JP5549847B2 - Process for producing N- (2-alkoxymethyl) triethylenediamines - Google Patents

Description

The present invention relates to a method for producing N- (2-alkoxymethyl) triethylenediamines.
N- (2-alkoxymethyl) triethylenediamines are compounds that are expected to be used for medical and agrochemical intermediates, anti-fading agents, catalysts for organic synthesis, staining agents, chemical adsorbents, antibacterial agents, and the like.

  In general, as a production method for obtaining N- (2-hydroxymethyl) triethylenediamine, piperazine and ethyl 2,3-dibromopropionate are reacted in an inert solvent such as toluene or benzene. A method is known in which ethyl 4-diazabicyclo [2.2.2] octane-2-carboxylate is prepared, and then the obtained ester is reduced using, for example, lithium aluminum hydride (for example, Patent Documents). 1).

  However, in this production method, ethyl 2,3-dibromopropionate used as a raw material is very expensive, and it is necessary to react piperazine with ethyl 2,3-dibromopropionate at a low substrate concentration. Have the disadvantage of being inferior. Furthermore, in the second step, lithium aluminum hydride, which has a high risk of ignition, is used as the reducing agent.

  In addition, as a general method for producing triethylenediamines, a method of cyclizing hydroxyethylpiperazine in the presence of an acid catalyst is known (for example, see Patent Document 2).

  However, an example of synthesizing N- (2-alkoxymethyl) triethylenediamine by a cyclization reaction from N- (2-hydroxy-3-alkoxypropyl) piperazines using the same production method is shown below. Not reported until.

  Furthermore, according to Patent Document 3, it is presumed that N- (2-alkoxymethyl) triethylenediamines are obtained by an etherification reaction from 2-hydroxymethyltriethylenediamine.

  By the way, the subject remained regarding the manufacturing method of N- (2-hydroxy-3-alkoxypropyl) piperazine which is an intermediate body used by this method.

  That is, N- (2-hydroxy-3-alkoxypropyl) piperazines are known to be obtained by an addition reaction between an epoxy compound and piperazine (see, for example, Non-Patent Document 1). It is difficult to selectively obtain a mono-substituted product because it is a by-product of a large amount.

  Similarly, there is an example in which 1-chloro-2-hydroxy-3-tert-butoxypropane and piperazine are reacted in the presence of potassium hydroxide in ethanol (see, for example, Non-Patent Document 2). Only an example of obtaining N, N′-bis (2-hydroxy-3-tert-butoxypropyl) piperazine substituted at both positions is shown.

  Furthermore, generally, as a method for selectively obtaining N-monosubstituted piperazines, a method of cyclizing diethanolamine and N-substituted amine using a zeolite catalyst is known (for example, see Non-patent Document 3). There is no reported example that N- (2-hydroxy-3-alkoxypropyl) piperazines were selectively obtained by this method.

  As described above, N- (2-hydroxy-3-alkoxypropyl) piperazines in which only one amino group of the piperazine ring is substituted are selectively synthesized and cyclized to produce N- (2 It has been extremely difficult to efficiently synthesize (alkoxymethyl) triethylenediamines.

JP 2001-504855 A JP-A-4-261177 JP 63-259565 A

Zhunal Prikladnoi Kimii (Sank-Peterburg, Russian Federation) (1984), 57 (9), p. 2138 Journal of Pharmacology and Pharmacology (1960), 12, 37. Journal of Organic Chemistry (1994), 59, 3998

  The present invention has been made in view of the above-described background art, and its purpose is to easily and safely use N- (2-alkoxymethyl) triethylenediamines without using a reducing agent with a high risk of ignition. It is to provide a method of manufacturing.

  As a result of repeated studies to solve the above problems, the present inventors have completed the present invention.

  That is, this invention relates to the manufacturing method of N- (2-alkoxymethyl) triethylenediamine as shown below.

  [1] The following formula (1)

（式中、Ｒは、メチル基、エチル基、直鎖状若しくは分枝状の炭素数３〜１２のアルキル基、又はベンジル基を表す。）
で示されるＮ−（２−ヒドロキシ−３−アルコキシプロピル）ピペラジン類を酸触媒の存在下で分子内脱水縮合反応させることを特徴とする下記式（２）

(In the formula, R represents a methyl group, an ethyl group, a linear or branched alkyl group having 3 to 12 carbon atoms, or a benzyl group.)
N- (2-hydroxy-3-alkoxypropyl) piperazines represented by formula (2) are subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst.

（式中、Ｒは上記と同じ定義である。）
で示されるＮ−（２−アルコキシメチル）トリエチレンジアミン類の製造方法。

(Wherein R has the same definition as above)
The manufacturing method of N- (2-alkoxymethyl) triethylenediamine shown by these.

  [2] The production method according to [1], wherein the acid catalyst contains one or more compounds selected from the group consisting of metal phosphates and organic phosphorus compounds.

  According to the production method of the present invention, it is possible to provide a method for producing N- (2-alkoxymethyl) triethylenediamine simply and safely without using a reducing agent having a high risk of ignition.

  Hereinafter, the present invention will be described in detail.

  In the production method of the present invention, N- (2-hydroxy-3-alkoxypropyl) piperazines represented by the above formula (1) are subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst. It is characterized by obtaining the N- (2-alkoxymethyl) triethylenediamines shown.

  In the above formula (1), R represents a methyl group, an ethyl group, a linear or branched alkyl group having 3 to 12 carbon atoms, or a benzyl group.

  N- (2-hydroxy-3-alkoxypropyl) piperazines represented by the above formula (1) are not particularly limited, and examples thereof include N- (2-hydroxy-3-methoxypropyl) piperazine, N -(2-hydroxy-3-ethoxypropyl) piperazine, N- (2-hydroxy-3-propoxypropyl) piperazine, N- (2-hydroxy-3-isopropoxypropyl) piperazine, N- (2-hydroxy-3) -Butoxypropyl) piperazine, N- (2-hydroxy-3-secbutoxypropyl) piperazine, N- (2-hydroxy-3-isobutoxypropyl) piperazine, N- (2-hydroxy-3-pentyloxypropyl) piperazine N- (2-hydroxy-3-hexyloxypropyl) piperazine, N- ( -Hydroxy-3-peptyloxypropyl) piperazine, N- (2-hydroxy-3-octyloxypropyl) piperazine, N- (2-hydroxy-3-nonoxypropyl) piperazine, N- (2-hydroxy-3) -Decaneoxypropyl) piperazine, N- (2-hydroxy-3-nonadecanoxypropyl) piperazine, N- (2-hydroxy-3-dodecanoxypropyl) piperazine and the like. Of these, N- (2-hydroxy-3-methoxypropyl) piperazine, N- (2-hydroxy-3-ethoxypropyl) piperazine, N- (2-hydroxy) are available because of the availability of raw material alcohol and economy. -3-Propoxypropyl) piperazine, N- (2-hydroxy-3-isopropoxypropyl) piperazine, and N- (2-hydroxy-3-butoxypropyl) piperazine are preferred.

In the formula (2), R represents the same definition as described above, that is, a methyl group, an ethyl group, a linear or branched alkyl group having 3 to 12 carbon atoms, or a benzyl group.
The N- (2-alkoxymethyl) triethylenediamine represented by the above formula (2) is not particularly limited, and examples thereof include N- (2-hydroxymethyl) triethylenediamine and N- (2-methoxymethyl). ) Triethylenediamine, N- (2-ethoxymethyl) triethylenediamine, N- (2-propoxymethyl) triethylenediamine, N- (2-isopropoxymethyl) triethylenediamine, N- (2-butoxymethyl) triethylenediamine, N -(2-secbutoxymethyl) triethylenediamine, N- (2isobutoxymethyl) triethylenediamine, N- (2-pentyloxymethyl) triethylenediamine, N- (2-hexyloxymethyl) triethylenediamine, N- (2 -Heptyloxymethyl) trie Range amine, N- (2-octyloxymethyl) triethylenediamine, N- (2-nonoxymethyl) triethylenediamine, N- (2-decanoxymethyl) triethylenediamine, N- (2-nonadecanoxymethyl) tri Examples include ethylenediamine, N- (2-dodecanoxymethyl) triethylenediamine, and N- (2-benzyloxymethyl) triethylenediamine. Of these, N- (2-methoxymethyl) triethylenediamine, N- (2-ethoxymethyl) triethylenediamine, N- (2-isopropoxymethyl) triethylenediamine, N- (2-butoxymethyl) triethylenediamine is preferred.

  In the production method of the present invention, an N- (2-hydroxy-3-alkoxypropyl) piperazine represented by the above formula (1) is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst, whereby the above formula (2) The acid catalyst for obtaining the indicated N- (2-alkoxymethyl) triethylenediamines is not particularly limited, and examples thereof include phosphorus-containing substances such as metal phosphates and organic phosphorus compounds, nitrogen-containing substances, and sulfur. Containing material, niobium containing material, silica, alumina, silica-alumina, silica-titania, zeolite, heteropoly acid, Group 4B metal oxide condensation catalyst, Group 6B metal containing condensation catalyst, Bronsted acid, Lewis acid, phosphoramide, etc. Of these, phosphorus-containing substances are particularly preferred.

  In the production method of the present invention, examples of the metal phosphate include metal salts such as phosphoric acid, phosphorous acid, and hypophosphorous acid. The metal that forms a salt with phosphoric acid is not particularly limited. For example, sodium, potassium, lithium, calcium, barium, magnesium, aluminum, titanium, iron, cobalt, nickel, copper, zinc, zirconium, palladium , Silver, tin, lead and the like.

  Further, the organic phosphorus compound may be a conventionally known one, and is not particularly limited. For example, a phosphoric acid ester such as methyl phosphate, a phosphoric acid diester such as dimethyl phosphate, and a triphosphate such as triphenyl phosphate. Phosphorous esters such as esters, methyl phosphite and phenyl phosphite, phosphorous diesters such as diphenyl phosphite, phosphorous triesters such as phosphorus triphenyl, arylphosphonic acids such as phenylphosphonic acid Alkylphosphonic acid such as methylphosphonic acid, alkylphosphonic acid such as methylphosphonic acid, arylphosphonic acid such as phenylphosphonic acid, alkylphosphinic acid such as dimethylphosphinic acid, arylphosphinic acid such as diphenylphosphinic acid, phenyl Alkylarylphosphinic acids such as methylphosphinic acid, dimethyl Alkylphosphinic acids such as phosphinic acid, arylphosphinic acids such as diphenylphosphinic acid, alkylarylphosphinic acids such as phenylmethylphosphinic acid, lauryl acid phosphate, tridecyl acid phosphate, stearyl acid phosphate, etc. Acid phosphate ester, salt of acid phosphate ester, etc. are mentioned.

  In this invention, 1 type, or 2 or more types chosen from these can be used.

  In the production method of the present invention, the amount of the acid catalyst to be used is not particularly limited, but the use of N- (2-hydroxy-3-alkoxypropyl) piperazines represented by the above formula (1), which is a raw material, is used. The amount is usually 0.01 to 20% by weight, preferably 0.1 to 10% by weight, based on the amount. If it is less than 0.01% by weight, the reaction may be remarkably slow, and even if it exceeds 20% by weight, it may be economically disadvantageous.

  In the production method of the present invention, the reaction may be performed in a gas phase or a liquid phase. In addition, the reaction can be carried out by batch, semi-batch, continuous, or fixed bed flow type using a suspended bed, but industrially, the fixed bed flow type is advantageous in terms of operation, equipment, and economy.

  In the production method of the present invention, as a diluent, an inert gas such as nitrogen gas, hydrogen gas, ammonia gas, water vapor or hydrocarbon, or an inert solvent such as water or inert hydrocarbon is used as a raw material. A certain N- (2-hydroxy-3-alkoxypropyl) piperazine represented by the above formula (1) can be diluted to allow the reaction to proceed. These diluents can be used in any amount, and are not particularly limited, but are [N- (2-hydroxy-3-alkoxypropyl) piperazines represented by the above formula (1)] / [Diluent] The molar ratio is preferably in the range of 0.01 to 1, and more preferably in the range of 0.05 to 0.5. When the molar ratio is 0.01 or more, the productivity of N- (2-alkoxymethyl) triethylenediamine represented by the above formula (2) is improved. When the molar ratio is 1 or less, the selectivity of N- (2-alkoxymethyl) triethylenediamine represented by the above formula (2) is improved.

  In the production method of the present invention, the diluent may be introduced into the reactor at the same time as the N- (2-hydroxy-3-alkoxypropyl) piperazine represented by the above formula (1), or the above formula ( The N- (2-hydroxy-3-alkoxypropyl) piperazine represented by 1) may be dissolved in a diluent and then introduced into the reactor as a raw material solution.

  In the production method of the present invention, when the reaction is carried out in the gas phase, it is usually carried out in the presence of a gas inert to the reaction such as nitrogen gas or argon gas. The amount of the gas used is usually in the range of 1 to 20 mol, preferably 2 to 10 mol, with respect to 1 mol of N- (2-hydroxy-3-alkoxypropyl) piperazine represented by the above formula (1). .

  In the production method of the present invention, the reaction temperature is usually in the range of 150 to 500 ° C, preferably 200 to 400 ° C. Since the decomposition of the raw material and the product is suppressed by setting the temperature to 500 ° C. or lower, the selectivity of N- (2-alkoxymethyl) triethylenediamine represented by the above formula (2) is improved, and is 150 ° C. or higher. By doing so, a sufficient reaction rate can be obtained.

  In the production method of the present invention, when the reaction is carried out in a gas phase, after completion of the reaction, a reaction mixed gas containing N- (2-alkoxymethyl) triethylenediamine represented by the above formula (2) is added to water or It is made to melt | dissolve through acidic aqueous solution and the reaction liquid mixture containing N- (2-alkoxymethyl) triethylenediamine shown by the said Formula (2) is obtained. Then, N- (2-alkoxymethyl) triethylenediamine represented by the above formula (2) can be obtained from the obtained reaction mixture by a desired separation and purification operation such as extraction and concentration. Moreover, it can also obtain as a hydrohalide salt using hydrohalic acid.

  On the other hand, N- (2-hydroxy-3-alkoxypropyl) piperazines represented by the above formula (1) are, for example, 1-chloro-2-hydroxy-3-alkoxypropane represented by the above formula (3), It can be obtained by reacting with piperazine in the presence or absence of a dehydrohalogenating agent.

  At that time, the amount of piperazine used in the reaction is preferably equimolar or more to 1-chloro-2-hydroxy-3-alkoxypropane, and if it is less than that, a decrease in yield is observed, and if it is equimolar or more, it is selected. In particular, the desired 2-hydroxy-3-alkoxypropylpiperazines are obtained. Further increase in the amount of piperazine is observed to improve selectivity and yield. However, even if piperazine is added in excess of 10-fold mol, the yield is nearly 100%, so the difference is reduced, and on the contrary, the operation such as recovery of piperazine becomes complicated, so the industrial meaning is small.

  In the production method of the present invention, when a dehydrohalogenating agent is used, the conversion rate and the yield are improved. The dehydrohalogenating agent used is not particularly limited. For example, alkali metal such as sodium metal, alkali hydride such as sodium hydride and calcium hydride, sodium hydroxide, potassium hydroxide, water Alkali metal or alkaline earth metal hydroxides such as lithium oxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, Mention may be made of one or more compounds selected from the group consisting of alkali metal hydrogen carbonates such as potassium hydrogen carbonate and alkaline earth metal oxides such as barium oxide. Of these, industrially easily available sodium hydroxide, potassium hydroxide, and sodium carbonate are preferred, and particularly economically advantageous sodium hydroxide is preferred.

  The amount of the dehydrohalogenating agent used for the reaction may be equal to or greater than the amount of 1-chloro-2-hydroxy-3-alkoxypropane used.

  Although it does not specifically limit as a solvent used for reaction, For example, water, methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, isobutanol, pentanol, hexanol, cyclohexanol, heptanol, Octanol, nonyl alcohol, decanol, dodecanol, ethylene glycol, diethylene glycol, triethylene glycol, glycerol and other alcohols, diethyl ether, diisopropyl ether, tetrahydrofuran and other ethers, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide hexa Dipolar aprotic solvents such as methyl phosphoramide, trimethylamine, triethylamine, tripropylamine, Ributylamine, tripentylamine, trihexylamine, tripentylamine, trioctylamine, tridodecylamine, triisobutylamine, dimethylbutylamine, N, N-dimethylcyclohexyl, N, N-dicyclohexylmethylamine, triphenylamine, N , N, N ′, N′-tetramethylethylenediamine, tertiary ethanol such as triethanolamine, triisopropanolamine, and triethylenediamine, and one or more compounds selected from the group consisting of pyridines. It is done.

The temperature suitable as the reaction temperature varies depending on the boiling point of the solvent to be used, but is usually 0 ° C to 200 ° C, preferably 30 ° C to 100 ° C, and more preferably 50 ° C to 80 ° C.
At a temperature lower than 0 ° C, a sufficient reaction rate cannot be obtained, and at a temperature of 200 ° C or higher,
Decomposition of the target product may occur.
As the purification method, the target product can be purified and isolated by distillation under reduced pressure after concentrating the solvent.

  The present invention will be described in more detail with reference to the following examples, but the present invention should not be construed as being limited thereto. In addition, the yield of the product in a present Example was confirmed with the gas chromatography.

  A gas chromatograph (Shimadzu GC-2014), a capillary column (J & W Scientific DB-1), and a detector (FID) were used for gas chromatography (temperature increase).

Further, for the measurement of ¹ H-NMR and ¹³ C-NMR of the compound, Gemini-200 manufactured by Varian was used.

Synthesis Example (1) Synthesis of 1-chloro-2-hydroxy-3-methoxypropane.
This compound is a reaction of alcohol and epichlorohydrin using boron trifluoride diethyl ether as a complex catalyst [see, for example, Industrial Chemical Journal, 66 (12), 1827 (1963)], or a method using a sulfuric acid catalyst (For example, refer nonpatent literature 3).

A 1000 ml reactor was charged with 320.4 g (10.0 mol) of methanol and 1.6 g (0.01 mol) of boron trifluoride diethyl ether complex, and the internal temperature was adjusted to 20 ° C. while stirring. Thereto, 370.1 g (4.0 mol) of epichlorohydrin was added dropwise over 1 hour while maintaining the internal temperature at 25 ° C. or lower, and reflux stirring was continued for 20 hours while maintaining the same temperature condition. 676.8 g of reaction solution was obtained. When 57.1 g was weighed from the obtained reaction liquid and distilled at normal pressure, 32.7 g of a distillate having a boiling point of 172 to 175 ° C. was obtained. The resulting distillate is 96.8% pure by analysis by gas ^{chromatography,} confirming that the 1 H-NMR and ¹³ C-NMR is 1-chloro-2-hydroxy-3-methoxypropane did it.
Moreover, as a result of quantifying the obtained reaction liquid by gas chromatography, the yield of 1-chloro-2-hydroxy-3-methoxypropane was 90.1%.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 3.98 (m, 1H), 3.63 (m, 1H), 3.59 (m, 1H), 3.51 (d, 2H), 3.41 (s, 3H), 2.65 (Bs, 1H).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 73.35 (CH), 70.23 (CH ₂ ), 59.34 (CH ₃ ), 46.04 (CH ₂ ).

Synthesis Example (2) Synthesis of 1-chloro-2-hydroxy-3-ethoxypropane.
As in Synthesis Example (1), 115.2 g (2.5 mol) of ethanol and 3.7 g (0.038 mol) of concentrated sulfuric acid were charged into a 300 ml reactor, and the internal temperature was adjusted to 30 ° C. while stirring. .

Then, 92.5 g (1.0 mol) of epichlorohydrin was added dropwise over 3 hours while keeping the internal temperature at 32 ° C. or less, washed with 4.4 g of ethanol, and further 5.5 g of concentrated sulfuric acid ( 0.055 mol) was added and reflux stirring was continued for 52 hours under the same temperature conditions to obtain 221.4 g of a colorless and transparent reaction solution. 1.0 g was weighed out from the obtained liquid, neutralized with sodium bicarbonate, and then the produced salt was filtered and concentrated to obtain 0.6 g of an oily substance. The resulting oil is 88.2% pure by analysis by gas ^{chromatography,} confirming that the 1 H-NMR and ¹³ C-NMR is 1-chloro-2-hydroxy-3-ethoxy propane It was.

Moreover, as a result of quantifying the obtained reaction liquid by gas chromatography, the yield of 1-chloro-2-hydroxy-3-ethoxypropane was 77.6%.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 3.97 (m, 1H), 3.64 to 3.48 (m, 6H), 2.62 (bs, 1H), 1.22 (t, 3H, J = 7.0).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 73.31 (CH), 70.34 (CH ₂ ), 67.05 (CH ₂ ), 46.12 (CH ₂ ), 15.19 (CH ₃ ).

Synthesis Example (3) Synthesis of 1-chloro-2-hydroxy-3-isopropoxypropane.
As in Synthesis Example (1), 15.0 g (0.25 mol) of isopropanol and 0.04 g (0.28 mmol) of boron trifluoride diethyl ether complex were charged into a 100 ml reactor, and the internal temperature was stirred. Was set to 20 ° C. 9.3 g (0.1 mol) of epichlorohydrin was added dropwise over 1 hour while keeping the internal temperature at 25 ° C. or lower, and reflux stirring was continued for 20 hours while maintaining the same temperature condition. 24.3 g was obtained. When 0.3 g (2.4 mmol) of 32% caustic aqueous solution was added to the obtained liquid, neutralized and distilled, 2.3 g of a distillate having a boiling point of 105 ° C./5.5 KPa (yield 15.2%). ) The resulting distillate is 95.7% pure by analysis by gas ^{chromatography,} it from 1 H-NMR and ¹³ C-NMR is 1-chloro-2-hydroxy-3-isopropoxy-propane It could be confirmed.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 3.93 (m, 1H), 3.64 to 3.52 (m, 5H), 2.64 (bs, 1H), 1.17 (d, 6H, J = 6.2).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 72.45 (CH), 70.49 (CH ₂ ), 68.60 (CH), 46.06 (CH ₂ ), 22.13 (CH ₃ ).

  Similarly, a reaction sample was synthesized.

  As in Synthesis Example (1), 150.3 g (2.5 mol) of isopropanol and 4.0 g (0.041 mol) of concentrated sulfuric acid were charged into a 1000 ml reactor, and the internal temperature was adjusted to 30 ° C. while stirring. . There, 92.5 g (1.0 mol) of epichlorohydrin was dropped over 4 hours while maintaining the internal temperature at 35 ° C. or lower, and 5.3 g (0.053 mol) of concentrated sulfuric acid was further added. Stirring was continued for 96 hours while maintaining the temperature condition to obtain 249.2 g of a colorless and transparent liquid. As a result of quantifying the obtained reaction liquid by gas chromatography, the yield of 1-chloro-2-hydroxy-3-isopropoxypropane was 56.0%.

Synthesis Example (4) Synthesis of 1-chloro-2-hydroxy-3-benzyloxypropane.
As in Synthesis Example (1), 27.3 g (0.25 mol) of benzyl alcohol and 0.4 g (4 mmol) of concentrated sulfuric acid were charged into a 100 ml reactor, and the internal temperature was adjusted to 20 ° C. while stirring. 9.3 g (0.10 mol) of epichlorohydrin was added dropwise over 1 hour while maintaining the internal temperature at 25 ° C. or lower, and reflux stirring was continued for 14 hours while maintaining the same temperature condition. 34.4 g was obtained. When the obtained liquid was neutralized by adding 11.4 g (8 mmol) of 6% aqueous sodium hydrogen carbonate solution and distilled, 5.6 g of a distillate having a boiling point of 108 ° C./0.1 KPa (yield 25.5%). ) The resulting oil is 90.7% pure by analysis by gas ^{chromatography,} confirming that the 1 H-NMR and ¹³ C-NMR is 1-chloro-2-hydroxy-3-benzyloxy-propane did it.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 7.40 to 7.24 (m, 5H), 4.51 (S, 2H), 3.99 (m, 1H), 3.68 to 3.57 (m, 4H), 2.59 ( bs, 1H).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 133.58 (benzene nucleus CH), 128.50 to 127.77 (benzene nucleus CH), 73.62 (CH ² ), 70.87 (CH), 70.30 (CH 2), 46.15 ( CH
2).

  Similarly, a reaction sample was synthesized.

  As in Synthesis Example (1), 136.3 g (1.26 mol) of benzyl alcohol and 2.0 g (0.02 mol) of concentrated sulfuric acid were charged into a 300 ml reactor, and the internal temperature was adjusted to 20 ° C. while stirring. did. Thereto, 46.6 g (0.50 mol) of epichlorohydrin was added dropwise over 3 hours while maintaining the internal temperature at 40 ° C. or lower, and reflux stirring was continued for 20 hours while maintaining the same temperature condition. 185.5 g was obtained. As a result of quantifying the obtained reaction liquid by gas chromatography, the yield of 1-chloro-2-hydroxy-3-benzyloxypropane was 61.9%.

  Next, synthesis of N- (2-hydroxy-3-alkoxypropyl) piperazine using the various 1-chloro-2-hydroxy-3-alkoxypropanes obtained will be described.

Synthesis example (5) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
Under a nitrogen atmosphere, 28.7 g (0.28 mol) of piperazine and 25.8 g of methanol were charged into a 100 ml reactor, and the internal temperature was adjusted to 60 ° C. while stirring. While maintaining the internal temperature at 72 ° C. or lower, 16.2 g (containing 0.086 mol) of 1-chloro-2-hydroxy-3-methoxypropane reaction solution obtained in Synthesis Example (1) was taken over 2 hours. Then, reflux stirring was continued for 14 hours while maintaining the same temperature condition to obtain 70.7 g of a colorless and transparent reaction solution. The liquid obtained was concentrated, 13.0 g (0.1 mol) of a 32% caustic aqueous solution was added, neutralized, filtered, concentrated, and distilled to obtain 9.7 g of a distillate having a boiling point of 133 ° C./27 Pa or less. (Yield 65.1%) was obtained. The obtained distillate had a purity of 98.9% as analyzed by gas chromatography and was N- (2-hydroxy-3-methoxypropyl) piperazine from ¹ H-NMR and ¹³ C-NMR. It could be confirmed.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 3.89 (m, 1H), 3.43 to 3.32 (m, 5H), 2.89 (m, 2H), 2.61 (bs, 1H), 2.43 to 2.31 ( m, 6H).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 75.06 (CH), 65.67 (CH ₂ ), 61.18 (CH ₃ ), 59.24 (CH ₂ ), 54.57 (CH ₂ ), 46.11 (CH ₂ ).

Moreover, as a result of quantifying the obtained reaction liquid by gas chromatography, the yield of N- (2-hydroxy-3-methoxypropyl) piperazine was 86.2%. The results of Synthesis Example (5) are shown in Table 1 along with other examples.

Synthesis example (6) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
The reaction was conducted in the same manner as in Synthesis Example (5) except that piperazine (7.4 g, 0.09 mol) was used instead of piperazine (28.7 g, 0.28 mol) in Synthesis Example (5) . . The results of Synthesis Example (6) are shown in Table 1 along with other examples.

Synthesis example (7) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
Instead of using 28.7 g (0.28 mol ) of piperazine in Synthesis Example (5) , 7.4 g (0.09 mol) of piperazine was used, and 2.9 g of 96% caustic as a dehydrohalogenating agent ( All reactions were carried out in the same manner as in Synthesis Example (5) except that 0.09 mol) was used. The results of Synthesis Example (7) are shown in Table 1 along with other examples.

Synthesis example (8) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
The reaction was conducted in the same manner as in Synthesis Example (5) except that 14.7 g (0.17 mol) of piperazine was used instead of 28.7 g (0.28 mol) of piperazine in Synthesis Example (5) . . The results of Synthesis Example (8) are shown in Table 1 along with other examples.

Synthesis example (9) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
In the same manner as in Synthesis Example (5) , 286.8 g (3.33 mol) of piperazine and 258.1 g of methanol were charged into a 1000 ml reactor under a nitrogen atmosphere, and the internal temperature was adjusted to 60 ° C. while stirring. Thereto, 162.4 g (containing 0.86 mol) of a 1-chloro-2-hydroxy-3-methoxypropane reaction solution obtained in the same manner as in Synthesis Example (1) while keeping the internal temperature at 70 ° C. or lower. The mixture was added dropwise over 2 hours, and the reflux stirring was continued for 24 hours while maintaining the same temperature condition. As a result of quantifying the obtained reaction liquid by gas chromatography, the yield of N- (2-hydroxy-3-methoxypropyl) piperazine was 87.6%. The results of Synthesis Example (9) are shown in Table 1 along with other examples. The obtained reaction solution was treated in the same manner as in Synthesis Example (5) to obtain 80.0 g (yield 52.2%) of N- (2-hydroxy-3-methoxypropyl) piperazine having a purity of 97.7% or more. %). The results of Synthesis Example (9) are shown in Table 1 along with other examples.

Synthesis example (10) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
The reaction was conducted in the same manner as in Synthesis Example (5) , except that 74.3 g (0.86 mol) of piperazine was used instead of 28.7 g (0.28 mol) of piperazine in Synthesis Example (5) . . The results of Synthesis Example (10) are shown in Table 1 along with other examples.

Comparative synthesis example (1) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
The reaction was performed in the same manner as in Synthesis Example (5) except that piperazine (6.0 g, 0.07 mol) was used instead of piperazine (28.7 g, 0.28 mol) in Synthesis Example (5) . . Table 1 shows the results of Comparative Synthesis Example (1) 1 together with other examples.

Comparative synthesis example (2) . Synthesis of N- (2-hydroxy-3-methoxypropyl) piperazine.
Instead of using 28.7 g (0.28 mol) of piperazine in Synthesis Example (5), 6.0 g (0.07 mol) of piperazine was used, and 2.9 g of 96% caustic as a dehydrohalogenating agent ( All reactions were performed in the same manner as in Synthesis Example (5) except that 0.07 mol) was used. The results of Comparative Synthesis Example (2) along with other examples are shown in Table 1.

合成例（１１）．Ｎ−（２−ヒドロキシ−３−エトキシプロピル）ピペラジンの合成．
合成例（５）と同様に、窒素雰囲気下、１０００ｍｌの反応器に、ピペラジン３３１．６ｇ（３．８５モル）とエタノール２９８．５ｇを仕込み、撹拌しながら内温を６０℃とした。そこに、内温を７０℃以下に保ちながら，合成例（２）で得られた１−クロロ−２−ヒドロキシ−３−エトキシプロパン反応液２２１．４ｇ（０．７８モル含有）を２時間かけて滴下し、更に同温度条件のまま還流撹拌を２４時間継続した。また、得られた反応液を実施例１と同様に３２％の苛性水溶液８３．８ｇ（０．６７ｍｏｌ）を加え中和後、ろ過、濃縮、蒸留処理して、沸点１３６℃／１ＫＰａ以下での留出物１１３．０ｇ（収率７１．４％）を得た。得られた留出物は、ガスクロマトグラフィーでの分析で純度９２．２％以上であり、^１Ｈ−ＮＭＲ及び^１３Ｃ−ＮＭＲからＮ−（２−ヒドロキシ−３−エトキシプロピル）ピペラジンであることが確認できた。

Synthesis example (11) . Synthesis of N- (2-hydroxy-3-ethoxypropyl) piperazine.
In the same manner as in Synthesis Example (5) , 331.6 g (3.85 mol) of piperazine and 298.5 g of ethanol were charged into a 1000 ml reactor under a nitrogen atmosphere, and the internal temperature was adjusted to 60 ° C. while stirring. While maintaining the internal temperature at 70 ° C. or lower, 221.4 g (containing 0.78 mol) of the 1-chloro-2-hydroxy-3-ethoxypropane reaction solution obtained in Synthesis Example (2) was taken over 2 hours. Then, the mixture was further stirred under reflux at the same temperature for 24 hours. Further, the obtained reaction solution was neutralized by adding 83.8 g (0.67 mol) of a 32% aqueous caustic solution in the same manner as in Example 1, followed by filtration, concentration, and distillation treatment to obtain a boiling point of 136 ° C./1 KPa or less. 113.0 g (yield 71.4%) of distillate was obtained. The obtained distillate has a purity of 92.2% or more by gas chromatography analysis, and is N- (2-hydroxy-3-ethoxypropyl) piperazine from ¹ H-NMR and ¹³ C-NMR. Was confirmed.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 3.89 (m, 1H), 3.52 to 3.36 (m, 4H), 2.87 (m, 2H), 2.56 (bs, 1H), 2.44 to 2.31 ( m, 2H), 1.21 (t, 3H, J = 7.0).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 73.11 (CH), 66.94 (CH ₂ ), 65.97 (CH ₂ ), 61.44 (CH ₂ ), 54.72 (CH ₂ ), 46.25 (CH ₂ ), 15 .22 (CH ₃ ).

Moreover, as a result of quantifying the obtained reaction liquid by gas chromatography, N- (2
The yield of (hydroxy-3-ethoxypropyl) piperazine was 79.4%.

Synthesis example (12) . Synthesis of N- (2-hydroxy-3-isopropoxypropyl) piperazine.
In the same manner as in Synthesis Example (5) , 186.9 g (2.17 mol) of piperazine and 180.0 g of isopropanol were charged into a 1000 ml reactor under a nitrogen atmosphere, and the internal temperature was adjusted to 60 ° C. while stirring. While maintaining the internal temperature at 75 ° C. or lower, 249.2 g (containing 0.56 mol) of 1-chloro-2-hydroxy-3-isopropoxypropane reaction solution obtained in Synthesis Example (3) was added for 2 hours. Then, the mixture was further stirred under reflux for 72 hours while maintaining the same temperature condition. In addition, the obtained reaction solution was neutralized by adding 83.8 g (0.67 mol) of a 32% caustic aqueous solution in the same manner as in Synthesis Example (5) , followed by filtration, concentration and distillation treatment, and a boiling point of 103 ° C./40 Pa or less. 58.2 g (yield 28.2%) was obtained. The obtained distillate has a purity of 97.7% or more as analyzed by gas chromatography and is N- (2-hydroxy-3-ethoxypropyl) piperazine from ¹ H-NMR and ¹³ C-NMR. Was confirmed.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 3.87 (m, 1H), 3.60 (q, 1H, J = 6.2), 3.44 to 3.40 (m, 2H), 2.87 (m, 4H), 2. 62-2.35 (m, 7H), 1.17 (d, 6H, J = 6.2).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 72.14 (CH), 70.73 (CH ₂ ), 66.21 (CH), 61.61 (CH ₂ ), 54.71 (CH ₂ ), 46.15 (CH ₂ ), 22.09 (CH ₃ ).

Moreover, as a result of quantifying the obtained reaction liquid by gas chromatography, N- (2
The yield of -hydroxy-3-isopropoxypropyl) piperazine was 44.3%.

Synthesis example (13) . Synthesis of N- (2-hydroxy-3-benzyloxypropyl) piperazine.
Similarly to Synthesis Example (5) , 104.2 g (1.21 mol) of piperazine and 100.4 g of methanol were charged into a 1000 ml reactor under a nitrogen atmosphere, and the internal temperature was adjusted to 60 ° C. while stirring. While maintaining the internal temperature at 70 ° C. or less, 85.3 g (containing 0.26 mol) of 1-chloro-2-hydroxy-3-benzyloxypropane reaction solution obtained in Synthesis Example (4) was added for 2 hours. Then, the mixture was further stirred under reflux at the same temperature for 24 hours. Next, 1.0 g was sampled from the obtained reaction liquid, neutralized with 96 g of caustic 0.1 g (2.4 mmol), filtered and concentrated, and then a silica gel column (Wako Pure Chemical Industries, Ltd., After purification at C-300), 0.1 g of a viscous product was obtained. The resulting viscous product has a purity of 83.4% as analyzed by gas chromatography and is N- (2-hydroxy-3-benzyloxypropyl) piperazine from ¹ H-NMR and ¹³ C-NMR. Was confirmed.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 7.35 to 7.27 (m, 5H), 4.57 (S, 2H), 3.91 (m, 1H), 3.50 to 3.46 (m, 2H), 2.86 ( m, 4H), 2.64-2.34 (m, 7H).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 138.11 (benzene nucleus CH), 128.37 to 127.64 (benzene nucleus CH), 73.55 (CH ₂ ), 72.65 (CH), 66.15 (CH ₂ ), 61.37 _{(CH 2), 54.94 (CH} 2), 46.15 (CH 2).

Further, the reaction solution was neutralized by adding 40.6 g (0.31 mol) of a 32% caustic aqueous solution in the same manner as in Synthesis Example (5) , filtered and concentrated to 97.2 g (yield 28.2). %).

Moreover, as a result of quantifying the obtained reaction liquid by gas chromatography, N- (2
The yield of -hydroxy-3-benzyloxypropyl) piperazine was 49.3%.

Example 1 . Synthesis of N- (2-methoxymethyl) triethylenediamine.
A quartz tube (inner diameter: 23 mm, length: 590 mm) filled with 20 ml of commercially available aluminum phosphate (manufactured by Wako Pure Chemical Industries, Ltd., for chemical use) was used as a fixed bed reactor, and 380 ° C. while flowing nitrogen at a flow rate of 60 ml / min. Then, water was circulated at 30 ml / hr ⁻¹ for 1 hour. In the cyclization reaction, a 20 wt% aqueous solution of N- (2-hydroxy-3-methoxypropyl) piperazine obtained in Synthesis Example (9) was fixed in a fixed bed reactor at the same temperature and gas space velocity (GHSV) A value obtained by dividing the apparent supply rate by the catalyst volume) was allowed to flow at a flow rate of 1,534 hr ⁻¹ , and the solution distilled from the reactor was received in the flask. When the obtained liquid was analyzed by GC-MS, a peak with a molecular weight of 156 was detected. Furthermore, when the viscous product obtained by concentrating 5.1 g of the reaction solution was isolated and purified with a silica gel column (C-300, manufactured by Wako Pure Chemical Industries, Ltd.), 0.1 g of a compound having a target peak was obtained. It was. The purified product obtained had a purity of 94.7% as analyzed by gas chromatography, and was confirmed to be N- (2-methoxymethyl) triethylenediamine from ¹ H-NMR and ¹³ C-NMR.

¹ H-NMR (CDCl ₃ , 200 MHz),
δ: 3.53 (m, 1H), 3.35 to 2.29 (m, 12H), 3.38 (s, 3H).

¹³ C-NMR (CDCl ₃ , 200 MHz),
δ: 73.07 (CH ₃ ), 59.16 (CH), 54.30 (CH ₂ ), 50.26 (CH ₂ ), 49.50 (CH ₂ ), 47.17 (CH ₂ ), 46 .30 (CH ₂ ), 41.30 (CH ₂ ).

Moreover, as a result of quantifying the obtained reaction liquid by gas chromatography, the yield of N- (2-methoxymethyl) triethylenediamine was 37.4%. The results of Example 1 are shown in Table 2 together with other examples.

Example 2 . Synthesis of N- (2-methoxymethyl) triethylenediamine.
The reaction was conducted in the same manner as in Example 1 except that the 20 wt% aqueous solution of N- (2-hydroxy-3-methoxypropyl) piperazine was passed at 380 ° C. in Example 1 except that it was passed at 360 ° C. The results of Example 2 are shown in Table 2 along with other examples.

Example 3 . Synthesis of N- (2-methoxymethyl) triethylenediamine.
The reaction was conducted in the same manner as in Example 1 except that in Example 1 , the 20 wt% aqueous solution of N- (2-hydroxy-3-methoxypropyl) piperazine was passed at 380 ° C., except that it was passed at 340 ° C. The results of Example 3 are shown in Table 2 along with other examples.

Example 4 .
In a 200 ml autoclave, 18.5 g (purity 94.5%, 0.10 mol) of N- (2-hydroxy-3-methoxypropyl) piperazine obtained in the same manner as in Synthesis Example (9) and 100 g of water as a solvent, As a catalyst, 5.0 g of phenylphosphonic acid (manufactured by Wako Pure Chemical Industries, Ltd., for chemical use) was charged and heated to 280 ° C. in a nitrogen atmosphere. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 2 hours.

As a result of analyzing the obtained reaction liquid by gas chromatography, the yield of N- (2-methoxymethyl) triethylenediamine was 1.0%. The results of Example 4 are shown in Table 2 along with other examples.

Comparative Example 1
In a 200 ml autoclave, 18.5 g (purity 94.5%, 0.10 mol) of N- (2-hydroxy-3-methoxypropyl) piperazine obtained in the same manner as in Synthesis Example (9) and 100 g of water as a solvent were added. Filled and heated to 280 ° C. under nitrogen atmosphere without addition of catalyst. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 2 hours.

As a result of analyzing the obtained reaction liquid by gas chromatography, the yield of N- (2-hydroxy-3-methoxypropyl) piperazine was 0%. The results of Comparative Example 1 are shown in Table 2 together with other examples.

Claims (2)

Following formula (1)

(In the formula, R represents a methyl group, an ethyl group, a linear or branched alkyl group having 3 to 12 carbon atoms, or a benzyl group.)
N- (2-hydroxy-3-alkoxypropyl) piperazines represented by formula (2) are subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst.

(Wherein R has the same definition as above)
The manufacturing method of N- (2-alkoxymethyl) triethylenediamine shown by these. The production method according to claim 1, wherein the acid catalyst contains one or more compounds selected from the group consisting of metal phosphates and organic phosphorus compounds.