JP2007112730A - Method for producing 4-[2-(2-aminoethoxy)ethyl]morpholines - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for readily and efficiently producing 4-[2-(2-aminoethoxy)ethyl]morpholines. <P>SOLUTION: The 4-[2-(2-aminoethoxy)ethyl]morpholines are obtained by bringing morpholines into contact with a metal catalyst containing palladium. In the production method, the reaction can be carried out in the coexistence of 2-(2-aminoethoxy)ethanols, and the reaction temperature and the reaction pressure can be selected from the range of 50-350°C, and the range of from normal pressure to 10 MPa respectively. The metal catalyst is preferably a supported metal catalyst, and more preferably the supported metal catalyst containing the palladium. The metal catalyst is preferably subjected to pretreatment in hydrogen flow, and more preferably the pretreatment in the hydrogen flow at a temperature selected from the range of from 50°C to 400°C. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing 4- [2- (2-aminoethoxy) ethyl] morpholines.

  4- [2- (2-Aminoethoxy) ethyl] morpholine is a compound with a wide range of industrial uses. For example, Non-Patent Document 1 discloses the use of 4- [2- (2-aminoethoxy) ethyl] morpholine as a raw material for pharmaceutical intermediates. Therefore, a simple synthesis method is desired, but only two synthesis examples are disclosed. In Non-Patent Document 1, 2- (2-chloroethoxy) ethanol is reacted with morpholine in the presence of a base to give 4- [2- (2-hydroxyethoxy) ethyl] morpholine, which is a zinc azide-pyridine complex. And a method for obtaining 4- [2- (2-aminoethoxy) ethyl] morpholine by hydrogenation, and then hydrogen reduction with diisopropyl azodicarboxylate. However, it is an industrial problem to be a multistage reaction, to use environmentally incompatible chlorine-containing compounds as raw materials, and to use explosive azide compounds. In addition, Patent Document 1 discloses that when morpholine is produced from diethylene glycol and ammonia using a catalyst, 4- [2- (2-aminoethoxy) ethyl] morpholine is 1.6 to 3.4% as a by-product. It is disclosed to produce trace amounts.

Journal of Medicinal Chemistry, 37, 2285, 1994 US Pat. No. 4,582,904

  The object of the present invention is to develop a simple method for producing 4- [2- (2-aminoethoxy) ethyl] morpholines.

  As a result of intensive studies to solve the above problems, the present inventors have produced 4- [2- (2-aminoethoxy) ethyl] morpholine from morpholine in the presence of a metal catalyst, and It has been found that 4- [2- (2-aminoethoxy) ethyl] morpholine is produced by reacting 2- (2-aminoethoxy) ethanol in the presence of a metal catalyst, and the present invention has been completed. That is, the present invention relates to a method for producing 4- [2- (2-aminoethoxy) ethyl] morpholines, which comprises contacting morpholines with a metal catalyst. The present invention is described in further detail below.

  In the present invention, morpholines are morpholines optionally having a substituent on the ethylene group forming the cyclic structure. Further, 4- [2- (2-aminoethoxy) ethyl] morpholines are the same on the ethylene group forming a cyclic structure and on the corresponding ethylene group of the side chain 2- (2-aminoethoxy) ethyl group. It is 4- [2- (2-aminoethoxy) ethyl] morpholine which may have a substituent. Furthermore, 2- (2-aminoethoxy) ethanol is 2- (2-aminoethoxy) ethanol having the same substituent on the ethylene group when the morpholine to be coexisted has a substituent.

  Although 4- [2- (2-aminoethoxy) ethyl] morpholine can be produced from morpholines alone by contacting with a metal catalyst by the method described in the present invention, morpholines and 2- (2-aminoethoxy) can be produced. ) It can also be produced from ethanol. In the case of producing from morpholines and 2- (2-aminoethoxy) ethanol, the molar ratio of morpholines to 2- (2-aminoethoxy) ethanol is not particularly limited, but preferably 1:10 to 10: 1. You can choose from a range of From the viewpoint of good yield, it is more desirable to use only morpholines as a raw material.

  Examples of the metal that can be used as the metal catalyst in the present invention include palladium, ruthenium, platinum, rhenium, rhodium, iridium, osmium, iron, cobalt, nickel, chromium, copper, lanthanum, cerium, neodymium, praseodymium, vanadium, molybdenum, Tungsten and the like can be listed, and metal salts such as chloride salts, bromide salts, iodide salts, nitrates, sulfates, carbonates, oxalates, acetates, oxide salts, etc., ammine complexes, acetyl A complex compound such as an acetonato complex may be used, and these metals, metal salts, or complex compounds may be used in combination as necessary. Palladium, ruthenium, platinum, rhenium, rhodium, iridium, cobalt, nickel, chromium, copper, lanthanum, cerium, neodymium, or a metal salt or complex thereof is desirable, and a metal salt or complex of palladium or palladium is preferable. It is further desirable to use the compound alone.

  Metal salts and complex compounds of palladium include sodium tetrachloropalladium (II), potassium tetrachloropalladium (II), sodium hexachloropalladium (IV), potassium hexachloropalladium (IV), tetraamminepalladium (II) chloride And dichlorodiammine palladium (II) and the like.

  These metal catalysts are desirably used as a supported metal catalyst by supporting a metal, a metal salt, a complex compound or the like on a suitable support. Examples of the carrier include γ-alumina, α-alumina, silica, magnesia, zirconia, titania, zinc oxide, thorium oxide, manganese dioxide, Y-type zeolite, A-type zeolite, X-type zeolite, mordenite, ZSM-5, smectite, Hydroxyapatite, hydrotalcite, mica tetrafluoride, montmorillonite, activated carbon, barium sulfate, barium carbonate, calcium carbonate, polyethylene-polystyrene resin, polystyrene resin, etc. can be listed, and these can be combined as necessary It may be used. From the viewpoint of good yield, γ-alumina, α-alumina, silica, magnesia, zirconia, titania, zinc oxide, thorium oxide, manganese dioxide, and activated carbon are desirable, and γ-alumina is more desirably used alone.

  A commercially available product may be used as the supported metal catalyst, but it may be prepared using the above-mentioned metal, metal salt, complex compound, or the like and a carrier as necessary. There is no restriction | limiting in particular in the preparation method of a supported metal catalyst, A general purpose impregnation method, a coprecipitation method, a sol-gel method, a kneading method, a chemical vapor deposition method, an ion exchange method etc. can be used.

  The amount of the metal catalyst used is preferably 0.001 to 10 mol%, more preferably 0.05 to 5 mol% in terms of metal relative to morpholines.

  The metal catalyst is preferably used after pretreatment in a hydrogen stream before the reaction. The pretreatment temperature is preferably set at a temperature appropriately selected from a range of 50 ° C to 400 ° C. 100 ° C. to 350 ° C. is more desirable in terms of good catalytic ability.

  This reaction can be carried out in an atmosphere of hydrogen, argon, nitrogen, air or the like. The initial pressure can be from atmospheric pressure (0.10 MPa) to 10 MPa. 0.5 MPa to 5 MPa is more desirable in terms of good yield.

  In the present invention, it is desirable to carry out the reaction without using a solvent in terms of a good yield. However, when a solvent is used in this reaction, there is no limitation as long as it does not inhibit the reaction. For example, water, tetrahydrofuran, diethyl ether, benzene, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, tetra Examples include chloroethane, acetonitrile, ethyl acetate and the like.

  Although there is no restriction | limiting in particular in reaction temperature, It is preferable to carry out at the temperature suitably selected from the range of 50 to 350 degreeC. The reaction time is 10 minutes to 48 hours depending on the reaction temperature.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but general-purpose methods such as precision distillation, solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation The object can be obtained by a simple method.

  The production method of the present invention is effective as a production method for easily obtaining 4- [2- (2-aminoethoxy) ethyl] morpholine, which is an important compound having a wide range of industrial uses such as pharmaceutical intermediates.

  EXAMPLES Next, although an Example demonstrates this invention in detail, this invention is not limited to these. In this example, the conversion, production rate and yield in the reactions (Examples 1 to 8) using only morpholine as a substrate are calculated by the following formulas (1) to (3).

Formula (1)
Conversion (%) = (1− [number of moles of morpholine after reaction] ÷ [number of moles of morpholine charged)] × 100
Formula (2)
Production rate (%) = (2 × [number of moles of 4- [2- (2-aminoethoxy) ethyl] morpholine after reaction obtained by GC analysis) ÷ [number of moles of morpholine charged]] × 100
Formula (3)
Yield (%) = (2 × [number of moles of 4- [2- (2-aminoethoxy) ethyl] morpholine after isolation] ÷ [number of moles of morpholine charged]) × 100
Further, the conversion rate and production rate in the reaction using morpholine and 2- (2-aminoethoxy) ethanol as substrates (Example 9) are calculated by the following formulas (4) and (5).

Formula (4)
Conversion (%) = (1− [number of moles of morpholine after reaction] ÷ [number of moles of morpholine charged)] × 100
Formula (5)
Production rate (%) = ([number of moles of 4- [2- (2-aminoethoxy) ethyl] morpholine after reaction obtained by GC analysis) ÷ [number of moles of morpholine charged]] × 100
(Catalyst Preparation Example 1)
0.691 g (3.68 mmol) of sodium tetrachloropalladium (II) was dissolved in 2.3 mL of water at 80 ° C. and cooled to room temperature. To this was added 5.0 g of Saint-Gobain alumina having a particle size of 3 mm, which was baked in air at 450 ° C. for 3 hours, and left at room temperature for 1 hour. Thereafter, the solvent was removed at 40 ° C. using an evaporator to obtain a 5 wt% palladium-supported alumina catalyst.

(Catalyst preparation example 2)
0.691 g (3.68 mmol) of sodium tetrachloropalladium (II) was dissolved in 7.1 mL of water at 80 ° C. and cooled to room temperature. To this was added 10 g of Mizusawa Chemical's alumina with a particle size of 6 mm, which was calcined in air at 450 ° C. for 3 hours, and left at room temperature for 1 hour. Thereafter, the solvent was removed at 40 ° C. using an evaporator to obtain a 2.5 wt% palladium-supported alumina catalyst.

(Catalyst Preparation Example 3)
0.691 g (3.68 mmol) of sodium tetrachloropalladium (II) was dissolved in 4.4 mL of water at 80 ° C. and cooled to room temperature. To this was added 10 g of alumina made by Saint-Gobain having a particle diameter of 3 mm, which was fired at 450 ° C. for 3 hours in air, and left at room temperature for 1 hour. Thereafter, the solvent was removed at 40 ° C. using an evaporator to obtain a 2.5 wt% palladium-supported alumina catalyst.

(Catalyst Preparation Example 4)
0.374 g (1.27 mmol) of sodium tetrachloropalladium (II) was dissolved in 7.0 mL of water at 80 ° C. and cooled to room temperature. To this, 3.0 g of alumina made by Saint-Gobain having a particle diameter of 3 mm, which was baked at 450 ° C. for 3 hours in air, was pulverized in an agate mortar, and left at room temperature for 1 hour. Thereafter, the solvent was removed at 40 ° C. using an evaporator to obtain a 4.3 wt% palladium-supported alumina catalyst.

Example 1
After putting 0.5 g of the catalyst obtained in Catalyst Preparation Example 1 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 300 ° C. at 5 ° C./min and heated to 300 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, 15 mL (172 mmol) of morpholine was added in a hydrogen stream, the autoclave was sealed, and the initial hydrogen pressure was set to 1.0 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated to 200 ° C. and heated at a rate of 5 ° C./min, and held at 200 ° C. for 6 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed by ¹ H-NMR, ¹³ C-NMR, IR, and GC-MS, and it was confirmed that the main product was 4- [2- (2-aminoethoxy) ethyl] morpholine. Furthermore, as a result of GC analysis in which dioxane was added as an internal standard, the morpholine conversion rate was 52.3% and the 4- [2- (2-aminoethoxy) ethyl] morpholine production rate was 28.2%. The filtrate was concentrated under reduced pressure to remove unreacted morpholine and low-boiling components, followed by precision distillation to obtain 4- [2- (2-aminoethoxy) ethyl] morpholine in a yield of 19.3%. (Colorless liquid).

¹ H-NMR (CDCl ₃ , ppm)
δ 1.39 (s, 2H), 2.52 (t, J = 4.8 Hz, 4H), 2.60 (t, J = 5.8 Hz, 2H), 2.86 (t, J = 5.3 Hz) , 2H), 3.48 (t, J = 5.3 Hz, 2H), 3.59 (t, J = 5.8 Hz, 2H), 3.70 (t, J = 4.8 Hz, 4H).
¹³ C-NMR (heavy acetone, ppm)
δ 51.7 (CH ₂ ), 54.9 (CH ₂ × 2), 58.9 (CH ₂ ), 67.2 (CH ₂ × 2), 69.4 (CH ₂ ), 71.8 (CH ₂ )
IR (neat)
[delta] (NH) = 1592 cm < ^-1 >. ν (NH) = 3293 cm ⁻¹ , 3372 cm ⁻¹ .
MS
M / z = 174 (molecular weight peak).

(Example 2)
After putting 0.5 g of the catalyst obtained in Catalyst Preparation Example 1 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 300 ° C. at 5 ° C./min and heated to 300 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, 15 mL (172 mmol) of morpholine was added in a hydrogen stream, the autoclave was sealed, and the initial hydrogen pressure was set to 1.0 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 3 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1. The conversion rate of morpholine was 28.9%, and the yield of 4- [2- (2-aminoethoxy) ethyl] morpholine was 20.4%.

(Example 3)
After putting 1.0 g of the catalyst obtained in Catalyst Preparation Example 2 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 250 ° C at 5 ° C / min and heated to 250 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, 15 mL (172 mmol) of morpholine was added in a hydrogen stream, the autoclave was sealed, and the initial hydrogen pressure was set to 1.0 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 3 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1 to obtain a morpholine conversion rate of 25.2% and a 4- [2- (2-aminoethoxy) ethyl] morpholine production rate of 17.0%.

Example 4
After putting 1.0 g of the catalyst obtained in Catalyst Preparation Example 3 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 300 ° C. at 5 ° C./min and heated to 300 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, 15 mL (172 mmol) of morpholine was added in a hydrogen stream, the autoclave was sealed, and the initial hydrogen pressure was set to 1.0 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 3 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1 to obtain a morpholine conversion rate of 23.0% and a 4- [2- (2-aminoethoxy) ethyl] morpholine production rate of 15.4% (Example 5).
After 0.5 g of 5 wt% palladium-supported alumina catalyst made by N Chemcat is put into a 100 mL stainless steel autoclave, hydrogen gas is circulated in the autoclave at 25 mL / min and heated to 300 ° C. at 5 ° C./min. And kept at 300 ° C. for 3 hours. After cooling to room temperature, 15 mL (172 mmol) of morpholine was added in a hydrogen stream, the autoclave was sealed, and the initial hydrogen pressure was set to 1.0 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 3 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1 to obtain a morpholine conversion rate of 19.8% and a 4- [2- (2-aminoethoxy) ethyl] morpholine production rate of 16.0%.

(Example 6)
After putting 0.5 g of the catalyst obtained in Catalyst Preparation Example 1 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 300 ° C. at 5 ° C./min and heated to 300 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, 15 mL (172 mmol) of morpholine and 0.3 mL (16.7 mmol) of water were added in a hydrogen stream, the autoclave was sealed, and the initial hydrogen pressure was set to 1.0 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 3 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1 to obtain a morpholine conversion rate of 33.4% and a 4- [2- (2-aminoethoxy) ethyl] morpholine production rate of 25.7%.

(Example 7)
After putting 0.5 g of the catalyst obtained in Catalyst Preparation Example 1 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 300 ° C. at 5 ° C./min and heated to 300 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, 15 mL (172 mmol) of morpholine was added in a hydrogen stream, the autoclave was sealed, and the initial argon pressure was set to 0.5 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 3 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1 to obtain a morpholine conversion rate of 35.0% and a 4- [2- (2-aminoethoxy) ethyl] morpholine production rate of 25.3%.

(Example 8)
After putting 2.0 g of the catalyst obtained in Catalyst Preparation Example 4 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 300 ° C. at 5 ° C./min and heated to 300 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, 60 mL (688 mmol) of morpholine was added in a hydrogen stream, the autoclave was sealed, and the initial argon pressure was set to 0.5 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 6 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1 to obtain a morpholine conversion rate of 52.9% and a 4- [2- (2-aminoethoxy) ethyl] morpholine production rate of 30.7%.

Example 9
After putting 0.5 g of the catalyst obtained in Catalyst Preparation Example 1 into a 100 mL stainless steel autoclave, hydrogen gas was circulated at 25 mL / min in the autoclave, heated to 300 ° C. at 5 ° C./min and heated to 300 ° C. Hold at 3 ° C. for 3 hours. After cooling to room temperature, morpholine 15 mL (172 mmol) and 2- (2-aminoethoxy) ethanol 17.2 mL (172 mmol) were added in a hydrogen stream, the autoclave was sealed, and the initial hydrogen pressure was set to 1.0 MPa. While stirring at 1000 rpm with a magnetic stirrer, the mixture was heated up to 200 ° C. at a rate of 5 ° C./min and held at 200 ° C. for 3 hours. After cooling to room temperature, the catalyst was filtered off. The filtrate was analyzed in the same manner as in Example 1. The morpholine conversion was 8.1%, the 2- (2-aminoethoxy) ethanol conversion was 8.1%, and 4- [2- (2-aminoethoxy) ethyl] morpholine. A yield of 1.1% was obtained.

Claims (8)

A method for producing 4- [2- (2-aminoethoxy) ethyl] morpholines, which comprises contacting morpholines with a metal catalyst. The process according to claim 1, wherein the reaction is carried out in the presence of 2- (2-aminoethoxy) ethanols. The production method according to claim 1 or 2, wherein the reaction temperature is from 50 ° C to 350 ° C. The production method according to any one of claims 1 to 3, wherein the reaction pressure is from atmospheric pressure to 10 MPa. The method according to any one of claims 1 to 4, wherein the metal catalyst is a supported metal catalyst. The production method according to claim 1, wherein the metal catalyst contains palladium. The production method according to any one of claims 1 to 6, wherein a metal catalyst pretreated in a hydrogen stream is used. The production method according to claim 7, wherein a metal catalyst pretreated at 50 ° C. to 400 ° C. is used.