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WO2018090670A1 - Procédé de préparation de droxidopa et de son intermédiaire - Google Patents

Procédé de préparation de droxidopa et de son intermédiaire Download PDF

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Publication number
WO2018090670A1
WO2018090670A1 PCT/CN2017/095604 CN2017095604W WO2018090670A1 WO 2018090670 A1 WO2018090670 A1 WO 2018090670A1 CN 2017095604 W CN2017095604 W CN 2017095604W WO 2018090670 A1 WO2018090670 A1 WO 2018090670A1
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WIPO (PCT)
Prior art keywords
dibenzyloxyphenyl
oxopropionate
dibenzylamino
reaction
group
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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.)
Ceased
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PCT/CN2017/095604
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English (en)
Chinese (zh)
Inventor
孙国栋
王仲清
王海龙
周自洪
许勇波
罗忠华
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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Priority to CN201780066794.3A priority Critical patent/CN110099893B/zh
Publication of WO2018090670A1 publication Critical patent/WO2018090670A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to an improved method for preparing cexidopa and a novel intermediate of cixidol.
  • Quxiedoba also known as L-threo-3-(3,4-dihydroxyphenyl)serine, is a compound of formula (VIII), a synthetic amino acid that causes abnormally reduced noradrenal cells in the brain.
  • the concentration of hormone returns to normal levels, thus improving various symptoms caused by norepinephrine deficiency, such as dizziness, dizziness and fatigue caused by orthostatic hypotension, gait stiffness in patients with Parkinson's disease, etc.
  • Patent US 3,920,728 discloses for the first time that 3,4-dibenzyloxybenzaldehyde and glycine are used as starting materials to react firstly to obtain racemic SU/Red-3-(3,4-dibenzyloxyphenyl).
  • EP0024210A1, EP0084928A1 have improved the sequence of the chiral resolving agent, protecting group and deprotecting group on the basis of this route.
  • the biggest disadvantage of this type of method is that it requires two splits to obtain cexidopa, resulting in lower overall yield and higher cost.
  • WO2013142093A1 uses L-ephedrine as a resolving agent, and the serine derivative can obtain the L-threo serine derivative in one step, but the theoretical yield is still low due to the absence of configuration conversion in the resolution. And ephedrine is a controlled drug and is more difficult to obtain.
  • JPH01228946 discloses a novel method for synthesizing cixidol (Scheme 2) which uses (S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid as a starting material.
  • the steps of esterification, reduction, acetylation, oxidation and the like form an oxazoline derivative substituted with an acetoxymethyl group at the 4-position, and the compound is subjected to ring opening, oxidation, and deprotection to obtain dicedopa.
  • the method can obtain xicidoba in a stereoselective manner, the route is too long, the operation is cumbersome and complicated, and the starting material contains a chiral center, and the cost is high.
  • the four ester-substituted oxazoline derivatives can be formed in one step by reacting an N-carbonyl derivative with a halogen radical initiator or a tetravalent phosphonium salt.
  • the product, dicedopa can be directly obtained by ring-opening and deprotection, but there are still disadvantages in that the raw material is expensive and the post-treatment requires column chromatography.
  • WO2005085178 uses protected 3,4-dihydroxybenzaldehyde as starting material (Scheme 4), constructs a chiral center through a chiral metal coordination compound, and then deprotects to obtain dripopa.
  • the chiral selectivity is not reported in the patent, but due to the use of an excessive amount of heavy metals such as nickel, copper, or zinc, a large amount of heavy metal ion wastewater is generated, and environmental pollution is severe.
  • WO2016147133A1 discloses a synthesis method of ceceidopa using a chiral sulfenamide as a chiral auxiliary (Scheme 7), which is expensive, and the three-membered ring intermediate is unstable and the reaction yield is low.
  • the present invention provides the preparation of (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionate of formula (V).
  • R 1 is C 1-4 alkyl or benzyl
  • the present invention provides a method for preparing cixidol using the above method as a key step.
  • the two methods have the advantages of high yield, high stereoselectivity, easy availability of raw materials, simple process, economical and environmental protection, and are suitable for industrial production.
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • alkyl denotes a saturated straight or branched monovalent hydrocarbyl group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally one or more Substituted by the substituents described in the invention.
  • the invention provides a novel preparation method of the intermediate (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionate of cixidol, which
  • the structure of the intermediate is as shown in formula (V):
  • the preparation method of the present invention comprises 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate having the following structure in an organic solvent ( IV)
  • the asymmetric hydrogenation reaction is carried out in the presence of a hydrogen donor reagent and an organic base.
  • R 1 represents C 1-4 alkyl or benzyl; in some embodiments, R 1 is methyl, ethyl, t-butyl or benzyl.
  • R 2 represents C 1-6 alkyl, optionally substituted C 1-6 alkyl, phenyl or optionally substituted phenyl; in some embodiments, R 2 is methyl, p-methylphenyl, p-trifluoro Methylphenyl, pentafluorophenyl, trifluoromethyl or perfluorobutyl.
  • R 3 and R 4 each represent a phenyl group or a substituted phenyl group, or R 3 and R 4 together represent a butylene group; in some embodiments, R 3 and R 4 are each a phenyl group.
  • Ar represents benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene; in some embodiments, the Ar is benzene or Isopropyltoluene or cyclopentadiene.
  • P represents oxygen, a chemical bond or CH 2 .
  • Q represents hydrogen or an alkyl group; in some embodiments, Q is hydrogen or methyl.
  • the rhodium catalyst (VII) or the rhodium catalyst (VIII) may be any rhodium catalyst conforming to the above definition; for example, the rhodium catalyst (VII) or the rhodium catalyst (VIII) may be a rhodium catalyst of the following structure:
  • the rhodium catalyst (VII) is catalyst VII-A, catalyst VII-B, catalyst VII-E, or catalyst VII-G; in some embodiments, rhodium catalyst (VIII) is catalyst VIII-A.
  • the asymmetric hydrogenation reaction can be carried out in any suitable organic solvent; for example, the organic solvent can be dichloromethane, toluene, N,N-dimethylformamide, tetrahydrofuran, or a combination thereof; In the embodiment, the organic solvent is dichloromethane, toluene, N,N-dimethylformamide or tetrahydrofuran.
  • the hydrogen donor reagent can be any suitable hydrogen donor reagent; in some embodiments, the hydrogen donor reagent is formic acid.
  • the organic base may be any suitable organic base; in some embodiments, the organic base is diethylamine, diisopropylamine, bicyclic Hexylamine, triethylamine, N,N-diisopropylethylamine, or a combination thereof.
  • the rhodium catalyst (VII) or the rhodium catalyst (VIII) may be used in an amount of any suitable catalyst; for example, relative to 1 mol of 3-(3,4-dibenzyloxyphenyl)-2-dibenzyl.
  • the amide catalyst (VII) or the ruthenium catalyst (VIII) may be used in an amount of from 0.001 mole to 0.1 mole; in some embodiments, relative to 1 mole of 3-(3, 4-Dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate, the rhodium catalyst (VII) or rhodium catalyst (VIII) is used in an amount of 0.015 mol.
  • the amount of the organic base may be any suitable amount of the organic base; for example, relative to 1 mole of 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionic acid
  • the ester may be used in an amount of from 1 mole to 10 moles; in some embodiments, relative to 1 mole of 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3.
  • An oxopropionate, the organic base being used in an amount of 7 moles.
  • the asymmetric hydrogenation reaction can be carried out at any suitable temperature; for example, the reaction is carried out at about 0 degrees Celsius or below; in some embodiments, the reaction is carried out at about 40 degrees Celsius, 60 degrees Celsius, or 80 degrees Celsius.
  • the reaction end point is monitored by high performance liquid chromatography (HPLC), when the compound of formula (IV) is 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3.
  • HPLC high performance liquid chromatography
  • the reaction is considered to be completed, and the reaction time is usually from 15 to 80 hours depending on the substrate and the catalyst.
  • the present invention also provides a method for synthesizing cixidol with the asymmetric hydrogenation reaction as a key step.
  • the method includes the following steps:
  • R 1 represents C 1-4 alkyl or benzyl
  • R 2 represents C 1-6 alkyl, optionally substituted C 1-6 alkyl, phenyl, or optionally substituted phenyl;
  • R 3 and R 4 each independently represent a phenyl group or a substituted phenyl group, or R 3 and R 4 together represent a butylene group;
  • Ar is a ligand selected from the group consisting of benzene, optionally substituted benzene, cyclopentadiene, and optionally substituted cyclopentadiene;
  • P represents oxygen, chemical bond or CH 2 ;
  • Q represents hydrogen or an alkyl group.
  • the organic solvent described in the step (b) may be any suitable organic solvent; in some embodiments, the organic solvent is tetrahydrofuran;
  • the inorganic base in the step (b) may be any suitable inorganic base; for example, the inorganic base may be an alkali metal hydroxide or a hydrate thereof; in some embodiments, the inorganic base is sodium hydroxide;
  • the organic solvent in the step (c) may be any suitable organic solvent; for example, the organic solvent may be methanol, ethanol, isopropanol, tetrahydrofuran, or a combination thereof; in some embodiments, the organic solvent is ethanol or isopropanol. ;
  • the aqueous hydrochloric acid solution may be any suitable concentration; for example, the concentration of aqueous hydrochloric acid may be 0-12 mol / L; in some embodiments, the concentration of aqueous hydrochloric acid solution is 3mol / L, 5mol / L;
  • the hydrogen pressure in step (c) may be any suitable pressure; for example, the hydrogen pressure may be from 1 to 50 atm; in some embodiments, the hydrogen pressure is from 1 atm, 30 atm.
  • the preparation method thereof can include the following steps:
  • the intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) can be obtained by the method of the following step (a1) or (a2);
  • R 1 is as defined above; and X is a halogen selected from chlorine, bromine or iodine.
  • the halogenating agent described in step (b) may be any suitable halogenating agent; for example, the halogenating agent may be sulfonyl chloride, N-chlorosuccinimide, N-bromosuccinimide, Dibromohydantoin, bromine or N-iodosuccinimide; in certain embodiments, the halogenating agent is sulfonyl chloride, N-bromosuccinimide, dibromohydantoin, N-iodine Desuccinimide
  • the acid binding agent described in the step (c) may be any suitable organic or inorganic base; for example, the acid binding agent may be an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium acetate, phosphoric acid. Dipotassium hydrogen, disodium hydrogen phosphate, or a combination thereof, an organic base such as triethylamine, pyridine, N,N-diisopropylethylamine, N-methylmorpholine, or a combination thereof; in some embodiments, The acid binding agent is potassium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, potassium acetate, diisopropylethylamine;
  • Step (c) can be carried out at any suitable temperature; for example, the reaction temperature can be 0 ° C ⁇ 150 ° C; in some embodiments, the reaction temperature is room temperature, 58 ° C, 76 ° C, 100 ° C;
  • Step (c) can be carried out in any suitable organic solvent; in some embodiments, the reaction solvent is N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, ethanol or a combination thereof.
  • the reaction solvent is N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, ethanol or a combination thereof.
  • the phenolic hydroxyl group and the protecting group of the amino group are unified into a benzyl group, which can be completely removed at one time, saving operation and improving production efficiency.
  • this protection method is also a key factor for ensuring high stereoselectivity, and the amino protecting group is benzyl. If the base is replaced, the asymmetric hydrogenation reaction cannot be made to have higher stereoselectivity. Therefore, the technology is more green and efficient, and more in line with the needs of industrial production.
  • Figure 1 is a synthetic route diagram of cixidoba.
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • mmol means millimolar
  • h means hour
  • g means gram
  • ml means liter
  • atm means standard atmospheric pressure
  • PE means petroleum ether
  • EA means ethyl acetate
  • DCM means dichloromethane
  • 1 H NMR means nuclear magnetic resonance spectrum
  • LCMS refers to liquid chromatography
  • HPLC high performance liquid chromatography
  • CDCl 3 refers to deuterated chloroform.
  • Phenylphosphonium dichloride [RuCl 2 (benzene)] 2 (118 mg), N-((1R,2R)-2-amino-1,2-diphenylethyl)trifluoromethyl was added sequentially in a Schlenk bottle.
  • Sulfonamide TfDPEN 150 mg
  • 0.5 mL of diisopropylethylamine and 5 mL of isopropanol the whole reaction system was replaced with nitrogen three times, the reaction was heated to 80 ° C, and the reaction was carried out for 1 hour to obtain a catalyst VII-G solution, and the temperature was lowered to room temperature. spare.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un intermédiaire de droxidopa (2S,3R)-3-(3,4-dibenzyloxyphényl)-2-dibenzylamino-3-hydroxypropionate, comprenant la mise en oeuvre d'une hydrogénation asymétrique en 3- (3,4-dibenzyloxyphényl)-2-dibenzylamino-3-oxo-propionate dans un solvant organique sous catalyse d'un catalyseur au ruthénium en présence d'un réactif donneur d'hydrogène et d'une base organique. La réaction introduit de manière hautement stéréosélective deux centres chiraux de droxidopa avec un rendement élevé en une seule étape. En outre, sur la base de la réaction, un procédé de préparation de droxidopa est décrit. Le procédé présente un processus simple et court, et peut synthétiser de manière stéréosélective la droxidopa.
PCT/CN2017/095604 2016-11-15 2017-08-02 Procédé de préparation de droxidopa et de son intermédiaire Ceased WO2018090670A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109811019A (zh) * 2019-03-22 2019-05-28 湖南引航生物科技有限公司 一种制备屈西多巴的方法
CN110357821A (zh) * 2019-07-23 2019-10-22 河南师范大学 一种合成手性反式碳环嘧啶核苷的方法
CN111217791A (zh) * 2018-11-27 2020-06-02 广东东阳光药业有限公司 依鲁司他中间体及其制备方法
CN115160162A (zh) * 2022-07-11 2022-10-11 南方科技大学 一种α氨基β酮酸酯的不对称氢化方法
CN115417766A (zh) * 2022-08-31 2022-12-02 天津药明康德新药开发有限公司 一种3-羟基-4,5二甲氧基苯甲酸叔丁酯的合成方法

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CN112079733B (zh) * 2020-09-25 2022-09-06 南京仁为医药科技有限公司 一种不对称合成重酒石酸去甲肾上腺素的方法
CN114685277A (zh) * 2020-12-31 2022-07-01 苏州瑞博生物技术股份有限公司 化合物及羟基丙酸盐类化合物的纯化方法

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111217791A (zh) * 2018-11-27 2020-06-02 广东东阳光药业有限公司 依鲁司他中间体及其制备方法
CN111217791B (zh) * 2018-11-27 2024-02-02 广东东阳光药业股份有限公司 依鲁司他中间体及其制备方法
CN109811019A (zh) * 2019-03-22 2019-05-28 湖南引航生物科技有限公司 一种制备屈西多巴的方法
CN110357821A (zh) * 2019-07-23 2019-10-22 河南师范大学 一种合成手性反式碳环嘧啶核苷的方法
CN115160162A (zh) * 2022-07-11 2022-10-11 南方科技大学 一种α氨基β酮酸酯的不对称氢化方法
CN115160162B (zh) * 2022-07-11 2023-11-28 南方科技大学 一种α氨基β酮酸酯的不对称氢化方法
CN115417766A (zh) * 2022-08-31 2022-12-02 天津药明康德新药开发有限公司 一种3-羟基-4,5二甲氧基苯甲酸叔丁酯的合成方法
CN115417766B (zh) * 2022-08-31 2024-05-17 天津药明康德新药开发有限公司 一种3-羟基-4,5二甲氧基苯甲酸叔丁酯的合成方法

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