、其制法与医药上的用途 |
CN109651275A (zh) * | 2017-10-12 | 2019-04-19 | 优缔新材料科技(苏州)有限公司 | 新颖三嗪类化合物、其组合物及其制备方法 |
CN110092740A (zh) * | 2018-01-29 | 2019-08-06 | 广州丹康医药生物有限公司 | 一种稠环化合物及其应用 |
-
2019
- 2019-09-29 CN CN201910937928.5A patent/CN112573999B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070292545A1 (en) * | 2005-10-18 | 2007-12-20 | Aaron Monte | Anti-infective agents and methods of use |
WO2010080414A2 (en) * | 2008-12-19 | 2010-07-15 | The University Of North Carolina At Chapel Hill | Substituted fno (2-[furan-2-yl] naphthalen-1-ol) derivatives as anti-cancer agents |
CN106243003A (zh) * | 2015-06-03 | 2016-12-21 | 上海海雁医药科技有限公司 | 环烃基取代的甲磺酰基苯甲酰胺衍生物、其制法与医药上的用途 |
CN109651275A (zh) * | 2017-10-12 | 2019-04-19 | 优缔新材料科技(苏州)有限公司 | 新颖三嗪类化合物、其组合物及其制备方法 |
CN110092740A (zh) * | 2018-01-29 | 2019-08-06 | 广州丹康医药生物有限公司 | 一种稠环化合物及其应用 |
Non-Patent Citations (3)
Title |
---|
HONG-SHUANG WANG 等: "Regioselective synthesis of gentisyl alcohol-type marine natural products", 《NATURAL PRODUCT RESEARCH》 * |
N.J.MCCORKINDALE 等: "Isolation and synthesis of 3-chlorogentisylalcohol—a metabolite of Penicillium canadense", 《TETRAHEDRON》 * |
RICHARD BELLINGHAM 等: "Discovery and Development of an Efficient, Scalable, and Robust Route to the Novel CENP-E Inhibitor GSK923295A", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Also Published As
Publication number | Publication date |
---|---|
CN112573999B (zh) | 2022-09-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kirilmis et al. | Synthesis and antimicrobial activity of some novel derivatives of benzofuran: Part 2. The synthesis and antimicrobial activity of some novel 1-(1-benzofuran-2-yl)-2-mesitylethanone derivatives | |
CN110528020B (zh) | 一种电催化下异噁唑并异喹啉酮衍生物的制备方法 | |
Pour et al. | 3-Phenyl-5-methyl-2H, 5H-furan-2-ones: tuning antifungal activity by varying substituents on the phenyl ring | |
CN107513050B (zh) | 一种烯酸溴内酯化的制备方法 | |
CN112062712A (zh) | 一种2-(5-溴-3-甲基吡啶-2-基)乙酸盐酸盐的制备方法 | |
CN112573999B (zh) | 一种3-氯龙胆醇的制备方法 | |
Das et al. | Total synthesis of racemic and (R) and (S)-4-methoxyalkanoic acids and their antifungal activity | |
Arcadi et al. | The reaction of alkyl 4-hydroxy-2-alkynoates and 4-hydroxy-2-alkyn-1-ones with palladium tributylammonium formate and with tributylamine: Preparation of 1, 4-dicarbonyl compounds | |
Wang et al. | An efficient synthesis of 2-formyl-1, 4, 5, 8-tetramethoxynaphthalene | |
Sun et al. | Highly stereoselective gram scale synthesis of all the four diastereoisomers of Boc-protected 4-methylproline carboxylates | |
Senboku et al. | Stereochemical study on electrochemical carboxylation of vinyl triflates | |
CN112479967B (zh) | 胆绿素类化合物及其制备方法和用途 | |
Knizhnikov et al. | A route to a wide range of cyclopentanecarboxylic acids via 4-substituted camphors | |
Zhang et al. | Copper-catalyzed tandem reaction of 2-bromobenzyl bromides with 1, 3-dicarbonyl compounds leading to 4H-chromenes | |
Liu et al. | A novel, stereoselective and practical protocol for the synthesis of 4β-aminopodophyllotoxins | |
Nishimura et al. | Asymmetric Michael–aldol tandem cyclization of ω-oxo-α, β-unsaturated esters with 10-mercaptoisoborneol methyl ether | |
CN108822072B (zh) | 一种制备伊力格鲁司他的方法 | |
Liu et al. | Carboxy mediated stereoselective reduction of ketones with sodium triacetoxyborohydride: synthesis of novel 3, 4-fused tetrahydropyran and tetrahydrofuran prolines | |
Chang et al. | One-pot synthesis of multisubstituted quaterphenyls and cyclopropanes | |
CN110204456B (zh) | 多取代萘衍生物及其合成方法 | |
CN109879775A (zh) | 一种5-氨基乙酰丙酸盐酸盐中间体的环保制备方法 | |
Xu et al. | An efficient and practical synthesis of mandelic acid by combination of complex phase transfer catalyst and ultrasonic irradiation | |
GB2290790A (en) | Asymmetric synthesis of 6-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes | |
Takeda et al. | Highly diastereoselective addition of allyltitanocenes to α-chiral ketones | |
Swaney et al. | The synthesis of 3-azabicyclo [4.3. 0] nonane scaffolds from brefeldin A |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |