WO1989007590A1 - Process of preparing n-(1-adamantyl) acetamide - Google Patents

Process of preparing n-(1-adamantyl) acetamide Download PDF

Info

Publication number
WO1989007590A1
WO1989007590A1 PCT/NO1989/000002 NO8900002W WO8907590A1 WO 1989007590 A1 WO1989007590 A1 WO 1989007590A1 NO 8900002 W NO8900002 W NO 8900002W WO 8907590 A1 WO8907590 A1 WO 8907590A1
Authority
WO
WIPO (PCT)
Prior art keywords
adamantyl
adamantane
reaction
preparing
nitric acid
Prior art date
Application number
PCT/NO1989/000002
Other languages
French (fr)
Inventor
Jan Magnus Bakke
Original Assignee
Chiron Laboratories A/S
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 Chiron Laboratories A/S filed Critical Chiron Laboratories A/S
Publication of WO1989007590A1 publication Critical patent/WO1989007590A1/en

Links

Classifications

    • 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

  • the present invention relates to a new process of preparin N-(l-adamantyl)a ⁇ ylamides from adamantane and nitriles.
  • N-(l-adamantyl)acylamides are valuable intermediates of synthetizing 1-aminoadamantane (amantadin) .
  • 1-aminoadamantane preferably in the form of mineral acid salts such as hydrochlorides or sulphates, is a valuable thera ⁇ Guideic active compound, e.g. in combatting virus.
  • the German Offenlegungsschrift 1,197,091, discloses the preparation of 1-aminoadamantane through N-(l-adamantyl)formamide as intermediate product, which is then hydrolysed by sodium hydroxyde in diethyleneglycol.
  • the preparation of N-(l-adamantyl)formamide is accomplished by reacting adamantane with sulphuric acid, hydrogen cyanide and tertiary butanol. The total yield is said to be 70% 1-amino ⁇ adamantane.
  • a new and enhanced process of preparing N-(l-adamantyl)acyl amides characterized by the reaction of adamantane with a nitrile in the presence of a strong mineral acid.
  • N-(l-adamantyl)acyl amides are prepared in one single operation step.
  • a mineral acid is used as acid or a mixture of mineral acids.
  • this mineral acid is nitric acid, and particu ⁇ larly fuming nitric acid (HN0 3 ) .
  • the reaction is carried out in an inert organic solvent, particularly cyclo ⁇ hexane, hexane and tetrachloromethane.
  • cyclohexane provides for good separation of a nitric acid phase comprising product and acetonitrile and a cyclohexane phase containing unreacted adamantane. By separating the phases prior to work up cyclohexane and possible unreacted adamantane may be recircula ⁇ ted.
  • the nitric acid may be recovered.
  • acetonitrile is used.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A process of preparing N-(1-adamantyl)- acyl amides by reacting adamantane and a nitrile wherein the reaction is performed in the presence of an oxidizing proton acid and optionally a co-oxidant.

Description

Process of preparing N-fl-adamantyDacetamide
The present invention relates to a new process of preparin N-(l-adamantyl)aσylamides from adamantane and nitriles.
N-(l-adamantyl)acylamides are valuable intermediates of synthetizing 1-aminoadamantane (amantadin) .
1-aminoadamantane, preferably in the form of mineral acid salts such as hydrochlorides or sulphates, is a valuable thera¬ peutic active compound, e.g. in combatting virus.
Several syntheses of preparing 1-aminoadamantane are previously known.
From the German Offenlegungsschrift 1,294,371 it is known to react l-bromoadamantane or l-chloroadamantane at elevated temperatures with urea or derivatives thereof. Among others e.g. l-bromoadamantane and urea were heated to 180°C till an exoterm reaction started, whereupon the temperature rose to 240°C. The reaction product was worked up and yielded 1-amino¬ adamantane in 95% yield in this step, l-bromoadamantane is prepared by the bromination of adamantane with Br2• The yield of the last step is attractive, but the exotermic reaction and elevated temperature may provide difficulties in monitoring the reaction - particularly on commercial scale as it is carried out without solvent.
Further it is known from the Belgian Patent 646.581 to prepare N-(l-adamantyl)acetamide as an intermediate of preparing 1-aminoadamantane by reacting l-bromoadamantane with acetoni- trile. The reaction is accomplished in the presence of concen¬ trated sulphuric acid. 1-aminoadamantane was prepared from the intermediate obtained by the hydrolysis with NaOH in (HOC2H4)2θ by heating at 180°C in 5 hours.
The reaction of l-bromoadamantane with acetonitrile to N-(l-adamantyl)acetamide yielded 90% in this step. The work up of the product is performed by dilution in great amounts of water. The synthesis from adamantane through the 1-bromo- derivative to N-(l-adamantyl)acetamide thus takes place in two steps. The bromination is said to yield 99%.
Further Bewic, A.; Edwards, C.J. ; Showns S.R. ; Miller, J.M. in Tetrahedron Letters 1976 (8) 631-4 describe the
SUBSTITUTE SHEET preparation of N-(l-adamantyl)acetamide by preparative electro¬ lysis of adamantane in acetonitrile and quenching the reaction with H20. The yield achieved is said to be 74%. This process includes 1 step less than the previous, however, equipment for preparative electrolysis is not standard equipment which is commonly available for industrial processes.
The German Offenlegungsschrift 1,197,091, (inventor Wolfgang Haaf) , discloses the preparation of 1-aminoadamantane through N-(l-adamantyl)formamide as intermediate product, which is then hydrolysed by sodium hydroxyde in diethyleneglycol. The preparation of N-(l-adamantyl)formamide is accomplished by reacting adamantane with sulphuric acid, hydrogen cyanide and tertiary butanol. The total yield is said to be 70% 1-amino¬ adamantane. Similar investigations performed by Wolfgang Haaf has among other in the same reaction substituted acetonitrile for hydrogen cyanide, and a yield of N-(l-adamantyl)acetamide of 35% of theoretical was then achieved, (Haaf,W. Ber 97. (1964) 3234) .
Although the synthesis with hydrogen cyanide provides satisfying yields, the handling of great amounts of hyrogen cyanide is undesirable in a commercial processs of preparation.
It was thus an aim of the present invention to provide a new and improved process of preparing N-(l-adamantyl)acyl amides from adamantane.
It was a particular aim of such a process that particularly toxic reactants such as hydrogen cyanide (HCN) should be eliminated, and also strongly exotermic reactions and elevated temperatures which are difficult to monitor in commercial processes.
According to the present invention a new and enhanced process of preparing N-(l-adamantyl)acyl amides is provided characterized by the reaction of adamantane with a nitrile in the presence of a strong mineral acid.
By this process N-(l-adamantyl)acyl amides are prepared in one single operation step.
Preferably a mineral acid is used as acid or a mixture of mineral acids.
SUBSTITUTE SHEET Preferably this mineral acid is nitric acid, and particu¬ larly fuming nitric acid (HN03) . Preferably the reaction is carried out in an inert organic solvent, particularly cyclo¬ hexane, hexane and tetrachloromethane. The use of cyclohexane provides for good separation of a nitric acid phase comprising product and acetonitrile and a cyclohexane phase containing unreacted adamantane. By separating the phases prior to work up cyclohexane and possible unreacted adamantane may be recircula¬ ted.
By continuous extraction of the nitric acid phase with e.g. tetrachloromethane the nitric acid may be recovered.
As the nitrile perferably acetonitrile is used.
The following experimental specification is illustrating but shall not be construed as limiting to the invention the scope of which is defined by the following claims.
Example 1-4
The reactions were performed under magnetic stirring. Prelimi¬ nary experiments with fuming nitric acid indicated that the reactions with adamantane were complete after 4-5 hours. The reactions were quenched by the addition of water, the products were extracted by dichloromethane, the organic phase separated and washed with aqueous NaHC03 and dried on Na2S04 before the solvent was evaporated. The yields of the examples are achieved by gasσhro atographic analysis (25M fused silica/SE30, p-nitrotoluene as internal standard) .
Reactants and yields of examples 1-4:
Example 1:
Adamantane (8 mg) , acetonitril (1 ml) , tetrachloromethane (3 ml), nitric acid (90%, 3 ml), - 74% of theoretical.
Example 2:
As example 1, but with Ru02xH20 (5 mg) - 69% of theoretical.
Example 3:
As example 1, but with 65% nitric acid, - 9% of theoretical, 80% adamantane recovered.
SUBSTITUTE SHEET Example 4:
As example 1, but without tetrachloromethane - 19% of theoretical.
Example 5-6:
In the reactions 5 and 6 the yields represent worked up and purified product. The products were identified by comparing the melting points and spectral characteristics 1H MR, 13CNMR and MS with the corresponding of authentic samples.
Example 5:
To a solution of adamantane (1.0 g, 7 mmole) and aceto¬ nitrile (6.5 ml, 124 mmole) in cyclohexane fuming nitric acid (17 ml, 405 mmole) was added and stirred on a water bath. The phases were worked up separately by adding NaOH to pH>7 followed by extraction with dichloromethane. The organic phases were washed with aqueous NaHCθ3 , dried on MgS04 and evaporated to dryness. The yield was 97 % of theoretical. Totally 99 % of the adamantane was reacted, whereas 1 % was recovered.
Example 6:
The reaction was performed as described in example 5. Subsequent to the separation of the phases the nitric acid phase was added H 0 (30 ml) and continuously extracted with CCI4. Washing of the CCI4 phase with NaOH (1 M) , drying on MgS04 and evaporation to dryness yielded 0,77 g product of 100 % purity representing a 54 % yield.
SUBSTITUTE SHEET

Claims

P a t e n t c l a i m s .
1. Process of preparing N-(l-adamantyl)acyl amides by reacting adamantane and a nitrile characterized in performing the reaction in the presence of an oxidizing protonic acid and optionally a co-oxidant.
2. The process of claim 1, characterized by the use of nitric acid (HNO3) as oxidizing proton acid.
3. The process of claim 2, characterized in that fuming nitric acid is used.
4. The process of claim 1-3 , characterized in that the reaction is performed in the presence of an inert non-water- miscible solvent.
5. The process of claim 4, characterized in that cyclohexane, hexane,petrol ether or tetrachloromethane is used as solvent.
7. The process of claim 1-6, characterized in that aceto¬ nitrile is used as a nitrile.
SUBSTITUTE SHEET
PCT/NO1989/000002 1988-02-15 1989-01-03 Process of preparing n-(1-adamantyl) acetamide WO1989007590A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NO88880650A NO880650L (en) 1988-02-15 1988-02-15 PROCEDURE FOR THE PREPARATION OF N- (1-ADAMANTYL) ACETAMIDE.
NO880650 1988-02-15

Publications (1)

Publication Number Publication Date
WO1989007590A1 true WO1989007590A1 (en) 1989-08-24

Family

ID=19890666

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NO1989/000002 WO1989007590A1 (en) 1988-02-15 1989-01-03 Process of preparing n-(1-adamantyl) acetamide

Country Status (2)

Country Link
NO (1) NO880650L (en)
WO (1) WO1989007590A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006009278A1 (en) * 2006-03-01 2007-09-13 Justus-Liebig-Universität Giessen Amidoadamantanes and process for their preparation
CN112853382A (en) * 2020-12-31 2021-05-28 北京工业大学 Electrochemical synthesis method of 1-acetamido adamantane

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE646581A (en) * 1964-04-15 1964-07-31
DE1197091B (en) * 1960-08-25 1965-07-22 Studiengesellschaft Kohle Mbh Process for the preparation of N- (tertiary alkyl) amines
DE2745193A1 (en) * 1976-10-12 1978-04-13 Kao Corp 1-ACETYLAMINOTRICYCLO (4.3.1.1 HIGH 2.5 )UNDECAN AND PROCESS FOR ITS PREPARATION

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1197091B (en) * 1960-08-25 1965-07-22 Studiengesellschaft Kohle Mbh Process for the preparation of N- (tertiary alkyl) amines
BE646581A (en) * 1964-04-15 1964-07-31
DE2745193A1 (en) * 1976-10-12 1978-04-13 Kao Corp 1-ACETYLAMINOTRICYCLO (4.3.1.1 HIGH 2.5 )UNDECAN AND PROCESS FOR ITS PREPARATION

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 103, (1985), abstract No. 141506b, Khimiya i Tekhnol. Elementorgan. Poluproduktov i Polimerov, Volgograd 1984, 29-32 (Russ), From Ref. Zh., Khim. 1985, Abstr. No. 8Zh146. *
TETRAHEDRON LETTERS, No. 8, pp. 631-634, 1976, (A. BEWICK et al.), "The electrochemical difunctionalisation of saturated hydrocarbons". *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006009278A1 (en) * 2006-03-01 2007-09-13 Justus-Liebig-Universität Giessen Amidoadamantanes and process for their preparation
DE102006009278B4 (en) * 2006-03-01 2010-06-02 Justus-Liebig-Universität Giessen Process for the direct formamidation or acetamidation of admantane and Admantanderivaten and their use for the production of Aminoadmantanen
CN112853382A (en) * 2020-12-31 2021-05-28 北京工业大学 Electrochemical synthesis method of 1-acetamido adamantane

Also Published As

Publication number Publication date
NO880650D0 (en) 1988-02-15
NO880650L (en) 1989-08-16

Similar Documents

Publication Publication Date Title
EP0414274B1 (en) Process for the preparation of 1 aminomethyl-1.cyclohexanacetic acid
EP1836157B1 (en) Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
DE602005000187T2 (en) Process for the preparation of (1S) -4,5-dimethoxy-1- (methylaminomethyl) -benzocyclobutane and its acid addition salts, and their use for the synthesis of ivabradine and their acid addition salts of pharmaceutically acceptable acid
KR850000945B1 (en) Process for preparing 5-carbamoyl-10,11-dihydro-5h-dibenz(b,f)azepine
WO1989007590A1 (en) Process of preparing n-(1-adamantyl) acetamide
Griffiths et al. Novel syntheses of gabapentin via addition of hydrocyanic acid to cyclohexylidenemalonate or cyano (cyclohexylidene) acetate
JPS5925779B2 (en) Isomerization method for stereoisomeric alicyclic diamines
US3931210A (en) Production of p-aminobenzoic acid
EP1295864B1 (en) Process for preparation of 1,5-diaminonaphthalenes
DE19524337C1 (en) Process for the preparation of beta-amino-alpha-hydroxycarboxylic acids and their derivatives
DE3104388A1 (en) METHOD FOR PRODUCING 1-ALKYL-2-CHLORINE-5-NITRO-4-BENZENE SULPHONIC ACIDS
CA1068302A (en) Process for the preparation of an acetonitrile derivative
WO2007025585A1 (en) Process for preparing 3,4-dichloroisothiazolecarboxylic acid
EP1468983B1 (en) Process for producing 2,5-bis(trifluoromethyl)nitrobenzene
US5847216A (en) Preparation of selegiline
JPS63145262A (en) Production of trifluoromethylbenzonitrile
KR20010102956A (en) Method for preparing polyhalogenated paratrifluoromethylanilines
EP0027658B1 (en) Process for the production of 3-nitro-4-aminotoluene
WO2000055138A1 (en) Method of producing oxcarbazepine (=10,11- dihydro- 10- oxo- 5h- dibenz(b,f)- azepine- 5- carboxamide) and its intermediate products
JP3193421B2 (en) Method for producing 2-amino-4-fluorobenzoic acid
EP1274677B1 (en) Method for producing oxime ethers
EP1775282B1 (en) Process for preparing methyl 4-aminomethylbenzoate
EP0423595B1 (en) Process for the preparation of 3-trichloromethyl pyridine
US2763686A (en) Production of oximes
US4751314A (en) Preparation of tetrachloro-3-iminoisoindolin-1-one

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE