JP4440167B2 - Highly fluorinated carboxylic acid derivative and method for producing the same - Google Patents

Description

The present invention relates to highly fluorinated carboxylic acid derivatives. Synthetic organic chemistry plays an extremely high role in the production of fine chemicals such as pharmaceuticals, food additives, cosmetics, liquid crystals, electronic materials, polymer material monomers, functional materials, and medical materials. Fluorous synthesis has been proposed as a technology that goes beyond the concept of conventional organic synthesis, and its development is desired. This is because perfluorocarbons do not dissolve in organic solvents and water, and the three parties can separate each other, and only highly fluorinated derivatives can be extracted into the perfluorocarbon layer to easily and safely purify compounds. It is a method.
For example, prior to the step of reacting Compound A and Compound B, a highly fluorinated carboxylic acid (a reagent for introducing a highly fluorinated group) is reacted with Compound A, and the highly fluorinated group is converted to Compound A It is introduced into a specific functional group such as an amino group. Thereafter, the reaction between the reaction product and compound B, which is the main reaction, is performed. This is the reaction of another functional group of Compound A, such as a carboxyl group, with Compound B, such as an amino group. Since the reaction product obtained in this way has a high fluorine content, when perfluorocarbon (solvent) is added to this reaction system, this reaction product easily migrates to the perfluorocarbon layer. Separation becomes extremely easy by the operation using. Thereafter, the highly fluorinated group added prior to the main reaction is removed from the reaction product by hydrolysis or the like, and the target reaction product can be obtained with high purity and efficiency.
On the other hand, it is expected that water repellency, lubricity, etc. can be imparted by utilizing the characteristics of fluorine atoms and highly fluorinating the material surface. However, in any case, as a method for highly fluorinated, a reagent for introducing a highly fluorinated group is required.

Until now, as a reagent for introducing a highly fluorinated group, a highly fluorinated compound (see Patent Documents 1, 2 and 3) has been developed and used for the synthesis of sugar chains and peptides. For example, a highly fluorinated carboxylic acid represented by the formula [IV] is not only used as a reagent for introducing a highly fluorinated acyl-type protecting group into a hydroxyl group, but also as described in Patent Documents 2 and 3. It is also used as a raw material for the synthesis of fluorinated compounds. However, the synthesis of the highly fluorinated carboxylic acid represented by the formula [IV] takes 5 steps and requires two purification steps by silica gel chromatography. Requires labor. Further, since the large number of steps is reflected in the production cost including labor costs, it can be considered that the number of steps becomes very expensive when being marketed as an introduction reagent for highly fluorinated acyl-type protecting groups.

JP 2002-338534 A JP2003-261523 JP2004-131458

  An object of the present invention is to provide a highly fluorinated carboxylic acid derivative that has the same performance as, for example, a highly fluorinated carboxylic acid represented by the formula [IV] and can be easily synthesized in a short process, and It is to provide an introduction reagent for an acyl-type protecting group.

（式中、Ｒｆは炭素数３〜16のパーフルオロアルキル基を、Ｒは水素、アルキル基、アラルキル基、アリール基、炭素数３〜16のパーフルオロアルキル基のいずれかを、Ｒ¹ は水素、アルキル基を、ｍは０〜８の整数を、ｎは１〜３の整数を、ｓは１〜３の整数を、ｔは１〜５の整数を表し、Ｒｆ、ｍ、ｎはその表示各位において同一である必要はない。）
で表される高度にフッ素化されたカルボン酸誘導体と式［II］

（式中、Ｒｆは、炭素数３〜１６のパーフルオロアルキル基を、Ｒは水素、アルキル基、アラルキル基、アリール基、炭素数３〜16のパーフルオロアルキル基のいずれかを、ｍは０〜８の整数を、ｎは１〜３の整数を、ｓは１〜３の整数を、ｔは１〜５の整数を表し、Ｒｆ、ｍ、ｎはその表示各位において同一である必要はない。）
で表される高度にフッ素化されたアルコールを酸化し、式［Ｉ］で表される高度にフッ素化されたカルボン酸を製造する方法および、式［III］

（式中、Ｒｆは、炭素数３〜１６のパーフルオロアルキル基を、Ｒは水素、アルキル基、アラルキル基、アリール基、炭素数３〜16のパーフルオロアルキル基のいずれかを、ｍは０〜８の整数を、ｎは１〜３の整数を、ｓは１〜３の整数を、ｔは１〜５の整数を表し、Ｒｆ、ｍ、ｎはその表示各位において同一である必要はない。）
で示される高度にフッ素化されたアシル基を水酸基やアミノ基、イミノ基、チオール基等の官能基の保護基として使用する方法である。なお、保護基とは有機化学反応でよく利用される、その単位プロセスで反応に係わらない官能基を保護するものである。 As a result of intensive studies, the present inventors have created the compound of the present invention.
That is, the present invention provides a compound of the formula [I]

(In the formula, Rf represents a C 3-16 perfluoroalkyl group, R represents hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group, and R ¹ represents hydrogen. , M represents an integer of 0 to 8, n represents an integer of 1 to 3, s represents an integer of 1 to 3, t represents an integer of 1 to 5, and Rf, m, and n are the indications thereof. (It doesn't have to be the same in every place.)
A highly fluorinated carboxylic acid derivative represented by the formula [II]

(In the formula, Rf represents a C 3-16 perfluoroalkyl group, R represents hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group, and m represents 0. -8 is an integer, n is an integer of 1 to 3, s is an integer of 1 to 3, t is an integer of 1 to 5, and Rf, m, and n need not be the same in each display position. .)
A method for producing a highly fluorinated carboxylic acid represented by formula [I] by oxidizing a highly fluorinated alcohol represented by formula [III]

(In the formula, Rf represents a C 3-16 perfluoroalkyl group, R represents hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group, and m represents 0. -8 is an integer, n is an integer of 1 to 3, s is an integer of 1 to 3, t is an integer of 1 to 5, and Rf, m, and n need not be the same in each display position. .)
The highly fluorinated acyl group represented by is used as a protective group for a functional group such as a hydroxyl group, an amino group, an imino group, or a thiol group. In addition, a protecting group protects a functional group that is often used in an organic chemical reaction and is not involved in the reaction in the unit process.

  The compound of the present invention is highly fluorinated because it requires fewer synthetic steps than the highly fluorinated carboxylic acid represented by the formula [IV], which is a conventional highly fluorinated acyl group introduction reagent. The acyl group-introducing reagent thus produced can be mass-produced and provided at a low cost.

Hereinafter, the present invention will be described in detail.
First, a method for producing an intermediate will be described.
Formula [II] (wherein Rf represents a C 3-16 perfluoroalkyl group, R represents any one of hydrogen, an alkyl group, an aralkyl group, an aryl group, and a C 3-16 perfluoroalkyl group. , M represents an integer of 0 to 8, n represents an integer of 1 to 3, s represents an integer of 1 to 3, t represents an integer of 1 to 5, and Rf, m, and n are the same in each display position. The intermediate represented by (2) is produced by reacting an amino alcohol derivative with a carboxylic acid having a perfluoroalkyl group in an organic solvent in the presence of a base.

（式中、Ｒｆはパーフルオロアルキル基を、ｍは０〜８の整数を表す。）
で示されるパーフルオロアルキル基を有するカルボン酸を用いる。パーフルオロアルキル基としては周知のパーフルオロアルキル基を用いることができる。たとえば、パーフルオロヘキシル基、パーフルオロヘプチル基、パーフルオロオクチル基、パーフルオロデシル基、パーフルオロテトラデシル基などを挙げることができる。さらに、分岐構造や立体異性体の有無などを問わないことは言うまでもない。フッ素原子の導入率を高めるにはパーフルオロアルキル基は長鎖の方が有効である。しかし、通常取り扱いや入手の容易さを考慮し、炭素数３〜１６の範囲の誘導体を使用する。好ましくは炭素数４〜１０の範囲の誘導体である。
パーフルオロアルキル基に結合しているメチレン鎖は何ら制限はなく、通常炭素数０〜８のメチレン鎖である。特に、炭素数１〜４のメチレン鎖が好ましい。 The starting carboxylic acid is represented by the formula [V]

(In the formula, Rf represents a perfluoroalkyl group, and m represents an integer of 0 to 8.)
A carboxylic acid having a perfluoroalkyl group represented by A well-known perfluoroalkyl group can be used as the perfluoroalkyl group. For example, a perfluorohexyl group, a perfluoroheptyl group, a perfluorooctyl group, a perfluorodecyl group, a perfluorotetradecyl group, and the like can be given. Furthermore, it goes without saying that it does not matter whether there is a branched structure or a stereoisomer. Longer chains of perfluoroalkyl groups are more effective for increasing the introduction rate of fluorine atoms. However, in consideration of normal handling and availability, derivatives having 3 to 16 carbon atoms are used. A derivative having 4 to 10 carbon atoms is preferred.
The methylene chain bonded to the perfluoroalkyl group is not limited at all, and is usually a methylene chain having 0 to 8 carbon atoms. In particular, a methylene chain having 1 to 4 carbon atoms is preferable.

（式中、Ｒは水素、アルキル基、アラルキル基、アリール基を、ｎは１〜３の整数を、ｓは１〜３の整数を、ｔは１〜５の整数を表す。）
で表される誘導体を使用できる。Ｒは、例えば水素もしくは炭素数１〜16のアルキル基、フェニル基、ナフチル基、アリル基、ベンジル基、フェネチル基などで、特にＲは水素、もしくは炭素数１〜４のアルキル基が好ましい。式[ＶI]で表されるアミノアルコール誘導体は、例えばポリアミン誘導体とハロゲン化アルキルアルコールを塩基存在下で反応させる、または、ポリアミン誘導体と不飽和アルコールとを反応させることにより容易に合成できるが、安価でかつ入手が容易なのは２−（２−アミノエチルアミノ）エタノールである。 The starting amino alcohol derivative is represented by the formula [VI]

(In the formula, R represents hydrogen, an alkyl group, an aralkyl group, or an aryl group, n represents an integer of 1 to 3, s represents an integer of 1 to 3, and t represents an integer of 1 to 5.)
The derivative | guide_body represented by these can be used. R is, for example, hydrogen or an alkyl group having 1 to 16 carbon atoms, a phenyl group, a naphthyl group, an allyl group, a benzyl group, or a phenethyl group, and particularly R is preferably hydrogen or an alkyl group having 1 to 4 carbon atoms. The aminoalcohol derivative represented by the formula [VI] can be easily synthesized by reacting, for example, a polyamine derivative and a halogenated alkyl alcohol in the presence of a base, or reacting a polyamine derivative and an unsaturated alcohol. It is 2- (2-aminoethylamino) ethanol that is easily available.

There is no limitation on the method of reacting the amino alcohol derivative with the carboxylic acid. A method in which a carboxylic acid having a perfluoroalkyl group to be reacted is converted into an acid halide, a mixed acid anhydride, a symmetric acid anhydride, an active ester and reacted, or N, N-dicyclohexylcarbodiimide (DCC), N, The method of making it react directly with condensation reagents, such as N-diisopropyl carbodiimide (DIC), is mentioned. Any derivative may be a known derivative. Specific examples include well-known derivatives such as acid chlorides, acid bromides, pivalic acid mixed acid anhydrides, pentafluorophenyl esters, p-nitrophenyl esters, and succinimide esters. Examples of the condensation reagent include DCC, PyBOP ^™ (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), BOP (benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexa Fluorophosphate) and the like.

As the organic solvent, a known solvent can be used. Dichloromethane, chloroform, hexane, benzene, toluene, tetrahydrofuran, ether, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, propionitrile, ethyl acetate, dimethyl sulfoxide, methyl ethyl ketone, perfluorohexane, perfluorocarbon (e.g. And Fluorinert ^™ FC72). Needless to say, the reaction can be carried out in a mixture, hydrated product, or heterogeneous system.

  There is no limitation on the base. For example, organic bases such as triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine and DBU, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, or organic metals such as butyllithium and phenyllithium A compound can be mentioned.

  There are no restrictions on the number of equivalents of both raw materials and base used. Either one component or two components can be used in excess. A base in the range of 1 to 15 equivalents and a carboxylic acid derivative represented by the formula [VI] (wherein Rf represents a perfluoroalkyl group and m represents an integer of 0 to 8) are used for the amino alcohol derivative. .

  There is no limitation on reaction time and reaction temperature. Each of them varies depending on individual derivatives and also varies depending on the base and the solvent, but is usually in the range of 1 hour to 7 days in the range from room temperature to the boiling point of the solvent.

Next, a method for producing a highly fluorinated carboxylic acid which is a compound of the present invention from an intermediate will be described.
In the presence of an oxidizing agent in an organic solvent, the formula [II] (wherein Rf is a perfluoroalkyl group having 3 to 16 carbon atoms, R is hydrogen, an alkyl group, an aralkyl group, an aryl group, or 3 to 16 carbon atoms). M represents an integer of 0 to 8, n represents an integer of 1 to 3, s represents an integer of 1 to 3, t represents an integer of 1 to 5, Rf, m , N do not have to be the same in each of the displayed positions.), And a highly fluorinated alcohol derivative is reacted.

  There is no limitation on the oxidizing agent. Examples thereof include potassium permanganate, potassium dichromate, chromium oxide (VI) -pyridine complex, and chromium oxide (VI) -sulfuric acid.

A well-known solvent can be used as an organic solvent. Diethyl ether, tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, dichloromethane, chloroformbenzene, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, propionitrile, ethyl acetate, dimethyl sulfoxide, methyl ethyl ketone, perfluorohexane Perfluorocarbons (for example, Fluorinert ^™ FC72) and the like. Needless to say, the reaction can be carried out in a mixture, hydrated product, or heterogeneous system.

  There is no limitation on reaction time and reaction temperature. Each of them varies depending on the individual derivatives and also varies depending on the oxidizing agent and the solvent, but is usually in the range from -100 ° C. to the boiling point of the solvent and in the range of 1 hour to 7 days.

  Moreover, the carboxylic acid derivative which is the compound of the present invention can be introduced as an acyl-type protecting group highly fluorinated in the target compound in the fluorous synthesis or the amino group or functional group on the surface of the material. Needless to say, a conventional acylation method can be used for the introduction. The compound having the acyl group introduced is easily extracted into the perfluorocarbon layer, and the purification operation is facilitated. Moreover, since the compound of the present invention or its derivative is easily extracted into the perfluorocarbon layer after being deprotected, it can be recovered and reused, and an environment-friendly production system can be established. In addition, it goes without saying that only the compound of the present invention can be used as a fluorous organic protonic acid catalyst.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited at all unless it exceeds the gist.

[Example 1]
2- (2-aminoethylamino) ethanol (1.01 g, 9.7 mmol) and 2H, 2H, 3H, 3H-perfluoroundecanoic acid (9.78 g, 19.9 mmol) were dissolved in chloroform, and N, N-diisopropylethylamine ( 8.4 ml, 48.5 mmol) and benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (12.7 g, 24.3 mmol) and stirred at 40 ° C. for 5.5 hours, then at room temperature overnight Stir. The precipitate is filtered through a glass filter and washed three times with chloroform, and the formula [II] (where Rf is C ₈ F ₁₇ , R is hydrogen, m is 2, n is 2, s is 1, t Represents 1.) 6.77 g (66%) of a white powder was obtained.
MALDI-TOF MASS: Calcd for C ₂₆ H ₁₉ F ₃₄ N ₂ O ₃ [M + H] ⁺ : 1053.09 (exact), Found: 1053.02

[Example 2]
The highly fluorinated alcohol (2.00 g, 1.90 mmol) obtained in Example 1 was dissolved in 160 ml of acetone and stirred at 0 ° C. for 10 minutes. After cooling, 1.8 ml (4.80 mmol) of 2.67M Jones reagent was added and stirred at room temperature for 1.5 hours. After adding 40 ml of 2-propanol and further stirring at room temperature for 1 hour, water was added to the reaction solution and extracted three times with dichloromethane. The dichloromethane layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting crude product is washed with dichloromethane to obtain the desired formula [I] (where Rf is C ₈ F ₁₇ , R and R ¹ Obtained 1.76 g (87%) of a highly fluorinated carboxylic acid represented by the following formula: hydrogen, m: 2, n: 2, s: 1, t: 1. Further, 0.15 g (7%) of white powder recrystallized from the filtrate was obtained.
MALDI-TOF MASS: Calcd for C ₂₆ H ₁₆ F ₃₄ N ₂ O ₄ Na [M + Na] ⁺ : 1089.05 (exact), Found: 1088.97 (exact)

[Example 3]
Compound 1 (152 mg, 0.35 mmol) of the following formula [VII] and the formula [I] obtained in Example 2 (where Rf is C ₈ F ₁₇ , R and R ¹ are hydrogen, m is 2, n Is a highly fluorinated carboxylic acid (1.16 g, 1.08 mmol) represented by 2), s is 1, and t is 1.) Dichloromethane (5 ml), ethyl perfluorobutyl ether (5 ml) and N, N -It dissolved in the mixed solvent of a dimethylformamide (5 ml), 4-dimethylaminopyridine (167 mg, 1.36 mmol) and DIC (0.31 ml, 2.10 mmol) were added sequentially, and it stirred at room temperature overnight. The reaction solution was partitioned and extracted with methanol (30 mL) and perfluorocarbon (FluorinertTMFC-72) (30 mL), and the FC-72 layer was concentrated under reduced pressure to protect the hydroxyl group with the acyl group (Bfa of formula [VII]). Compound 2 (1.05 g, 83%) was obtained.
MALDI-TOF MASS: Calcd for C ₁₀₄ H ₇₀ F ₁₀₂ N ₆ O ₁₅ Na [M + Na] ⁺ : 3604.53, Found: 3605.13

[Example 4]
5.2M NaOMe (100 μL) was added to a mixed solution of the following compound [VIII] compound 3 (325 mg, 89 μmol) in ethyl perfluorobutyl ether (7 mL) and methanol (7 mL), and the mixture was stirred overnight at room temperature for deprotection. Amberlite (IR-120; H + form) was added to neutralize and filtered. The filtrate concentrated under reduced pressure was partitioned and extracted with a mixed solvent of ethyl perfluorobutyl ether (20 mL) and ethyl acetate (10 mL) and water (20 mL), the aqueous layer was lyophilized, and methyl = O- (β-D- Galactopyranosyl)-(1 → 6) -α-D-mannopyranoside (Formula [VIII] Compound 4) (24 mg, 74%):
¹ H-NMR (CDCl ₃ ): δ 3.38 (3H, s), 3.47 (1H, dd, J = 3.44, 9.62 Hz), 3.51 (1H, m), 3.55 (1H, dd, J = 7.56, 9.62 Hz), 3.65-3.66 (3H, m), 3.70-3.78 (3H, m), 3.81-3.84 (2H, m), 4.13 (1H, D, J = 10.31 Hz), 4.32 (1H, d, J = 7.56 Hz), 4.62 (1H, d, J = 1.38 Hz).

On the other hand, the organic layer was concentrated under reduced pressure to give the formula [I] (where Rf is C ₈ F ₁₇ , R is hydrogen, R ¹ is a methyl group, m is 2, n is 2, s is 1, t is Methyl ester of a highly fluorinated carboxylic acid represented by formula (VIII) compound 5; Bfa-OMe) (290 mg, quant.):
¹ H-NMR (CDCl ₃ ): δ 2.42-2.64 (8H, m), 3.43-3.48 (2H, m), 3.55-3.61 (2H, m), 3.79 and 3.81 (each s, 3H, sprit of OMe peak ), 4.02 and 4.10 (each s, 2H, sprit of C H ₂ -COOMe peak).

  Since the compound of the present invention can be produced simply and inexpensively, it becomes easy to use a reagent for introducing a highly fluorinated acyl group. The compound of the present invention can also be recycled after synthesis of the target compound. Fluorous synthesis using the compounds of the present invention is a complex natural product such as pharmaceuticals, food additives, cosmetics, liquid crystals, electronic materials, polymer materials monomers, functional materials, production of fine chemicals such as medical materials, peptides, sugar chains, nucleic acids, etc. It is certain to facilitate the manufacture of objects and their analogs. Further, it can be used as a fluorous protonic acid catalyst or a material surface modifier, and the industrial value and ripple effect of the compound of the present invention are extremely large.

Claims (4)

The following formula [I]

(In the formula, Rf represents a C 3-16 perfluoroalkyl group, R represents hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group, and R ¹ represents hydrogen. , M represents an integer of 0 to 8, n represents an integer of 1 to 3, s represents an integer of 1 to 3, t represents an integer of 1 to 5, and Rf, m, and n are the indications thereof. (It doesn't have to be the same in every place.)
A highly fluorinated carboxylic acid derivative represented by: Rf is C ₈ F ₁₇ , R is hydrogen or a methyl group, R ¹ is hydrogen, a methyl group or an ethyl group, s is 1 to 2, m is 2, n is 2, and t is an integer of 1 to 2. 2. A highly fluorinated carboxylic acid derivative according to 1. The following formula [II]

(In the formula, Rf represents a C 3-16 perfluoroalkyl group, R represents hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group, and m represents 0. -8 is an integer, n is an integer of 1 to 3, s is an integer of 1 to 3, t is an integer of 1 to 5, and Rf, m, and n need not be the same in each display position. .)
A method for producing a highly fluorinated carboxylic acid represented by the formula [I] according to claim 1 by oxidizing a highly fluorinated alcohol represented by the formula: Formula [III]

(In the formula, Rf represents a C 3-16 perfluoroalkyl group, R represents hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group, and m represents 0. -8 is an integer, n is an integer of 1 to 3, s is an integer of 1 to 3, t is an integer of 1 to 5, and Rf, m, and n need not be the same in each display position. .)
A method in which a highly fluorinated acyl group represented by the above is used as a protecting group.