WO1998015516A1 - Process for the preparation of a pharmaceutical intermediate - Google Patents

Process for the preparation of a pharmaceutical intermediate Download PDF

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Publication number
WO1998015516A1
WO1998015516A1 PCT/HU1997/000058 HU9700058W WO9815516A1 WO 1998015516 A1 WO1998015516 A1 WO 1998015516A1 HU 9700058 W HU9700058 W HU 9700058W WO 9815516 A1 WO9815516 A1 WO 9815516A1
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WIPO (PCT)
Prior art keywords
formula
solvent
dichloro
phenyl
naphthalene
Prior art date
Application number
PCT/HU1997/000058
Other languages
French (fr)
Inventor
Peter KÓTAY NAGY
József Barkóczy
Gyula Simig
Ilona SZTUHÁR
László BALÁZS
Imre Domán
Zoltán Greff
Zoltán RÁTKAI
Péter SERES
György CLEMENTIS
Tamás KARANCSI
László LADÁNYI
Original Assignee
EGIS Gyógyszergyár Rt.
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Publication date
Priority claimed from HU9602762A external-priority patent/HUP9602762A2/en
Application filed by EGIS Gyógyszergyár Rt. filed Critical EGIS Gyógyszergyár Rt.
Priority to AU48788/97A priority Critical patent/AU4878897A/en
Priority to SK341-99A priority patent/SK284671B6/en
Priority to PL332779A priority patent/PL192111B1/en
Priority to RO99-00294A priority patent/RO120194B1/en
Publication of WO1998015516A1 publication Critical patent/WO1998015516A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation

Definitions

  • This invention relates to a process for the preparation of a pharmaceutical intermediate.
  • the compound of the Formula I is a valuable intermediate which can be used in pharmaceutical industry for the preparation of pharmaceutical active ingredients.
  • the compound of the Formula I is useful in the preparation of sertraline, a known medicine which can be used against mental depression.
  • the chemical nomenclature of sertraline is cis-(1S,4S)-N-methyl-N-(3,3-dichloro-phenyl)-1 ,2,3,4-tetrahydro- -1 -naphthalene-amine.
  • the yield can be increased to 33 %
  • the contaminating isomer of the Formula II is a new compound not described in prior art.
  • the presence of this by-product is not desirable because if the amount of the 2,3-isomer of the Formula II in the desired 3,4-isomer of the Formula I exceeds 1 %, the corresponding contaminating 2,3-isomer appears also in the sertraline end product; in analoguous reactions this isomer cannot be removed to the desired extent.
  • the above object is achieved by subjecting the crude reaction product of the Formula I to a crystallization process to be described below and thereby reducing the amount of the isomer of the Formula II below a still tolerable limit.
  • the present invention is based on the recognition that the new 2,3-isomer of the Formula II not described in prior art has been isolated, identified by spectroscopical methods and a suitable process has been elaborated for the removal of this contamination A capillary GC and HPLC method has been elaborated for the qualitative side-by-side determination of the isomers of the Formulae I and II This process enables the control of isomer purity and served as basis for the elaboration of a purification method resulting highly pure compound of the Formula I
  • a C ⁇ -13 alkane methanol, ethanol, n-propanol or isopropanol
  • One may proceed preferably by using methanol for the crystallization
  • a C 6 10 alkane e g n-hexane, n-heptane, n- -octane
  • ether e g dioxane, diethyl ether, methyl tert butyl ether etc
  • One may proceed preferably by using as apolar solvent n-hexane or methyl-tert butyl ether
  • a solvent mixture containing an apolar solvent may also be used (e g a mixture of n-hexane and ethyl acetate or n-hexane and isopropanol)
  • the order of succession of the steps of the crystallization procedure are optional It is possible to crystallize the crude product at first from a polar solvent and thereafter from an apolar solvent or vica versa According to a preferred embodiment of the process one may proceed advantageously by crystallizing the crude product first from a polar solvent and thereafter from an apolar solvent or a solvent mixture containing an apolar solvent According to the process of the present invention, a 3,4- -isomer of the Formula I contaminated by less than 1 % - preferably less than 0.5 % - of the 2,3-isomer of the Formula II can be obtained.
  • the crude product of the Formula I used as starting material can be prepared by reacting o-dichloro-benzene and ⁇ -naphthol in a solvent as medium in the presence of a Friedel-Crafts catalyst.
  • an excess of the g-dichloro-benzene reagent plays the role of the solvent.
  • nitro-benzene, dichloro ethane, trichloro ethylene or carbon disulfide can be used.
  • the reaction is carried out in the presence of a Friedel- Crafts catalyst. It is preferred to use aluminium chloride, aluminium bromide, stannous (II) chloride or antimonic (V) pentafluoride, preferably aluminium chloride.
  • the reaction may be preferably carried out by using the ⁇ -naphthol : Friedel-Crafts catalyst : g-dichloro-benzene components in a molar ratio of 1:2:3 - 1:10:100.
  • the molar ratio of said components is particularly advantageously 1 :3:10.
  • the reaction may be performed at a temperature between 30°C and 200°C, preferably about 90°C.
  • the reaction takes place within some hours; the reaction time is generally 3-6 hours.
  • the reaction mixture may be worked up by known methods One may proceed preferably by pouring the reaction mixture in icecold water, extracting with an organic solvent (e g halogenated alkanes such as dichloro methane, chloroform, or other water-immiscible solvents, such as ethyl acetate) and washing, filtering and evaporating the organic layer
  • an organic solvent e g halogenated alkanes such as dichloro methane, chloroform, or other water-immiscible solvents, such as ethyl acetate
  • a HPLC method is used for the control of the standards.
  • TEAA buffer 10 ml triethyl amine, 10 ml glacial acetic acid, 1000 ml water
  • Injected volume 20 ml (about 4-5 mg/dissolved in 10 ml of acetonitrile, diluted with eluent)
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are heated to reflux in 188 ml of n-hexane until all the product goes into solution.
  • the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of n-hexane each.
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are stirred in 55 ml of a 9:1 mixture of n-hexane and ethyl acetate under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. In order to make crystallization complete the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of icecold n-hexane each.
  • the product thus obtained is stirred in 210 ml of n- hexane under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to render crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of icecold methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are heated in 50 ml of a 3:4 mixture of n-hexane and isopropanol to reflux until all the product is dissolved.
  • the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of ice-cold n-hexane each.
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are stirred in 40 ml of methyl-tert. butyl ether under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of ice-cold n-hexane each.
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a process for the preparation of highly pure 4-(3,4-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of formula (I), by reacting o-dichloro-benzene and α-naphthol in a solvent as medium in the presence of a Friedel-Crafts catalyst which comprises crystallizing the crude reaction product of formula (I) at least once from a polar solvent and at least once from an apolar solvent, whereby said crystallization steps can be carried out in optional order of succession, and whereby the amount of the by-product 4-(2,3-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of formula (II) is decreased below 1 %. The compound of formula (I) is a useful pharmaceutical intermediate. The advantage of the process is that the described compound is obtained in highly pure form.

Description

Process for the preparation of a pharmaceutical intermediate
Technical field of the invention
This invention relates to a process for the preparation of a pharmaceutical intermediate.
More particularly it is concerned with the preparation of 4-(3,4-dichloro-phenyl)-3,4-dihydro-1 (2H)-naphthaiene-1 -one of the Formula
Figure imgf000003_0001
Background of the invention
The compound of the Formula I is a valuable intermediate which can be used in pharmaceutical industry for the preparation of pharmaceutical active ingredients. Thus the compound of the Formula I is useful in the preparation of sertraline, a known medicine which can be used against mental depression. The chemical nomenclature of sertraline is cis-(1S,4S)-N-methyl-N-(3,3-dichloro-phenyl)-1 ,2,3,4-tetrahydro- -1 -naphthalene-amine.
Several methods are known for the preparation of the compound of the Formula I. The process disclosed in US patent Ns 4,536,518 is shown on reaction scheme 1 In the first step o-dichloro-benzene and benzoyl chloride are reacted to give the corresponding substituted benzophenone derivative In the next step said benzophenone derivative is subjected to a base catalyzed Stobbe condensation by reacting with diethyl succinate In the next step of the reaction sequence hydrolysis and decarboxylation are performed, e g in the presence of hydrogen bromide The mixture of the E- and Z-4,4-dιaryl-butane acids thus obtained is reduced with hydrogen in the presence of a catalyst From the 4,4-dιaryl- -butane acid derivative thus obtained acid chloride is formed with thionyl chloride which is converted to 4-(3,4-dιchloro- -phenyl)-3,4-dιhydro-1(2H)-naphthalene-1-one by cyclization in the presence of aluminium trichloride The disadvantage of the process is that it consists of many reaction steps and according to the US patent the overall yield is only 8 %
According to the method of Williams [Chem and Ind 316 (1990)] the yield can be increased to 33 %
In US patent Ns 4,777,288 a new and improved process is described for the preparation of suitably substituted 4,4- -diphenyl-butane acids The reaction is shown in reaction scheme 2 In the first step o-dichloro-benzene is reacted with succinic anhydride in the presence of a catalyst The 4-(3,4- -dιchloro-phenyl)-4-keto-butane acid thus obtained is reduced with sodium borohydπde, whereupon the butirolactone derivative formed is in situ subjected to Friedel-Crafts reaction with benzene without isolation Benzene acts as solvent too The diaryl butane acid derivative thus obtained is converted into the compound of the Formula I as described earlier in US patent Ns 4,536,518 The drawback of this process resides in the large number of the reaction steps, according to the US patent the overall yield is 60 %
The process disclosed in US patent N° 4,839,104 is shown in reaction scheme 3 The butirolactone derivative is converted into the desired naphthalene-1-one of the Formula I in the presence of a strong acid in one step without isolating the diaryl butane acid derivative formed as intermediate product As strong acid 98 % sulfuric acid, tnfluoromethyl sulfonic acid or hydrogen fluoride is used According to the US patent the highest yield (the overall yield of the 3 steps amounts to 82 %) can be achieved with hydrogen fluoride However the use of hydrogen fluoride requires an apparatus manufactured from poly-(tπfluoro-monochloro-ethylene) - Daiflon The drawback of this process is that a Daiflon apparatus is very expensive This process is accompanied by the further drawback that hydrogen fluoride is an extremely corrosive substance which can be used on industrial scale manufacture only under taking serious and expensive safety measures On using tπfluoro sulfonic acid good yield can be achieved too However this agent is so expensive that it makes the process uneconomical on industrial scale production When the reaction is carried out in the presence of sulfuric acid the yield is only 53 %, which value is not higher than that disclosed in US patent Ns 4,777,288 According to EP-A 346,226 4-aryl-substituted-1- -tetralone derivatives are prepared by reacting α-naphthol with the corresponding disubstituted benzene in the presence of an aluminium trihalide catalyst. According to the EP-A 4-(3,4- -dichloro-phenyl)-3,4-dihydro-1 (2H)-naphthalene-1-one of the Formula I is prepared as follows (the process is shown on reaction scheme 4).
A mixture of 1 mole of α-naphthol, 1.3 mole of o- -dichloro-benzene and 2.1 moles of aluminium trichloride is stirred at 65°C for 3 hours. The reaction mixture is poured on ice and the aqueous layer is extracted with g-chloro-benzene. The organic layer is dried, evaporated, the residue is dissolved in methyl-ethyl-ketone and clarified with charcoal. After filtration methanol is added, the solution is cooled to 0-4°C under stirring and the precipitated crystals are filtered. According to EP-A 346,226 the precipitated compound of the Formula I is obtained with a yield of 61 % and a GC purity of 98-99 %.
On reproducing the Example of EP-A 346,226 and subjecting the product having a GC purity of 98-99 % to profound analysis it has been found that it is not a uniform product but an about 95:5 mixture of 4-(3,4-dichloro-phenyl)- -3,4-dihydro-1(2H)-naphthalene-1-one of the Formula I and 4- -(2,3-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula
Figure imgf000007_0001
The contaminating isomer of the Formula II is a new compound not described in prior art. The presence of this by-product is not desirable because if the amount of the 2,3-isomer of the Formula II in the desired 3,4-isomer of the Formula I exceeds 1 %, the corresponding contaminating 2,3-isomer appears also in the sertraline end product; in analoguous reactions this isomer cannot be removed to the desired extent. Summary of the invention
It is the object of the present invention to prepare a highly pure compound of the Formula I which contains the contaminating 2,3-isomer of the Formula II in an amount below 1 %.
According to the present invention the above object is achieved by subjecting the crude reaction product of the Formula I to a crystallization process to be described below and thereby reducing the amount of the isomer of the Formula II below a still tolerable limit.
According to the present invention there is provided a process for the preparation of highly pure 4-(3,4-dichloro- -phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula
Figure imgf000008_0001
by reacting o-dichloro-benzene and α-naphthol in a solvent as medium in the presence of a Friedel-Crafts catalyst which comprises crystallizing the crude reaction product of the Formula I at least once from a polar solvent and at least once from an apolar solvent, whereby said crystallization steps can be carried out in optional order of succession, and whereby the amount of the by-product 4-(2,3-dichloro-phenyl)-3,4- -dihydro-1(2H)-naphthalene-1-one of the Formula
Figure imgf000008_0002
is decreased below 1 %.
Detailed description of the invention
The present invention is based on the recognition that the new 2,3-isomer of the Formula II not described in prior art has been isolated, identified by spectroscopical methods and a suitable process has been elaborated for the removal of this contamination A capillary GC and HPLC method has been elaborated for the qualitative side-by-side determination of the isomers of the Formulae I and II This process enables the control of isomer purity and served as basis for the elaboration of a purification method resulting highly pure compound of the Formula I
According to the process of the present invention preferably a Cι-13 alkane (methanol, ethanol, n-propanol or isopropanol) is used as polar solvent One may proceed preferably by using methanol for the crystallization
According to the process of the present invention as apolar solvent a C6 10 alkane (e g n-hexane, n-heptane, n- -octane) or ether (e g dioxane, diethyl ether, methyl tert butyl ether etc ) can be used One may proceed preferably by using as apolar solvent n-hexane or methyl-tert butyl ether
In the process of the present invention a solvent mixture containing an apolar solvent may also be used (e g a mixture of n-hexane and ethyl acetate or n-hexane and isopropanol)
According to the process of the present invention the order of succession of the steps of the crystallization procedure are optional It is possible to crystallize the crude product at first from a polar solvent and thereafter from an apolar solvent or vica versa According to a preferred embodiment of the process one may proceed advantageously by crystallizing the crude product first from a polar solvent and thereafter from an apolar solvent or a solvent mixture containing an apolar solvent According to the process of the present invention, a 3,4- -isomer of the Formula I contaminated by less than 1 % - preferably less than 0.5 % - of the 2,3-isomer of the Formula II can be obtained.
The crude product of the Formula I used as starting material can be prepared by reacting o-dichloro-benzene and α-naphthol in a solvent as medium in the presence of a Friedel-Crafts catalyst.
Preferably an excess of the g-dichloro-benzene reagent plays the role of the solvent. One may proceed preferably by carrying out the reaction in the absence of a further solvent, in an excess of the o-dichloro-benzene used as reactant. One may however also proceed by performing the reaction in an inert solvent. For this purpose e.g. nitro-benzene, dichloro ethane, trichloro ethylene or carbon disulfide can be used.
The reaction is carried out in the presence of a Friedel- Crafts catalyst. It is preferred to use aluminium chloride, aluminium bromide, stannous (II) chloride or antimonic (V) pentafluoride, preferably aluminium chloride.
The reaction may be preferably carried out by using the α-naphthol : Friedel-Crafts catalyst : g-dichloro-benzene components in a molar ratio of 1:2:3 - 1:10:100. The molar ratio of said components is particularly advantageously 1 :3:10.
The reaction may be performed at a temperature between 30°C and 200°C, preferably about 90°C. The reaction takes place within some hours; the reaction time is generally 3-6 hours. The reaction mixture may be worked up by known methods One may proceed preferably by pouring the reaction mixture in icecold water, extracting with an organic solvent (e g halogenated alkanes such as dichloro methane, chloroform, or other water-immiscible solvents, such as ethyl acetate) and washing, filtering and evaporating the organic layer
The advantage of the process of the present invention is that it is feasible economically and simply on industrial scale too, and gives highly pure compound of the Formula I which contains less than 1 % of the contaminating isomer of the Formula II
Further details of the present invention are to be found in the Examples without limiting the scope of protection to said Examples
Examples
Physical characteristics of the desired 4-(3,4-dichloro-phenyl)-
-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula I
Mp.: 101-102T
Elementary analysis Ci6H12CI20
C H CI calc. % 66.00 4.15 24.35 found % 65.77 4.05 25.15
IR (KBr) cm"1: 2952, 1675, 1593, 1471 , 1450, 1400, 1346, 1331 , 1287, 1252, 1204, 1153, 1028, 882, 823, 771 , 726, 670, 555, 447
1H-NMR (CDCI3): δ ppm (numbering Fig. 4): [8.12 dd (8Hz, 2Hz) (1 H), (H-8)]; [7.3-7.5 m(3H) (H-5, H-6, H-7)]; [7.24 d(1 H)(H-2')]; [6.95 m(2H),(H-5')(H-6')]; [4.28 dd(Jax8Hz, Jeq 4.5Hz) (1 H), (H-4)]; [2.68 m(2H)(H-2)]; [2.5 m(1 H)(H-3); 2.3m (1 H)(H-3)].
13C-NMR (CDCI3): δ ppm (numbering Fig. 4): (197.2 C-1);
(144.9 C-4a); (144.1 C-8a); (133.8 C-6); (132.8 C-3'); (132.7 C-4');
(130.99 C-1'); (130.57 C-2'); (130.49 C-5'); (129.2 C-6'); (127.9
C-5); (127.5 C-7); (127.36 C-8); (44.47 C-4); (36.4 C-2); (31.6
C-3).
MS AP I 291.
Physical characteristics of the contamination 4-(2.3-dichloro-
-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula II
Mp.: 66-70X
Elementary analysis Ci6H12CI20 C H CI calc % 6600 415 2435 found % 6567 4.01 2410
IR (KBr) v cm"1 2951, 1680, 1598, 1450, 1419, 1330, 1287, 1232, 1172, 1116, 1043, 922, 839, 772 739, 711, 558
1H-NMR (CDCI3) δ ppm (numbering Fig 4) [8 13 dd (8Hz, 2Hz) (1 H), (H-8)], [7 37-748 m(3H) (H-5, H-6, H-7)], [7,09 t (8Hz) (1 H) (H-5')], [6 95 dd (8Hz, 2Hz), (1H), (H-6')], [6 70 dd (8Hz, 2Hz) (1H) (H-4')([4 90 dd(Jax6 7Hz, Jeq 4 7 Hz) (1H), (H-4)], [2 66 m(2H)(H-2)], [2 39 m(2H)(H-3)
13C-NMR (CDCI3) δ ppm (numbering Fig 4) (197 7 C-1), (144 8 C-4a), (143,3 C-8a), (133 98 C-2'), (133 77 C-3'), (133 15 C-1'), (132 49 C-6), (129 38 C-6'), (129 04 C-4'), (128 33 C-5'), (127 53 C-7), (127 34 C-8), (127 27 C-5), (42 46 C-4), (36 12 C-2), (29 01 C-3) MS APXI 291
The following GC and HPLC conditions are used for the separation of the two isomers GC
GC Shimadzu GC9A column SUPELCO SPB5(15mx02mmlD- FD 02μm) temperature 50-250X, grad 10 mιn carrier gas N2 (19 8 cm/sec) inj at 250X 0 25 μl solution (MeOH) detector FID temperature 270X Retention time of 2.3-isomer: 11.08 min.
Retention time of 3.4-isomer: 11.83 min.
HPLC:
A HPLC method is used for the control of the standards.
Column: Cyclobond I (b-ciklodextrine) 5 mm, 25 cm x 4.6 mm (ASTEC)
Eluent: acetronitrile - 1 % TEAA buffer (25:75)
TEAA buffer: 10 ml triethyl amine, 10 ml glacial acetic acid, 1000 ml water
Flow velocity: 1.0 ml/minute
Detection: UV 254 nm
Injected volume: 20 ml (about 4-5 mg/dissolved in 10 ml of acetonitrile, diluted with eluent)
Calibration: 1.716 mg/ml
Retention time of the 2,3-isomer: 5.57 minutes
Retention time of the 3,4-isomer: 6.88 minutes
Example 1
4-(3,4-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one To a mixture of 5.19 g (36 millimoles) of α-naphthol and
30 g of 1.2-dichloro-benzene 15 g (112 millimoles) of anhydrous aluminium trichloride are added. The reaction mixture is heated to an internal temperature of 90X under slow stirring. The reaction mixture is kept at this temperature for 3 hours, poured on 170 g of crushed ice and extracted 4 times with 45 ml of ethyl acetate each. The organic phase is dried, clarified on charcoal and evaporated at 40-60X under a pressure of 53 Pa.
The substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux. The solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of methanol each.
The crystals thus obtained are dried under an infrared lamp for 24 hours. The dry crystals are heated to reflux in 188 ml of n-hexane until all the product goes into solution. The solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of n-hexane each.
Thus 8.2 g of the desired title compound are obtained, yield 60 %. The purity of the product amounts to 99.5 %, the amount of 4-(2,3-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene- -1-one formed in the reaction as by-product is below 0.5 %. Example 2 4-(3,4-dichloro-phenyl)-3,4-dihydro-1 (2H)-naphthalene-1 -one
To a mixture of 5.19 g (36 millimoles) of α-naphthol and 30 g of 1.2-dichloro-benzene 15 g (112 millimoles) of anhydrous aluminium trichloride are added. The reaction mixture is heated to an internal temperature of 90X under slow stirring. The reaction mixture is kept at this temperature for 3 hours, poured on 170 g of crushed ice and extracted 4 times with 45 ml of ethyl acetate each. The organic phase is dried, clarified on charcoal and evaporated at 40-60X under a pressure of 53 Pa.
The substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux. The solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of methanol each.
The crystals thus obtained are dried under an infrared lamp for 24 hours. The dry crystals are stirred in 55 ml of a 9:1 mixture of n-hexane and ethyl acetate under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. In order to make crystallization complete the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of icecold n-hexane each.
Thus 7.0 g of the title compound are obtained, yield 68 %. The purity of the product amounts to 99.5 %; the amount of 4-(2,3-dichloro-phenyl)-3,4-dihydro-1 (2H)- -naphthalene-1 -one formed in the reaction as by-product is below 0.5 %. Example 3
4-(3,4-dichloro-phenyl)-3,4-dihvdro-1 (2H)-naphthalene-1 -one
To a mixture of 5.19 g (36 millimoles) of α-naphthol and 30 g of 1.2-dichloro-benzene 15 g (112 millimoles) of anhydrous aluminium trichloride are added. The reaction mixture is heated to an internal temperature of 90X under slow stirring. The reaction mixture is kept at this temperature for 3 hours, poured on 170 g of crushed ice and extracted 4 times with 45 ml of ethyl acetate each. The organic phase is dried, clarified on charcoal and evaporated at 40-60X under a pressure of 53 Pa.
To the residue (9.8 g) at OX 30 ml of methanol are added. The precipitated crystals are filtered and washed twice with 5 ml of icecold methanol each.
The product thus obtained is stirred in 210 ml of n- hexane under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to render crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of icecold methanol each.
The crystals thus obtained are dried under an infrared lamp for 24 hours. The dry crystals are heated in 50 ml of a 3:4 mixture of n-hexane and isopropanol to reflux until all the product is dissolved. The solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of ice-cold n-hexane each.
Thus 7.0 g of the title compound are obtained, yield 67 %. The purity of the product amounts to 99.5 %; the amount of 4-(2,3-dichloro-phenyl)-3,4-dihydro-1 (2H)- -naphthalene-1 -one by-product formed in the reaction is below 0.5 %. Example 4 4-(3.4-dichloro-phenyl)-3,4-dihvdro-1(2H)-naphthalene-1-one
To a mixture of 5.19 g (36 millimoles) of α-naphthol and 30 g of 1.2-dichloro-benzene 15 g (112 millimoles) of anhydrous aluminium trichloride are added. The reaction mixture is heated to an internal temperature of 90X under slow stirring. The reaction mixture is kept at this temperature for 3 hours, poured on 170 g of crushed ice and extracted 4 times with 45 ml of ethyl acetate each. The organic phase is dried, clarified on charcoal and evaporated at 40-60X under a pressure of 53 Pa.
The substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux. The solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of methanol each.
The crystals thus obtained are dried under an infrared lamp for 24 hours. The dry crystals are stirred in 40 ml of methyl-tert. butyl ether under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of ice-cold n-hexane each.
Thus 6.1 g of the title compound are obtained, yield 58 %. The purity of the product amounts to 99.5 %; the amount of 4-(2,3-dichloro-phenyl)-3,4-dihydro-1 (2H)-naphthalene- -1-one formed in the reaction as by-product is below 0.5 %. Example 5 4-(3,4-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one
To a mixture of 5.19 g (36 millimoles) of α-naphthol and 30 g of 1.2-dichloro-benzene 15 g (112 millimoles) of anhydrous aluminium trichloride are added. The reaction mixture is heated to an internal temperature of 90X under slow stirring. The reaction mixture is kept at this temperature for 3 hours, poured on 170 g of crushed ice and extracted 4 times with 45 ml of ethyl acetate each. The organic phase is dried, clarified on charcoal and evaporated at 40-60X under a pressure of 53 Pa.
To the evaporation residue 125 ml of n-hexane are added at room temperature. A solution is formed; precipitation of crystals begins after about an hour. The mixture is stirred at room temperature for a further 12 hours and cooled to a temperature between -5X and -10X. The crystals are filtered, washed with 10 ml of ice-cold methanol and dried under an infrared lamp for 24 hours.
The substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux. The solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of methanol each.
Thus 6.6 g of the title compound are obtained. Yield 63 %. The purity of the product amounts to 99.5 %; the amount of 4-(2,3-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene- -1-one formed in the reaction as by-product is below 0.5 %.

Claims

What we claim is,
1) Process for the preparation of highly pure 4-(3,4- -dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula
Figure imgf000021_0001
by reacting g-dichloro-benzene and α-naphthol in a solvent as medium in the presence of a Friedel-Crafts catalyst w h i c h c o m p r i s e s crystallizing the crude reaction product of the Formula I at least once from a polar solvent and at least once from an apolar solvent, whereby said crystallization steps can be carried out in optional order of succession, and whereby the amount of the by-product 4-(2,3- dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula
Figure imgf000021_0002
is decreased below 1 %. 2) Process according to Claim 1 which comprises using a C1-3 alkanol as polar solvent.
3) Process according to Claim 2 which comprises using methanol as polar solvent.
4) Process according to Claim 1 which comprises using as apolar solvent a C5-ι0 alkane or an ether or a solvent mixture containing such solvent.
5) Process according to Claim 4 which comprises using as apolar solvent n-hexane or methyl-tert. butyl ether.
6) Process according to any of Claims 1-5 which comprises crystallizing the crude reaction product of the Formula I at first from a polar solvent and thereafter from an apolar solvent or a solvent mixture containing an apolar solvent.
7) Process according to any of Claims 1-6 which comprises decreasing the amount of the by-product of the Formula II below 0.5 %.
PCT/HU1997/000058 1996-10-09 1997-10-08 Process for the preparation of a pharmaceutical intermediate WO1998015516A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU48788/97A AU4878897A (en) 1996-10-09 1997-10-08 Process for the preparation of a pharmaceutical intermediate
SK341-99A SK284671B6 (en) 1996-10-09 1997-10-08 Process for the preparation of highly pure 4-(3,4-dichlorophenyl)-3,4,dihydro-1(2H)-naphtalene-1-one
PL332779A PL192111B1 (en) 1996-10-09 1997-10-08 Method of obtaining a pharmaceutic transient compound
RO99-00294A RO120194B1 (en) 1996-10-09 1997-10-08 Process for preparing high purity 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalene-1-one

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HUP9602762 1996-10-09
HU9602762A HUP9602762A2 (en) 1996-10-09 1996-10-09 Process for producing naphtalene derivatives
HUP9701137 1997-07-02
HU9701137A HU218599B (en) 1996-10-09 1997-07-02 Process for producing 4-(3,4-dichlor-phenyl)-3,4-dihydro-1-(2h)-naphthalene-1-on

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506940B1 (en) 2000-01-04 2003-01-14 Sun Pharmaceuticals Industries Ltd. Process for converting stereoisomers of sertraline into sertraline
JP2003514794A (en) * 1999-11-16 2003-04-22 チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド Method for preparing ketoimine
CN116041160A (en) * 2021-10-28 2023-05-02 上虞京新药业有限公司 Method for converting isossertraline into sertraline

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346226A1 (en) * 1988-06-08 1989-12-13 Synthelabo Process for the preparation of 4-aryl disubstituted-1-tetralones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346226A1 (en) * 1988-06-08 1989-12-13 Synthelabo Process for the preparation of 4-aryl disubstituted-1-tetralones

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 120, no. 9, 28 February 1994, Columbus, Ohio, US; abstract no. 106497, REPINSKAYA I B ET AL: "Condensation of 1-naphthol with ortho-dichlorobenzene in the presence of aluminum halides" XP000443777 *
SIB. KHIM. ZH. (SKZHEC);93; (3); PP.73-6, NOVOSIB. GOS. UNIV.;NOVOSIBIRSK; RUSSIA (RU) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003514794A (en) * 1999-11-16 2003-04-22 チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド Method for preparing ketoimine
EP1230212B1 (en) * 1999-11-16 2005-05-11 Ciba SC Holding AG Process for the preparation of ketimines
US6506940B1 (en) 2000-01-04 2003-01-14 Sun Pharmaceuticals Industries Ltd. Process for converting stereoisomers of sertraline into sertraline
CN116041160A (en) * 2021-10-28 2023-05-02 上虞京新药业有限公司 Method for converting isossertraline into sertraline

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SK34199A3 (en) 2000-03-13
CZ295766B6 (en) 2005-10-12
HUP9701137A3 (en) 1999-05-28
PL192111B1 (en) 2006-08-31
HU218599B (en) 2000-10-28
AU4878897A (en) 1998-05-05
HU9701137D0 (en) 1997-08-28
CZ120799A3 (en) 1999-09-15
HUP9701137A2 (en) 1999-04-28
SK284671B6 (en) 2005-08-04
RO120194B1 (en) 2005-10-28

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