WO2001009100A1 - Reductive methylation of tetrahydroisochinoline in a static micromixer - Google Patents

Abstract

The invention relates to a novel method of reductively methylating primary and secondary amines, preferably aliphatic, allylic, benzylenic and aromatic amines with methylation reagents that are known in the art.

Description

REDUCTIVE METHYLATION OF TETRAHYDROISOCHINOLINE IN A STATIC MICROMIC

The invention relates to a new process for the reductive methylation of primary and secondary amines, preferably of aliphatic, allylic, benzylic and aromatic, with methylation reagents known from the literature.

Reductive methylation is a common reaction in organic chemistry. The first step in this reaction is the reaction of an amine with formaldehyde. The imine formed as an intermediate is then reduced. The reduction can be carried out catalytically with hydrogen (Organikum, p.475, Johann Ambrosius Barth Verlag, Heidelberg and Leibzig, 1996; Loibner, H., Pruckner, A. and Stütz, A., Tetrahedron Letters 25, 2535, (1984) ) or chemically with complex hydrides (GW Gribble, CF Nutaitis, Synthesis (1987), 709). Both reactions cannot be transferred to the technical scale without special security measures.

Another very well-known reaction is the Leukart-Wallach reaction (Organikum, p. 534, Johann Ambrosius Barth Verlag, Heidelberg and Leipzig, 1996). Here, amines with carbonyl compounds are reductively converted by formic acid. The disadvantage of this reaction is that higher alkylated amines are formed as by-products and an excess of 85% formic acid has to be used under strongly acidic conditions.

A variant of this reaction, the Eschweiler-Clarke reaction, the well-to permethylating of amines suitable (Jerry March, Advanced Organic Chemistry ^3rd Ed. (1985) 799-800, John Wiley & Sons, New York).

A reaction is also known from the literature in which salts of phosphorous acid are used as reducing agents (Loibner, H., Pruckner, A. and Stütz, A., Tetrahedron Letters 25, 2535, (1984). Disadvantage of this reaction is that with strongly caustic phosphorous acid, which is blunted to pH 5-9 with sodium hydroxide solution, and with Formaldehyde, which is classified as carcinogenic, must be worked on.

It was therefore an object of the present invention to provide a process for the reductive methylation of primary and secondary amines which can be carried out simply and inexpensively and which does not pose any environmental hazard. It was also an object of the present invention to provide a simple and inexpensive process for the preparation of N-methyl-1, 2,3,4-tetrahydroisoquinoline.

The object is achieved by a process for the reductive methylation of primary and secondary amines, in that a) an aqueous NaH ₂ PO ₃ solution having a pH of about 6 is prepared from 30% phosphorous acid and aqueous NaOH solution, and this with b) an organic amine, or its hydrochloride, bromide, or iodide, preferably an aliphatic, allylic, benzylic or aromatic amine in liquid form or in solution, c) in a temperature-controlled microreactor, the outlet channel of which, if appropriate, with a temperature-controlled capillary is intensively mixed during a sufficient residence time, and the product formed during the reaction is isolated from the collected reaction mixture.

The microreactor used in the process is a temperature-controlled miniaturized flow reactor, with the aid of which the process can be carried out continuously. It is preferably a miniaturized flow reactor, the channels of which have a diameter of 25 μm to 1 mm.

The course of the reaction is followed by gas chromatography.

To carry out the process, the flow rate in the microreactor is set so that a residence time is obtained which corresponds at least to the maximum reaction time. The invention thus relates to a corresponding process in which the flow rate in the microreactor is set as process parameters such that a residence time of 1 min to 5 hours is achieved. In particular, a flow rate from 3 μl / min to 10 ml / min, preferably from 5 to 100 μl / min, is set.

The reaction temperature is in the range from 0 to 95 ° C. The reaction is preferably carried out at a temperature in the range from 30 to 60.degree.

A compound selected from the group of primary and secondary aliphatic, benzylic, allylic, aromatic and heterocyclic amines can be used as the organic amine in the process according to the invention. In particular, 1, 2, 3, 4-tetrahydroisoquinoline can be used as the amine.

If the amine to be reacted has to be dissolved for the reaction, a solvent selected from the group consisting of water, alcohol, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone and dioxane can be used as the solvent in the process according to the invention.

A solution can be used for the reductive methylation of primary or secondary amines, prepared from a NaH ₂ PO ₃ solution and an aqueous formaldehyde solution, in which NaH ₂ PO ₃ and formaldehyde in a molar ratio of 1: 1 to 1: 1.5, preferably 1 : 1 to 1: 1, 2 are included. At the same time, the molar ratio of the organic amine to the methylating agent is 0.8: 1 to 1: 1.5, preferably 1: 1 to 1.1: 1, 3.

Von den oben genannten Reaktionen erschien es am sinnvollsten, die in der Literatur beschriebene reduktive Methylierung mit Salzen der phosphorigen Säure als Reduktionsmittel näher zu untersuchen, da in diesem Fall weder feste Substanzen noch Wasserstoff oder Hydride in der Reaktion eingesetzt werden.Since N-methylated quinoline derivatives are important intermediates in the pharmaceutical industry, the N-methylation of 1, 2,3,4-tetrahydriisoquinoline to N-methyl-1, 2,3,4-tetrahydroisoquinoline should be considered here as a model:

Of the reactions mentioned above, it seemed to make the most sense to investigate the reductive methylation described in the literature with salts of phosphorous acid as reducing agents, since in this case neither solid substances nor hydrogen or hydrides are used in the reaction.

This reaction was also favored because all the reactants of these reactions are in solution. It therefore makes sense to try to investigate the applicability of the miniaturized flow reactors described in various publications and patent applications in recent years for these reactions. A particular advantage of these reactors is that there are only small amounts of reaction mixture in the reactor at all times. This type of reactor is therefore suitable for reactions that have to be carried out using particularly aggressive or environmentally hazardous chemicals.

Experiments have shown that under the condition that all substances remain in the dissolved liquid phase during the passage through the microsystems and do not precipitate out, reductive methylations with the following in the literature (Loibner, H., Pruckner, A. and Stütz, A., Tetrahedron Letters 25, 2535, (1984)) can be carried out.

Appropriate reactors were used for the experiments, which can be produced using technologies that are used in the production of silicon chips (Schwesinger, N., Marufke, O., Stubenrauch, M., Hohmann, M. and Wurziger, H. in MICRO SYSTEM Technologies 98, VDE-Verlag GmbH, Berlin and Offenbach 1998). Such reactors are preferably produced by connecting thin silicon structures to one another. However, comparable reactors can also be used which are made from other materials which are inert to the reaction media. What these miniaturized reactors have in common is that they have very thin channels which in themselves tend very easily to become blocked by particles contained or formed in the reaction solution. It has been found that the methylations according to the invention which

• aqueous formaldehyde solution and salts of phosphorous acid

be carried out in a static micromixer with good to very good yields. It has also been found that the selectivity of these reactions can be influenced by varying various parameters, such as concentration, temperature or residence time.

The advantage of methylation in microfluidic systems compared to the types of reactors commonly used is better mass and heat transport, improved control of the reaction time and increased safety with regard to a possible environmental hazard. This is due in particular to the very small amounts of reagent in the system.

Particularly good test results were achieved by using aqueous formaldehyde solutions and sodium dihydrogenphosphite solutions for the reductive amination.

Optimization experiments have shown that this reaction can be carried out in a continuous process with good to very good product yields in the miniaturized flow reactor under consideration. In this way, very small quantities can be used at any time. Sufficient product can be obtained at the same time per unit of time, since on the one hand, in contrast to a batch process, there are no idle times and, on the other hand, several reactions can be carried out in parallel in different reactors due to the small space and investment requirements for a single microreactor.

As primary amines in the process according to the invention, aliphatic amines selected from the group of open-chain, branched, cyclic and heterocyclic amines, allylic amines selected from the group of piperidines and pyrrolidines benzylic amines selected from the group benzylamine, N-alkyl-benzylamine, N-cycloalkyl-benzylamine, N-allyl-benzylamine, N-propargylbenzylamine and heteroaromatic methylamines (Ar-CH ₂ -NH ₂ ), aromatic amines selected from the group Anilines and heteroaromatic amines are used, and aliphatic amines selected from the group of open-chain, branched and cyclic amines, piperidines and pyrrolidines, allylic amines selected from the group of N-alkyl-N- as secondary amines. allyl- and the propargylamines benzylic amines, and aromatic amines, are used.

Compounds which are liquid at room temperature are preferably used as amines. However, it is also possible, as shown in the examples, to heat and liquefy the amine before mixing in the temperature-controlled microreactor. In such a case, however, it is more advantageous to dissolve it in a solvent which is inert in the reaction. Suitable solvents for this purpose are those from the group of hydrocarbons, ethers, chlorinated hydrocarbons, such as. B. dichloromethane, trichloromethane and carbon tetrachloride, alcohols, esters, tetrahydrofuran, and dioxane. In the process according to the invention, organic amines, preferably primary and secondary aliphatic, allylic, aromatic or heteroaromatic compounds, such as 1, 2,3,4-tetrahydroisoquinoline, can be reductively N-methylated.

To carry out the process according to the invention, the liquid or dissolved primary or secondary amine is reacted with an aqueous formaldehyde-containing sodium dihydrophosphite solution, the molar ratio of amine to formaldehyde being in the range from 0.8: 1 to 1: 1.5. Solutions are preferably used in which the ratio is between 1: 1 to 1.1: 1, 3, in particular with those at 1: 1. The selected ratio is based on the reactivity of the amine and the optimal value can therefore be very different. It is not only the molar ratio of the amine to the formaldehyde which has an influence on the result. The sodium dihydrophosphite contained as a reducing agent also has a decisive influence on the result. In general, aqueous formaldehyde-containing sodium dihydrophosphite solutions with a molar ratio of NaH ₃ PO ₃ to formaldehyde of 1: 1 to 1: 1.5 can be used. Those with a ratio of 1: 1 to 1: 1, 2 are preferably used and lead to good yields.

While test trials with 1, 2,3,4-tetrahydroisoquinoline at a flow rate of 100μl / min and a reaction temperature of 20 ° C did not lead to product formation, under otherwise identical test conditions but a temperature of 60 ° C in addition to 57.9% of the starting material Yield of N-methylated product of 35.8% found.

The flow rate was also changed in further experiments (see FIG. 1). At a flow rate of 10 μl / min and a reaction temperature of 30 ° C., a product yield of 25.75% was found in addition to 75.3% of the starting compound. By increasing the reaction temperature to 60 ° C, the ratio shifted optimally in favor of the desired product. 95.7% product and 4.3% starting material were found

Specifically, it was found that depending on the amine used, good to very good yields were achieved at flow rates of 3 μl / min to 10 ml / min. Particularly high yields were achieved with flow rates of 5 to 100 μl / min and otherwise optimally set process conditions.

The yield achieved is particularly influenced by the reaction temperature. While the reaction rate is generally very slow at 20 ° C, good product yields can already be achieved at 25 ° C, but especially at 30 ° C. By further increasing the reaction temperature to temperatures of up to about 70 ° C, the yield can be increased to almost quantitative values. Particularly in the reaction of 1, 2,3,4-tetrahydroisoquinoline, as already described above, an almost quantitative reaction takes place at a temperature of 60 ° C. under otherwise optimal conditions.

By varying both the flow rate and the temperature, the product yield and possibly also the formation of by-products in a reductive amination are strongly influenced.

However, it is possible for a person skilled in the art to optimally set these parameters in accordance with the respective reaction.

All attempts to carry out this reaction in the given flow reactor under otherwise constant process conditions but with higher flow rates than that which led to maximum product yields at a temperature of 60 ° C. were associated with reduced product yields, which is due to the fact that the reduced residence time in the reactor, the reaction obviously cannot be ended.

To increase the amount of product obtained per unit of time, it is also possible for the person skilled in the art to achieve an extended residence time with unchanged reaction conditions by varying the miniaturized flow reactor used, which makes it possible for him to increase the flow rate and at the same time tig to increase the achievable product quantity. However, it is also possible to pass the reaction mixture through two or more miniaturized flow reactors connected in series, so that the reaction can be terminated at an increased flow rate and the product quantity obtained can thus be increased.

A variation of the miniaturized flow reactor used is also to be understood to mean that, on the one hand, an increased number of the individual structures making up the flow reactor can be connected to one another, as a result of which the length of the thin tubules located in the flow reactor is increased. However, it is also possible for the person skilled in the art to achieve an extension by changing the position of the channels in the structures connected to one another. Various solutions to this problem are known from the patent literature.

To carry out the method according to the invention, such miniaturized flow reactors are particularly suitable whose channels have a diameter of at least 25 μm. It is even possible to use microreactors whose channels have a diameter of 1 mm, since the advantages described above can also be demonstrated here.

If the reductive methylation of a primary or secondary amine is carried out in a flow-through reactor with a larger diameter of the tubules through which flow passes, as already indicated above, the flow-through rate must be adjusted so that the residence time of the reaction mixture in the reactor is so long that the desired reaction can be ended, and an optimal product yield can be achieved. To end the reaction, however, it is also possible to connect the outlet channel of the static micromixer through which flow is carried out with a suitably long capillary tube of suitable diameter. After flowing through this capillary, the product formed can be worked up.

It is crucial for the choice of the miniaturized flow reactor to be used that the reaction mixture is uniformly mixed intensively in each volume element,

the channels are so wide that an unimpeded flow is possible without an undesirable pressure building up or that they become blocked by inhomogeneities,

the length and the diameter of the tubules through which flow takes place ensure a sufficient residence time for the reaction to end,

- A uniform temperature control is guaranteed in every volume element of the reactor, - Dense and secure connection options for supply and discharge of liquids, if necessary also for other equipment for reaction control or for analysis purposes,

- A tight connection of the individual parts or structures forming the microreactor is given both inside and outside, so that the

Liquid-carrying channels are separated from each other and no liquid can escape to the outside,

- Easy handling is guaranteed in the event of malfunctions.

For better understanding and clarification of the present invention, model examples are given below which are within the scope of the scope of the present invention but are not suitable for restricting the invention to these examples. As already mentioned above, the scope of the present invention also includes those reductive methylations of amines which are carried out using static miniaturized flow reactors which are also known to the person skilled in the art, but the flow reactors used for producing larger amounts of product in the same time unit can allow larger flow rates and also ensure both uniform temperature control and homogeneous mixing in each volume element of the reactor.

Examples

Starting solutions were prepared from: a) 10 ml of 30% phosphorous acid of commercial quality were mixed with 45 ml of a 1 N NaOH solution. The resulting solution solution had a pH of 6. 1 ml of a 35% strength aqueous formaldehyde solution was added to an aliquot of 10 ml of this NaH ₃ PO ₃ solution.

b) 1, 2,3,4-tetrahydroisoquinoline (0.3g) was dissolved in 10 ml of dioxane.

Two 2 ml disposable spouts were each filled with the 1, 2,3,4-tetrahydroisoquinoline solution and the NaH ₂ P0 ₃ / formaldehyde solution. The two disposable syringes were connected on the one hand to a "Harvard Apparatus pump 22" and on the other hand connected to a static silicone micromixer, to the outlet channel of which a 30 cm long Teflon capillary was connected.

The course of the reaction was monitored by gas chromatography using a Merck Hitachi HPLC instrument (L 6200 pump, variable wavelength UV detector and D 2500 chromato integrator). A Merck Lichrocart RP Select B 250/4 was used as the separation column. A mixture of 5% acetonitrile and 95% water, which in turn contained 1% trifluoroacetic acid, was used as the solvent. The wavelength of the detector was set to 215 nm.

Claims

PATENT CLAIMS 1. A process for the reductive methylation of primary and secondary amines, characterized in that a) an aqueous NaH ₃ P0 ₃ solution having a pH of about 6 is prepared from 30% phosphoric acid and aqueous NaOH solution, and this with b) an organic amine, preferably an aliphatic, allylic, benzylic or aromatic amine in liquid form or in solution, c) in a temperature-controlled microreactor, the outlet channel of which is optionally connected to a temperature-controlled capillary, is intensively mixed for a sufficient residence time, and the product formed during the reaction is isolated from the collected reaction mixture. 2. The method according to claim 1, characterized in that the microreactor used is a temperature-controlled miniaturized flow reactor. 3. The method according to claims 1 to 3, characterized in that it is a continuous process. 4. The method according to claims 1 to 4, characterized in that the course of the reaction is followed by gas chromatography. 5. The method according to claims 1 to 4, characterized in that a flow reactor is used, the channels of which have a diameter of 25 microns to 1 mm. 6. The method according to one or more of the preceding claims, characterized in that the flow rate in the microreactor is adjusted so that a residence time is obtained which corresponds at least to the maximum reaction time. 7. The method according to claim 6, characterized in that the Flow rate in the microreactor is set so that a residence time of 1 min to 5 hours is achieved. 8. The method according to claim 6, characterized in that a flow rate of 3 ul / min to 10 ml / min, preferably from 5 to 100 ul / min is set. 9. The method according to claims 1 to 8, characterized in that the reaction takes place at a temperature in the range of 0 to 95 ° C. 10. The method according to claims 1 to 8, characterized in that the reaction takes place at a temperature in the range of 30 to 60 ° C. 11. The method according to claims 1 to 10, characterized in that a compound selected from the group of primary and secondary aliphatic, benzylic, allylic, aromatic, heterocyclic amines and 1, 2,3,4-tetrahydroisoquinoline are used as the organic amine , 12. The method according to claims 1 to 11, characterized in that a solvent selected from the group as a solvent Water, alcohol, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone and dioxane is used. 13. The method according to claims 1 to 15, characterized in that a solution is used for reductive methylation, which is prepared from a NaH ₂ P0 ₃ solution and an aqueous formaldehyde solution, and wherein NaH ₂ P0 ₃ and formaldehyde in a molar ratio of 1: 1 to 1: 1, 5, preferably 1: 1 to 1: 1, 2, are included. 14. The method according to claims 1 to 13, characterized in that the molar ratio of the organic amine to the methylating agent is 0.8: 1 to 1: 1.5, preferably 1: 1 to 1.1: 1, 3. 15. The method according to claims 1 to 14 for the preparation of N-methyl-1, 2,3,4-tetrahadroisoquinoline.