LV12955B - Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine) - Google Patents

Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine) Download PDF

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LV12955B
LV12955B LVP-02-193A LV020193A LV12955B LV 12955 B LV12955 B LV 12955B LV 020193 A LV020193 A LV 020193A LV 12955 B LV12955 B LV 12955B
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methyl
palladium
naphthalenemethanamine
reaction
terbinafine
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LVP-02-193A
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Latvian (lv)
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Ivan Kakalik
Vladimir Oremus
Vendel Smahovsky
Vladislav Snuparek
Dusan Vandak
Ivan Varga
Marian Zemanek
Valdemar Stalmach
Ladislav Jezek
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Slovakofarma As
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton

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  • Organic Chemistry (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The method for the preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine (terbinafine) from N-methyl-1-naphthalenemethanamine and (E)-1,3-dichloropropene and by subsequent reaction with 3,3-dimethylbut-1-yne characterized in that the whole reaction sequence is carried out without any isolation of intermediates. All sequential reactions are carried out in the solvent system common for the whole reaction sequence and inert to the reactants and intermediates present in the process. The method according to the present invention may also include additional purification steps.

Description

LV 12955
Method for the preparation of (£)-iV-(6,6-dimethyl-2-hepten-4-ynyl)-iV-methyl-l-naphthalenemethanamine (terbinafine)
Technical Field
Present invention relates to the method for the manufacture of (£)-//-(6,6-dimethyl-2-hepten-4-ynyl)-iV-methyl-1 -naphthalenemethanamine (terbinafine) of formula V, wherein the process of the preparation in two steps is without any isolation or purification of intermediates (so called one pot reaction). Furthermore the method of optimai purification operations leading to the pharmaceutically usable terbinafine hydrochloride is described.
(V)
Background Art
Terbinafine belongs to the group of allylamine fungistatic antimycotics. Terbinafine blocks ergosterol synthesis by squalene epoxidase inhibition, affects fungicidally upon dermatophytes, yeasts, dimorphous fungi and micromycetes. It possesses with a wide antimycotic spectrum and is accessible also for peroral application. Its pharmacokinetic characteristics are very advantageous (a long biological half-life) and has a very good passage into adipose tissue (skin and nails).
The preparation of terbinafine has been described in patent application and subsequently, in publication by A. Stuetz. ( A. Stuetz: Eur. Pat. Appl. 24,587 (1981 Sandoz), A. Stuetz, G. Petranyi et al: J. Med. Chem. 27, 1539 (1984)).
Terbinafine as specific inhibitor of squalene epoxidase, the key enzyme in ergosterol biosynthesis in fungi, has been described by G. Petranyi et at in Science, 224.1239 (1984) and by N. S. Ryder in Antimicrob. Ag. Chemother. ZL, 252 (1985). 1
Preparation of terbinafine from N-methyl-l-naphthalenemethanamine has been described in number of documents.
In European Patent Appl. 24587 and subsequently in J. Med. Chem., 23, 1539 (1984) and J. Med. Chem., 36, 2820 (1993) the preparation of terbinafine has been described as follows: at first 6,6-dimethylhepten-4-ynyl-l-bromide (E:Z = 3:1) is prepared, which subsequently reacts with N-methyl-l-naphthalenemethanamine to afford the isomeric mixture (E:Z = 3:1) of terbinafine. Desired E-isomer is isolated by chromatography on silica gel (Scheme 1).
Later in the Swiss patent CH 678527 of Sandoz Company was disclosed the method for the separation of E and Z terbinafine isomers via its addition salt with inorganic acid, preferably hydrochloric acid. Starting from the mixture of E and Z isomers (3:1) of terbinafine hydrochloride in ethylacetate, only pure E isomer was precipitated.
Scheme 1
Canadian patent CA 1 157023 relates to the method for preparation of terbinafine by reduction amination of naphthylamine with (E)-6,6-dimethylhept-2-ene-4-yne-l-al in the presence of formaldehyde and borohydride natrium (Scheme 2).
Scheme 2
iCH a, NaBH4 b, HCHO NaBH4 2 LV 12955
In the New Zealand patent NZ 280065 is starting compound 2,3-epoxypropane or (3-alkyl-l-propargyl)triphenylphosphonium bromide (Scheme 3). In the first case N-methyl-l-naphthalenemethanamine reacts with epichlorhydrin in the basie medium to afford N-methyl-l-naphthylmethyl-2,3-epoxypropane. The epoxide formed is subsequently with lithium feri-butylacetylene in the presence of boron trifluoride etherate opened to form secondary alcohol. Free hydroxy group is protected by easy leaving group such as methansulfonate or tosylate. In the last step easy leaving group is removed by strong base of l,8-diazabicyclo[5.4.0]undecan-7-ene to give the mixture of terbinafine isomers.
In the second process N-methy 1-1 -naphthalenemethanamine reacts with bromoacetaldehyde dialkylacetal in the basie medium to give amine acetal, which is hydrolyzed in acidic medium, whereby aldehyde is formed, from which by Wittig reaction isomeric mixture of terbinafine is prepared. Both mentioned methods afford isomeric mixture of terbinafine what is undesirable.
Scheme 3
According to the method deseribed in Tetrahedron Lett., 22, 1509 (1988), the preparation starts with lithium salt of N-methyI-l-naphthalenemethanamine, which subsequently reacts with propargyl bromide to give propargyl amine derivative. The product obtained is hydrozirconated by treating with zirconocene chlorohydride and after adding iodine (£)-3-iodoallyl amine is formed which reacts with zinc salt of 3,3-dimethylbut-l-yne using bivalent palladium catalyst (Scheme 4). 3
Scheme 4
The most simple preparation utilized the reaction of (£)-1,3-dichloropropene with //-methyl-1-naphthalenemethanamine and the product obtained, (£)-A/-(3-chloro-2-propenyl)-/V-methyl-1-naphthalenemethanamine further reacts with tm-butylacetylene in the presence of palladium catalyst, base and Cul (Scheme 5).
The preparation of the mixture E and Z (9:1) isomers of /V-(3-chloro-2-propenyl)-/V-methyl-1-naphthalenemethanamine has been described in detail in patents EP 0421302 and US 5231183 (JP 257310/89), wherein the starting reactant was the mixture of E and Z isomers of 1,3-dichloropropene and by subsequent purification by colon chromatography on silica gel pure E isomer vvas obtained, from which in the second step pure E-isomer of terbinafine was prepared.
Scheme 5
4 LV 12955
Sandoz company also introduced the simplificated preparation of terbinafine by the same synthetic way but for the preparation of (£)-N-(3-chloro-2-propenyl)-./V-methyl-l-naphthalenemethanamine pure (ZsH^-dichloropropene was used (Chimia 50, No. 4, 154, (1996)).
The preparation of (£)-jV-(3-chloro-2-propenyl)-A^-methyl-l-naphthalenemethanamine also in another publication: Teīrahedron Lett., 37, 57, (1996) has been described, wherein the isomeric pure (£)-l,3-dichloropropene was using as starting reactant, too.
Disclosure of the Invention
In the follovving, the process according to the present invention will be described. In the Scheme 6 reaction sequence of terbinafine preparation in the preferred embodiment of the invention is described. Starting materiāls as well as ali reactants are commercially available.
Scheme 6
(E)*isomer
Step 2 piperidine Et3N Cul, Pd2+ Y
CH3 —ch3 ch3
The advantages of the process described in present invention can be summarized into follovving points: 5 present invention discloses the process for the preparation of terbinafine in two reaction steps, described in Scheme 6, without any isolation and purification of intermediates (so called one pot reaction); the process is carried out in one solvent system common for the whole reaction sequence; the process by this way eliminates a time needed in steps of intermediates isolation and purification and eliminates the necessity for change of solvent system, resp., and therefore is far more effective than a process of step-by-step (stepped) preparation, what permits to enhance the capacity of manufacture; surprisingly terbinafine prepared by the process according to the present invention is qualitatively same as terbinafine prepared by step-by-step process, and a great surprise is quantitative yield of terbinafine; utilisation of pure isomer (£)-1,3-dichloropropene enables to prepare raw terbinafine without impurities of second isomer (Z).
Raw terbinafine obtained by the process of present invention may be purified in additional step and/or may be transformed into pharmaceutically acceptable salts. Method of optimal purification steps for terbinafine is described below.
Detailed Description of the Invention
In the first step N-methyl-l-naphthalenemethanamine reacts with (E)-l,3-dichloropropene, which is preferably in moderate excess, in the presence of base and catalyst natrium iodide in an inert solvent.
The excess of (£)-1,3-dichloropropene can be used from 0 to 100 %, wherein the optimum excess of this reactant is 10 % (mole percent).
The most preferable base in this step used is potassium carbonate, but natrium carbonate, natrium hydroxide, potassium hydroxide, natrium hydrogencarbonate, potassium 6 LV 12955 hydrogencarbonate, triethylamine, pyridine, n-butylamine, N,N-dimethylaniline, diisopropylamine or a mixture thereof can be used, too.
The amount of catalyst used natrium iodide can be in the range of 1 to 20 %, preferably is 10 % (mole percent).
As inert solvent can be acetone, ethylmethyl ketone, methylisobutyl ketone, dimethylformamide or a mixture thereof used, the most preferably acetone is used.
The reaction is carried out at temperature betvveen room temperature and the reflux temperature of solvent used. The most preferably reflux temperature for acetone and ethylmethyl ketone and temperature 80 °C for dimethylformamide is used.
Reaction time depends on reaction temperature and can be in the range from 1 to 48 hours, for the most preferably temperatures of solvents used is optimum reaction time two hours.
In the second step catalyst and co-catalyst together with a moderate excess of 3,3-dimethylbut-l-yne and excess of the base are added into the reaction mixture. As an solvent, the solvent system after the first step is ķept.
As catalysts in this step can be complexes of palladium with tertiary phosphines or combinations of palladium salts and palladium complexes with tertiary phosphines used.
The term "complex of palladium with tertiary phosphines" means the complex of zerovalent palladium or bivalent palladium with tertiary phosphines such as trialkyl or triaryl phosphines, comprising e. g. bis(triphenylphosphine)palladium chloride, bis(trimethylphosphi-ne)palladium chloride, bis(triphenylphosphine)palladium bromide, tetrakis (triphenylphosphi-ne)palladium.
The term "palladium salts" means salts formed by bivalent palladium, as e. g. palladium (II) chloride, palladium (II) bromide, palladium acetate or palladium sulfate.
The term "palladium complexes" means above mentioned complexes of palladium - tertiary phosphine and other complexes of zerovalent or bivalent palladium, as e.g. bis(benzonitrile) palladium chloride, bis(benzonitrile)palladium bromide, bis(acetonitrile)pa-lladium chloride, bis(phenylethylamine)palladium chloride. 7
The most preferably bis(benzonitrile)palladium chloride or bis(acetonitrile)palladium chloride is used. The amount of the catalyst used can be in the range from 0.2 to 10.0 %, the most preferably is the range from 0.5 to 1.0 % (mole percent).
As co-catalysts copper(I) or copper(II) salts are used, e. g. copper(l) chloride, copper(I) bromide, copper(I) iodide, copper(II) chloride, copper(II) bromide or copper(II) iodide.
The most preferably copper(I) iodide is used. The amount of the co-catalyst used can be in the range from 0.4 to 20.0 %, the range from 1.0 to 2.0 % (mole percent) is the most preferable.
As the base in the second step organic bases such as triethylamine, pyridine, piperidine, N,N-dimethylaniline, pyrrolidine, l-methylpiperazine, hexamethyleneimine, 4-dimethyl-aminopyridine or inorganic bases such as natrium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or a mixture thereof can be used. The most preferably piperidine is used, in the amount from 1 to 10 molar equivalents, optimally in the amount of 5 molar equivalents.
The second reaction step may be carried out at the temperature range from 5 to 40 °C, optimally at the temperature from 20 to 30 °C.
The following examples are intended to illustrate the invention without limiting its scope.
Examples
Example 1 fZP-N-f6.6-dimethvl-2-hepten-4-ynvl)-N-methyl-l-naphthalenemethanamine N-methyl-l-naphthalenemethanamine hydrochloride (20.77 g, 0.1 mol), potassium carbonate (29.02 g, 0.21 mol), (£)-1,3-dichloropropene (12.21 g, 0.11 mol), natrium iodide (1.50 g, 0.01 mol) and acetone (280 ml) are weighed into one litre three-necked flask equipped with magnetic stirrer, thermometer and reflux cooler. The mixture is then under stirring heated to the reflux temperature during two hours. Thereafter the mixture is cooled to room temperature and bis(benzonitrile)palladium dichloride (0.38 g, 0.001 mol), copper(I) iodide (0.38 g, 0.002 8 LV 12955 mol), piperidine (49.5 ml, 0.5 mol) and 3,3-dimethylbut-l-yne (16.0 ml, 0.13 mol) are added, and the mixture is stirred for the further 18 hours at room temperature.
Thereafter the mixture is concentrated under reduced pressure and concentrate obtained is stirred in the mixture of isohexanes (300 ml) and filtered through aluminium oxide layer (4 cm), subsequently the layer is once more with the mixture of isohexanes (300 ml) washed. The combined filter liquors are concentrated under reduced pressure to give about 31.0 g of raw terbinafine (quantitative yield). HPLC 96.3% (of area).
Example No. Change in the procedure in comparison with the procedure described in Example No. 1 Yield (%) HPLC (% of area) 2 instead of bis(benzonitrile)palladium chloride (0.38 g, 0.001 mol) bis(acetonitrile)palladium chloride (0.26 g, 0.001 mol) is used quantitative 95.1 3 instead of potassium carbonate (29.02 g, 0.21 mol) natrium carbonate (22.26 g, 0.21 mol) is used quantitative 96.1 4 instead of potassium carbonate (29.02 g, 0.21 mol) triethylamine (29.3 ml, 0.21 mol) is used quantitative 94.8 5 instead of acetone (280 ml, reflux) ethylmethyl ketone (280 ml, reflux) is used quantitative 95.3 6 instead of acetone (280 ml, reflux) dimethylformamide (280 ml, 80 °C) is used 85 90.2 7 instead of piperidine (49.5 ml, 0.5 mol) pyrrolidine (41.7 ml, 0.5 mol) is used quantitative 94.7 8 instead of copper(I) iodide (0.38 g, 0.002 mol) copper(I) bromide (0.29 g, 0.002 mol) is used quantitative 92.7 9 instead of piperidine (49.5 ml, 0.5 mol) triethylamine (69.7 ml, 0.5 mol) is used 23 85.9 10 instead of piperidine (49.5 ml, 0.5 mol) potassium carbonate (69.1 g, 0.5 mol) is used 9
Example 11 ('F)-N-('6.6-dimethvl-2-hepten-4-vnvlVN-methvl-l-naphthalenemethanamine hvdrochloride
Raw terbinafine from the Example 1 (31.0 g) is dissolved in isopropylalcohol (10 ml) and subsequently to this solution is added dropwise at temperature 5 °C up 10% solution of hydrogen chloride in isopropylalcohol (40 ml). After the adding is completed, mixture of isohexanes (40 ml) is added and the solution is stirred at temperature from 0 to 5 °C for two hours. Precipitated white crystalline product is aspirated, washed with mixture of isohexanes (10 ml) and dried to yield 29.8 g (91%) of terbinafine hydrochloride.
Melting temperature: 205-208 °C. HPLC: 99.7 % by weight.
Industrial Applicabilitv
The method according to this invention enables to prepare terbinafine or any of pharmaceutically acceptable salts thereof by the high effective and economic manner in the purity and quality used for active substance in medicament preparation. 10 LV 12955
CLAIMS 1. A method for the manufacture of (£)-N-(6, 6-dimethyl-2-hepten-4-ynyl)-N-methyl-l-naphthalenemethanamine (terbinafine) from N-methyl-l-naphthalenemethanamine comprising the following reaction steps:
Step 1:
Step 2 :
//-methyl-l-naphthaleae- propene
^-//-(3-cIiIoro-2-propcnyI)-Ar-methyl· 1 -naphthalcnemcthanamine i2£M,3-dlchlon>
(E}~N-Q -chIoro-2-propenyl>-iV-m£thy l-
H3C 3,3*diciethylbut-l-yiie
catalyst co-cataIyst base ®-/'/'-<6,6-<ūraethyl-2-heptea-4-ynyl)- //-racthyl-l-naphthaleaemethanainine characterized in that the amount of (£)-1,3-dichloropropene used is in the range of from 1.0 to 2.0 molar equivalent and that said reaction steps are carried out in the consecutive order without isolation and purification of the intermediate formed during 11 the process, as one-pot reaction, using one solvent system common for both the reaction steps. 2. The method according to claim 1 characterized in that the solvent system used for both reaction steps is acetone, ethylmethyl ketone, methylisobutyl ketone, dimethylformamide or a mixture thereof, preferably acetone. 3. The method according to claim 1 characterized in that the amount (£)-1,3-dichloropropene used is in the range of from 1.1 to 1.3 molar equivalent. 4. The method according to claim 1 characterized in that the base used in the first step is potassium carbonate, natrium carbonate, natrium hydroxide, potassium hydroxide, natrium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, n-butylamine, N,N-dimethylaniline, diisopropylamine or a mixture of these bases, preferably potassium carbonate. 5. The method according to claim 1 characterized in that the catalyst in the first step natrium iodide is preferably in an amount from 0.01 to 0.2 molar equivalent, more preferably in the amount of 0.1 molar equivalent. 6. The method according to claim 1 characterized in that the first step of the reaction sequence is carried out at the temperature preferably in the range from room temperature to reflux temperature of the solvent system used, more preferably at the temperature from 50 to 80 °C. 7. The method according to claim 1 characterized in that the catalyst in the second step is a palladium compound containing zerovalent or bivalent palladium, preferably complexes of palladium with tertiary phosphines, or combinations of palladium salts or palladium complexes, the most preferably bis(benzonitrile)palladium chloride or bis(acetonitrile)palladium chloride. 8. The method according to claim 1 characterized in that the co-catalyst of the second step of the reaction sequence is copper(I) halogenide or copper(II) halogenide, preferably copper(I) iodide. 12 LV 12955 9. The method according to claim 1 characterized in that the base used in the second step is piperidine, natrium carbonate, potassium carbonate, natrium hydroxide, potassium hydroxide, natrium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, n-butylamine, N,N-dimethylaniline, pyrrolidine, l-methylpiperazine, hexamethyleneimine, 4-dimethylaminopyridine or a mixture of these bases, in an amount of 1.0 to 10. 0 molar equivalents, preferably of 2.5 to 6.0 molar equivalents, the most preferably piperidine in the amount of 2 to 5 molar equivalents. 10. The method according to claim 1 characterized in that the second step of the reaction sequence is carried out at the temperature preferably in the range from +5 °C to reflux temperature of the solvent system used, more preferably at the temperature from 20 to 30 °C. 11. The method according to any of claims 1 to 10 characterized in that the resulting (£)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-l-naphthalenemethanamine is further purifīed in an additional purification step. 13 LV 12955
ABSTRACT
The method for the preparation of (£)-N-(6,6-dimethyl-2-hepten-4-ynyl)-/V-methyl-1 -naphthalenemethanamine (terbinafine) from A-methyl-1 -naphthalenemethanamine and (£)-l,3-dichloropropene and by subsequent reaction with 3,3-dimethylbut-l-yne characterized in that the whole reaction sequence is carried out without any isolation of intermediates. Ali sequential reactions are carried out in the solvent system common for the whole reaction sequence and inert to the reactants and intermediates present in the process. The method according to the present invention may also include additional purification steps.

Claims (4)

LV 12955 IZGUDROJUMA FORMULA 1. (£)-A/-(6,6-dimetil-2-hepten-4-inil)-A/-metil-1 -naftalīnmetānamīna (terbinafīna) ražošanas paņēmiens no /V-metil-1 -naftalīnmetānamīna, kas ietver sekojošas stadijas: 1. stadija:1. A method for the preparation of (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethanamine (terbinafine) from N-methyl-1 - \ t Naphthalene Methanamine, which includes the following steps: Step 1: /V-metil-1-naftalīn- (E)-1,3-dihlor- metānamīns propāns (£)-A/-(3-hlor-2-propenil)-/V-metil-1 -naftalīnmetānamīns 2. stadijaN-Methyl-1-naphthalene- (E) -1,3-Dichloro-methanamine propane (E) - N - (3-Chloro-2-propenyl) - N -methyl-1-naphthalenemethanamine Step 2 (E)-A/-(3-hlor-2-propenil)-/V-metil-1 -naftalīnmetānamīns H3C 3,3-dimetilbuM -īns(E) - N - (3-Chloro-2-propenyl) - N -methyl-1-naphthalenemethanamine H 3 C 3,3-dimethylbuM -in (£)-/V-(6,6-dimetil-2-hepten-4-inil)-/V-metil-1 -naftalīnmetānamīns katalizators, ko-katalizators, bāze raksturīgs ar to, ka izmantotais (£)-1,3-dihlorpropēna daudzums ir robežās no 1,0 līdz 2,0 molekvivalentiem un ka minētās reakcijas stadijas tiek veiktas secīgā kārtībā kā vienreaktora process bez starpprodukta, kas radies procesa laikā, izdalīšanas un attīrīšanas, 5 2 2 5 2 2 3. 10 4. 15 20 5. 6. 25 7. 30 35 8. izmantojot vienu šķīdinātāju sistēmu, kas ir kopēja abām reakcijas stadijām. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka abām reakcijas stadijām izmantotā šķīdinātāju sistēma ir acetons, etilmetilketons, metilizobutilketons, dimetilformamīds vai to maisījums, labāk acetons. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka izmantotais (E)-1,3-dihlorpropēna daudzums ir robežās no 1,1 līdz 1,3 molekvivalentiem. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka pirmajā stadijā izmantotā bāze ir kālija karbonāts, nātrija karbonāts, nātrija hidroksīds, kālija hidroksīds, nātrija hidrogenkarbonāts, kālija hidrogenkarbonāts, trietilamīns, piridīns, n-butilamīns, N,N-dimetilanilīns, diizopropilamīns vai šo bāzu maisījums, labāk kālija karbonāts. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka pirmajā stadijā katalizators nātrija jodīds labāk ir daudzumā no 0,01 līdz 0,2 molekvivalentiem, vislabāk daudzumā 0,1 molekvivalents. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka reakcijas gaitas pirmā stadija tiek veikta temperatūrā labāk robežās no istabas temperatūras līdz izmantotās šķīdinātāju sistēmas atteces temperatūrai, vislabāk temperatūrā no 50 līdz 80 °C. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka katalizators otrajā stadijā ir pallādija savienojums, kas satur nullvērtīgu vai divvērtīgu pallādiju, labāk pallādija kompleksus ar trešējiem fosfīniem vai pallādija sāju vai pallādija kompleksu kombinācijas, vislabāk bis(benzonitrila)pallādija hlorīds vai bis(acetonitrila)pallādija hlorīds. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka ko* katalizators reakcijas gaitas otrajā stadijā ir vara (I) halogenīds vai vara (II) halogenīds, labāk vara (I) jodīds. 3 LV 12955The (E) - [N- (6,6-dimethyl-2-hepten-4-ynyl) - N -methyl-1-naphthalenemethanamine catalyst, co-catalyst, is characterized by the use of (E) -1, The amount of 3-dichloropropene ranges from 1.0 to 2.0 molecular equivalents, and the said reaction steps are carried out sequentially as a single-reactor process without separation and purification of the intermediate produced during the process, 5 2 2 5 2 2 3. 10 4. 15 20 5. 6. 25 7. 30 35 8. Using a single solvent system common to both stages of the reaction. Method according to claim 1, characterized in that the solvent system used for both reaction steps is acetone, ethylmethylketone, methylisobutylketone, dimethylformamide or a mixture thereof, preferably acetone. Method according to claim 1, characterized in that the amount of (E) -1,3-dichloropropene used is between 1.1 and 1.3 molecular equivalents. Method according to claim 1, characterized in that the base used in the first stage is potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, n-butylamine, N, N-dimethylaniline, diisopropylamine or a mixture of these bases, preferably potassium carbonate. Method according to claim 1, characterized in that in the first step the catalyst iodide is preferably in an amount of from 0.01 to 0.2 molar equivalents, preferably in an amount of 0.1 molar equivalents. A method according to claim 1, characterized in that the first step of the reaction is carried out at a temperature preferably in the range of room temperature to the reflux temperature of the solvent system used, preferably at a temperature of 50 to 80 ° C. Method according to claim 1, characterized in that the catalyst in the second step is a palladium compound containing null or divalent palladium, preferably palladium complexes with tertiary phosphines or palladium soy or palladium complex combinations, preferably bis (benzonitrile) palladium chloride or bis (acetonitrile) palladium chloride. Method according to claim 1, characterized in that the catalyst in the second step of the reaction is a copper (I) halide or a copper (II) halide, preferably copper (I) iodide. 3 EN 12955 9. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka otrajā stadijā izmantotā bāze ir piperidins, nātrija karbonāts, kālija karbonāts, nātrija hidroksīds, kālija hidroksīds, nātrija hidrogenkarbonāts, kālija 5 hidrogenkarbonāts, trietilamīns, piridīns, n-butilamīns, N,N- dimetilanilīns, pirolidīns, 1-metilpiperazīns, heksametilēnimins, 4-dimetilaminopiridīns vai šo bāzu maisījums daudzumā no 1,0 līdz 10,0 molekvivalentiem, labāk no 2,5 līdz 6,0 molekvivalentiem, vislabāk piperidins daudzumā no 2 līdz 5 molekvivalentiem. 10Method according to claim 1, characterized in that the base used in the second stage is piperidine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium 5 hydrogen carbonate, triethylamine, pyridine, n-butylamine, N , N-dimethylaniline, pyrrolidine, 1-methylpiperazine, hexamethylenimine, 4-dimethylaminopyridine or a mixture of these bases in an amount of from 1.0 to 10.0 molar equivalents, preferably from 2.5 to 6.0 molecular equivalents, preferably piperidine in an amount of 2 to 5 molecular equivalents . 10 10. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka reakcijas gaitas otrā stadija tiek veikta labāk temperatūrā robežās no +5 °C līdz izmantotās šķīdinātāju sistēmas atteces temperatūrai, vislabāk temperatūrā no 20 līdz 30 °C. 15Method according to claim 1, characterized in that the second stage of the reaction is carried out at a temperature between + 5 ° C and the reflux temperature of the solvent system used, preferably at a temperature of 20 to 30 ° C. 15 11. Paņēmiens saskaņā ar jebkuru punktu no 1. līdz 10. punktam, kas raksturīgs ar to, ka rezultātā iegūtais (E)-/V-(6,6-dimetil-2-hepten-4-inil)-A/-metil-1-naftalīnmetānamīns tālāk tiek attīrīts papildus attīrīšanas stadijā.Method according to any one of claims 1 to 10, characterized in that the resulting (E) - N - (6,6-dimethyl-2-hepten-4-ynyl) -A-methyl -1-Naphthalene-methanamine is further purified at an additional purification stage.
LVP-02-193A 2000-04-07 2002-11-06 Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine) LV12955B (en)

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