WO2000053569A1 - Procede de preparation d'un 2-[2-(4-benzene alkyl)-ethyl]-2-amino-propadeniol et son produit intermediaire - Google Patents

Procede de preparation d'un 2-[2-(4-benzene alkyl)-ethyl]-2-amino-propadeniol et son produit intermediaire Download PDF

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Publication number
WO2000053569A1
WO2000053569A1 PCT/CN2000/000046 CN0000046W WO0053569A1 WO 2000053569 A1 WO2000053569 A1 WO 2000053569A1 CN 0000046 W CN0000046 W CN 0000046W WO 0053569 A1 WO0053569 A1 WO 0053569A1
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WIPO (PCT)
Prior art keywords
ethyl
compound
product
vii
alkylphenyl
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PCT/CN2000/000046
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English (en)
Chinese (zh)
Inventor
Dali Yin
Donghui Wang
Yonghua Zhang
Original Assignee
Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd.
Institute Of Materia Medica, Chinese Academy Of Medical Sciences
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.)
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Application filed by Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd., Institute Of Materia Medica, Chinese Academy Of Medical Sciences filed Critical Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd.
Priority to AU31426/00A priority Critical patent/AU3142600A/en
Publication of WO2000053569A1 publication Critical patent/WO2000053569A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings

Definitions

  • the present invention relates to a method for preparing 2- [2- (4-alkylphenyl) -ethyl] -2-amino-propanediol, and more particularly, to a method for preparing a compound of the following structural formula (I), and in the preparation An intermediate produced in the process. Background technique
  • FTY-720 The compound of the following structural formula is abbreviated as FTY-720, and its chemical name is 2-amino-2- [2- (4-octylphenyl) ethyl] -1,3-propanediol hydrochloride.
  • This compound was originally disclosed in PCT / JP93 / 01515, has immunosuppressive activity, and is expected to become a new immunosuppressant for clinical use (see PCT / JP93 / 01515).
  • the method disclosed in the above PCT application uses protected phenylethanol as a starting material, and the entire synthetic route undergoes 10 steps of reaction.
  • the main disadvantage of this method is that, due to the instability of the phenylethanol acetate compound, the Fnedle-Crafts acylation reaction of phenylethanol acetate and octanoyl chloride is low, and the total yield is lower than this. Low and not suitable for large-scale preparation. Therefore, the object of the present invention is to provide an improved method for preparing fluorenylphenylethylaminopropanediol, which overcomes the defects of the prior art, and has the advantages of low reaction cost and high yield.
  • the present invention includes a method for preparing 2- [2- (4-fluorenylphenyl) -ethyl] -2-amino-propanediol of the following general formula (I):
  • R is a C1-10 alkyl group
  • the method includes the following steps:
  • Fluorenylbenzene (II) reacts with acetyl chloride in the presence of Lewis acid to form p-fluorenylacetophenone (III);
  • the product (III) is formed into p-alkyl ⁇ -haloacetophenone (IV) by conventional methods in the presence of a small amount of Lewis acid;
  • the present invention includes an intermediate product obtained in the above preparation method
  • the preparation method of the present invention uses fluorenylbenzene II as a starting material, wherein the fluorenyl group R is a linear or branched fluorenyl group of C1-10, preferably n-octyl.
  • the Fnedel-Crafts reaction of II with acetyl chloride is carried out under the catalysis of a Lewis acid, preferably A1C1 3 , to produce the product (III).
  • III has sufficient purity and can be used in the following reactions without purification.
  • Compound IV can be prepared by ⁇ -halogenation of III, and the reaction is performed according to a conventional method known to those skilled in the art, using a small amount of Lew 1S acid, preferably A1 (3 ⁇ 4) as a catalyst for the reaction.
  • X is Br or Cl, and Br is preferred.
  • Condensation of IV and V under basic conditions to obtain the key intermediate VI of the present invention, as described above; is (: 1 to 4 acyl, preferably acetyl; but (1 to 4 alkyl, preferably Methyl and ethyl.
  • Common bases such as sodium ethoxide, sodium methoxide, sodium hydride, potassium tert-butoxide, etc., of which sodium ethoxide and sodium methoxide are preferred.
  • the molar ratio of reactants IV to V is 1: 1 to 1: 2.
  • the ratio of Na to IV is 1-1.5: 1.
  • the reducing agents used are aluminum or boron rehydrides and their derivatives, preferably LiAlH 4 , NaBH 4 , KB ⁇ n LiBH 4 , and most preferably NaBH 4 .
  • the solvent used in the reaction in this step is a common solvent when using a dehydrogenated compound, such as water, methanol or ethanol. It is obvious to those skilled in the art that the reaction of this step also requires the participation of a buffer of borate or phosphate.
  • the intermediate VII is hydrolyzed to obtain yet another important intermediate VIII of the present invention, wherein R is the same as the aforementioned ⁇ .
  • This step can be performed with a strong base such as NaOH, KOH, LiOH or a strong acid such as HC1, ⁇ 04 in water or an alcohol (eg, methanol, ethanol).
  • target compound I can also be prepared by first hydrolyzing the compound VII and then hydrolyzing the N-acyl group.
  • the product VI can also be subjected to hydrogenolysis as described above to form 2-amido-2- [2-p-alkylphenylmonoethyl] malonate, whose structural formula is as follows , -. Wherein R n R 3 is as described above, and then the ester is reduced and hydrolyzed as described above to finally obtain compound I.
  • Compound I can further form salts with acids.
  • the acid may be HC1, H 2 S0 4 ,
  • the total yield is about 5% (based on the salt-forming material).
  • the method according to the present invention not only has the characteristics of short synthetic route and simple operation, but also has a relatively high yield in each step. High, the total yield can reach about 20-25% (based on the material after salt formation). Therefore, the method of the present invention is a more economical, faster and more effective method for preparing 2- [2- (4-fluorenylphenyl) -ethyl] -2-amino-propanediol.
  • Example 1 The present invention will be further described by examples below, but these examples are only used to illustrate the present invention and not to limit the scope of the present invention.
  • Example 1
  • the 2-acetamido-2- [2- (4-octylphenyl) -2-oxo-ethyl] -1,3-dimalonate (1.76 g, 4.0 mmol) was dissolved in 30 ml of methanol, and 100 mg of 10% Pd-C and HC10 4 (0.8 g, 5.5 mmol) were added.

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

Abstract

L'invention concerne un procédé de préparation d'un 2-[2-(4-benzène alcoyl)-éthyl]-2-amino-propadéniol de formule (I), dans laquelle R désigne un alkyle C1-10 sélectionné dans un octyle droit. Ce procédé consiste à faire réagir un benzène alkyle (II) avec un éther éthanoyle restant dans l'acide de Lewis, puis à transformer ce reste de l'acide de Lewis selon une opération standard en para-alkyl α-halogeno-phénylalcool (IV); à condenser le produit obtenu sous (IV) avec un 2-amido-acide malonique dans des conditions d'alcalinité pour obtenir un 2-amido-2-[2-para-alkylphényl-2-O-éthyl]ester d'acide malonique (VI); à générer à partir du produit obtenu sous (VI) un 2-amido-2-[2-para-alkylphényl-2-hydroxy-éthyl]ester d'acide malonique; et à soumettre le produit obtenu sous (VII) à une hydrolyse et à une hydrogénolyse pour former la composition de formule (I). Le procédé est caractérisé par la brièveté des étapes de synthèse et par la simplicité d'obtention du produit escompté tout en faisant preuve d'une réactivité globale relativement élevée. L'invention concerne aussi un produit intermédiaire obtenu pendant le procédé de fabrication.
PCT/CN2000/000046 1999-03-11 2000-03-10 Procede de preparation d'un 2-[2-(4-benzene alkyl)-ethyl]-2-amino-propadeniol et son produit intermediaire WO2000053569A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31426/00A AU3142600A (en) 1999-03-11 2000-03-10 Method for preparing 2-2((4-alkylphenyl)-ethyl)-2-amino-propanediol and intermediates useful in such preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB991028791A CN1144779C (zh) 1999-03-11 1999-03-11 制备2-[2-(4-烷基苯基)-乙基]-2-氨基-丙二醇的方法以及其中制得的中间产物
CN99102879.1 1999-03-11

Publications (1)

Publication Number Publication Date
WO2000053569A1 true WO2000053569A1 (fr) 2000-09-14

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PCT/CN2000/000046 WO2000053569A1 (fr) 1999-03-11 2000-03-10 Procede de preparation d'un 2-[2-(4-benzene alkyl)-ethyl]-2-amino-propadeniol et son produit intermediaire

Country Status (3)

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CN (1) CN1144779C (fr)
AU (1) AU3142600A (fr)
WO (1) WO2000053569A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7910617B2 (en) 2004-02-24 2011-03-22 Sankyo Company, Limited Method for suppressing the number of peripheral blood lymphocytes using an amino alcohol compound
US8067396B2 (en) 2002-01-11 2011-11-29 Sankyo Company, Limited Amino alcohol compounds or phosphonic acid derivatives thereof
JP2012508216A (ja) * 2008-11-11 2012-04-05 ノバルティス アーゲー 有機化合物
WO2012056458A2 (fr) 2010-10-28 2012-05-03 Mapi Pharma Ltd. Composés intermédiaires et procédé de préparation de fingolimod
WO2014111949A1 (fr) 2013-01-21 2014-07-24 Natco Pharma Limited Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur
US8809571B2 (en) 2008-03-19 2014-08-19 Novartis Ag Process for the production of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols, and to compounds for use therein

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100360124C (zh) * 2003-02-25 2008-01-09 杭州华东医药集团生物工程研究所有限公司 2-氨基-2（2-（4-辛基苯基）乙基）-1，3-丙二醇在制备预防或治疗免疫性肝损伤药物中的应用
CN1310869C (zh) * 2005-11-22 2007-04-18 江苏吴中苏药医药开发有限责任公司 2－氨基－2－[2－(4－烷基苯基)乙基]－1,3－丙二醇的制备方法
CN102260178A (zh) * 2010-05-25 2011-11-30 中国医学科学院药物研究所 羟基丙二醇类衍生物、其制备方法和其药物组合物与用途
WO2012041358A1 (fr) 2010-10-01 2012-04-05 Synthon B.V. Procédé de fabrication de cristaux de chlorhydrate de fingolimod
US9266816B2 (en) * 2010-11-25 2016-02-23 Shilpa Medicare Limited Fingolimod polymorphs and their processes
EP2658840B1 (fr) 2010-12-28 2019-07-03 Synthon BV Procédé de fabrication de cristaux de chlorhydrate de fingolimod
CN102120720B (zh) * 2011-01-25 2013-05-22 上海华升生物科技有限公司 盐酸芬戈莫德的合成新方法
CN102850319A (zh) * 2011-06-27 2013-01-02 中国药科大学 一种制备{5-[2-(4-正辛基苯基)乙基]-2,2-二甲基-1,3-二氧六环-5-基}氨基甲酸叔丁酯的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0627406A1 (fr) * 1992-10-21 1994-12-07 Yoshitomi Pharmaceutical Industries, Ltd. Compose 2-amino-1,3-propanediol et immunosuppresseur
CN1112786A (zh) * 1993-07-23 1995-11-29 药制品公司 2-氨基-4-苯基-4-氧代丁酸衍生物
JPH10147587A (ja) * 1996-11-19 1998-06-02 Fujisawa Pharmaceut Co Ltd ２−アミノ−１，３−プロパンジオール誘導体およびその医薬用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0627406A1 (fr) * 1992-10-21 1994-12-07 Yoshitomi Pharmaceutical Industries, Ltd. Compose 2-amino-1,3-propanediol et immunosuppresseur
CN1112786A (zh) * 1993-07-23 1995-11-29 药制品公司 2-氨基-4-苯基-4-氧代丁酸衍生物
JPH10147587A (ja) * 1996-11-19 1998-06-02 Fujisawa Pharmaceut Co Ltd ２−アミノ−１，３−プロパンジオール誘導体およびその医薬用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CA: Chemical Substance Index, Vol. 122, (1995), pages 67CS-68CS *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067396B2 (en) 2002-01-11 2011-11-29 Sankyo Company, Limited Amino alcohol compounds or phosphonic acid derivatives thereof
US8101650B2 (en) 2002-01-11 2012-01-24 Daiichi Sankyo Company, Limited Method for treating a immunology-related disease
US7910617B2 (en) 2004-02-24 2011-03-22 Sankyo Company, Limited Method for suppressing the number of peripheral blood lymphocytes using an amino alcohol compound
US8809571B2 (en) 2008-03-19 2014-08-19 Novartis Ag Process for the production of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols, and to compounds for use therein
US9133096B2 (en) 2008-03-19 2015-09-15 Novartis Ag Process for the production of 2-amino-2[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols, and to compounds for use therein
JP2012508216A (ja) * 2008-11-11 2012-04-05 ノバルティス アーゲー 有機化合物
JP2014139179A (ja) * 2008-11-11 2014-07-31 Novartis Ag 有機化合物
JP2016028056A (ja) * 2008-11-11 2016-02-25 ノバルティス アーゲー 有機化合物
WO2012056458A2 (fr) 2010-10-28 2012-05-03 Mapi Pharma Ltd. Composés intermédiaires et procédé de préparation de fingolimod
US8735627B2 (en) 2010-10-28 2014-05-27 Mapi Pharma Ltd. Intermediate compounds and process for the preparation of fingolimod
WO2014111949A1 (fr) 2013-01-21 2014-07-24 Natco Pharma Limited Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur

Also Published As

Publication number Publication date
CN1266844A (zh) 2000-09-20
AU3142600A (en) 2000-09-28
CN1144779C (zh) 2004-04-07

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