The way of transformation of racemic trans-n-methyl-4-(3,4 - dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine in the cis - isomer

 

(57) Abstract:

A new way of turning the TRANS-isomer of N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine in the CIS-isomer of N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine.

The method includes providing interoperability of the TRANS-isomer of N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine or mixtures thereof with up to an equal weight parts with the corresponding CIS-isomer, with the main equilibrium agent such as tert-butoxide potassium in a reaction-inert polar organic solvent to a final obtain a mixture of CIS/TRANS-isomers, in which the number of CIS-amine present reaches a constant value of about 2:1 in calculating the weight/weight.

The above obtained mixture can be used as an intermediate product from which the result is pure CIS-/1S/ /4S/-H-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine (sertraline), which is known as an antidepressant. 6 C.p. f-crystals,.

The present invention relates to a method of recycling the TRANS-amine in the CIS-amine. More specifically, it relates to a new method of transformation of the TRANS-isomer of N-methyl-4-/3,4-dichlorophenyl-1,2,3-tetrahydro-1-naphthalenamine connection which leads to the obtaining of antidepressant known as CIS-/1S/ /4S/ N - methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine (sertraline).

In U.S. patent N 4536518 and 4556676 W. M. Welch, Jr. et. al. and in the article by W. M. Welch, Jr. et. al in the Journal of Medicinal Chemistr, Vol. 27, No. 11, p. 1508(1984) described a multi-stage method for the synthesis of pure racemic CIS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine, based on readily available 3,4-dichlorobenzophenone.

At the last stage of the synthesis of N-4-/3,4-dichlorophenyl/-3,4-dihydro-1-/2H/-naphthalenide/methenamine restore catalytic hydrogenation or using complex metalhydride to N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine, which in fact is a mixture of CIS - and TRANS-isomers in the form of a racemate.

Then the above isomeric mixture is separated into components by conventional means, for example, by fractional crystallization of the salts or hydrochloric through column chromatography with silica gel of the corresponding free base.

Separation of selected CIS-racemate free base compound in solution with optically-active selectively precipitating acid, for example, D -/-/-intertrain).

However, the above method of obtaining pure CIS -/1S//4S/ N - methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalenamine not profitable, as obtained at the same time large quantities of unwanted racemic TRANS-isomer (which inevitably leads to the formation of undesirable TRANS/1S//4S/-enantiomer), which must, in the end, to be discarded, thereby reducing the overall yield of the desired CIS-/1S//4S/-enantiomer and increases the cost of the product. Therefore, the aim of the present invention was used unwanted transisomer, which is the product, together resulting in the above synthesis, thereby reducing the total cost of production.

Another and more specific objective of the present invention is the conversion of the above transliterate free base to the corresponding CIS-isomer, and due to this recycling unwanted previously TRANS-isomer back to the method of the present invention obtain the target CIS-isomer.

Another and more specific objective of the present invention is the conversion of previously unwanted chiral TRANS/1S//4R/-isomer to the corresponding chiral CIS-/S//4S/-isomer, which is sertralina N-methyl-4-/3,4 - dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine in the CIS-isomeric N - methyl-4-/3,4 dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine, and this method includes the interaction of TRANS-isomeric N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4 tetrahydro-1-naphthalenamine in the absence or presence of up to equal the weight of the corresponding CIS-isomer with primary equilibrium agent such as 1,3 diazabicyclo [5,4,0] round-7-he, or low (C1-C4) an alkoxide of an alkali metal, such as tert.-piperonyl potassium, in a reaction-inert polar organic solvent at a temperature in the range of from about 55oC up to about 125oC as long as the number of target CIS-amine in the mixture of CIS/TRANS-isomers reaches a constant value of about 2:1 based on weight.

In this connection it should be borne in mind that when using the term TRANS-isomeric N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4 - tetrahydro-1-naphthalenamine imply that it includes not only racemic TRANS-compound, but also the corresponding chiral TRANS/1S//4R/- enantiomer, which can easily get out of it by dividing by the L -(+)-almond acid, which was first reported by W. M. Welch Jr. et. al. in the above with circulatory source material, such as pure racemic TRANS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalenamine, or 1:1 by weight mixture of the indicated TRANS-isomer with the corresponding CIS-isomer is converted into a mixture comprising up to about 2:1 by weight of CIS/TRANS-isomers in the simplest way.

As mentioned earlier, the last 2:1 resulting mixture is suitable as an intermediate product, which leads to the production of pure CIS -/1S//4S/-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalenamine (sertraline), which is known as an antidepressant.

Similarly chiral TRANS/1S//4R/ -N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydrofuryl-1 - naphthalenamine or 1:1 by weight mixture of the indicated TRANS-isomer with the corresponding CIS-isomers (i.e., chiral CIS-/1S//4S/-enantiomer) also turn in a mixture containing up to about 2:1 by weight of CIS/TRANS-isomers in the simplest way.

However, in the latter case, the resulting 2:1 CIS/TRANS mixture of chiral isomers leads directly to the receiving sertraline, as they do not require phase separation.

In accordance with the method of the present invention the reaction trims usually are using a molar excess of a basic agent ravnovesnogo material/, that is, the TRANS-isomer with up to about equal the weight part of the CIS isomer/, etc., and preferably, using the molar ratio of starting material/reagent in the range of from between below and up to about one mole of the specified source material per mole of the primary balancing agent, and a more preferred range from about 1.0:1.0 to about 1.0:3,0 to realize the target of the transformation of the TRANS-isomer to CIS-isomer, as discussed earlier.

Usually the way to lead in a reaction-inert polar organic solvent at a temperature in the range of from about 55oC to about 125oC and preferably in the range of from about 65oC to about 90oC as long, until it reaches the target conversion to a constant ratio of 2:1 (by weight) CIS/TRANS mixture.

The reaction usually trim requires a period of time at least four hours, although in practice it is preferable to conduct the reaction for about 40 hours.

Preferred reaction inert polar organic solvents for use in this connection include simple lower dialkyl (C4-C4) ethers containing a total of at least five carbon atoms, such as the e esters, as tetrahydrofuran and dioxane, alkylated glycols containing only four to eight carbon atoms, such as 1,1-diethoxyethane, 1,2-dimethoxyethane, 2-ethoxyethanol, 2-n-butoxyethanol, dimethyl ether of butyleneglycol and di-n-propyl ether of ethylene glycol, and lower N, N-dialkyl/lower/alkanolamide containing up to six carbon atoms (with at least one of these atoms is present in N, N - unsubstituted alkanolamides fragment), such as dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, dimethylpropanamide etc.

The preferred balancing agents that are used for the purposes of the present invention include 1,8-diazabicyclo[5.4.0] under-7-ene, 1,5-diazabicyclo[4,3.0]non-5-ene, 1,4-diazabicyclo[2.2.2] Octan, di-isopropylated lithium and tetramethylpiperidine lithium, and various lower alkoxides (C1-C4) metals, such as lower alkoxides (C1-C4) alkali metals, for example, ethoxide sodium tert-piperonyl potassium.

Optimal results are usually reached in the case when using dimethylformamide and similar alkanolamide together with the first three of these fundamental balancing agents, and t is their agents, such as tert.-piperonyl potassium, etc.

In the latter case, especially if tetrahydrofuran is used as solvent together with a balancing agent alkoxide type often proves to be more convenient and advantageous in practice to use a small amount of the corresponding lower alkanol to "activate" the above ether solvent, and thereby serve to further increase the solubility of the starting material and the final products contained in the selected solvent system.

Usually a small number of alkanol, for example 5 volume per total volume of the ether solvent, are sufficient for this purpose.

After completion of the reaction balancing target product, namely the pure racemic CIS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine or pure chiral CIS-/1S//4S/-enantiomer, can easily be distinguished from the reaction mixture by such conventional methods as, for example, first removing the solvent (viparita it under reduced pressure, and then dissolving the resulting residue in a lower chlorinated hydrocarbon solvent, such as methylene chloride, S-tetrachlorethane, chloroforme or che is astorias under reduced pressure to obtain previously served 2:1 (by weight) CIS/TRANS mixture (which is determined according to such analytical methods, as thin layer chromatography, liquid chromatography high-pressure spectroscopy nuclear magnetic resonance, and so on) in the form of the residue with oil.

If this oil is then dissolved in an ethereal solvent, for example tetrahydrofuran, and treated with dry gaseous kaleidotrope, for example, anhydrous hydrogen chloride, the target CIS-amine precipitates from the solution in crystalline form kaleidotrope salt, while the corresponding TRANS-amine remains in solution.

Thus, this source material as undesirable TRANS - N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-nataliyin or 1: 1 (by weight) mixture of the target CIS-isomer is easily converted into pure crystalline CIS - N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenemethanol, i.e. above 2:1 (by weight) CIS/TRANS mixture.

Similarly, unwanted chiral TRANS/1S//4R/-enantiomer is transformed into the target chiral CIS-/1S/-/4S'/ -enantiomer, i.e. CIS-/1S'//4S'/-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalene - minhydrochloride, as discussed earlier.

Pure racemic TRANS-N-methyl-4- /3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine source material, the cat is howling racemic CIS-Amin-target product, both are described as hydrochloric salt in the article W. M Welch, Jr. et. al. as described in Journal of Medicinal chemistry, 27, 11, p.1508/1984/ along with the corresponding free bases, and approximately 1:1 (by weight) mixture of racemic CIS - and TRANS-isomers (in the form of free amine bases) in crude form.

Pure racemic CIS-aminogidrohlorid also described in U.S. patent 4536518 W. M. Welen, Jr. et al. along with the crude mixtures of the two isomers in the form of a hydrochloric salt, whereas pure racemic TRANS-amidohydrolase also described in U.S. patent 4556676 W. M Welch et. al.

Pure chiral TRANS/1S//4R/-N-methyl-4- /3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine - source material, as described, as the hydrochloric salt in the above mentioned article W. M: Welch, Jr. et. al. along with the appropriate aminoven free basis.

As mentioned previously, a mixture of 2:1 (by weight) CIS/translucency N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine isomers is obtained as the end product of the method of the present invention and is a valuable intermediate product, which results in antidepressant known as sertraline or CIS-/1S//4S/-N-methyl-1,2,3,4 - tetrahydro-1-naphthalenamine.

,2,3,4 - tetrahydro-1-naphthalenamine grounds first converted into the corresponding hydrochloric salt in the system of the ether solvent, such as pure tetrahydrofuran, the solution is allocated exclusively pure crystalline racemic salt of CIS-amine in the form of a crystalline precipitate to obtain pure racemic CIS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalenamine-hydrochloride, which is then isolated and transformed back into pure racemic free base, and then divide by classical methods, using methods described by W. M. Welch Jr. et. al. in the above operation until final receipt target pure CIS-/1S//4S/N-methyl-4- /3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine (sertraline) in the form of a hydrochloric salt.

The corresponding 2: 1 (by weight) CIS/TRANS mixture of chiral N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalenamine isomeric bases obtained as the final product obtained by the method of the present invention in the form of an intermediate product to obtain sertraline, but there is no need to phase separation, as the target pure chiral CIS -/1S//4S/Amin (sertraline) get directly n the Oia offers a way of transforming undesirable TRANS-isomeric N-methyl-4- /3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1-naphthalenamine back to target pure CIS-isomer (racemic or chiral), and thus effectively recycle unwanted previously TRANS-isomer back in this way to obtain the specified target CIS-isomer.

The latter, in turn, is a major improvement compared with the known level, given the significant relief and ease of operation, reduced amounts of impurities and reduce the cost of production.

Example 1

A mixture consisting of 5.0 g (0,0164 mole) of racemic TRANS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalenamine (W. M. Welch, Jr. et. al. Journal of Medicinal Chemistry, Vol. 27, No. 11, 1508 (1984), dissolved in 60 ml of tetrahydrofuran, which also contains 3,09 ml of tert-butanol and 3,68 g (0,0328 mole) of tert-butoxide potassium, and heated to boiling under reflux for 48 hours.

After completion the solvent is removed, viparita under reduced pressure, and the obtained residue is placed in methylene chloride and washed successively with three portions of 60 ml of water, then dried over anhydrous magnesium sulfate.

After removal of the drying agent by filtration, and solvent

evaporation under reduced pressure the residue receive oil, which is 2: 1 (by weight) mixture of racemic qi is a furan, and then treated with anhydrous gaseous hydrogen chloride, CIS-amine precipitates in the form of hydrochloride, whereas TRANS-aminogidrohlorid remains in solution.

Thus, end up with 3.5 g (62) of pure racemic CIS-N-methyl-4-/3,4-defloriani/-1,2,3,4-tetrahydro-1 - naphthalenemethylamine (so pl. 275 277oC) in the form of a selected crystalline salt.

The melting points given in the literature for pure CIS - amine-hydrochloride and pure racemic transteminologization salt were 275 277oC 214 216oC, respectively, according to W. M Weleh, Jr. et. al B. Journal of Medicinal Chemistry, vol 27, N 11, p 1508 (1984).

Example 2

In the method of example 1 using as starting materials 5.0 g (0,0164 mole) of 1:1 (by weight) mixture of pure racemic TRANS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4 - tetrahydro-1-naphthalenamine and pure racemic CIS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydronaphthalene instead of one only of the corresponding pure TRANS-isomer, using the same molar ratio.

In this particular case, we get the corresponding final product is a residual oil, which, according to nuclear magnetic resonance, is 2:1 and 1.

Then the resulting mixture emit pure racemic CIS-N-methyl-4-/3,4-dichlorophenyl/-1,2,3,4-tetrahydro-1 - naphthalenemethanol (so pl. 275 277oC) according to the method of example 1.

In this case, the yield of pure product reaches 61% (based on the total number used in the source material.

1. The way of transformation of racemic TRANS-N-methyl-4-(3,4 - dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine in the corresponding racemic CIS-isomeric product, characterized in that the boil racemic TRANS-N-methyl-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine may contain up to about equal the weight of the corresponding CIS-isomer, with C1WITH4the alkoxide of the alkali metal in tetrahydrofuran in the presence of a1WITH4-AlkOH up until the number of target CIS-amine in the resulting CIS/TRANS-mixture reaches a constant value of about 2 to 1 in the calculation of the weight.

2. The method according to p. 1, characterized in that racemic TRANS-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine as the source material does not contain any significant amounts of the corresponding CIS-isomer.

3. The method according to p. 1, characterized in that as the source machackova TRANS-N-methyl-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalene-amine.

4. The method according to p. 1, characterized in that use molar excess agent equilibrium in relation to the total amount of N-methyl-4-(3,4-dichlorophenyl) 1,2,3,4-tetrahydro-1-naphthalenamine - source material.

5. The method according to p. 1 or 4, characterized in that the molar ratio of starting material N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4 - tetrahydro-1-naphthalenamine to C1WITH4-AlkOH is in the range from about 1.0 1.0 to about 1.0, and 3.0, respectively.

6. The method according to p. 1, characterized in that the use of tetrahydrofuran, mixed with a smaller amount of tert-butanol.

7. The method according to p. 1, characterized in that the pure racemic CIS-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine extracted from received 2 1 CIS/TRANS mixture in the form of kaleidotrope salt.

 

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5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing aniline and N-methylaniline. Method involves gas-phase catalytic reduction of nitrobenzene with methanol or formaldehyde aqueous solutions in preparing aniline and N-methylaniline and formaldehyde aqueous solutions in preparing aniline. Preferably, in preparing aniline and N-methylaniline method involves reduction with methanol an aqueous solution in the concentration 60-80 wt.-% in the molar ratio nitrobenzene to methanol = 1:(1.1-3.5). In preparing aniline method involves preferable reduction with formaldehyde aqueous solution in the mole ratio nitrobenzene to formaldehyde = 1:(1.5-4.0) and temperature 220-250°C. Also, invention relates to applying catalyst in preparing aniline and N-methylaniline comprising zinc, copper and chrome oxides on aluminum oxide and promoting with metal oxides from group comprising iron, manganese, bismuth, cobalt and molybdenum. The content of zinc is 0.1-10% of the catalyst mass, the total content of cooper and chrome is 0.05-15% to zinc mass, and the total content of other metals is 1.0-3.0% to the mass of zinc-copper-chrome components. Proposed method provides carrying out the process without feeding molecular hydrogen to the system with conversion of nitrobenzene up to 100% and the preferable preparing aniline and N-methylaniline depending on parameters of the process. On its base the effective manufacturing aniline and N-methylaniline can be organized using free powers of gas-phase catalytic manufactures.

EFFECT: improved preparing method.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel derivatives of fullerenes comprising organic amines and hydrogen atoms bound to fullerene-C60 molecule by 6,6-double bonds of the general formula: C60Hn(R1R2N)n wherein R1 means -C6H5CH2; R2 means -C6H5CH2; n = 4 (tetra-(dibenzylaminohydro)[60]fullerene); R1 means -C5H9; R2 means hydrogen atom (H); n = 3 (tri-(cyclopentylaminohydro)[60]fullerene). Also, invention relates to using derivatives of fullerenes, in particular, (tetra-(benzylaminohydro)[60]fullerene, (tetra-(dibenzylaminohydro)[60]fullerene, tri-(cyclopentylaminohydro)[60]fullerene, 2-(azahomo[60]fullereno)-5-nitropyrimidine, 1,3-dipropyl-5-[5'-(azahomo[60]fullereno)pentyl]-1,3,5-triazin-2,4,6(1H,3H,5H)-trione, O,O-dibutyl-(azahomo[60]fullereno)phosphate as acceptors of electrons in composites polymer/fullerene designated for photovoltaic cells. Also, invention relates to photovoltaic device comprising mixture of poly-conjugated polymer and abovementioned fullerene derivative or their mixture as an active layer. Also, invention relates to a method for synthesis of derivatives of fullerenes comprising aromatic amines and hydrogen atoms bound to fullerene-C60 molecule by 6,6-double bonds. Method involves interaction of C60 with the corresponding organic amine in solution, and this reaction is carried out in aromatic solvent medium in amine excess at temperature 25-70°C for 2-5 days followed by evaporation of solution and precipitation of the end product by addition of alcohol.

EFFECT: improved method of synthesis.

6 cl, 1 tbl, 2 dwg, 6 ex

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