WO2006072818A2 - Procede pour preparer de la benzazepine - Google Patents

Procede pour preparer de la benzazepine Download PDF

Info

Publication number
WO2006072818A2
WO2006072818A2 PCT/IB2005/003804 IB2005003804W WO2006072818A2 WO 2006072818 A2 WO2006072818 A2 WO 2006072818A2 IB 2005003804 W IB2005003804 W IB 2005003804W WO 2006072818 A2 WO2006072818 A2 WO 2006072818A2
Authority
WO
WIPO (PCT)
Prior art keywords
galanthamine
salt
free base
hydrobromide
tartarate
Prior art date
Application number
PCT/IB2005/003804
Other languages
English (en)
Other versions
WO2006072818A3 (fr
Inventor
Milind Moreshwar Gharpure
Baburao Manikrao Bhawal
Umesh Rewaji Zope
Mangala Babu Govankar
Satish Ramanlal Mehta
Original Assignee
Emcure Pharmaceuticals Limited
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 Emcure Pharmaceuticals Limited filed Critical Emcure Pharmaceuticals Limited
Publication of WO2006072818A2 publication Critical patent/WO2006072818A2/fr
Publication of WO2006072818A3 publication Critical patent/WO2006072818A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to a process for manufacture of galanthamine in an enantio enriched form by stereoselective reduction to get the desired isomer of galanthamine. It also discloses the method for escalating the chiral and chemical purity of galanthamine and galanthamine salts.
  • Galanthamine is an alkaloid of the morphine group, which can be obtained from plants viz snowdrops (Galanthus woronowii, G. nivalis etc.) and other Amaryllidaceae. Racemic Galanthamine (I) is extracted from daffodil bulbs. (-) Galanthamine (II), and its derivatives thereof, are useful for the treatment of Alzheimer's disease.
  • Tetrahedron (1989), 45(11), 3329-45 describes a process for preparation of racemic galanthamine (I) by making use of potassium ferricyanide for oxidative coupling as shown in Scheme II.
  • the amine (VIII) is reacted with the acid chloride yielding the intermediate (X), which on oxidative coupling gave the dienone (XI), which further on reduction gave racemic galanthamine.
  • This scheme has the disadvantage of resolution of racemic galanthamine and epigalanthamine, which limits its industrial application.
  • the shortcomings of this process are that for the resolution of narwedine on a large scale, the narwedine has a tendency to self-seed, sometimes giving material of poor enantiomeric excess, or even the opposite enantiomer of narwedine. For the purpose of industrial manufacture these factors compromise the reproducibility of the process.
  • narwedine used can also sometimes give the poor enantiomeric excess as narwedine has a tendency to self-seed. Further, there is danger to handle narwedine as it is a sensitizing agent and can cause allergic skin reactions.
  • This publication disclosed a method for the synthesis of galanthamine using phenyliodine(III) bis(t ⁇ fluoroacetate) (PIFA) as an oxidant.
  • This invention avoided the highly allergenic intermediate narwedine, but involved the complex reagent PIFA.
  • PIFA phenyliodine
  • XVII oxidative coupling of (XVI) using (PIFA) gave (XVII), which underwent Michael Addition to give (XVIII).
  • the overall reaction sequence was of 14 steps, which demands higher manpower, increased time cycle, higher utilities etc, further increasing the cost of the product obtained by this route. Hence this process is not advisable on the industrial scale.
  • WO 2004/042116 described the process for preparation of galanthamine, according to Scheme (VI), by making use of oxidative phenolic coupling reaction of (XIX) to yield (XX).
  • the reaction utilizes an electrochemical cell for the oxidative coupling which is very expensive and tedious on an industrial scale.
  • making use of the cell on an industrial level is not feasible, due to large scale and also the cleaning of the cell is a tedious job.
  • this method for producing galanthamine, using electrochemical cell is not suitable for commercial purpose.
  • US 6407229 discloses the preparation of Galanthamine and its derivatives. The process involves the condensation of aldehyde and the amine to form imine, which on reduction gives secondary amine. Further, the formylation of the NH group of secondary amine is carried out, which is followed by the oxidative cyclisation. Subsequent reduction and debromination results in the final product.
  • the purification process is always with respect to the impurities present in the material, which is to be purified. Further, the impurities present are certainly related to the source of the compound to be purified. US 6,617,452 B2 teaches the recrystallization procedure. However, the impurities present in the natural extract would be different from the impurities present in the synthetic process.
  • the literature patent neither teaches as to how the synthetically obtained galanthamine can be purified (to achieve the desired chemical purity) nor the process of enrichment of synthetically obtained galanthamine or its salts, having unacceptable optical purity. Hence, there is a need to develop the process by which the chemical purity and optical purity of the desired isomer of galanthamine or its salts can be obtained.
  • US 6087495 Bl discloses the enantiomeric enrichment of galanthamine salt in which the counter ion is achiral. It also discloses the enrichment of enantiomerically enriched galanthamine salt. This patent discloses the process to obtain enantiomerically enriched galanthamine hydrobromide by using seeding method. The seed crystals used are (-) galanthamine hydrobromide. Thus, even to obtain seed crystals, there is a need to have a process, which can provide (-) galanthamine hydrobromide with the higher optical purity. Further, the enantiomeric enrichment of (-) galanthamine hydrobromide from racemic galanthamine hydrobromide gives very poor enantiomeric excess.
  • This invention also discloses the enantiomeric enrichment of an enantiomerically enriched salt of galanthamine.
  • the enrichment of (-) galanthamine hydrobromide is carried out by crystallizing (-) galanthamine hydrobromide using EtOH as a solvent.
  • EtOH a solvent
  • use of EtOH on an industrial scale is the major limitation. In various countries, in order to obtain EtOH, one needs the government permit. Also, the cost of ethanol is high, which makes the process costlier. Further, solubility of galanthamine hydrobromide is also very poor in ethanol. Thus, the higher quantities of ethanol are necessary, which need to be avoided.
  • L-selectride is costly, highly flammable and a corrosive reagent. It is explosive when dry. It causes burns, irritation of eyes, skin and respiratory system. Reacts violently with water and emits explosive gases. This reagent may impair fertility. It may also cause long term effects in the environment. Taking into consideration these adverse effects, there remains a need to find a better reducing agent in place of L-Selectride, which can be conveniently used on industrial scale.
  • the present inventors have developed a synthetic route for preparation of galanthamine, starting from methylamine and 4-benzyloxyphenyl acetyl chloride, which not only suppresses the need for complicated separation of racemic galanthamine from epigalanthamine but also gives galanthamine of high purity and in good yields.
  • the present inventors have also made an approach to prepare galanthamine by avoiding the highly allergic intermediate narwedine.
  • the present invention makes use of selective reducing agents for selective reduction to avoid the formation of mixture of galanthamine and epigalanthamine, which is complicated to separate, thus decreasing the yields.
  • the racemic galanthamine formed is separated to give galanthamine by reacting it with a chiral acid.
  • the present invention also makes an approach to expand a method for enhancing the enantiomeric excess of galanthamine salts like galanthamine hydrobromide and galanthamine tartarate.
  • the present embodiment also describes the reprocessing course of action in case of chiral purity failure and chemical (RS) purity failure of galanthamine salts.
  • First object of the present invention is to provide an improved process for the preparation of galanthamine of formula (II) by a synthetic route, which is novel from the routes disclosed in prior art.
  • Second object of the invention is to provide galanthamine by avoiding the highly allergic intermediate i.e. narwedine.
  • Third object of the invention is to provide galanthamine with high optical purity.
  • Fourth object of the invention is to provide galanthamine in appreciable yields.
  • Fifth object of the invention is to provide a selective reduction process to obtain galanthamine substantially free from epigalanthamine.
  • Sixth object of the invention is to provide a simple, industrially feasible, economical and safe method to prepare galanthamine of high purity and high yields.
  • Seventh object of the invention is to provide a process, using novel intermediate (XXIX).
  • Eighth object of the invention is to provide a method for increasing the enantiomeric excess of galanthamine salts, which avoids making use of seeding step.
  • Ninth object of the invention is to bring about an enrichment of (-) galanthamine without making use of the seeding process to achieve almost 100% chiral purity and recovery of the resolving agent used in the subsequent process.
  • Tenth object of the invention is to provide an economical and industrially feasible method for increasing the chemical purity and enantiomeric excess of galanthamine salts.
  • Eleventh object of the invention is to provide the alternative procedure for reduction while avoiding the use of L-selectride.
  • One aspect of the invention relates to a process for the preparation of galanthamine of formula (II) of high purity and good yield.
  • Another aspect of the invention relates to a selective reduction method for preparation of galanthamine, which comprises reaction of methyl amine (XXI) with 4- benzyloxyphenyl acetyl chloride (XXII), to give an acetamide (XXIII), which on reduction with LiAlH 4 gives a phenyl amine (XXIV).
  • This phenyl amine on further treatment with the substituted benzoyl chloride (XXV) gives a substituted N-methyl benzamide (XXVI), which on further debenzylation and cyclisation with K 3 Fe(CN) 6 gave the dienone (XXVIII).
  • the dienone on reduction with L-selectride/Sodium borohydride gave the enol form (XXIX), which was treated with LiAlH 4 / Vitride for denomination and the reduction of amide.
  • the galanthamine (II) obtained is converted into its hydrobromide salt by making use of hydrobromic acid, which is used as an active pharmaceutical ingredient in many of the formulations of galanthamine.
  • the desired chiral purity or the desired chemical purity of the salt may not be obtained.
  • the hydrobromide salt is broken down to its free base, which is converted to its tartarate salt and then further the tartarate salt is converted to the desired salt, especially hydrobromide, through the free base.
  • the enriched tartarate salt obtained in the process can also be directly converted to galanthamine salt e.g. hydrobromide using hydrobromic acid.
  • the same is broken down to its free base, further converted to the tartarate salt, which is converted to the galanthamine hydrobromide via the galanthamine free base.
  • solubility of (-) galanthamine is very low in ethanol, this operation of conversion of the same to its tartarate salt through its free base to (-) galanthamine hydrobromide, with high purity, facilitates easy operation on an industrial scale.
  • the enantiomeric enrichment of the galanthamine tartarate salt can also be done by recrystallization, using various solvents.
  • the present invention describes the selective reduction process for the preparation of galanthamine.
  • the reaction sequence includes the reaction of methyl amine (XXI) with 4-benzyloxyphenyl acetyl chloride (XXII) in presence of NaOH to give 4-benzyloxy N- methyl Acetamide (XXIII).
  • This amide is further reduced with LiAlH 4 to give 5- benzyloxy N-methyl phenyl amine (XXIV) which on treatment with 5 benzyloxy 2 bromo 4 methoxy benzoyl chloride gives 5-benzyloxy-N-(4-benzyloxyphenethyl)2- bromo-4-methoxy-N-methylbenzamide (XXVI).
  • This compound on further treatment with HBr gave 5-hydroxy-N-(4-hydroxyphenethyl)-2-bromo-4-methoxy-N- methylbenzamide (XXVII).
  • the intermediate (XXV) can be prepared from 5-hydroxy-2-bromo-4-methoxy benzaldehyde by benzylation to give 5-benzyloxy-2-bromo-4-methoxy benzaldehyde, which on treatment with K 2 Cr 2 O 7 or KMnO 4 can give 5-benzyloxy-2-bromo-4-methoxy benzoic acid, which on treatment with SOCl 2 can give the benzoyl chloride (XXV).
  • the intermediate (XXIV) can be prepared from tyramine by bringing formylation of NH 2 group, benzylation of hydroxy at the fourth position, and reduction with lithium aluminium hydride or Vitride to give intermediate (XXIV).
  • the intermediate (XXVII) can also be prepared by the route of Scheme (II) (Tetrahedron (1989), 45(11), 3329-45) the only difference being the methylation, which needs to be carried out if started with tyramine. Also, if needed the phenolic -OH groups can as well be protected before condensation step.
  • This product on treatment with K 3 Fe(CN) 6 gave a cyclised product (XXVIII), which on treatment with reducing agents selected from the group comprising of L-Selectride, K- Selectride, KS- Selectride, LS- Selectride, DiBAl, REDAL, 9-BBN, Sodium borohydride, sodium-cyanoborohydride, chiral oxazaborolidine agent(CBS)/NaBH 4 , CBS/BH 3 .H 2 S, BH 3 -H 2 S etc.
  • reducing agents selected from the group comprising of L-Selectride, K- Selectride, KS- Selectride, LS- Selectride, DiBAl, REDAL, 9-BBN, Sodium borohydride, sodium-cyanoborohydride, chiral oxazaborolidine agent(CBS)/NaBH 4 , CBS/BH 3 .H 2 S, BH 3 -H 2 S etc.
  • galanthamine (I) was separated using di-p-toluoyl -D- (+) tartaric acid or di-p-toluyl- (-) tartaric acid to give galanthamine (II).
  • the reduction of compound (XXVIII) is carried out by using L-Selectride.
  • the reduction is selective, wherein the ketone functionality is reduced, while keeping the amide functionality intact.
  • the inventors have developed a process for reduction of compound (XXVIII), by making use of Sodium borohydride as a reducing agent.
  • Sodium borohydride is cheap reagent. It is easily available. It can be stored easily. It is less harmful and less explosive reagent. The work up conditions using sodium borohydride reagent are less stringent.
  • the reduction by using NaBH 4 is carried out at 0 to 5 0 C.
  • This reaction sequence includes (a) conversion of compound (XXX) to compound (XXXI) by bromination (b) conversion of (XXXI) to (XXXII) by demethylation (c) conversion of (XXXII) to (XXXIII) by benzylation and (d) conversion of (XXXIII) to (XXXIV) by oxidation.
  • the second part of the scheme involves (a) conversion of tyramine (XXXV) to aldehyde (XXXVI) (b) conversion of (XXXVI) to (XXXVII) by benzylation and (c) conversion of (XXXVII) to (XXIV). Further, the acid chloride (XXV) and the amine (XXIV) are reacted as per Scheme (VII). ,
  • the chemical purity as well as the chiral purity is of utmost importance.
  • the reprocessing is necessary. After formation of galanthamine hydrobromide from (-) galanthamine salt, the chiral purity or the chemical purity of the salt may not be obtained to the desired extent. For this reason, the reprocessing step of galanthamine salt at appropriate stage becomes crucial. According to the present invention, the following procedures for the improvement of the same are given:
  • galanthamine salt e.g. galanthamine hydrobromide
  • the reprocessing of galanthamine salt is carried out by conversion of galanthamine hydrobromide to free base. This conversion is done using solvent methylene dichloride and ammonia as base. This free base is converted to galanthamine tartarate salt using di-p-toluyl-(-)-tartaric acid and the resulting tartarate salt having acceptable optical purity is converted into galanthamine free base, which is then converted to galanthamine hydrobromide using hydrobromic acid, which results in an increased chiral purity of galanthamine hydrobromide.
  • the galanthamine tartarate salt obtained with acceptable optical purity can be directly converted to hydrobromide salt using hydrobromic acid. (Scheme IX). The same procedure is also applicable for the enrichment of galanthamine salts, in general.
  • the galanthamine tartarate salt formed is not having the chiral purity as per the expectation, reprocessing of the same becomes indispensible. Under such circumstances, the galanthamine tartarate salt is converted into the free base using methanol and ammonia, which is then converted to the tartarate salt using di-p-toluyl-(- )-tartaric acid . The tartarate salt thus obtained is converted to the free base, which is further converted to the galanthamine hydrobromide with an improved chiral purity.
  • the galanthamine tartarate salt with the unpassing chiral purity can also be enriched by making use of recrystallisation process using various solvents such as ketones, alcohols, esters, hydrocarbons, amides, water etc.
  • the galanthamine tartarate salt with passing chiral purity can be directly converted to galanthamine salt e.g. hydrobromide with desired chiral purity by making use of hydrobromic acid. (Scheme X).
  • the aqueous layer was extracted with ethylene dichloride (1.0 litre). The ethylene dichloride layer was concentrated. The thick residue was diluted under stirring with n-hexane (18.0 litres). The mixture was stirred for 30 minutes, and the solid separated out was filtered and dried.
  • the cyclised product (XXVIII) (1.0 kg; 2.64 moles) was added to tetrahydrofuran (10 litres) at 25-30 0 C.
  • L-Selectride (4 litres) was added dropwise to the cooled reaction mixture at -15° to -10°C.
  • methanol 1.0 litres was added.
  • the reaction mixture was concentrated and water (5.0 litres) followed by methylene dichloride (5.0 litres) were added.
  • the solid was filtered through hyflo.
  • the methylene dichloride was separated.
  • the aqueous layer was extracted with methylene dichloride (1.5 litres).
  • the solvent was distilled out completely.
  • the slurry was triturated with isopropyl alcohol (2.5 litres) and stirred for 30 minutes at 28 - 32 °C.
  • the solid was filtered and dried 28-32 0 C under vacuum for 6-7 hours.
  • Tetrahydrofuran (10 litres) and compound (XXIX) (1.0kg; 2.63 moles) were charged into a round bottom flask and stirred at 28 - 32 0 C.
  • Vitride (2.3 litres; 7.8 moles) was added dropwise at 28 - 32 0 C and the reaction mass was refluxed for 2 to 3 hours.
  • Methanol (1.5 litres) was added dropwise and stirred for 30 minutes.
  • the reaction mixture was concentrated under vacuum at 40 - 50° C. Water (5.0 litres) and methylene dichloride (5.0 litres) were added and stirred for 30 minutes.
  • Example 6a Recrystallization of Galanthamine tartarate.
  • Example 6b Conversion of Galanthamine tartarate to Galanthamine free base:
  • Example 7g Conversion of Galanthamine free base to Galanthamine HBr: (-) Galanthamine free base (3.8 g; 0.0132 moles), obtained from example 7e was added to ethanol (30.0 ml) and stirred for 15 minutes till dissolution. Charcoal (norrit) was added and stirred for 30 minutes at 25-32 0 C. The mixture was filtered and washed with ethanol (8.0 ml). The solution was concentrated under vacuum to 6 volumes. Hydrobromic acid 48% (1.8 ml; 0.015 moles) was added dropwise at 25 - 32 0 C and stirred for 30 minutes at 25 - 32 0 C. The mixture was cooled to 0 °C to 5 0 C and stirred for 2 hours. The solid was filtered and dried under vacuum. The solid was washed with chilled ethanol (1.0 ml) and dried under vacuum at 25 - 32 0 C. Yield: 4.8g % Yield: 98.56% (RS purity 99.53%)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé pour préparer de la galanthamine, qui comprend une étape de réduction stéréosélective permettant d'obtenir l'isomère de galanthamine souhaité. Ce mode de réalisation concerne aussi un procédé pour améliorer la pureté chirale et chimique de galanthamine et de sels de galanthamine.
PCT/IB2005/003804 2005-01-04 2005-12-16 Procede pour preparer de la benzazepine WO2006072818A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN3MU2005 2005-01-04
IN3/MUM/2005 2005-01-04
IN863/MUM/2005 2005-07-21
IN863MU2005 2005-07-21

Publications (2)

Publication Number Publication Date
WO2006072818A2 true WO2006072818A2 (fr) 2006-07-13
WO2006072818A3 WO2006072818A3 (fr) 2006-08-24

Family

ID=36202462

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/003804 WO2006072818A2 (fr) 2005-01-04 2005-12-16 Procede pour preparer de la benzazepine

Country Status (1)

Country Link
WO (1) WO2006072818A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007010412A2 (fr) * 2005-05-03 2007-01-25 Medichem, S.A Syntheses et preparations de narwedine et de nouveaux composes associes
WO2008127560A1 (fr) 2007-04-12 2008-10-23 Scinopharm Taiwan Ltd. Procédé de fabrication de galantamine
CN104592243A (zh) * 2014-12-19 2015-05-06 北京大学 加兰他敏和力克拉敏的不对称合成方法
WO2019222817A1 (fr) * 2018-05-23 2019-11-28 Sopharma Ad Procédé de préparation de bromhydrate de galantamine purifié

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030092700A1 (en) * 1996-04-19 2003-05-15 Laszlo Czollner Benzazepine derivatives, medicaments containing the same and their use to prepare medicaments
US20060009640A1 (en) * 2004-07-08 2006-01-12 Bolugoddu Vijaya B Preparation of (-)-galantamine hydrobromide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030092700A1 (en) * 1996-04-19 2003-05-15 Laszlo Czollner Benzazepine derivatives, medicaments containing the same and their use to prepare medicaments
US20060009640A1 (en) * 2004-07-08 2006-01-12 Bolugoddu Vijaya B Preparation of (-)-galantamine hydrobromide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VLAHOV R ET AL: "SYNTHESIS OF GALANTHAMINE AND RELATED ALKALOIDS - NEW APPROACHES. I" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 45, no. 11, 1989, pages 3329-3345, XP000562833 ISSN: 0040-4020 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007010412A2 (fr) * 2005-05-03 2007-01-25 Medichem, S.A Syntheses et preparations de narwedine et de nouveaux composes associes
WO2007010412A3 (fr) * 2005-05-03 2007-08-30 Medichem Sa Syntheses et preparations de narwedine et de nouveaux composes associes
WO2008127560A1 (fr) 2007-04-12 2008-10-23 Scinopharm Taiwan Ltd. Procédé de fabrication de galantamine
EP2146719A1 (fr) * 2007-04-12 2010-01-27 ScinoPharm Taiwan, Ltd. Procédé de fabrication de galantamine
JP2010523658A (ja) * 2007-04-12 2010-07-15 シノファーム タイワン，リミテッド ガランタミンの製造方法
EP2146719A4 (fr) * 2007-04-12 2012-07-04 Scinopharm Taiwan Ltd Procédé de fabrication de galantamine
CN104592243A (zh) * 2014-12-19 2015-05-06 北京大学 加兰他敏和力克拉敏的不对称合成方法
WO2019222817A1 (fr) * 2018-05-23 2019-11-28 Sopharma Ad Procédé de préparation de bromhydrate de galantamine purifié

Also Published As

Publication number Publication date
WO2006072818A3 (fr) 2006-08-24

Similar Documents

Publication Publication Date Title
EP0763010B1 (fr) Preparation enantioselective d'albuterol optiquement pure
US20090312548A1 (en) Modified pictet-spengler reaction and products prepared therefrom
US9040738B2 (en) Intermediate compounds of tamiflu, methods of preparation and uses thereof
US20110275855A1 (en) Separation of an enantiomer mixture of (r)- and (s)-3-amino-1-butanol
WO2006072818A2 (fr) Procede pour preparer de la benzazepine
US9771317B2 (en) Process for preparing lacosamide and related compounds
US20110245508A1 (en) Processes For Making Pregabalin And Intermediates Therefor
US20070112191A1 (en) Process for the manufacturing of pharmaceutically active compounds
US7915421B2 (en) Method for preparing phenyl acetic acid derivatives
JP5441883B2 (ja) ガランタミンの製造方法
JP4031203B2 (ja) （１ｒ，２ｓ，４ｒ）−（−）−２−［（２’−｛ｎ，ｎ−ジメチルアミノ｝−エトキシ）］−２−［フェニル］−１，７，７−トリ−［メチル］−ビシクロ［２．２．１］ヘプタン及びその薬学上許容される酸付加塩の製法
US8742162B2 (en) Method for producing optically active 1-amino-2-vinylcyclopropanecarboxylic acid ester
US7423152B2 (en) Process for the manufacture of intermediates in camptothecin production
US20060009640A1 (en) Preparation of (-)-galantamine hydrobromide
ES2446365T3 (es) Procedimiento de preparación de neramexane
JPH02233650A (ja) 新規なテトラリン誘導体
CN100443466C (zh) 环烷基氨基酸化合物及其制备方法和用途
Amedio et al. A practical manufacturing synthesis of 1-(R)-hydroxymethyl-DTPA: an important intermediate in the synthesis of MRI contrast agents
US7470816B2 (en) Tramadol recovery process
JPH02256655A (ja) 光学活性なスレオージヒドロキシフェニルセリン誘導体の製造方法
JPH09500626A (ja) Ｏ−置換ヒドロキシルアンモニウム塩の製法
JP2007515459A (ja) トルテロジンを得るための方法
US6906197B2 (en) Process for the preparation of optically active amines or salts thereof
MXPA96006100A (en) Asymmetric synthesis of substitute methanamins with alpha-cyclal
JPH08501306A (ja) キラルなキノロン誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05850695

Country of ref document: EP

Kind code of ref document: A2

WWW Wipo information: withdrawn in national office

Ref document number: 5850695

Country of ref document: EP

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)