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WO2001009100A1 - Methylation reductive de tetrahydroisoquinoline dans un micromelangeur statique - Google Patents

Methylation reductive de tetrahydroisoquinoline dans un micromelangeur statique Download PDF

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Publication number
WO2001009100A1
WO2001009100A1 PCT/EP2000/006319 EP0006319W WO0109100A1 WO 2001009100 A1 WO2001009100 A1 WO 2001009100A1 EP 0006319 W EP0006319 W EP 0006319W WO 0109100 A1 WO0109100 A1 WO 0109100A1
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WO
WIPO (PCT)
Prior art keywords
reaction
solution
temperature
microreactor
amines
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2000/006319
Other languages
German (de)
English (en)
Inventor
Hanns Wurziger
Norbert Schwesinger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Priority to AU65617/00A priority Critical patent/AU6561700A/en
Priority to EP00953012A priority patent/EP1200407A1/fr
Priority to JP2001514303A priority patent/JP2003506357A/ja
Publication of WO2001009100A1 publication Critical patent/WO2001009100A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/04—Formation or introduction of functional groups containing nitrogen of amino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00889—Mixing

Definitions

  • 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.
  • 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 ⁇ m to 1 mm.
  • 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.
  • a flow rate from 3 ⁇ l / min to 10 ml / min, preferably from 5 to 100 ⁇ l / 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.
  • 1, 2, 3, 4-tetrahydroisoquinoline can be used as the amine.
  • 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.
  • 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.
  • 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:
  • the reaction 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.
  • 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.
  • 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
  • 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
  • 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.
  • amines which are liquid at room temperature are preferably used as amines.
  • 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.
  • organic amines preferably primary and secondary aliphatic, allylic, aromatic or heteroaromatic compounds, such as 1, 2,3,4-tetrahydroisoquinoline, can be reductively N-methylated.
  • 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.
  • 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.
  • 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.
  • 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.
  • Various solutions to this problem are known from the patent literature.
  • miniaturized flow reactors are particularly suitable whose channels have a diameter of at least 25 ⁇ m. 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.
  • 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.
  • the channels are so wide that an unimpeded flow is possible without an undesirable pressure building up or that they become blocked by inhomogeneities,
  • Liquid-carrying channels are separated from each other and no liquid can escape to the outside,
  • 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.
  • 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.
  • the wavelength of the detector was set to 215 nm.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de méthylation réductive d'amines primaires et secondaires, de préférence, d'amines aliphatiques, allyliques, benzyliques et aromatiques par des réactifs de méthylation connus.
PCT/EP2000/006319 1999-07-29 2000-07-05 Methylation reductive de tetrahydroisoquinoline dans un micromelangeur statique Ceased WO2001009100A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU65617/00A AU6561700A (en) 1999-07-29 2000-07-05 Reductive methylation of tetrahydroisochinoline in a static micromixer
EP00953012A EP1200407A1 (fr) 1999-07-29 2000-07-05 Methylation reductive de tetrahydroisoquinoline dans un micromelangeur statique
JP2001514303A JP2003506357A (ja) 1999-07-29 2000-07-05 スタチックミクロミキサでのアミンの還元的メチル化

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1999135694 DE19935694A1 (de) 1999-07-29 1999-07-29 Reduktive Methylierung von Aminen im statischen Mikromischer
DE19935694.7 1999-07-29

Publications (1)

Publication Number Publication Date
WO2001009100A1 true WO2001009100A1 (fr) 2001-02-08

Family

ID=7916509

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/006319 Ceased WO2001009100A1 (fr) 1999-07-29 2000-07-05 Methylation reductive de tetrahydroisoquinoline dans un micromelangeur statique

Country Status (5)

Country Link
EP (1) EP1200407A1 (fr)
JP (1) JP2003506357A (fr)
AU (1) AU6561700A (fr)
DE (1) DE19935694A1 (fr)
WO (1) WO2001009100A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63101351A (ja) * 1986-10-17 1988-05-06 Ajinomoto Co Inc Ｎ，Ｎ―ジメチル―α―アミノ鎖状脂肪酸の製造法
WO1996030113A1 (fr) * 1995-03-30 1996-10-03 Merck Patent Gmbh Dispositif de melange de petites quantites de liquides

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3638151B2 (ja) * 1996-03-28 2005-04-13 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング 少量液体の混合デバイス
DE19708472C2 (de) * 1997-02-20 1999-02-18 Atotech Deutschland Gmbh Herstellverfahren für chemische Mikroreaktoren

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63101351A (ja) * 1986-10-17 1988-05-06 Ajinomoto Co Inc Ｎ，Ｎ―ジメチル―α―アミノ鎖状脂肪酸の製造法
WO1996030113A1 (fr) * 1995-03-30 1996-10-03 Merck Patent Gmbh Dispositif de melange de petites quantites de liquides

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; COLLS-ALSIUS, JOSE: "Process for the preparation of 3,4,5,6-tetrahydro-5-methyl-1-phenyl- 2,5-benzoxazocine", XP002150605, retrieved from STN Database accession no. 107:39880 *
LOIBNER, H. ET AL: "Reductive methylation of primary and secondary amines with formaldehyde and phosphorous acid salts", TETRAHEDRON LETT., vol. 25, no. 24, 1984, pages 2535 - 2536, XP002150603 *
NELSON J. LEONHARD; GERHARD W. LEUBNER: "Reactions of Nitroparaffins with Pseudo Bases Related to Dihydroisoquinolinium", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 71, 1949, pages 3408 - 3411, XP002150604 *
PATENT ABSTRACTS OF JAPAN vol. 012, no. 344 (C - 528) 16 September 1988 (1988-09-16) *

Also Published As

Publication number Publication date
JP2003506357A (ja) 2003-02-18
AU6561700A (en) 2001-02-19
EP1200407A1 (fr) 2002-05-02
DE19935694A1 (de) 2001-02-01

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