US20060173215A1 - Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride - Google Patents

Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride Download PDF

Info

Publication number
US20060173215A1
US20060173215A1 US11/330,681 US33068106A US2006173215A1 US 20060173215 A1 US20060173215 A1 US 20060173215A1 US 33068106 A US33068106 A US 33068106A US 2006173215 A1 US2006173215 A1 US 2006173215A1
Authority
US
United States
Prior art keywords
dimethyladamantane
acetamido
memantine
amino
halo
Prior art date
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.)
Abandoned
Application number
US11/330,681
Other languages
English (en)
Inventor
Valeriano Merli
Silvia Mantovani
Paola Daverio
Stefano Bianchi
Alessandro Spreafico
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceuticals USA Inc
Original Assignee
Teva Pharmaceuticals USA Inc
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 Teva Pharmaceuticals USA Inc filed Critical Teva Pharmaceuticals USA Inc
Priority to US11/330,681 priority Critical patent/US20060173215A1/en
Assigned to TEVA PHARMACEUTICALS USA, INC. reassignment TEVA PHARMACEUTICALS USA, INC. ASSIGNMENT OF RIGHTS IN BARBADOS Assignors: TEVA PHARMACEUTICAL FINE CHEMICALS S.R.L.
Assigned to TEVA PHARMACEUTICAL FINE CHEMICALS S.R.I. reassignment TEVA PHARMACEUTICAL FINE CHEMICALS S.R.I. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIANCHI, STEFANO, DAVERIO, PAOLA, MANTOVANI, SILVIA, MERLI, VALERIANO, SPREAFICO, ALESSANDRO
Publication of US20060173215A1 publication Critical patent/US20060173215A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • U.S. Pat. No. 3,391,142 discloses the synthesis of memantine hydrochloride and its precursor, n-acetyl-memantine, according to following scheme, where the reported yield of the first step is 100 percent, the reported yield of the second step is 69.8 percent, and the reported overall yield is 69.8 percent.
  • Chinese Patent Publication No. CN 1335299 discloses memantine hydrochloride synthesis according to the scheme.
  • U.S. Pat. No. 5,599,998 discloses memantine synthesis with a yield of 48 percent according to the following scheme.
  • the invention is directed to a “one pot” process for the synthesis of memantine from 1-halo-3,5-dimethyladamantane without the isolation of n-acetyl-3,5-dimethyladamantane.
  • the memantine prepared by the above processes is subsequently converted into a memantine hydrochloride.
  • the memantine prepared by the above processes has a yield which is not less than 80%.
  • the desired product may be recovered by a variety of methods well known in the art.
  • recovery is preformed by extracting the n-acetamido-3,5-dimethyladamantane using water and n-butyl alcohol, adjusting the pH using a strong base, washing, and then concentrating the organic phase by distillation, suspending the resulting residue in acetone and water, cooling, and isolating the crystals.
  • the present invention is also directed to a crystalline form of a memantine intermediate n-acetamido-3,5-dimethyladamantane, designated herein as Form I, characterized by at least one of an x-ray powder diffraction pattern, having peaks at about 6.1, 12.2, and 15.5 degrees 2 ⁇ , and an x-ray powder diffraction pattern substantially as depicted in FIG. 1 .
  • Form I can be further characterised by x-ray powder diffraction peaks at about 12.9, 13.9, 16.8, 18.3, 19.0, 20.4, and 24.5 degrees 2 ⁇ .
  • the solution of 1-amino-3,5-dimethyladamantane is then converted into a memantine acid addition salt form, preferably memantine hydrochloride, as summarized in Scheme 3.
  • HCl is combined with 1-amino-3,5-dimethyladamantane to obtain memantine HCl, and memantine HCl is recovered.
  • the solution of 1-amino-3,5-dimethyladamantane is first concentrated under 50 mm Hg vacuum at a temperature of about 55° C., to obtain a residue which is suspended in an organic solvent, such as ethyl acetate, while maintaining the temperature at about 50° C. The suspension is then cooled to about 20° C. for about one hour, washed with water, and dried to obtain memantine HCl.
  • the invention is directed to a “one pot” process for the synthesis of memantine hydrochloride from 1-halo-3,5-dimethyladamantane without the isolation of n-acetamido-3,5-dimethyladamantane.
  • the process of the invention comprises:
  • the solution of 1-amino-3,5-dimethyladamantane is then converted into memantine's acid addition salt form, most preferably memantine hydrochloride.
  • the 50 g (0.2259 mol) of n-acetyl-memantine, 200 ml of n-butanol, and 80.29 g of 89.9 percent potassium hydroxide flakes (1.288 mol) were introduced into a three necked round bottom flask equipped with a thermometer, condenser, and mechanical stirrer at room temperature.
  • the resulting suspension was heated to 130° ⁇ 2° C., and maintained at 130° ⁇ 2° C. for 10 to 11 hours.
  • the reaction mixture was cooled to 50° C., and 150 ml of water were added.
  • the phases were separated, 75 ml of water were added to the rich organic phase, and the pH is brought to 10.5-11 with 37% HCl. After stirring, the phases were separated, and 75 ml of water were added to the rich organic phase. After stirring, the phases were separated again.
  • memantine hydrochloride may be produced in a “one pot” process.
US11/330,681 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride Abandoned US20060173215A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/330,681 US20060173215A1 (en) 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US64295705P 2005-01-11 2005-01-11
US67759905P 2005-05-03 2005-05-03
US11/330,681 US20060173215A1 (en) 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride

Publications (1)

Publication Number Publication Date
US20060173215A1 true US20060173215A1 (en) 2006-08-03

Family

ID=36282949

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/330,681 Abandoned US20060173215A1 (en) 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
US11/331,263 Expired - Fee Related US7462743B2 (en) 2005-01-11 2006-01-11 Polymorphs of memantine hydrochloride

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/331,263 Expired - Fee Related US7462743B2 (en) 2005-01-11 2006-01-11 Polymorphs of memantine hydrochloride

Country Status (12)

Country Link
US (2) US20060173215A1 (sl)
EP (2) EP1836154A1 (sl)
AT (1) ATE444950T1 (sl)
CA (2) CA2591666A1 (sl)
DE (1) DE602006009619D1 (sl)
ES (1) ES2334579T3 (sl)
HR (1) HRP20090676T1 (sl)
IL (2) IL183237A0 (sl)
MX (2) MX2007007302A (sl)
PT (1) PT1836157E (sl)
SI (1) SI1836157T1 (sl)
WO (2) WO2006076560A1 (sl)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090247644A1 (en) * 2008-03-28 2009-10-01 Forest Laboratories Holdings Limited Memantine formulations
US9452971B2 (en) 2013-01-23 2016-09-27 Mitsubishi Gas Chemical Company, Inc. Manufacturing process for memantine

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20050833A1 (it) 2005-05-10 2006-11-11 A M S A S P A Anonima Materie Sintetiche Affini Nuovo procedimento per la sintesi di aminoadamantani
WO2007132476A2 (en) * 2006-05-15 2007-11-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride
JP2009542647A (ja) * 2006-07-05 2009-12-03 テバ ファーマシューティカル インダストリーズ リミティド メマンチン医薬組成物
CN101038280B (zh) * 2007-04-11 2010-09-15 山东省医药工业研究所 一种盐酸美金刚中有关物质的hplc-elsd测定方法
WO2010069555A1 (en) 2008-12-17 2010-06-24 Merz Pharma Gmbh & Co. Kgaa Method for producing memantine
EP2555616A4 (en) * 2010-04-08 2014-04-02 Hetero Research Foundation METHOD FOR PRODUCING MEMANTINE HYDROCHLORIDE
WO2012051333A1 (en) 2010-10-12 2012-04-19 The Johns Hopkins University Antitussive compositions comprising memantine
CN102875387A (zh) * 2012-10-23 2013-01-16 滨州泓瑞医药科技有限公司 一种盐酸金刚烷胺的制备工艺
MX2021001169A (es) 2013-11-15 2023-02-10 Akebia Therapeutics Inc Formas sólidas de ácido {[5-(3-clorofenil)-3-hidroxipiridin-2-carb onil]amino}acético, composiciones, y usos de las mismas.
EP3474831A1 (en) 2016-06-23 2019-05-01 Corium International, Inc. Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent
KR102545643B1 (ko) 2016-07-27 2023-06-21 코리움, 엘엘씨 도네페질 경피 전달 시스템
KR102424270B1 (ko) 2016-07-27 2022-07-25 코리움, 인크. 경구 전달과 생물학적으로 동등한 약물동역학을 가진 경피 전달 시스템
EP3490544A1 (en) 2016-07-27 2019-06-05 Corium International, Inc. Memantine transdermal delivery systems
AU2018392686A1 (en) 2017-12-20 2020-07-09 Corium Pharma Solutions, Inc. Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point
JP2019156756A (ja) * 2018-03-13 2019-09-19 宇部興産株式会社 １−アミノ−３，５−ジメチルアダマンタン塩酸塩の結晶
PE20220936A1 (es) 2019-05-31 2022-05-31 Tecnimede Soc Tecnico Medicinal Sa Composiciones farmaceuticas de combinacion a dosis fijas de liberacion inmediata, metodos y usos de las mismas
CN111909041B (zh) * 2020-08-12 2023-06-16 山东罗欣药业集团恒欣药业有限公司 一种用于治疗神经功能疾病药物的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3391142A (en) * 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
US4122193A (en) * 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US5061703A (en) * 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
US5599998A (en) * 1994-10-24 1997-02-04 Iowa State University Research Foundation, Inc. Method for the synthesis of adamantane amines
US5614560A (en) * 1991-04-04 1997-03-25 Children's Medical Center Corporation Method of preventing NMDA receptor-mediated neuronal damage
US6333198B1 (en) * 1998-06-10 2001-12-25 Glaxo Wellcome, Inc. Compound and its use
US7355080B2 (en) * 2003-09-10 2008-04-08 Shanghai Institute Of Pharmaceutical Industry Method of preparing memantine hydrochloride

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ282398B6 (cs) * 1994-04-13 1997-07-16 Lachema A. S. Způsob výroby 1-R1-3-R2-tricyklo(3,3,1,1,3,7)decyl-5-aminu
JP2002275142A (ja) 2001-03-14 2002-09-25 Daicel Chem Ind Ltd アミド化合物の製造法
CN1125033C (zh) 2001-08-29 2003-10-22 中国科学院广州化学研究所 美金刚胺盐酸盐的合成方法
CN1400205A (zh) 2002-08-30 2003-03-05 中国科学院广州化学研究所 美金刚胺盐酸盐的制备方法
WO2005069742A2 (en) * 2003-12-10 2005-08-04 Sun Pharmaceutical Industries Limited Crystal form ii of memantine hydrochloride
WO2005062724A2 (en) 2003-12-31 2005-07-14 Sun Pharmaceutical Industries Limited Novel process for the preparation of aminoadamantane derivatives
WO2007132476A2 (en) 2006-05-15 2007-11-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3391142A (en) * 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
US4122193A (en) * 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US5061703A (en) * 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
US5614560A (en) * 1991-04-04 1997-03-25 Children's Medical Center Corporation Method of preventing NMDA receptor-mediated neuronal damage
US5599998A (en) * 1994-10-24 1997-02-04 Iowa State University Research Foundation, Inc. Method for the synthesis of adamantane amines
US6333198B1 (en) * 1998-06-10 2001-12-25 Glaxo Wellcome, Inc. Compound and its use
US7355080B2 (en) * 2003-09-10 2008-04-08 Shanghai Institute Of Pharmaceutical Industry Method of preparing memantine hydrochloride

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090247644A1 (en) * 2008-03-28 2009-10-01 Forest Laboratories Holdings Limited Memantine formulations
US9452971B2 (en) 2013-01-23 2016-09-27 Mitsubishi Gas Chemical Company, Inc. Manufacturing process for memantine

Also Published As

Publication number Publication date
CA2591487A1 (en) 2006-07-20
US20060217573A1 (en) 2006-09-28
MX2007007301A (es) 2008-02-11
IL183244A0 (en) 2007-08-19
PT1836157E (pt) 2009-11-24
US7462743B2 (en) 2008-12-09
IL183237A0 (en) 2007-08-19
EP1836157A1 (en) 2007-09-26
CA2591666A1 (en) 2006-07-20
ES2334579T3 (es) 2010-03-12
ATE444950T1 (de) 2009-10-15
WO2006076562A1 (en) 2006-07-20
EP1836157B1 (en) 2009-10-07
EP1836154A1 (en) 2007-09-26
SI1836157T1 (sl) 2009-12-31
HRP20090676T1 (hr) 2010-01-31
DE602006009619D1 (de) 2009-11-19
WO2006076560A1 (en) 2006-07-20
MX2007007302A (es) 2008-02-11

Similar Documents

Publication Publication Date Title
US20060173215A1 (en) Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
KR100649289B1 (ko) (1ｓ)-4,5-다이메톡시-1-(메틸아미노메틸)-벤조사이클로부탄 및 이의 부가 염을 합성하는 방법, 및 이바브라딘 및약제학적으로 허용되는 산 부가염의 합성에서의 용도
US20090082596A1 (en) Process for the Preparation of Adamantanamines
RU2388753C2 (ru) Способ получения промежуточного продукта, участвующего в синтезе ирбесартана
WO2008062472A2 (en) Process for the preparation of memantine
JP3723464B2 (ja) １１−アミノ−３−クロロ−６，１１−ジヒドロ−５，５−ジオキソ−６−メチル−ジベンゾ〔ｃ，ｆ〕〔１，２〕チアゼピンの製造方法及びチアネピンの合成への応用
JP5916721B2 (ja) 集中的還元的アミノ化によるフェロキンの合成方法
WO2009057140A2 (en) Improved process for memantine hydrochloride
US6730809B2 (en) Processes for the production of α-difluoromethyl ornithine (DFMO)
ZA200304484B (en) A process for the preparation of 1-(aminomethyl)cyclohexaneacetic acid.
US9902693B2 (en) Preparation method for pyrrolidine-2-carboxylic acid derivatives
KR20100118747A (ko) 사포그릴레이트 염산염의 개선된 제조방법
KR101442716B1 (ko) 자일릴렌디아민의 제조방법
WO1999014184A1 (en) Novel stereoselective processes for the preparation of gabapentin analogues
WO2013150020A1 (en) Process for making bendamustine
WO2010133909A2 (en) Process for preparation of 5-substituted tetrazoles
JP4366854B2 (ja) １２−アミノ−４，８−ドデカジエンニトリル及びその製造法
US20120022292A1 (en) Method for preparing eplivanserin hemifumarate
KR100342919B1 (ko) 트랜스체 염산 트라마돌의 분리 제조방법
KR101578190B1 (ko) 자일릴렌디아민의 제조방법
US20100029983A1 (en) Process for preparing gabapentin
JP2007529569A (ja) メシル酸フェノルドパムの調製方法
EP2834215A1 (en) Process for making bendamustine
SK121999A3 (en) Process for the preparation of terbinafine and an intermediate of its preparation of e-isomer (e)-n-(3-chloro-2-propenyl)-n- -methyl-1-naphtalene methylamine tosylate salt
US20140336380A1 (en) Process for the preparation of agomelatine

Legal Events

Date Code Title Description
AS Assignment

Owner name: TEVA PHARMACEUTICALS USA, INC., PENNSYLVANIA

Free format text: ASSIGNMENT OF RIGHTS IN BARBADOS;ASSIGNOR:TEVA PHARMACEUTICAL FINE CHEMICALS S.R.L.;REEL/FRAME:017433/0982

Effective date: 20060327

Owner name: TEVA PHARMACEUTICAL FINE CHEMICALS S.R.I., ITALY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MERLI, VALERIANO;MANTOVANI, SILVIA;DAVERIO, PAOLA;AND OTHERS;REEL/FRAME:017433/0968

Effective date: 20060322

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION