WO2006104249A1 - Methode de fabrication de l’alcool 1-(2-thienyl)-3-alkylaminopropylique - Google Patents

Methode de fabrication de l’alcool 1-(2-thienyl)-3-alkylaminopropylique Download PDF

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Publication number
WO2006104249A1
WO2006104249A1 PCT/JP2006/307162 JP2006307162W WO2006104249A1 WO 2006104249 A1 WO2006104249 A1 WO 2006104249A1 JP 2006307162 W JP2006307162 W JP 2006307162W WO 2006104249 A1 WO2006104249 A1 WO 2006104249A1
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WO
WIPO (PCT)
Prior art keywords
alcohol
alkylaminopropyl
chenyl
carbon atoms
formula
Prior art date
Application number
PCT/JP2006/307162
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English (en)
Japanese (ja)
Inventor
Toshirou Yamada
Kei Sakamoto
Kazunori Watanabe
Yasushi Nakano
Original Assignee
Zeon Corporation
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 Zeon Corporation filed Critical Zeon Corporation
Priority to JP2007510582A priority Critical patent/JPWO2006104249A1/ja
Publication of WO2006104249A1 publication Critical patent/WO2006104249A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for preparing 1- (2-chenyl) -1-3-alkylaminopropyl alcohol, [3- (2-Chel) -1-3-hydroxy] propylalkylaryloxycarbonylamine, and [1-(2-Chel) 1-3- (Aryloxycarbonylalkylamino) propyloxy] 1-5-substituted bicyclo [3.3.0]-2-oxaoctane. More specifically, the present invention efficiently produces high-yield, high-yield high-strength 1- (2-cenyl) -1-3-alkylaminopropyl alcohols useful as medical intermediates.
  • 2-Chenyl) 1-Methylaminopropyl alcohol, S is an important intermediate as an anti-antigen, and various production methods have been tried.
  • 2-acetylthiophene, benzylmethylamine, and formalin are placed under acid cattle to give 2-phenyl-1-N-benzylamino N-methylaminoethylenoketone, which is asymmetrically reduced to 1- (2- 1) -Benzylmethinoreaminopropinole alcohol was obtained, and then a method for producing a photo 1- (2-cell) -1-3-methylaminopropyl alcohol by applying a benzyl group was proposed.
  • EP 1 5 0 6 9 6 5 Disclosure of Invention The present invention relates to a high yield of optical yarns useful as an intermediate for medicines and agricultural chemicals (2-cenyl) -1-3-aminoalkylaminopropyl alcohol in a high yield and high yarn breakage (the proportion of the alcohol).
  • This is a new substance useful as an intermediate in the manufacturing method and the wording method, which can be efficiently produced by simply calling it “Fiber” and using it as “Optical yarn”.
  • the present inventors have found that the allyloxycarbonyl group of [3- (2 1-cenyl) 1 3-hydroxy] propynolealkylalyoxycarbonylamine is Reduced or easily crushed by 3 ⁇ 43 ⁇ 40 ⁇ ⁇ , with a gentle cow, and with time, 3 ⁇ 4 high optical efficiency of 1- (2-cenyl) 1- 3 alkylalkylaminopropinole alcohol in high yield and high purity. Based on this knowledge, the present invention was concealed. That is, the present invention
  • One wiping [1] is the process of reducing the chemical ⁇ or the process of irrigating the water.
  • R 1 is an alkyl group having from 3 to 3 carbon atoms.
  • R 1 is the same as the knitting self, and R 2 is rudely a group having 1 to 20 carbon atoms having a leaving group, a non-preserving group or having 2 substituents having carbon atoms.
  • the chemical formula 1 represented by [3] is the two kinds of Gisterre of the compound: ⁇ Mixed ⁇ ! Is a diastereomer obtained by separating each diastereomer, and a 1- (2-chenyl) 1-3-alkylaminopropyl alcohol is formed by light. (2) or (3), which is a fertile body, 1- (2-Chenyl) 1-3 1 alkylamine knob
  • R 1 and R 2 are the same as Tatsumi.,
  • F ig .1 is a reaction path from the first process to the fifth process in Example 1
  • F ig .2 is a reaction path from the sixth process to the racemic process in Example 1.
  • the production method of 1- (2-chenyl) 1 3 1 alkylaminopropyl alcohol (represented by 1 [2]) of the present invention is represented by the formula -i «[1] ⁇ ; It has a process of reducing or hydrolyzing [3- (2-phenyl) -l-hydroxy] propynolealkylalkyloxycarbonylamine).
  • R 1 is an alkyl group having 1 to 3 carbon atoms, ie, methyl group, an Echiru group, a propyl group or an isopropyl group.
  • ⁇ ⁇ 1 represented by [1] converts the carbonyloxylevonyl group into propylene and silicon dioxide, forming a secondary amine.
  • the method for reducing the chemical compound represented by [1] there is no particular limitation on the method for reducing the chemical compound represented by [1], and for example, it can be carried out using a hydrogen compound under a reducing catalyst.
  • transitions such as platinum, palladium, rhodium, northenium, nickel, and copper are preferable, S is more preferable, palladium is more preferable, and divalent palladium such as palladium chloride, palladium iodide and palladium!
  • triphenylenphosphine etc.
  • phosphorous ⁇ phosphorous ⁇
  • transitions M are, for example, carbon support, triphenylphosphine. It can also be used as a complex, dibenzylidene-aceton complex,., Raney catalyst, etc.
  • a hydrogen body for example, GI ⁇ 3 ⁇ 4HI ⁇ charcoal 1 to 3 carboxylic acids; 1 to 3 carbon atoms such as ammonium formate, sodium formate, potassium formate and ammonium acetate; hydrogen hydride, sodium hydrogen hydride, lithium aluminum lithium, and Suisoi ⁇ Jie Su Wu Chino Real hydrides such as mini ⁇ beam; or force, and the like hydrogen s, carboxylic ⁇ X with carbon number from 1 to 3 from the viewpoint of yield a salt thereof are preferred, carbon atoms 1 A carboxylic acid of ⁇ 3 is more preferred, and moth is particularly preferred.
  • liquid phase uniform force S is preferable when the above divalent palladium is used. When the liquid phase is uniform ⁇ , is 20 ° C. or higher, preferably 50 to 150 ° C.
  • the solvent for example, ether such as dioxane can be used.
  • the method for adding the compound represented by the general formula [1] is not particularly limited, and can be performed, for example, under a butterfly or a tt3 ⁇ 4 angle butterfly.
  • the butterfly include hydrochloric acid, sulfuric acid, and paratoluenesulfonic acid.
  • 7_sodium oxide, potassium hydroxide, and the like can be cited as cucumbers.
  • the allyloxycarbonyl group has a higher optical purity and purity than 1- (2-Cenyl). 3-Alkylaminopropyl alcohol can be obtained in high yield. Comparing reduction with Karo-water, reduction SJ ⁇ is preferable because it can be carried out in milder conditions, and higher boats can be obtained. .
  • the method further comprises the step of adding an alcohol to the alkyl group (chale) -1- (allyloxycarbonylalkylamino) propyloxy] -5-substituted biscigro [3.3.0] _2-oxaoctane). ,.
  • R 1 is the same as Riki
  • R 2 is an unsubstituted or substituted alkyl group having 1 to 20 carbon atoms, ⁇ or has a substituent.
  • R 2 is preferably a aryl group, a phenyl group or a diphenylmethyl group, and a allyl group is particularly preferable.
  • ⁇ g] can be alcoholized by heating in ⁇ g and alcohol.
  • the conversion include, for example, sulfuric acid, and paratoluenesulfonic acid.
  • alcohols include methanol, ethanol, propanol, and isopropanol.
  • R 2 is the same as disgust
  • the compound represented by general formula [3] used in the method of the present invention is a compound represented by general formula [1] and a compound represented by general formula [1] ⁇ 1 (5-substituted bicyclo [3] . 3.0] - 2- Okisa one 1- Okute down) and additional Koyori getting force s preferred les.
  • R 2 is the same as tiff himself.
  • non-protonic solvents include cyclohexane, benzene, toluene, xylene, mesitylene, n -decane, tetrahydrofuran, dioxane, cyclopentinolemethyl ether, acetone, methyl isobutyl ketone, dimethyl sulfoxide, dimethyl
  • examples include formamide, acetonitrile, and xamethylphosphonoleamide.
  • the process for producing 1- (2-chenyl) 1 3 1 alkylaminopropinole alcohole according to the present invention is used for the production of 1- (2-Chel) -3-alkylaminopropyl alcohol having light 14. It can be particularly preferably applied.
  • 1_ (2-Chenyl) 1-3-alkylaminopropyl alcohol the carbon atom to which the hydroxyl group is attached is an asymmetric carbon atom and is covered by the optical isomer.
  • 1- (2-Chenyl) 1-alkylaminopropyl alcoholone obtained by optical resolution of optical isomers is particularly important as an intermediate for medicines and agrochemicals.
  • 1- (2-chenyl) -3 monoalkylaminopropyl alcohol having a high optical yarn size can be easily produced in a high yield and high yield.
  • the optical yarn breakage of 1- (2-phenyl) -3 monoalkylaminopropyl alcohol obtained by the method of the present invention is preferably 98% e e or more, more preferably 99% e e or more.
  • R 1 and R 2 are the same as ⁇ ⁇ .
  • Ichibune wipe [3] TiJlS 2 kinds of Giastere ⁇ one! ⁇ Can be separated into diastereomers as shown by the formula [7] by distillation, recrystallization, column chromatography, transfer chromatography and the like. Diastereomers can be efficiently divided by choosing the appropriate method because they have different physics and rationality.
  • the method of racemization is not particularly limited, but, for example, the light ⁇ S ⁇ organism of the compound represented by the above general formula [1] or [3] is rarely dissolved, and is below 10-50. ,:! ⁇ 20 hours ", almost complete racemization.
  • [3-(2-Cenyl) 1-3-hydroxy] propyl alkyl carboxylamine of the present invention has a structure represented by [1] [3-(2-Cenyl) 1-3-hydroxy] propyl Alkylary oxycarbonylamine.
  • R 1 is the same as SfJtS.
  • R 1 and R 2 are the same as Kamami.
  • the cat U in the filtrate was distilled off to obtain 0.8 g of a pale yellow oily substance.
  • 2.0 g of toluene was added and dissolved at 60 ° C, and then cooled to 25 ° C to precipitate crystals. I let you.
  • the crystals were separated by filtration and washed with 5 mL of cooled toluene.
  • the crystals were placed under the arm to obtain light 1 _ (2-chenyl) -1-methylaminopropyl alcohol 0 ⁇ 4 g (10) as white crystals (yield 29.8%, optical « 99.5% ee or less ⁇ ).
  • Step 7 Synthesis of 1- (2-Cha) -1-3-methylamino-propyl alcohol by the awakening of the carboxycarbonyl group, rapid hydrolysis method
  • the toluene layer was dried over magnesium sulfate, 50 g of hexane was added to the residue, and the precipitated crystals were collected by filtration.
  • the obtained crystals were further recrystallized with a hexane-2-propanol mixed solvent (ratio 5/1), and then light, 1 to 1- (2-cenyl) -1-3-methylaminopropyl alcohol was obtained. 3.0 g (10) of a monolayer was obtained as white crystals (yield 45.0%, optical contribution 99.5% ee or more).
  • the [3- (2-Chell) -l-hydroxy] propylalkylaryl carboxycarbonylamine's alkynanol diol group is reduced or reduced with water, and mild.
  • the optical fiber 3 ⁇ 4 which is useful as an intermediate for medicines and agricultural chemicals, has a high yield of 1- (21) and 31-alkyl alkylaminopropyl alcohol. Can be fired.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L’invention concerne une méthode de fabrication de l’alcool 1-(2-thiényl)-3-alkylaminopropylique caractérisée en ce qu’elle comprend une étape de réduction ou d’hydrolyse d’un composé représenté par la formule générale [1] ci-dessous. L’invention concerne également les intermédiaires d’une telle méthode, à savoir la [3-(2-thiényl)-3-hydroxy]propylalkylaryloxycarbonylamine et le 1-[1-(2-thiényl)-3-(aryloxycarbonylalkylamino)propyloxy]-5-substitué bicyclo[3.3.0]-2-oxaoctane. Dans la formule générale [1] ci-dessous, R1 représente un groupe alkyle ayant 1 à 3 atomes de carbone. La méthode de fabrication permet d’obtenir efficacement de l’alcool 1-(2-thiényl)-3-alkylaminopropylique de grande pureté, utile comme produit chimique agricole et pharmaceutique et ayant une grande pureté optique, avec un rendement élevé. L’invention concerne également de nouvelles substances utiles, constituant des intermédiaires d’une telle méthode de fabrication.
PCT/JP2006/307162 2005-03-29 2006-03-29 Methode de fabrication de l’alcool 1-(2-thienyl)-3-alkylaminopropylique WO2006104249A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2007510582A JPWO2006104249A1 (ja) 2005-03-29 2006-03-29 １−（２−チエニル）−３−アルキルアミノプロピルアルコールの製造方法

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JP2005-095277 2005-03-29
JP2005095277 2005-03-29

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WO2006104249A1 true WO2006104249A1 (fr) 2006-10-05

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072505A1 (fr) * 2001-02-26 2002-09-19 Zeon Corporation Systeme de resolution optique et procede de resolution optique d'alcool utilisant celui-ci
WO2003070720A1 (fr) * 2002-02-22 2003-08-28 Degussa Ag Preparation de derives de n-methyl-3-hydroxy- 3-(2-thienyl)propylamine via de nouveaux derives de thiophene contenant des groupes carbamates en tant qu'intermediaires
WO2003097632A1 (fr) * 2002-05-20 2003-11-27 Mitsubishi Rayon Co., Ltd. Derives de propanolamine, procede de preparation de 3-n-methylamino-1-(2-thienyl)-1-propanols et procede de preparation de derives de propanolamine
WO2004103990A1 (fr) * 2003-05-22 2004-12-02 Sumitomo Seika Chemicals Co. Ltd. Procede de production d'un compose de n-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif et son intermediaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072505A1 (fr) * 2001-02-26 2002-09-19 Zeon Corporation Systeme de resolution optique et procede de resolution optique d'alcool utilisant celui-ci
WO2003070720A1 (fr) * 2002-02-22 2003-08-28 Degussa Ag Preparation de derives de n-methyl-3-hydroxy- 3-(2-thienyl)propylamine via de nouveaux derives de thiophene contenant des groupes carbamates en tant qu'intermediaires
WO2003097632A1 (fr) * 2002-05-20 2003-11-27 Mitsubishi Rayon Co., Ltd. Derives de propanolamine, procede de preparation de 3-n-methylamino-1-(2-thienyl)-1-propanols et procede de preparation de derives de propanolamine
WO2004103990A1 (fr) * 2003-05-22 2004-12-02 Sumitomo Seika Chemicals Co. Ltd. Procede de production d'un compose de n-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif et son intermediaire

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