JP6399814B2 - Method for producing dichloromethyl alkyl ether compound - Google Patents

Description

  The present invention relates to a method for efficiently producing a dichloromethyl alkyl ether compound.

  1,1-dichloromethyl-2-alkyl ether is used as a special chlorinating agent capable of performing a reaction that cannot be performed by other chlorinating agents (see Non-Patent Document 1). Alternatively, it is a useful compound having high reaction activity as a formylating agent such as a wide range of aromatic compounds (see Non-Patent Document 2). On the other hand, the synthesis method has been limited so far. For example, a method of reacting formate with phosphorus pentachloride or phosgene is known (see Non-Patent Document 3 and Patent Document 1).

JP 08-239338 A

Organic Syntheses, Coll.Vol.7, p.467 (1990), Vol.61, p.1 (1983) Chemical Berichte Jahrg.93, pp.88-94 (1955) Organic Syntheses, Coll. Vol.5, p.365 (1973); Vol.47, p.51 (1967)

  Phosphorus pentachloride is highly toxic in itself, and disposal of phosphorus after use becomes a problem. Phosgene is also known to be a highly toxic chemical. The demand of the times is to produce useful compounds in an environmentally friendly and safe manner. From such a viewpoint, an object of the present invention is to provide a process for producing a dichloromethyl alkyl ether compound that is safe and easy to handle and has little influence on the environment. Moreover, it aims at contributing to provision of a chlorinated compound and a formylation compound useful in the field | areas, such as an agricultural chemical, a pharmaceutical, a fragrance | flavor, and a functional polymer material.

  The present inventor diligently studied to solve the above problems, and by reacting a formic acid ester compound with a chloride compound such as oxalic acid dichloride in the presence of an N-phenylformamide catalyst, 1 The inventors have found that 1-dichloromethyl-2-alkyl ether (hereinafter sometimes abbreviated as “DCMAE”) can be produced, and the present invention has been completed. That is, the present invention has the following means.

（式中、Ｘはメチル基または置換基を有していてもよいフェニル基を表す。Ｒ’は炭素数１〜６のアルキル基またはハロゲン原子を表す。ｍは０〜５の整数を表す。Ｒは炭素数１〜６のアルキル基を表す。ｎは１または２を表す。）
〔２〕前記ホルムアニリド化合物を前記ギ酸エステル化合物に対して０．０５〜０．２当量用いる〔１〕に記載のジクロロメチルアルキルエーテル化合物の製造方法。
〔３〕前記ギ酸エステル化合物と前記クロリド化合物との反応を無溶媒で行う〔１〕または〔２〕に記載のジクロロメチルアルキルエーテル化合物の製造方法。
〔４〕前記ギ酸エステル化合物のＲの炭素数が３〜６であり、当該ギ酸エステル化合物と前記クロリド化合物とを反応させる反応温度を６０℃以上８０℃以下とする〔１〕〜〔３〕のいずれか１つに記載のジクロロメチルアルキルエーテル化合物の製造方法。
〔５〕 〔１〕〜〔４〕のいずれか１つに記載の製造方法でジクロロメチルアルキルエーテル化合物を得た後、当該ジクロロメチルアルキルエーテル化合物と原料化合物とを反応させ、当該原料化合物のホルミル化化合物を得るホルミル化化合物の製造方法。
〔６〕前記原料化合物が、芳香族化合物および複素芳香族化合物から選ばれる〔５〕に記載のホルミル化化合物の製造方法。 [1] A formic acid ester compound represented by the following general formula [2] is reacted with a chloride compound represented by the following general formula [P] in the presence of a formanilide compound represented by the following general formula [1]. The manufacturing method of the dichloromethyl alkyl ether compound represented by General formula [3].

(In the formula, X represents a methyl group or a phenyl group which may have a substituent. R ′ represents an alkyl group having 1 to 6 carbon atoms or a halogen atom. M represents an integer of 0 to 5). R represents an alkyl group having 1 to 6 carbon atoms, and n represents 1 or 2.)
[2] The process for producing a dichloromethyl alkyl ether compound according to [1], wherein 0.05 to 0.2 equivalent of the formanilide compound is used with respect to the formate compound.
[3] The process for producing a dichloromethyl alkyl ether compound according to [1] or [2], wherein the reaction between the formate compound and the chloride compound is carried out without a solvent.
[4] The carbon number of R of the formate compound is 3 to 6, and the reaction temperature for reacting the formate compound and the chloride compound is 60 ° C. or higher and 80 ° C. or lower. The manufacturing method of the dichloromethyl alkyl ether compound as described in any one.
[5] After obtaining the dichloromethyl alkyl ether compound by the production method according to any one of [1] to [4], the dichloromethyl alkyl ether compound and the raw material compound are reacted to obtain a formylation compound of the raw material compound. A process for producing the formylation compound obtained.
[6] The method for producing a formylation compound according to [5], wherein the raw material compound is selected from an aromatic compound and a heteroaromatic compound.

  The production method of the present invention can provide a method for producing a dichloromethyl alkyl ether compound that is safe and easy to handle and has little influence on the environment. Moreover, it can contribute to provision of a chlorinated compound and a formylation compound useful in fields, such as an agricultural chemical, a pharmaceutical, a fragrance | flavor, and a functional polymer material.

  Hereinafter, the present invention will be described in detail focusing on preferred embodiments thereof.

-Formanilide compound In the manufacturing method of this invention, a formanilide compound is represented by the following general formula [1], and is used as a catalyst. A preferable application amount is preferably 0.01 equivalent or more, more preferably 0.03 equivalent or more, and particularly preferably 0.05 equivalent or more, based on the formate compound. As an upper limit, 1 equivalent or less is preferable, 0.5 equivalent or less is more preferable, and 0.2 equivalent or less is especially preferable. Although details will be described later, by setting it within the above upper and lower limits, the reverse reaction of the production reaction to obtain the target compound can be suppressed, while sufficient reaction activity (catalysis) can be obtained.

In the formula, X represents a methyl group or a phenyl group which may have a substituent. R ′ represents a lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 3) or a halogen atom (chlorine atom, fluorine atom). Among them, R ′ is preferably a methyl group, an ethyl group, a propyl group, or a halogen atom (chlorine atom, fluorine atom). m represents an integer of 0 to 5, preferably 0 to 2, and more preferably 0 or 1.
Examples of the substituent of the phenyl group which may have a substituent include the above R ′. The phenyl group which may have a substituent is preferably represented by the following formula (T-1), and more preferably a substituent represented by the formula (T-2). R ′ is synonymous with the formula (1). R ″ is a hydrogen atom or a substituent represented by R ′. * Represents a bonding position with N.

-Formate compound One of the substrates in the production method of the present invention is a formate compound represented by the following formula [2]. The application amount may be arbitrarily adjusted, and can be typically applied in a stoichiometric amount.

  R represents an alkyl group having 1 to 6 carbon atoms. R has preferably 3 or more carbon atoms. As an upper limit, 5 or less is preferable.

Both methyl formate and ethyl formate have a low flash point of minus 20 ° C. and may be difficult to handle in large quantities. In this respect, butyl formate is a liquid having a flash point of 16 ° C., and is also active as a chlorinating agent or a formylating agent. In a preferred embodiment of the present invention, a formic acid ester compound having 3 to 5 carbon atoms is selected, and oxalic acid dichloride (oxalyl chloride) is used as the chloride compound, so that the production method is extremely safe and easy to handle. Can be provided.
The formate compound used as the raw material preferably has a boiling point of 60 ° C. or higher. In consideration of the availability of commercially available products and by-products after the reaction in the next step, R in formula [2] is preferably an alkyl group having 3 to 5 carbon atoms as described above.

-Chloride compound Another substrate in the production method of the present invention is a chloride compound represented by the following formula [P]. The chloride compound is phosgene when n = 1 and oxalic acid dichloride when n = 2. In the present invention, n = 2 oxalic acid dichloride is particularly preferable from the viewpoints of safety and handleability.

  In the formula, n represents 1 or 2, and n is preferably 2.

・ Dichloromethyl alkyl ether compounds

  R is synonymous with the formula [2].

Hereinafter, the difference between the prior art and the present invention will be clarified in more detail by comparison based on the reaction scheme.
Patent Document 1 discloses a production method in which methyl formate or ethyl formate is limited to 1,1-dichloromethyl-2-methyl ether or 1,1-dichloromethyl-2-ethyl ether. Examples disclosed in the Examples are methods using triphenylphosphine oxide (TPPO) or N, N-dibutylformamide (DBF) as a catalyst and phosgene as a raw material. It is understood that these catalysts are converted into chloride compounds by phosgene, which reacts with methyl formate or ethyl formate (Scheme 1).
However, according to Example 5 of Patent Document 1, when DBF was used as a catalyst, the yield of dichloromethyl methyl ether was only 31%. Patent Document 1 describes oxalic acid dichloride in the text, but there is no example, and the yield and other details are unknown.

As shown in the Examples section below, in the results of the additional test using oxalic acid dichloride, the yield by GC of the reaction using TPPO as a catalyst (Comparative Example 1) was 74%. However, the swollen solid precipitated and could not be distilled. In the method using DBF as a catalyst (Comparative Example 2), the reaction system was contaminated and the yield was low. However, in the method using dimethylformamide as a catalyst (Comparative Example 3), the reaction system was further contaminated and the target product could not be isolated. Thus, the method using dimethylformamide and oxalic acid dichloride does not give 1,1-dichloromethyl-2-butyl ether in sufficient yield and purity.
In the present invention, these problems have been solved by introducing a phenyl group into the formamide catalyst. The reason for this improvement effect is that the thermal stability of the imidoyl chloride intermediate formed in the system is improved by introducing a phenyl group, and it is possible to prevent an increase in side reactions and a decrease in reaction rate due to decomposition of the catalyst. It is done.
A synthesis reaction according to a preferred embodiment of the present invention is represented by the formula decomposed for the process, as shown in the following scheme 2. Here, at least one of R ₁ and R ₂ is a phenyl group which may have a substituent. According to the inventor's examination from the experimental facts, it can be explained as follows. In Formula (1), the reaction proceeds promptly near room temperature. On the other hand, the compound [iii] of the formula (2) is very reactive, and its reverse reaction tends to proceed. Considering only suppression of the reverse reaction of formula (2), the smaller the amount of compound [i] used, the better. However, if the amount is excessively reduced, the reaction of formula (1) becomes slow, which is not practical. Considering both, it is preferable that the use amount of the compound [i] (formanilide compound represented by the above formula (1)) among the reaction components is adjusted to a suitable range.

  The reaction temperature at which the formate compound and the chloride compound are reacted is preferably 20 ° C. or higher, more preferably 40 ° C. or higher, and further preferably 60 ° C. or higher. As an upper limit, 80 degrees C or less is preferable. This temperature setting is particularly suitable when the carbon number of R in the formate compound represented by the formula [2] is 3-6.

In the present invention, the reaction solvent can be eliminated. Although a solvent may be used, it often requires extra effort such as reduction in volumetric efficiency, separation of the product and the solvent, and recovery of the solvent, and it is preferable that the reaction can be performed without using the solvent.
Since the reaction of the formula (1) is fast, the compound [iv] is preferably added dropwise. Since carbon monoxide and carbon dioxide are generated, when they are added all at once, the gas generation is intense and the reaction may proceed excessively.

  According to the present invention, dichloromethyl alkyl ether can be obtained with a purity of 90 to 95% without requiring a purification operation. Since the upper limit is limited by the reverse reaction of dichloromethyl alkyl ether, it is preferable to adjust the amount of the formamide compound to a suitable range as described above also from this viewpoint. The product can be used as it is for formylation of aromatic compounds. Reactions with aromatic compounds are described in Chem. Ber. 1960, 93, 88-94 can be applied to a wide range of aromatic compounds. Even if inexpensive zinc chloride, iron (III) chloride, or the like is used as a catalyst instead of known titanium, tin, and aluminum, the formylation reaction proceeds with good yield. As an example, the synthesis of piperonal is described as Reference Example 1. Piperonal is a useful compound in the industry as a high-quality fragrance, but it is interesting that it can be produced in a high yield by the reaction of dichloromethylbutyl ether and iron chloride, which is carried out by a multi-step synthesis method.

As an example of the chlorination reaction, a sulfonic acid compound such as an alkylsulfonic acid (for example, methanesulfonic acid) or a salt thereof and 1,1-dichloromethyl-2-alkyl ether (DCMAE) are reacted to obtain an alkylsulfonyl chloride ( For example, a reaction for obtaining methanesulfonyl chloride is known (Rieche, A and Gross, H. Chem. Ber. 1959, 92, pp. 83-91). In addition, a reaction in which a ketone compound (RCOR ′) and DCMAE are reacted to obtain a dichloroalkyl compound is known (Ottenheijim, HCJ and Tijhuis, MW, OS VII p.467 (1970), Ottenheijim, HCJ and Deman). , JHM Synthesis 1975, pp.163-164).
As an example of the formylation reaction, as described above, a method is known in which an aromatic compound or a heteroaromatic compound is reacted with DCMAE to formylate to obtain various (hetero) aromatic formylation compounds (the above non-formation). See Patent Document 2, Rieche, A, Gross, H, and Hoft, E.OS V p.49, Rieche, A, Gross, H, and Hoft, E.Chem.Ber. 1960, 93, pp.88-94 ). Examples of the compound obtained by this synthesis method include benzaldehyde, cuminaldehyde, 3,4-dimethylbenzaldehyde, mesitylaldehyde, phenylbenzaldehyde, naphthaldehyde, fluorenealdehyde, anthracene aldehyde, phenanthrenealdehyde, pyrenealdehyde, fluorobenzaldehyde, methoxy Examples include benzaldehyde, veratramaldehyde, methoxynitrobenzaldehyde, methoxynaphthaldehyde, thiophene aldehyde, and the like.
By applying this reaction, it is possible to synthesize a compound having a complicated structure such as pyronal as described above. Or even if it is a compound which is difficult to introduce | transduce a functional group like fluorobenzene, a fluorobenzaldehyde can be simply obtained by making this and DCMAE react (US5,138,099).

  Hereinafter, the present invention will be described in more detail through examples, but the present invention is not construed as being limited thereto.

Example 1
1.40 g (10.4 mmol) of N-methylformanilide and 10.2 g (100 mmol) of butyl formate were placed in an oil bath at 60 ° C., and 16.2 g (128 mmol) of oxalic acid dichloride was added over 1 hour and 30 minutes with stirring. And dripped. Thereafter, stirring was continued for 7 hours and 30 minutes until no more gas was generated at the same temperature. It was confirmed by GC analysis that 87% of dichloromethylbutyl ether was produced. The reaction solution was light brown. The reaction solution was distilled under reduced pressure to obtain a fraction of 20 torr, 59 ° C., 13.0 g (crude yield 83%) and GC purity 92%. (Reference value 48-49 ° C./15 torr: Rieche, A, Gross, H, and Hof, E. Chem. Ber. 1960, 93, 88-94) It was confirmed by GCMS that it was consistent with the standard product. m / z = 113, 83, 57 (maximum), 41.
The GC purity was measured by diluting dichloromethylbutyl ether with dichloromethane dried with molecular sieves and introducing the solution directly into GC.

Examples 2-4
A dichloromethyl alkyl ether was produced in the same manner as in Example 1 except that a formic acid ester having 3 to 6 carbon atoms was used instead of butyl formate. The results are shown in Table 1 together with the results of other examples.

  Reaction conditions: Raw material (100 mmol), N-methylformanilide (10 mmol), oxalic acid dichloride (130 mmol) dropwise at 60 ° C. for 2 hours, then stirred at 60 ° C. for 7 hours

Example 5
1.97 g (4.9 mmol) of N, N-diphenylformamide and 10.2 g (100 mmol) of butyl formate were placed in an oil bath at 60 ° C., and 16.2 g (128 mmol) of oxalic acid dichloride was stirred for 1 hour and 30 minutes. It was dripped over. Thereafter, stirring was continued for 2 hours at the same temperature. It was confirmed by GC analysis that 80% of dichloromethylbutyl ether was produced. Thereafter, the reaction was continued, but the amount produced was not changed. The reaction solution was light brown.

Example 6
The reaction was conducted in the same manner as in Example 5 except that the amount of N, N-diphenylformamide in Example 5 was reduced to 0.96 g (4.9 mmol). According to the analysis of dropping for 1 hour and stirring for 3 hours, the production of dichloromethyl butyl ether was 60%, and even when the stirring was continued for 4 hours, the amount of production was unchanged. When 1.0 g (7.9 mmol) of oxalic acid dichloride was added and stirred for 2 hours, the production of dichloromethylbutyl ether was 67%.

Example 7
2.72 g (20.1 mmol) of N-methylformanilide and 12.0 g (200 mmol) of methyl formate were placed in an oil bath at 30 ° C. and 32.0 g (252 mmol) of oxalic acid dichloride was added dropwise over 6 hours while stirring. did. During that time, a gentle reflux was observed. Thereafter, stirring was continued for 3 hours until no more gas was generated at the same temperature. GC analysis confirmed that little methyl formate remained. The reaction solution was light brown. This was distilled to obtain 14 g of a fraction having a boiling point of 70-72 ° C. GCMS analysis revealed a mixture of 57% dichloromethyl methyl ether and 43% oxalic acid dichloride. Each matched the mass spectrum of the standard. The first fraction contained 36% dichloromethyl methyl ether. When they were combined, the isolated yield of dichloromethyl methyl ether was 52% in terms of pure content.

Example 8
1.38 g (10.2 mmol) of N-methylformanilide and 10.2 g (100 mmol) of butyl formate were placed in an oil bath at 25-30 ° C., and 16.0 g (126 mmol) of oxalic acid dichloride was stirred for 30 hours. It was added dropwise over a period of minutes. Thereafter, stirring was continued for 27 hours until no more gas was generated at the same temperature. It was confirmed by GC analysis that 80% of dichloromethylbutyl ether was produced. The reaction solution was light brown.

Comparative Example 1
To a mixture of 2.86 g (10.0 mmol) of triphenylphosphine oxide and 10.4 g (102 mmol) of butyl formate, 16.2 g (128 mmol) of oxalic acid dichloride was added dropwise at 60 ° C. over 2 hours, followed by Stir for 7 hours. White crystals precipitated from the middle of the dropping and remained as a slurry until the end. When GC analysis was performed, 74% of dichloromethylbutyl ether was produced, but a large amount of white crystals that seemed to be triphenylphosphine oxide were precipitated, making distillation difficult.

Comparative Example 2
N, N-dibutylformamide (1.57 g, 10.0 mmol) and isobutyl formate (8.23 g, 80.7 mmol) were placed in an oil bath at 50 ° C., and 13.4 g (106 mmol) of oxalic acid dichloride was stirred for 3 hours with stirring. It was dripped over. Thereafter, stirring was continued at 70 ° C. for 5 hours, and GC analysis revealed that 43% of dichloromethyl isobutyl ether was formed in the entire area, but 57% of isobutyl formate remained. The reaction solution was dark brown.

Comparative Example 3
0.77 g (10.5 mmol) of N, N-dimethylformamide and 8.8 g (100 mmol) of isopropyl formate were placed in an oil bath at 60 ° C. and 16 g (126 mmol) of oxalic acid dichloride was added over 1 hour and 30 minutes while stirring. It was dripped. Then, it stirred at 60 degreeC for 6 hours and 30 minutes. Upon standing, a dark brown component sinked to the bottom and the upper layer was a clear, light brown color. When the upper layer was analyzed by GC, the raw material isopropyl formate disappeared and the formation of dichloromethyl isopropyl ether was confirmed. However, when the product was distilled, the target product was hardly obtained.

Reference example 1
A solution obtained by suspending 1.20 g (10 mmol) of 1,2-methylenedioxybenzene and 1.6 g (10 mmol) of iron (III) chloride in 5 mL of dichloromethane was cooled in an ice bath and obtained in Example 1. Dichloromethyldibutyl ether 1.90 g (12 mmol) was added and stirred for 0.5 hour. Then, after stirring at room temperature for 0.5 hour, 2M-HCl was added and reaction was stopped. GCMS analysis of the organic layer confirmed that piperonal was produced in 91% yield. m / z = 150 (M ⁺ ), which agreed with the mass spectrum of the sample. The dichloromethane layer was separated and distilled with Kugelrohr (180 ° C./5 torr) to isolate 1.0 g (yield 67%) of white piperonal. Melting point: 36.1 ° C. (literature value, 36 ° C. Journal of Chemical Society of Japan, 1940, 61: 583-591).

Claims (6)

In the presence of a formanilide compound represented by the following general formula [1], a formic acid ester compound represented by the following general formula [2] is reacted with a chloride compound represented by the following general formula [P]. A method for producing a dichloromethyl alkyl ether compound represented by [3].

(In the formula, X represents a methyl group or a phenyl group which may have a substituent. R ′ represents an alkyl group having 1 to 6 carbon atoms or a halogen atom. M represents an integer of 0 to 5). R represents an alkyl group having 1 to 6 carbon atoms, and n represents 1 or 2.)   The method for producing a dichloromethyl alkyl ether compound according to claim 1, wherein 0.05 to 0.2 equivalent of the formanilide compound is used with respect to the formate compound.   The method for producing a dichloromethyl alkyl ether compound according to claim 1 or 2, wherein the reaction between the formate compound and the chloride compound is carried out without a solvent.   The carbon number of R of the said formate ester compound is 3-6, The reaction temperature which makes the said formate ester compound and the said chloride compound react is 60 degreeC or more and 80 degrees C or less. The manufacturing method of the dichloromethyl alkyl ether compound of description.   After obtaining a dichloromethyl alkyl ether compound by the manufacturing method of any one of Claims 1-4, the said dichloromethyl alkyl ether compound and a raw material compound are made to react, and the formyl which obtains the formylation compound of the said raw material compound Method for producing chemical compound. The method for producing a formylation compound according to claim 5, wherein the raw material compound is selected from an aromatic compound and a heteroaromatic compound.