WO2018214327A1 - Procédé de préparation de lanostérol, dérivé de médicament anticancéreux - Google Patents

Procédé de préparation de lanostérol, dérivé de médicament anticancéreux Download PDF

Info

Publication number
WO2018214327A1
WO2018214327A1 PCT/CN2017/100112 CN2017100112W WO2018214327A1 WO 2018214327 A1 WO2018214327 A1 WO 2018214327A1 CN 2017100112 W CN2017100112 W CN 2017100112W WO 2018214327 A1 WO2018214327 A1 WO 2018214327A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
lanosterol
tetrahydrofuran
reaction
compound
Prior art date
Application number
PCT/CN2017/100112
Other languages
English (en)
Chinese (zh)
Inventor
谢伟东
Original Assignee
东莞中山大学研究院
广州如亲医药科技有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 东莞中山大学研究院, 广州如亲医药科技有限公司 filed Critical 东莞中山大学研究院
Publication of WO2018214327A1 publication Critical patent/WO2018214327A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C07J71/0015—Oxiranes at position 9(11)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • the invention belongs to the field of drug synthesis and relates to a method for synthesizing a novel lanosterol derivative which can be used for treating cancer.
  • lanosterol is likely to prevent protein condensation that leads to cataracts.
  • lanosterol was used to treat the lens of dogs, rabbits and human eyes. It was found that the degree of opacity of the lens and the volume of cataract were reduced, the symptoms were alleviated, and the visual field became clearer. The inclusion of lanosterol in eye drops has proven to be an effective treatment for cataracts. The results of this study have brought good news to cataract patients who cannot undergo surgery.
  • the lanosterol can be prepared from a chain squalene ring, and a large amount of lanosterol needs to be extracted from the unsaponifiable matter in the lanolin. Due to the special bone structure of lanosterol tetracyclic triterpenes, it is often used in the research and development of drugs.
  • the method also uses lanosterol as a raw material, and is subjected to upper protection, double hydroxylation, oxidation, epoxidation, acylation, and deprotection to obtain LD.
  • the reaction time of the system is long, the yield is not high, and the amount of synthesis is small.
  • the use of heavy metal catalysts for many times is not conducive to industrial production and meets the requirements of clinical medicinal.
  • the synthesis method of the invention optimizes the key processes of each step reaction, including the reaction method of each step reaction, the reaction solvent, the feed amount, the reaction temperature, the post-treatment mode and the like, and the optimized process reduces the number of times of the column and reduces the number of times.
  • Product production costs increase synthesis efficiency. This process is sufficient to support the scale-up of the production of 50 g/batch of the batch product and the resulting product is of high purity and has good industrial use value.
  • a preparation method of a new anticancer drug lanosterol derivative, the synthetic route of the method is as follows:
  • the invention is characterized in that the LD is used as a starting material, and the target LD is finally obtained by upper protection, Sharpless asymmetric double hydroxylation, Swern oxidation, acetylation, deprotection and epoxidation, and the corresponding intermediate LD is obtained in the process. -a, LD-b, LD-c, LD-d, LD-e. Specifically, the following reaction steps are included:
  • the lanosterol is reacted with 2,6-lutidine as a base in a solvent of dichloromethane, and tert-butyldimethylsilyl triflate to give an LD-a compound.
  • LD-a in the presence of oxidant N-methyl-N-oxidized morpholine and catalyst ruthenium tetroxide, tetrahydrofuran and acetone as a mixed solvent, the occurrence of Sharpless asymmetric dihydroxylation reaction to form the diol-based compound LD-b .
  • LD-b is oxidized by an oxidizing agent to form an ⁇ -hydroxyketone compound LD-c with a mixed solvent of dichloromethane and tetrahydrofuran.
  • LD-c is reacted with acetic anhydride in methylene chloride with triethylamine and 4-dimethylaminopyridine as a base to form an LD-d compound.
  • the LD-d compound is deprotected in the presence of hydrofluoric acid to form an LD-e compound.
  • the target lanosterol derivative LD is obtained by epoxidation of LD-e in a dichloromethane solution under the action of an oxidizing agent.
  • the reaction temperature is 25 ° C - 40 ° C, preferably 30 ° C - 40 ° C;
  • the solvent used is selected from untreated dichloromethane and re-distilled dichloromethane, in order to better fit the industry , preferably untreated methylene chloride;
  • lanosterol used: tert-butyldimethylsilyl trifluoromethanesulfonate: 2,6-lutidine molar ratio 1:1.5 to 2.5:2.7 , priority 1:2:2.7.
  • the reaction temperature is 25 ° C -35 ° C, preferably 30 ° C -35 ° C; the volume ratio of the mixed solvent tetrahydrofuran and acetone used is selected from 10:7 and 7:4, preferably 7:4;
  • the LD-a:N-methyl-N-oxidized morpholine: osmium tetroxide has a molar ratio of 1:1.5 to 2.5:0.005 to 0.01, preferably 1:1.5:0.007.
  • the reaction mode is Swern oxidation, PCC reaction, DMP oxidation, preferably Swern oxidation.
  • the oxidizing agent used is selected from the group consisting of dimethyl sulfoxide and trifluoroacetic anhydride, dimethyl sulfoxide and oxalyl chloride, DMP, pyridinium chlorochromate, preferably dimethyl sulfoxide and oxalyl chloride.
  • the reaction temperature is from 25 ° C to 35 ° C, preferably from 30 ° C to 35 ° C;
  • the triethylamine used is selected from untreated triethylamine and re-distilled triethylamine, for better Suitable for production amplification, preferably untreated triethylamine; during post-treatment purification, it is preferred to use ethanol pulping instead of column purification.
  • the reaction temperature is preferably about 65 ° C;
  • the solvent used is one or two of tetrahydrofuran or acetonitrile, preferably tetrahydrofuran;
  • the reaction conditions are selected from tetrahydrofuran and acetic acid, tetrahydrofuran and potassium carbonate, tetrahydrofuran and
  • the reaction conditions of hydrofluoric acid preferably tetrahydrofuran and hydrofluoric acid; in the post-treatment extraction, it is preferred to use methyl tert-butyl ether instead of ethyl acetate to reduce the amount of solvent.
  • the oxidizing agent used is selected from the group consisting of hydrogen peroxide and m-chloroperoxybenzoic acid, preferably m-chloroperoxybenzoic acid; during the post-treatment, the insoluble by-product m-chlorobenzoic acid produced during the reaction of the step is filtered.
  • the invention has prepared a novel drug having an anticancer effect.
  • Figures 1 and 2 show the nuclear magnetic resonance spectrum and carbon spectrum of LD-b, respectively.
  • Figures 3 and 4 show the nuclear magnetic resonance spectrum and carbon spectrum of LD-c, respectively.
  • Figures 5 and 6 show the nuclear magnetic resonance spectrum and carbon spectrum of LD-d, respectively.
  • Figures 7 and 8 show the nuclear magnetic resonance spectrum and carbon spectrum of LD-e, respectively.
  • Figures 9 and 10 show the nuclear magnetic resonance spectrum and carbon spectrum of LD, respectively.
  • Figure 11 is a mass spectrum of the LD.
  • Figure 12 is a liquid chromatogram of LD.
  • the area normalization method showed that the lanosterol was less than 0.5%, and it was judged that the reaction end point was reached.
  • the mixture was allowed to stand for separation, and the organic phase was collected.
  • the aqueous phase was extracted twice with dichloromethane (500 ml each time) and the aqueous phase was discarded.
  • the combined organic phases were washed with 1500 ml of brine, and the mixture was partitioned, the aqueous phase was discarded, and the organic phase was dried over anhydrous sodium sulfate. After filtration, it was concentrated to dryness under reduced pressure to give crude material.
  • the area normalization method showed that LD-a was less than 2%, and it was judged that the reaction end point was reached.
  • the aqueous phase was extracted twice with methyl tert-butyl ether (500 ml each time) and the aqueous phase was discarded.
  • the combined organic phases were washed with 2000 ml of saturated brine, and emulsified during the extraction.
  • the reaction was slowly warmed to room temperature, the reaction was stirred overnight, and the reaction was sampled, and the reaction was monitored by HPLC. When the area normalization method showed that LD-b was less than 25%, it was judged that the reaction end point was reached. After adding 1200 ml of a saturated ammonium chloride solution and stirring for 10 minutes, the mixture was allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted twice with dichloromethane (500 ml each time) and the aqueous phase was discarded.
  • the aqueous phase was extracted with 300 ml of dichloromethane and the aqueous phase was discarded.
  • the organic phase was washed with saturated brine, and the mixture was partitioned, the aqueous phase was discarded, and the organic phase was dried over anhydrous sodium sulfate. After filtration, it was concentrated to dryness under reduced pressure to give crude material.
  • the organic phase was added dropwise with saturated sodium bicarbonate solution to adjust the pH to about 7.0, and about 51.8 ml was consumed; stirring was continued for 15 min, and the layer was allowed to stand.
  • the organic phase was washed with a saturated aqueous solution of sodium chloride, and then the mixture was partitioned, the aqueous phase was discarded, and the organic phase was dried over anhydrous sodium sulfate. After filtration, it was concentrated to dryness under reduced pressure to yield crude product LD-f 78.52 g.
  • To the crude product LD-f 205 ml of tetrahydrofuran was added, and the temperature was raised to 50-55 ° C, and the crude product was completely dissolved.
  • the LD was also subjected to mass spectrometry and liquid chromatography testing and identification, and the results are shown in Fig. 11 and Fig. 12, respectively.
  • test mode of mass spectrometry is to directly analyze the ionization source positive ions:
  • Detection wavelength 210 nm
  • Injection volume 20 ⁇ L
  • Mobile phase acetonitrile is mobile phase A, methanol is mobile phase B, and water is mobile phase C;

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte au domaine technique de la synthèse de médicaments et concerne un procédé de préparation d'un nouveau dérivé d'un médicament anticancéreux, à savoir le lanostérol. Dans le procédé de la présente invention, du lanostérol est utilisé comme matériau de départ pour produire un intermédiaire LD-a à travers une protection par tert-butyldiméthylsilyle (TBS), l'intermédiaire LD-a subit une double réaction d'hydroxylation asymétrique de Sharpless sous l'action de tétroxyde d'osmium (OsO4) pour produire un composé LD-b diol vicinal, le composé LD-b subit une oxydation de Swern dans des conditions alcalines de triéthylamine pour produire un composé LD-c α-hydroxycétone, LD-c est acylé avec de l'anhydride acétique pour obtenir un intermédiaire LD-d, LD-d subit une déprotection TBS pour obtenir un intermédiaire LD-e, et enfin l'intermédiaire LD-e est époxydé pour donner un dérivé LD de lanostérol cible. La présente invention présente des conditions de réaction relativement modérées dans les étapes de préparation et les étapes de synthèse courte, évite l'utilisation de réactifs hautement toxiques ou coûteux, produit un produit de pureté élevée, et peut être utilisée pour une production industrielle.
PCT/CN2017/100112 2017-05-26 2017-09-01 Procédé de préparation de lanostérol, dérivé de médicament anticancéreux WO2018214327A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710383415.5A CN108929363B (zh) 2017-05-26 2017-05-26 一种抗癌药物羊毛甾醇衍生物的制备方法
CN201710383415.5 2017-05-26

Publications (1)

Publication Number Publication Date
WO2018214327A1 true WO2018214327A1 (fr) 2018-11-29

Family

ID=64396129

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/100112 WO2018214327A1 (fr) 2017-05-26 2017-09-01 Procédé de préparation de lanostérol, dérivé de médicament anticancéreux

Country Status (2)

Country Link
CN (1) CN108929363B (fr)
WO (1) WO2018214327A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023030332A1 (fr) * 2021-08-31 2023-03-09 广州润尔眼科生物科技有限公司 Composé stéroïdien, son procédé de préparation et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103204898A (zh) * 2012-01-16 2013-07-17 谢伟东 抗癌化合物及其应用
CN105377372A (zh) * 2013-02-01 2016-03-02 广州如亲医药科技有限公司 一种通过rho途径治疗癌症的指令和方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102013001372B4 (de) * 2013-01-28 2018-02-15 Voith Patent Gmbh Montageverfahren für ein Schiffsantrieb

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103204898A (zh) * 2012-01-16 2013-07-17 谢伟东 抗癌化合物及其应用
CN105377372A (zh) * 2013-02-01 2016-03-02 广州如亲医药科技有限公司 一种通过rho途径治疗癌症的指令和方法

Also Published As

Publication number Publication date
CN108929363A (zh) 2018-12-04
CN108929363B (zh) 2021-06-25

Similar Documents

Publication Publication Date Title
IL98191A (en) A process for the enantioselective preparation of phenylisosarine history
JP2018512066A (ja) デオキシコール酸の作製方法
WO2018214327A1 (fr) Procédé de préparation de lanostérol, dérivé de médicament anticancéreux
HU205894B (en) Process for producing optically active ceramide type compounds
RU2448957C2 (ru) Фторированные производные катарантина, их получение и применение в качестве прекурсоров димерных алкалоидов vinca
RU2650192C2 (ru) Синтетическое промежуточное соединение максакальцитола, способ его получения и его применение
CN114380884A (zh) 一种具有抗肿瘤活性的齐墩果酸衍生物及其制备方法
US20100317868A1 (en) Method of preparing taxane derivatives and intermediates used therein
CN108530510A (zh) 一种c19-酰基化雷公藤甲素的制备方法
CN109134577B (zh) 一种3α-羟基-5α-胆烷酸的合成方法
CN109824748A (zh) B-降胆甾醇氧化衍生物及其合成方法和应用
Pilipenko et al. Eleuthesides and their analogs: VII. Synthesis of menthane derivatives by the Diels-Alder reaction of levoglucosenone with (2 E, 4 E)-hexa-2, 4-dien-1-yl acetate
WO2020155613A1 (fr) Procédé de préparation de composé d'ectéinascidine et d'un intermédiaire de celui-ci
CN108997232B (zh) 一种组蛋白去乙酰化酶抑制剂的合成方法
CN115716859B (zh) 一种脑甾醇中间体胆甾-5,24-双烯-3-醋酸酯的制备方法
CN115819307B (zh) 一种***素e1的制备方法
JP2011526297A (ja) シュワインフルチンアナログ
TWI744448B (zh) 甘草酸及半乳糖醛酸甘草酸之製造方法與該製造方法中所使用之中間體
JP2011526297A5 (fr)
CN114249706A (zh) 一种用于合成环***素衍生物的中间体的制备方法
WO2024032799A1 (fr) Procédé de préparation de tétrodotoxine et de son analogue
JP3682291B2 (ja) オレアノール酸誘導体の製造方法
JP2501604B2 (ja) コレスタ―１，４，６−トリエン−３−オン類の製造法
JP3228486B2 (ja) ヒドロキシケトン誘導体およびその製造方法
KR100835604B1 (ko) 항암 효과를 갖는 불포화 케톤 및 그 유도체의 제조 방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17911308

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 24/01/2020)

122 Ep: pct application non-entry in european phase

Ref document number: 17911308

Country of ref document: EP

Kind code of ref document: A1