HK1060879B - Method for the production of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1h-pyrrolizin-5-ylacetic acid - Google Patents

Description

The present invention relates to a process for the manufacture of 6- ((4-Chlorphenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl-acetic acid (ML300) and for the manufacture of intermediates resulting from this process

ML 3000 is a promising inhibitor of cyclooxygenase and 5-lipoxygenase and is therefore suitable for the treatment of rheumatic diseases and the preventive treatment of allergy-induced diseases, see for example Drugs of the Future 1995, 20 (10): 1007-1009. Other

The conversion is carried out into methylene chloride, ethanol or diethyl ether, and the hydrogen bromide formed during the reaction is captured by the addition of aqueous sodium bicarbonate solution.

The addition of the acetic acid residue to position 5 can then be achieved by transformation with diazoesist, an oxaliester chloride or oxalichlchloride and subsequent hydration or hydration and reduction of the ketone group with hydrazine.

The following implementation is described in Arch. Pharm. 312, 896-907 (1979):

The COCOCI grouping is then converted with diethylamine instead of the acetic acid group.

Raw material ML 3000, which is obtained as potassium salt after the hydrazine process and then excreted from the reaction mixture acidified with mineral acid, contains hydrazine, by-products and decomposition products (decarboxylation product and dimer) as impurities in addition to the water-soluble potassium salts, which require additional purification operations.

PCT/EP 01/00852 shows a process for the preparation of ML 3000 by conversion of 6- ((4-Chlorphenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H pyrrolizine with oxalic chloride and hydrazine, followed by a special treatment process, whereby, after conversion of the pyrrolizine with oxalic chloride, the resulting product is treated with hydrazine and an alkali metal hydroxide in an aqueous phase at elevated temperature, after finishing treatment, by addition of an ether which is not or only slightly miscible with water, a three-phase system is produced and ML 3000 is obtained by acidification of the intermediate phase.

In total, the synthesis is carried out at the steps given in the following formula:

The conversion of 2,2-dimethyl-1,3-propandiol with thionyl chloride is carried out in an inert organic solvent, e.g. a halogenated hydrocarbon or an ether, preferably at 0 to 60 °C. The further conversion of the resulting 5,5-dimethyl-1,3,2-dioxathiane-2-oxides with sodium cyanide to 4-hydroxy-3,3-dimethylbutyronitrile is carried out in DMSO at 80 to 120 °C. Step 1 yields about 93 to 99% and step 2 yields about 55 to 60% with good quality.

For step 3, conversion to 4-Chlor-3,3-dimethylbutyronitrile with thionyl chloride, a high purity precursor is required.

The 4-Chlor-3,3-dimethylbutyronitrile obtained in step 3 also needs to be distilled because of the high purity required for the subsequent Grignard reaction.

Additional technical problems arise from the fact that the raw materials from Stage 1 and 3 are highly acidic and lead to corrosion effects on the equipment.

If the 4-Chlor-3,3-dimethylbutyronitrile is of the required purity, the addition of the benzylmagnesium chloride-Grignard reagent at step 4 to 5-Benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrol and the subsequent cycling with ω-Brom-4-chloracetophenone at step 5 6- (((4-Chlorphenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine shall be of good quality and yield between 40 and 45% over both steps.

The pyrrolizine obtained in step 5 is finally converted by reaction with oxalic chloride, followed by reduction with hydrazine in the presence of an alkali metal hydroxide and acids, to 6- ((4-chlorophenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl acetic acid (ML 3000).

The known method provides ML 3000 with acceptable purity and yield but has some disadvantages such as problematic second and third stage chemistry, the need for extensive cleaning of intermediates before further reaction, particularly before the Grignard reaction, long operating times, and corrosion problems on the equipment when cleaning the highly acidic reaction products from Stages 1 and 3.

The present invention is therefore intended to provide a method for the production of 6- ((4-chlorophenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl-acetic acid (ML3000) which avoids these disadvantages of the state of the art. The method according to the invention is intended in particular to overcome the technical difficulties in stages I to 4 of the previous synthesis, to avoid the unpleasant chemistry of the second and third reaction stages of the synthesis, to avoid the Grignard reaction, to increase the total yield, to reduce stand times and thus to achieve a more economical overall synthesis.

The problem is solved by the formula I compounding method, Other wherein (a) the compound of formula IV Other in the compound of formula III Other The following is a list of the a) uses the compound of formula IV at a purity of more than 90% (w/w) and hydrolyzes it catalytically with anhydrous Raney nickel in toluene or a mixture of toluene and a C1 to C4 alcohol, or Other in which the R-residue, which may be equal or different, is converted to C1-C4-alkyl or to C2-C3-alkyl together and the ketal is catalytically hydrated with anhydrous Raney nickel at 5-50 bar hydrogen pressure in an alcoholic or aromatic solvent at a temperature in the range of room temperature to 70 °C; Other (c) introduces an acetic acid residue into the compound of formula II.

The present invention also relates to a method for the production of the compound of formula III by hydration of a compound of formula IV and ring closure, and the corresponding method for the production of the intermediate of formula II.

The introduction of the acetic acid residue into the compound of formula II is preferably by transformation with oxalic chloride and reduction of the ketone group, preferably with hydrazine and an alkali metal hydroxide.

The preferred method of the invention can be illustrated by the following reaction scheme:

The synthesis of compound IV is preferably carried out in the following steps: Manufacture of 2- (N-methylanil) acrylonitrile (V) from chloral acetaldehyde, N-methylaniline and an alkali metal cyanide, e.g. potassium cyanide. 2,2-Dimethyl-4-oxo-5-phenylvaleronitrile (IV) is produced by Michael's addition of isobuteroacid nitrile, deprotonated with a strong base, to the compound of formula V, benzylation of the Michael's addition product and hydrolysis of the resulting 2-benzyl-4,4-dimethyl-2- ((N-methylanilino) glutaronytryl. Other

The compounds of formulae IV and V and their production are known, for example, 2- ((N-methylanilino) acrylonitrile (V) is produced according to H. Ahlbrecht and K. Pfaff, Synthesis, 1980, 413.

However, the method for the production of 2- ((N-methylanilino) acrylonitrile (V) according to the above literature has the disadvantages that neither the conversion with sodium or potassium cyanide nor the basic elimination results in a complete turnover, that ether must be used for extraction and the product must be distilled for purification, with high losses due to decomposition. According to the invention, it is therefore preferable to modify and improve the literature methods and combine them in a multi-stage synthesis to produce the compound of formula III or formula II or I respectively.

The improvements of the invention are described below. They may be used individually or preferably in combination. According to the invention, the disadvantages described are avoided by using the starting products in different molar ratios and/or by introducing N-methylaniline instead of chloral acetaldehyde and adding the reaction partners and/or elimination in a two-phase system of hydrocarbon/sodium alkali with the addition of a transfer catalyst, preferably benzyl ethyl ammonium chloride. The preferred process conditions are given below:

Chloral acetaldehyde, N-methylaniline and potassium cyanide are used in a molar ratio of 1.1 to 1.3:1:1:1 to 1.3, in particular about 1.2:1:1:2. The addition of N-methylaniline is exothermic and cooling and/or rate of addition should be chosen so that the temperature does not exceed 25 °C. For this purpose, N-methylaniline can be dosed, for example, to a mixture of ice and concentrated hydrochloric acid.

Chloral acetaldehyde is added to N-methylaniline hydrochloride, preferably as an aqueous solution, maintaining a maximum temperature of 20 °C by appropriate rate of application and cooling if necessary, and potassium cyanide is added as an aqueous solution.

The addition of N-methylaniline, chlor acetaldehyde and potassium cyanide can also be carried out at significantly lower temperatures, for example below 0 °C. However, temperatures close to these upper limits are preferred as they allow for faster addition and require less cooling effort without adversely affecting the yield and quality of the product.

If the N-methylanil content of the suspension formed is less than about 10%, a non-miscible solvent with water, preferably an aliphatic or aromatic hydrocarbon, in particular toluene, is added and the intermediate 3-chloro-2- ((N-methylanilino) propionitrile is extracted into the organic phase. Elimination is then carried out in the two-phase toluene/sodium brine system. To accelerate and achieve complete elimination, a phase transfer catalyst, preferably benzyl triethylammonium chloride, is used. The temperature of the NaOH addition should not exceed 15°C, which may accelerate its concentration. The use of sodium hydroxide instead of potassium oxide may be used for elimination.

When the reaction mixture has reached a content of less than 0,5% 3-Chlor-2- ((N-methylanilino) -propionitrile, the product phase is separated and washed, if necessary, for example first with water and then with citric acid water. The organic phase is then dried, for example with magnesium sulphate, and if necessary filtered, preferably through a pressure filter. The resulting solution of 2- ((N-methylanilino) -acryl nitrile in toluene can be easily stored under nitrogen at - 15 °C to - 20 °C until further processing. Decomposition does not occur at these temperatures. The product is obtained in an excellent ca. 95%, based on methylanilene, nitrogenous.

The cyanide-containing waste water and washing fluids, as well as the filter residue, are treated.

The process to produce 2,2-dimethyl-5-phenyl-4-oxo-valeronitrile (IV) according to the above literature requirement works until benzylation of the Michael addition product at -78 °C. Benzylation is carried out with expensive benzyl bromide and hydrolysis and cyanide decomposition in acetonitrile requires a reaction time of approximately 40 to 50 hours.

The modification of the process to produce compound IV according to the invention does not require distillation of the raw product. The purification is carried out exclusively by recrystallization. The cyanide separation is carried out in the aqueous/organic system with the addition of a phase transfer catalyst, which can significantly reduce the reaction time. The process according to the invention is also simpler in that it does not require deprotonation and condensation at -78 °C. Further activation by carcinogenic hexamethylphosphoric acid triamide (HMPT) and the use of tetrahydramine and tetrahydramine to dry the process is not necessary. Finally, the use of benzyl benzyl chloride in place of pre-treated oil can be indicated in the following procedure conditions:

Isobutyronitril is dosed to a solution of a strong base in an inert solvent. For example, sodium amide, sodium naphthalenide and preferably lithium diisopropylamide (LDA) are suitable as strong bases. Deprotonation is preferably carried out in a hydrocarbon such as ethyl benzene as a solvent and at temperatures below 10 °C. The compound of formula V, preferably as a solution in toluene, is then dosed, with the temperature also preferably below 10 °C. The rate of accumulation of isobutyronitril and V compound should be chosen accordingly.

The preferred reaction temperature for the Michael addition is approximately -10 to -20 °C.

If the content of compound V in the reaction mixture has fallen below about 2%, benzyl chloride is dosed, preferably starting at a low temperature (about -10 to -20 °C) and then heating to, for example, about 50 to 55 °C.

When the content of 2,2-dimethyl-4- ((N-methylanilino) -glutaric acid nitrile has fallen to below about 2%, which takes several hours, cyanide separation is performed. For this purpose, the benzylized Michael addition product is generally not isolated, but is converted by acid hydrolysis, releasing hydrogen cyanide and methyl aniline, recombining the carbonyl group into 2,2-dimethyl-4-oxo-5-phenylvaleronitrile (IV). The hydrolysis is carried out after water addition, preferably under phase transfer catalysis.

For cyanide decomposition/hydrolysis, a strong mineral acid such as hydrobromic acid or hydrochloric acid is added and the reaction mixture is allowed to react, preferably at elevated temperatures, until the benzyl Michael addition product is reduced to less than about 0.5%. The organic phase is then processed in the usual way and the toluene is distilled. The temperature at the time of distillation should not exceed 50 °C. The residue of the distillation can then be purified by recrystallization or subjected to a single or multiple evaporation with isopropanol to remove toluene residues before recrystallization.

The recrystallization can be carried out in isopropanol, but toluene and mixtures of isopropanol and toluene are also suitable.

Because of the good solubility of Compound IV in isopropanol, it is necessary to cool it to crystallize, preferably at temperatures of -15 °C to -20 °C.

The resulting product may still be contaminated with Michael addition product after recrystallization, but such contamination is not a problem as it is easily removed during further conversions.

The next reaction step is to catalytically hydrate the resulting 2,2-dimethyl-4-oxo-5-phenylvaleronitrile (IV) to 2-benzyl-4,4-dimethyl-1-pyrroline (III).

In Arch. Pharm. 299, 518 (1966) the production of 2- ((4-hydroxyphenyl) -4,4-dihydro-3H-pyrrol by hydrogenation of 4-oxo- ((4-hydroxyphenyl) butanoic acid nitrile with Raney nickel is described.

Therefore, attempts have been made to shorten the reaction time and to reduce the formation of by-products, particularly by overhydration to pyrrolidine, showing that neither the increase in hydrogen pressure nor the increase in reaction temperature significantly shorten the reaction time, but that under these more energetic conditions the proportions of by-products, especially partial hydration products, oligomeric condensation products and hyperhydrogenated pyrrolidine, increase.

Surprisingly, it has now been found that the quality (purity) of the starting compound used in formula IV has a strong influence on both the time course and the by-product distribution of the hydration.

In the hydration of the nitrile ketone compound of formula IV using pyrroline of formula III, a tertiary nitrile group is reduced in two hydrate sub-stages to the neopentylamine group, which spontaneously condenses to the cyclic imine group under water cleavage with the ketone group. The cyclic imine group of pyrroline can be further hydrated to the secondary cyclic amine group in pyrrolidine. To prevent this, Raney nickel is used as a catalyst, but not, as usual, in aqueous form, but essentially anhydrous.

Another way to prevent overhydration is to introduce an acetal (ketal) protective group for the ketone group of the nitrile ketone, using the compound formula IVa. The hydration of the tertiary nitrile group to the neopentylamine group can be carried out under less selective conditions, using a compound of formula IVb Other The free pyrroline base is obtained by alkalizing the acidic aqueous solutions of the pyrrolynium salts, which can be separated by organic solvents which are not miscible with water and obtained in a highly pure form after removal of these solvents.

The preferred reaction conditions for the direct production of compound III by hydrogenation of the compound of formula IV are given below:

When a mixture of toluene and methanol is used as a solvent, preferably about 8 to 12 parts by volume of toluene/methanol per part by weight of compound V, the reaction temperature is generally about 50-60 °C. When hydrated in pure toluene, the temperature is chosen to be slightly lower, for example 20-30 °C, to prevent overhydration.

The Raney nickel submitted is dried prior to the reaction, for example by single or multiple slurries with absolute methanol or by azeotropic distillation.

If the reaction comes to a standstill before the theoretical amount of hydrogen is absorbed, the reaction mixture can be azeotropically distilled and fresh solvent added.

The Raney nickel is then sedimented and the remaining reaction solution is filtered. The catalyst can be used for further hydration if necessary. The solvent is distilled from the reaction solution. The product can be purified by salt formation, e.g. by hydrochloride formation and release of the compound of formula IV with a base, e.g. ammonia, and back-extraction.

Alternatively, only part of the solvent can be distilled, e.g. methanol in a toluene/methanol solvent mixture, in which case the distillation residue is preferably washed first with water and the product can be cleaned as described above after the water phase has been separated.

In the reaction line of the invention, the hydration can be greatly accelerated and by-reactions can be limited, in particular by using anhydrous Raney nickel as a catalyst and toluene or a mixture of toluene and methanol as a solvent.

The preferred reaction conditions for the production of compounds of formula III by hydration of cyclic or acyclic acetal (ketal) intermediates are given below:

The nitrile ketone of formula IV is converted to ketone by an alcohol in the presence of an acid catalyst in a solvent that forms an azeotropic with water or by the ketone conversion to ketone in an alcohol in the presence of equivalent amounts of an acetal or ketone of a low-boiling aldehyde or ketone.

Another preferred embodiment is the conversion to the dimethyl ketal in methanol with 1,1-dimethoxyethane in the presence of pyridinium tosylate at about 40 to 60 °C. The ketals are then treated with alkali and hydrated in the presence of a hydride catalyst. The invention is performed by hydrolysing the dioxyethane derivatives in the presence of Reta nitrate at a temperature of 5 to 50 °C. The product can be carried out in a fully aromatic solution, usually in the form of a solution of methanol or a solution of mineral amine, but usually in the form of a solution of alkali, such as in the case of the product RT III, where the product is formed by the formation of a catalyst.

The 2-benzyl-4,4-dimethyl-1-pyrroline of formula IV is then cycled with ω-brom-4-chloracetophenone to 6- ((4-chlorophenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine of formula III. The reaction is known from the state of the art mentioned at the beginning.

The implementation of the compounding of formula III with ω-bromo-4-chloracetophenone is generally done in a polar organic solvent. Suitable polar organic solvents are in particular C1-C4 alcohols, such as methanol, ethanol, isopropanol or ethers, such as diethyl ether, tetrahydrofuran (THF), or dioxane. According to the present invention, methanol is particularly preferred as a solvent. The reaction partners can be used in equimolar amounts. However, it is preferred to use the ω-bromo-4-chloracetophenone in excess, for example in an excess of 10 to 40% mol.

In order to intercept the hydrogen bromide released during the reaction, work is done in the presence of a base. Preferably, an inorganic base, especially an alkali metal hydrocarbonate or alkali metal carbonate, is used, with the sodium and potassium compounds being particularly preferred. The inorganic base can be used in the form of an aqueous solution. However, it has been shown to be particularly preferred to use the inorganic base in a solid form. This facilitates the separation of the inorganic reaction products and reduces the by-product stream.

The resulting raw product of formula II is separated, for example by centrifugation, and purified in the usual way by removing the mineral accompanying substances. To this end, the raw product is preferably immersed in warm water, for example at 40 to 45 °C, and treated for 1 to 2 hours. This results in the formula II compound having an average yield of 58% and a purity of at least 97%. The content of the isomer with the 4-chlorophenyl group at the 5 position is less than 2%, the content of bromine-4-chlorophenone is less than 0,1% and the content of mineral accompanying substances is less than 0,5%.

For the preparation of ML 3000 (1), an acetic acid side chain is introduced at the 5th position of the compound of formula II. This is preferably done by conversion of the compound of formula II to oxalic chloride and subsequent reduction with hydrazine and an alkali metal hydroxide. The reaction is described, for example, in WO95/32971, example 5C, and PCT/EP 01/00852. Different ways are described to purify the reaction product. According to ML 95/32971, the reaction product is isolated with a sub-lactate, acidified and the excess carbonic acid is absorbed in diethyl ether. The product is purified by draining the etheric solution with a drying agent, which is then further cooled to a temperature such as sodium sulphate or magnesium sulphate, while some of the concentrated sodium is concentrated and absorbed. In this process, some of the purified products are converted into water and some are allowed to stand for a further period of time.

The alternative purification method uses an ether and water added to the reaction mixture, if necessary at a higher temperature, after reduction with hydrazine and an alkali metal hydroxide. Preferably, an ether that is only slightly miscible with water, e.g. diethyl ether or methyl t-butyl ether, is used. The addition of the ether results in the formation of a three-phase system, the middle phase being the product phase, which consists essentially of the 3000 ml salt with the alkali metal hydroxide used in the conversion. The uppermost phase is the ether phase, in which the organic impurities are highly dissolved, and the highest phase is an alkaline phase, which contains organic fluids.

The phases are separated and the intermediate phase is mixed with a mixture of water and ether which is only slightly miscible with water, and then acidified with an inorganic or organic acid.

The extraction of ML 3000 from the ether phase may be carried out, for example, by evaporation of the ether and crystallization of ML 3000 from ethyl acetate or isopropanol to obtain solvates with 1 molecule of diethyl ether on 2 molecules of ML 3000 or 1 molecule of ethyl acetate on 2 molecules of ML 3000.

A substantially solvent-free crystalline modification of ML 3000 is obtained by adding to the ether phase at least one higher than ether boiling hydrocarbon, which, if necessary, is at least partially distilled from the ether and which normally separates the solid crystalline form of ML 3000 from the parent alkali.

The following examples illustrate the invention without limiting it.

Example 1 A) 2- (N-methylanilino) acrylonitrile (approximately 50% solution in toluene)

The greenish-yellow solution is stirred for 5-10 minutes at 15-20 °C. Starting at this temperature, an aqueous solution of chloraldehyde (45%, 34.2 kg, 196.1 mol) is stirred in water so that the internal temperature is kept below 20 °C (30 min). The reaction mixture is further stirred at 15-20 °C for 5-10 minutes and then stirred at this temperature with a solution of potassium (12.7 mol/l, 195.1 kg) in water for 5-10 minutes. The reaction is then carried out at a temperature of 110 °C (19.2 kg/l) and a critical solution of methacrylic acid is added to the solution.

The exiting bluonic acid is retained in a NaOH-filled absorber.

When the agitator is turned off, the water phase (114 kg, cyanide wastewater1) is deposited and transferred to a tank for disposal in a closed system.

To the blue-coloured organic phase, benzyltriethylammonium chloride (0.3 kg) is added and cooled to -5 to 0 °C. When this internal temperature is reached, sodium salt (30%, 32.6 kg) is added so that the internal temperature does not exceed 15 °C (30 min). After complete addition, the reaction mixture is heated on RT and stirred for another 50-70 min.

GC analysis of a sample shows a level of less than 0,5% for the intermediate 3-chlor-2- ((N-methylanilino) propionitrile. When this level is reached, wash with water (40,7 kg): add water, stir the two-phase mixture for 5-10 min, then settle the water phase (79 kg, cyanide waste water 2) and transfer it to the tank (to cyanide waste water I).

Wash the organic phase again in the same way with water (40,7 kg) acidified with citric acid (0,81 kg).

This citric acid water phase (45 kg, cyanide wastewater 3) is combined with the other cyanide wastewater. The organic phase is dried at RT (room temperature) using magnesium sulfate (3.8 kg) for 10-20 min. A Karl-Fischer titration results in a water content below 0.2%; this toluene solution (50-52 kg) is filtered through a pressure filter and filled for use in the next step. The filter residue (4.8 kg) is combined with the cyanide wastewater. These cyanide wastewater is added to the wastewater treatment. The solution is further processed at room temperature 45. The unstable solution of 2-N-Mylanethyl-acryl nitrile (53.86 mL) is removed to a high temperature of 0.2%.

Cyanide waste water is treated with 30% H2O2 and NaOH at pH 10-12 to a residual cyanide content below 30 mg/kg (< 30 ppm).

(b) 2,2-dimethyl-4-oxo-5-phenylvaleronitrile

Fill the dry, protective gas-washed apparatus (250 L steel boiler) with a lithium diisopropylamide solution in THF/n-hexane (25.1% w/w LDA solution, approximately 2M, 80.7 kg, 188.7 mol) and cool it to -15 to -20 °C by solar cooling under nitrogen. Under cooling, add isobutyronitrile (11.4 kg, 165 mol) to a temperature not exceeding -10 °C. After complete addition, rinse the intake vessel with toluene (2 kg) for 45 minutes.

The reaction mixture is stirred at temperatures of -10 to -20 °C for 55-65 min. The toluene solution of 2-N-methylanilino-acrylonitrile (47.1%; 52.8 kg; 157.2 mol) is then dosed in such a way that the temperature inside does not rise above -10 °C (90 min) at -20 °C under solar cooling. The intake vessel and ducts are rinsed with toluene (5.0 kg). The red-brown reaction mixture is stirred at -10 to -20 °C for 60-90 min. The content of educt (2-N-methylanilino-acrylonitrile) in a gasrinatographic analysis is below 2%.

When the cooling is switched off, benzyl chloride (23.9 kg, 188.8 mol) is added starting at -10 to -20 °C, increasing the internal temperature to 5 °C. When this temperature is exceeded, water cooling is used.

The reaction mixture is maintained at 50 °C to 55 °C for 3 to 4 hours, with a content of 2,2-dimethyl-4- ((N-methylanilino) -glutaric acid nitrile in a gas chromatographic sample below 2%.

The approach is then cooled to below 25 °C and transferred to a boiler containing a three-phase mixture of ice (22.6 kg), water (45.2 kg) and toluene (22.6 kg) (10 min). To rinse, toluene (14 kg) is used. This toluene/water phase mixture is then heated to 35-40 °C and the phases are separated. The clear backing (water phase, 75 kg) is removed and the intermediate layer is left in the organic product phase.

For the organic phase, benzyl triethylammonium chloride (3.4 kg) and ice (34.7 kg) are first administered and then hydrogen bromoacid (48%, 69.4 kg, 411.6 mol) is added for 10 min at 0-15 °C. This raises the temperature in the solution to about 50 °C and depletes the blue acid, which is retained in a solvent filled with baking soda (32%). After 6 h stirring at 50-60 °C, a sample is taken of the reddish-brown reaction mixture. The content of 4-benzyl-2,2-dimethyl-4-N-methylanil- (N-methylanil) -glutaric acid in the mixture should be below 0.5% according to GC analysis (GC = gas chromatography).

If this condition is met, the phases are allowed to settle for 10-15 min at an internal temperature below 60 °C and the dark water phase containing hydrocyanic acid (hydrocyanic acid, 90-110 kg) is transferred to a tightly sealed tank. The dark organic phase is cooled below 30 °C and then stirred with a mixture of water (22.5 kg) and baking soda (30% - 2.5 kg) for 5-10 min at 15-25 °C. The brightly coloured alkaline phase (pH 10-14) is allowed to settle and left to settle in a tank for further treatment (cyanide, 2.25 kg). The organic phase is then dissolved with water (25 kg) at 15-25 °C for 10-15 min, dissolved in water after being completely dissolved and the alkaline phase should be separated at pH 7-9 °C.

The toluene phase is transferred to a distillation apparatus, boilers and feedstock are rinsed with toluene (5 kg), toluene is completely distilled in a vacuum to a maximum of 50 °C (distillate 1a, 110-120 kg), the residue of distillation is absorbed into isopropanol (22,7 kg) and the solvent is then completely distilled in a vacuum to a maximum internal temperature of 60 °C (distillate 1b, 23 kg), and the azeotropic distillation with isopropanol (22,7 kg) is repeated in the same manner (distillate 1c, 23 kg).

The residual azeotropic distillation is taken at 25-30 °C with isopropanol (16 kg) and added to a mixture of isopropanol (8.0 kg) and heptane (26 kg) which is added to control crystallization of crystal germs of 2,2-dimethyl-4-oxo-5-phenylvaleronitrils (0.05 kg). The intake vessel and connecting lines are rinsed with isopropanol (2.0 kg). The suspension is cooled from - 15 °C to - 20 °C and stirred. The total is dried for at least 2 hours but not more than 16 hours. The crystal mass is sucked and analyzed in a pre-cooled mixture of isopropanol (8 kg) and heptanol (815 kg) at 90 - 120 °C. After a vacuum analysis, a further analysis of the product is obtained with a purity of 22,6 - 26,3 kg.

C) Purification of 2,2-dimethyl-4-oxo-5-phenylvaleronitrile

In a 250-I enamel reactor, 2,2-dimethyl-4-oxo-5-phenylvaleronitrile (85-90%, 22,3 kg, 110.8 mol) is suspended in a mixture of isopropanol (40.0 kg) and toluene (4.4 kg) and is fully dissolved by heating this mixture to 50-55 °C under stirring. The solution then cooled to 25-30 °C is filled on a stir-fryer filled with isopropanol (5 kg), the solution is injected with crystalline 2,2-dimethyl-4-oxo-5-phenylvaleronitrile (0.05 kg) and then cooled slowly to 5-10 °C. The solution is stirred until such a dipstict is dissolved.

The product is rubbed and washed twice with isopropanol (4,8 kg each) pre-cooled to -15 to -20 °C. The wet crystal mass (26,6 kg) is vacuum dried at 30-35 °C to obtain 16,6 kg of product (74,4% yield) with a purity of 96,1% (GC analysis).

D) 2-benzyl-4,4-dimethyl-I-pyrroline

Raney nickel (7.7 kg), previously removed from the aqueous residue by decanting, is coated with nitrogen gas in a 250-I steel autoclave and then suspended in methanol (67 kg) for 15 min. After the stirring is stopped, the Raney nickel is allowed to settle for 15-30 min and the methanol residue is squeezed with nitrogen through a pressure filter coated with Dicalite® via a plunger tube. The catalyst is coated with the solution of 2,2-dimethyl-4-oxo-5-phenyl-valeronitrile (13.2 kg) in toluene (92.4 kg) at 15-20 °C and coated with methanol (14.3 kg), which is rinsed after the addition of the tank of the diluent, diols the nitrogen. The catalyst is filled with up to 3 kg of nitrogen to release the nitrogen and release it into the air.Hydrogen is then flushed three times at I bar and finally the hydrogen pressure is increased to 4.5 - 5.5 bar. Hydration is started at 5.0 bar and 55 - 60 °C by turning on the stirrer. Hydrogen uptake stops after about 3 h, during which time 3.3 m3 of hydrogen is absorbed. The reaction mixture is cooled to 15-20 °C, the conduction is turned off and the hydrogen overpressure is relaxed. The apparatus is flushed with nitrogen 4 times and a sample is taken for reaction control.The two-phase mixture is stirred for 5-10 min, left for 20-30 min for phase separation and then the water phase (47-51 kg) is removed. At 15-20 °C, the organic phase (44 kg) and water (44 kg) are added and concentrated hydrochloric acid (32%, 17,7%) is added and stirred for about 5 minutes. The water-hydrochloric acid phase has a pH of 1-2 kg. The two phases are held for 5-10 min.The pH in the aqueous phase of the phase mixture should be 9-11 . The two-phase mixture is stirred for 5-10 min. The phases are then allowed to settle and the aqueous phase is separated. The toluene phase is transferred to a distillation apparatus by rinsing with toluene (5.5 kg) and the toluene is fully distilled in a vacuum at a temperature not exceeding 50 °C. The toluene phase can be used for extraction distillation.The pyrroline content is determined in an aliquot of the toluene phase (50 g) from which the dry residue is first determined by complete evaporation of the toluene in a vacuum, and this dry residue has a content of 70% of the desired 2-benzyl-4,4-dimethyl-1-pyrroline by GC.

From 100,7 kg of product solution, a yield of 54.7 mol 2-benzyl-4,4-dimethyl-1-pyrroline is calculated at a dry weight ratio of 13.74% in the 50 g sample and a GC content of 74.1%; with respect to oxovaleronitrile used, this yield is 84%.

E) 6- ((4-Chlorphenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

For the direct subsequent ring-termination synthesis of pyrrolizine, ω-bromo-4-chloracetophenone in 10 mol% excess (60,2 mol) and sodium hydrocarbonate in 36 mol% excess (74,4 mol) are used to the specific pyrroline (54,7 mol).

The stage D distillation residue is transferred to methanol (49 kg) at 15-20 °C, then to sodium hydrocarbonate (6.25 kg) and finally to ω-bromo-4-chloracetophenone (14.06 kg) under refrigeration. The resulting light yellow, thin liquid suspension is stirred in the absence of light for 17-20 h at 18-25 °C. The suspension is centrifuged and the centrifuge is washed with methanol (11 kg) in two portions.

The methanol sludge and methanol wash solutions are disposed of. 16.5-18.5 kg of wet raw material is obtained, which is slurred in water (88 kg) and stirred at 40-45 °C for 1-2 h. The mineral washed raw material is decentrifuged and washed with water (22 kg) in 2 portions. The yield of wet raw materials is 14-16 kg. The watery sludge and watery washing phases are discarded.

The raw product is dried in a vacuum at 35-40 °C. When dried, the weight of the product is reduced to 12,5-13,5 kg (38,4 mol-41,95 mol) 6- (dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine with a content of 97,3% (HPLC). This corresponds to a yield of 71,0-76,7% in relation to the pyrroline obtained in the hydration and a yield of 59-64% in relation to the oxo-valeronitrile used in the hydration. The content of isomeric 5- (dimethyl-7-phenyl-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine) is 2%, below the concentration of ω-B-chloroacetate and 0,1% below the concentration of 0,4% (A-B-chloroacetate).

Example 2

Steps A to C were carried out as in example I.

E) 2-benzyl-2- ((2-cyano-2-methyl_propyl) - 1,3-dioxolan

Oxovaleronitrile (50 g, 0.25 mol) is distilled with ethylene glycol (75 g, 1.21 mol) and p-toluol sulphonic acid (9.2 g, 0.048 mol) in toluol (300 ml, 260.1 g, 2.82 mol) and the reaction mixture is slowly heated to boil (2.5 h). After another 2 h of reflux, the solution is checked by GC. The toluol is distilled during the heating and reflux phases and replaced by dry solvents (185.3 g). The solution is cooled to dry N2 until processed. To process the solution, the raw product is separated by an ice-cold water extractor (25 g, 0.625 mol NaOH) on 150 g of ice. The solution is then filtered with magnesium nitrate (0.4 g, 127.5 mol) and the result is a magnesium nitrate (0.3 g, 127.5 mol) after filtration.

F) 2-benzyl-4,4-dimethyl-1-pyrroline

The raw solution of the dioxolan obtained under E) is introduced into a 1L autoclave and then 20 g of Raney nickel B113W (MG 58.71, 0.34 mol) which has been leached three times with anhydrous methanol is added together with 71.1 g of toluene. By pressing nitrogen three times and then relaxing, air oxygen is displaced from the autoclave. Hydration starts after three successive hydrogen injections and venting, a total hydration pressure of 48 bar is applied and the mantle temperature of the autoclave is set to 63°C (takes 3 h). Hydration in the 1L-A van requires further refilling with hydrogen after a further 23 h (approximately 17 h) of hydration and after a further 18 h (approximately 26 h) of hydration and 18 h (approximately 17 h) of pressurization.

The acetal is then broken down directly by taking the raw product into dilute hydrochloric acid (HCl 32%, 50 g, 0,43 mol in H2O, 200 g) and stirring it for 1 h at 30 °C. The organic residue (toluol phase) is removed and the aqueous phase is alkalinized at 0 to 5 °C with concentrated aqueous ammonia (25 %, 50 g, 0,73 mol) to a pH of 9 to 10. The separated pyrroline is taken up and separated into diethyl ether (200 g). After evaporation of the ether, 32,1 g of the product remains in the vacuum. The 2-benzyl-4,4-dimethyl-I-pyrroline is obtained in a purity of 69% and a purity of 92,6 % (GC).

When the dioxolan is purified by distillation (92%, GC) before use in the hydrogenation process, a higher rate of hydrogenation is achieved at lower pressures (5 bar) and lower temperatures.

Example 3 Manufacture of ML 3000: A) 5- (4-chlorophenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

17.9 kg (95.5 mol) of 2-benzyl-4,4-dimethyl-1-pyrroline (based on pyrrole content), 29.7 kg (127.2 mol, 1.33 equivalent) o-bromo-4-chloracetophenone and 226.6 kg methanol produced in accordance with example 1 or 2 are submitted to a reactor (500 1). After adding 12.7 kg (151.2 mol, 1.58 equivalent) sodium hydrocarbonate, the reaction is stirred to form a beige suspension at 17-24 °C under lighting conditions. The reaction is continued until the residual pyrrole content in the mixture is < 5%. After 17 h a sample is taken and examined for pyrrole content by chromatography. The product is obtained by an analysis of a 2 per cent concentration of methanol, which is a solid at a temperature of 18-22 °C, with a concentration of 14,8 kg. The product is then agitated in a gas containing two portions of methanol, and the product is agitated at a temperature of 14,8-22 °C.

The still moist raw product (25.8 kg) is suspended in 150 kg of water, then heated to an internal temperature of 50-60 °C within 15 min and stirred for 40 min The suspension cooled to 40 °C (40 min) is centrifuged and the bright yellow crystalline solid obtained by centrifugation is washed with 27 kg of water in two portions. The product is vacuum dried at 50-60 °C for 12-24 h. This gives 18,6 kg of 6- ((4-Chlorphenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, containing 0.33% ash and an isomeric content of 5- ((4-Chlorphenyl) -2,2-dimethyl-7-dihydro-2,3-dihydro-pyrrolizine of 1.0%.

B. 6- (4-chlorophenyl) -2,2-dimethy) -7-phenyl-2,3-dihydro-1H-pyrrolizine 5-yl acetic acid (ML-3000)

In a 250 1 reactor, after three evacuations and N2 injecting, 11.5 kg (35.7 mol) 6- (4-chlorophenyl) 2,2-dimethyl-7-phenyl-2,3-dihydro-1H pyrrolizine is introduced into 60 kg tetrahydrofuran (THF). The yellow solution is cooled to 10-15 °C at 0.5 bar nitrogen (N2) flow. Then 6.8 kg (54.7) mol oxalic chloride is added from a tank for 35 minutes at N2 at a temperature not exceeding 20 °C.

After completion of addition, the dark green thin suspension is stirred for 20 to 30 minutes at an internal temperature of 18-25 °C.

In a 500 1 reactor, 18 kg of ice is put in shells and the 25 °C warm suspension is added to this ice for 5 min so that the internal temperature of the mixture does not exceed 20 °C.

The reaction mixture is stirred for 10-20 min at an internal temperature of 25-35 °C. The still green solution is diluted at 25-35 °C with 62.2 kg diethylene glycol. Then 14.9 kg (298 mol) of hydrazine hydrate is added from a cooling container for 10-15 min. The internal temperature rises to a maximum of 40-45 °C. By gradually raising the temperature for 1.5 h, the meanwhile beige-colored suspension is heated to an internal temperature of 70-75 °C, with THF distilled.

The reaction mixture is cooled to 50-55 °C and, in 8 to 10 servings, spread over 45 min, placed in a total of 26.4 kg of potassium hydroxide in flakes (KOH), with the internal temperature rising to 65-70 °C already after the first 5 kg of KOH and the initially thick suspension turning yellow, becoming thinner and with a short-term slight reflux.

This suspension is heated from 15 °C/h to 90 °C, with a slight foaming and thickening of the suspension starting at 85 °C. With a temperature increase of 2 °C/h, the internal temperature is raised to 102 °C and at the same time, with increased turning speed, nitrogen is blown through the reaction mixture by the submersible tube. By strong foaming and additional gas development, the volume of the reactor core increases to double.

The reaction mixture is stirred for 10-15 min at an internal temperature of 30-33 °C, then the phases are allowed to settle. The resulting three-phase system is separated. The lower apparatus aqueous phase, weighing 154.9 kg, is colorless and only slightly turbid. It is disposed of as wastewater. The yellowish, cloudy intermediate phase of oily consistency is as much as 29.6 kg and contains the main product of calcium. The upper, clear, yellowish, distilled ether phase is removed at 30 °C. The extraction phase is carried out in a 10 to 10 minutes (19.9 to 10 kg) with an extraction phase of 10 to 10 kg of water and the extraction phase is dissolved in water and dissolved in water.

A mixture of 6.0 kg of 32.5% hydrochloric acid and 6.0 kg of water is then dosed over a receptacle for 15 min to a maximum internal temperature of 10 °C and a pH of 1-2. If this pH is not reached, a further 0.2 kg of 32.5% hydrochloric acid is added to the mixture with 0.2 kg of water. After this pH is reached, the phases are stirred well for another 5-10 min and then left to stand for 10-20 min in a phase-off stirring.

The hydrochloric acid phase is drained, the ether phase is re-administered through the intake vessel with a mixture of 9.5 kg hydrochloric acid and 19 kg water and stirred well for 5-10 min at an internal temperature not exceeding 10 °C. The phases are separated and the hydrochloric acid treatment is repeated up to 3 times if desired.

The ether phase is then mixed with 30 kg of demineralized water, stirred well for 10-20 min and heated to 15-20 °C. The phases are separated and the extraction is repeated.

The acid-free ether phase is replaced by 6,5 kg anhydrous magnesium sulphate and 0,4 kg activated carbon (Acticarbon 2S) which are slurried in 1 kg diethyl ether and stirred for 30-45 min at 18 °C. The suspension is clear-filtered into a distillation apparatus using a pressure filter with a cell flock of 0,5 kg. The filter and apparatus are rinsed with 8 kg diethyl ether.

The resulting crystal suspension is cooled to an internal temperature of 13-18 °C and stirred for 0.5 to 1.5 h at this temperature. The crystals are then decentrifuged. The resulting wet product is washed with 23.0 kg of heptane in 2 servings, the wet product is dried overnight at 50-60 °C in the dryer and ground if desired.

Claims (12)

1. Process for the preparation of the compound of the formula I, where

   a) the compound of the formula IV is converted into the compound of the formula III by

   a1) employing the compound of the formula IV in a purity of more than 90% (m/m) and catalytically hydrogenating the compound using anhydrous Raney nickel in toluene or a mixture of toluene and a C₁-C₄-alcohol, or

   a2) converting the compound of the formula IV into the ketal of the formula IVa in which the radicals R, which can be identical or different, are C₁-C₄-alkyl or together are C₂-C₃-alkylene, and catalytically hydrogenating the ketal using anhydrous Raney nickel at 5-50 bar hydrogen pressure in an alcoholic or aromatic solvent at a temperature in the range from room temperature to 70°C,

   b) reacting the compound of the formula III mit ω-bromo-4-chloroacetophenone to give a compound of the formula II and

   c) introducing an acetic acid radical into the compound of the formula II.
2. Process for the preparation of the compound of the formula II where the compound of the formula IV is converted into the compound of the formula III by

   a1) employing the compound of the formula IV in a purity of more than 90% (m/m) and catalytically hydrogenating the compound using anhydrous Raney nickel in toluene or a mixture of toluene and a C₁-C₄-alcohol, or

   a2) converting the compound using anhydrous Raney nickel in toluene or a mixture of toluene and a C₁-C₄-alcohol, into the ketal of the formula IVa in which the radicals R, which can be identical or different, are C₁-C₄-alkyl or together are C₂-C₃-alkylene, and catalytically hydrogenating the ketal using anhydrous Raney nickel at 5-50 bar hydrogen pressure in an alcoholic or aromatic solvent at a temperature in the range from room temperature to 70°C, and

   b) reacting the compound of the formula III with ω-bromo-4-chloroacetophenone to give a compound of the formula II.
3. Process for the preparation of the compound of the formula III where the compound of the formula IV is converted by catalytic hydrogenation into the compound of the formula III by

   a1) employing the compound of the formula IV in a purity of more than 90% (m/m) and catalytically hydrogenating the compound using anhydrous Raney nickel in toluene or a mixture of toluene and a C₁-C₄-alcohol, or

   a2) converting the compound of the formula IV into the ketal of the formula IVa in which the radicals R, which can be identical or different, are C₁-C₄-alkyl or together are C₂-C₃-alkylene, and catalytically hydrogenating the ketal using anhydrous Raney nickel at 5-50 bar hydrogen pressure in an alcoholic or aromatic solvent at a temperature in the range from room temperature to 70°C.
4. Process according to one of the preceding claims, characterized in that the compound of the formula IV is employed in a purity of at least 95%.
5. Process according to one of the preceding claims, characterized in that the compound of the formula IV is obtained by Michael addition of isobutyronitrile to a compound of the formula V benzylation of the Michael addition product to give 2-benzyl-4,4-dimethyl-2-(N-methyl-anilino)glutaronitrile and hydrolysis of this nitrile.
6. Process according to Claim 5, characterized in that the isobutyronitrile is deprotonated using lithium diisopropylamide in toluene.
7. Process according to Claim 5 or 6, characterized in that the reaction temperature in the Michael addition is in the range of approximately -10°C bis -20°C.
8. Process according to Claims 5 to 7, characterized in that the hydrolysis of the nitrile in the acid is carried out in acidic medium in a two-phase system under phase-transfer catalysis.
9. Process according to Claims 5 to 8, characterized in that the compound of the formula V is obtained by reaction of chloroacetaldehyde, N-methylaniline and an alkali metal cyanide and subsequent basic elimination.
10. Process according to Claim 9, characterized in that chloroacetaldehyde and then the alkali metal cyanide are added to N-methylaniline.
11. Process according to Claim 9 or 10, characterized in that chloroacetaldehyde, N-methyl-aniline and the alkali metal cyanide are employed in a molar ratio of approximately 1.1 to 1.3:1:1.1 to 1.3.
12. Process according to Claims 9 to 11, characterized in that the basic elimination is carried out in the two-phase system under phase-transfer catalysis.