JP2006306784A - Highly fluorinated alcohol derivative and method for easily re-using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a highly fluorinated compound easy to re-use by cutting off a highly fluorinated group attached to the objective compound after the synthesis thereof in a fluorous synthesis method and then regenerating. <P>SOLUTION: This compound is a highly fluorinated alcohol derivative represented by formula [I]: HO-(CH<SB>2</SB>)<SB>m</SB>-CH<SB>n</SB>-[-(CH<SB>2</SB>)<SB>p</SB>-N(-R<SP>f</SP>)ä-(CH<SB>2</SB>)<SB>q</SB>-N(-R<SP>f</SP>)-}<SB>s</SB>-R]<SB>3-n</SB>(wherein R<SP>f</SP>is a highly fluorinated acyl group having one or a plurality of perfluoroalkyl groups; R is H, alkyl, aralkyl, aryl or 3-16C perfluoroalkyl; m is an integer of 0 to 6; n is 0 to 2; p is 0 to 6; q is 1 to 6; s is 0 to 2; and R<SP>f</SP>, R, p, q and s need not be the same in each displayed site). The derivative can be used as an experimental agent for synthesis by binding a linker thereto to enhance versatility. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to highly fluorinated alcohol 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. In order to synthesize various compounds using this technique, it is necessary to introduce a highly fluorinated group suitable for the structure of the target compound, but the highly fluorinated alcohol derivative of the present invention Can be used as a reagent for this synthesis.

Various highly fluorinated synthesis reagents have been reported so far (for example, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, Non-Patent Document 1, Non-Patent Document 2, Non-patent) However, most of them are discarded after synthesizing the target product, because when the highly fluorinated group is separated from the target compound, the structure becomes difficult or impossible to regenerate. There was no choice but to reuse. For example, the terminal structure of the benzyl type is converted to a toluene type by catalytic reduction using palladium black, and the p-alkoxybenzyl type is converted to a complex compound by a reaction under acidic conditions such as trifluoroacetic acid and trifluoromethanesulfonic acid. And the structure will change. Highly fluorinated derivatives that have changed to these structures are very difficult or impossible to recycle.
In addition, it is necessary to design highly fluorinated synthesis reagents suitable for the compounds to be bound to the compounds and reactions, and many kinds of highly fluorinated synthesis reagents are required to carry out various reactions. Must be prepared.

In order to synthesize various compounds efficiently by the fluorous synthesis method, the development of highly fluorinated groups that can be reused and reused in various reactions can be carried out if environmental and economic considerations are taken into consideration. Is indispensable.
Japanese Patent Application No. 2002-063985 Japanese Patent Application No. 2002-338534 Japanese Patent Application No. 2003-261523 Japanese Patent Application No. 2004-131458 Zhiyong Kuo, John Williams, Roger W. Read and Dennis P. Curran, “Fluorous Boc (FBoc) Carbamates: New Amine Protecting Groups for Use in Fluorous Synthesis”, The Journal of Organic Chemistry, 2001, Vol. 66, p.4261-4266. Dennis P. Curran, Rafael Ferritto and Ye Hua, `` Preparation of a Fluorous Benzyl Protecting Group and Its Use in a Fluorous Synthesis Approach to a Disaccharide '', Tetrahedron Letters, 1998, Vol. 39, p.4937-4940. Kohtaro Goto, Tsuyoshi Miura, Mamoru Mizuno, Hiromi Takaki, Nobuyuki Imai, Yasuoki Murakami, Toshiyuki Inazu, “Rapid Oligosaccharide Synthesis on a Novel Benzyl-Type Fluorous Support”, Synlett, 2004, p.2212-1223.

  The object of the present invention is to remove a highly fluorinated group added to the target product after completion of the synthesis of the target compound in the fluorosynthetic method, and to recycle and recycle this highly fluorinated group. It is to provide a compound.

As a result of intensive studies, the present inventors have found that it is difficult or impossible to reuse a highly fluorinated group by inserting a linker that can be easily separated from the target compound in order to efficiently recycle and reuse the group. The highly fluorinated group that was previously was facilitated and the present invention was completed.
Further, by adapting the structure of the linker to each reaction, the highly fluorinated alcohol derivative of the present invention that can be easily recycled and reused can be a reagent for the synthesis of many kinds of reactions. For example, it can be used as a reagent for synthesizing sugar chains and peptides, and the synthesis of sugar chains, peptides, glycopeptides and the like is facilitated.

（式中、Rfは、パーフルオロアルキル基を１つまたは複数箇所有する、高度にフッ素化されたアシル基を、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０〜６の整数を、ｎは０〜２の整数を、ｐは０〜６の整数を、ｑは１〜６の整数を、ｓは０〜２の整数を表し、Rf、R、p、q、s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誘導体と、その合成用試剤としての使用である。 That is, the present invention provides a compound of the formula [I]

(Wherein Rf is a highly fluorinated acyl group having one or more perfluoroalkyl groups, R is hydrogen, an alkyl group, an aralkyl group, an aryl group, or a perfluorocarbon having 3 to 16 carbon atoms. Any one of the alkyl groups, m is an integer of 0 to 6, n is an integer of 0 to 2, p is an integer of 0 to 6, q is an integer of 1 to 6, and s is an integer of 0 to 2. Rf, R, p, q, and s need not be the same in each display position.
A highly fluorinated alcohol derivative represented by the formula (1) and its use as a synthesis reagent.

  Since it is easy to recycle and reuse, it is possible to provide a fluorous synthesis agent that is environmentally friendly and economical. It can also be applied to various reactions by sandwiching a linker.

Hereinafter, the present invention will be described in detail.
In the formula [I], Rf is a highly fluorinated acyl group having one or more perfluoroalkyl groups. As the perfluoroalkyl group, a known perfluoroalkyl group can be used. 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 view of normal handling and availability, the number of carbon atoms is preferably 3 to 16, and more preferably 4 to 10 carbon atoms. Since the fluorine content increases as the number of perfluoroalkyl groups increases, it is preferable as a reagent for synthesis, but may be selected according to the compound to be introduced. In general, the number is 1 to 12, preferably 1 to 6, and examples thereof include the following formula [II] or [III].

  R is any one of hydrogen, an alkyl group, an aralkyl group, an aryl group, and a C 3-16 perfluoroalkyl group. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Examples include n-butyl group. A methyl group, an ethyl group, and an n-propyl group are preferable. Examples of the aralkyl group include benzyl group, phenethyl group, 9-fluorenylmethyl group, naphthylmethyl and the like. Preferably, they are a benzyl group and a phenethyl group. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a pyrenyl group. Preferably, they are a phenyl group and a naphthyl group. Examples of the C 3-16 perfluoroalkyl group include a perfluorobutyl group, a perfluorohexyl group, a perfluoroheptyl group, a perfluorooctyl group, a perfluorodecyl group, and a perfluorotetradecyl group. A perfluorobutyl group, a perfluorohexyl group, and a perfluorooctyl group are preferable.

m is 0-6, n is 0-2, p is 0-6, q is 1-6, s is an integer of 0-2, preferably m is 0 or 1, n is 0 or 2, p is 1, q is 1 or 2, and s is an integer of 0 or 1.
Examples of the compound of the formula [I] include the formula [IV], [V] (wherein Rf represents the formula [II] or [III]).

  The compound of the present invention represented by the formula [I] is obtained by reacting, for example, an amino group of a polyaminoalcohol derivative with a carboxyl group of a highly fluorinated carboxylic acid having one or more perfluoroalkyl groups. Can be synthesized. For example, highly fluorinated carboxylic acids are converted into acid halides, mixed acid anhydrides, symmetric acid anhydrides, active esters and reacted in advance, or condensation such as N, N-dicyclohexylcarbodiimide (DCC) The method of making it react with a reagent directly is mentioned. Any derivative may be a known derivative. Specific examples include known derivatives such as acid chlorides, acid bromides, pivalic acid mixed acid anhydrides, pentafluorophenyl esters, p-nitrophenyl esters, and succinimide esters.

Condensation reagents include the aforementioned DCC, PyBOP ^™ (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), BOP (benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate ), DMTMM (4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine chloride) and the like.

（式中、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０〜６の整数を、ｎは０〜２の整数を、ｐは０〜６の整数を、ｑは１〜６の整数を、ｓは０〜２の整数を表し、Rf、R、p、q、sはその表示各位において同一である必要はない。）

The polyamino alcohol used as a raw material is represented by the formula [I ′], and examples thereof include formulas [VI] and [VII].

(In the formula, R represents hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group, m represents an integer of 0-6, n represents an integer of 0-2, p represents an integer of 0 to 6, q represents an integer of 1 to 6, s represents an integer of 0 to 2, and Rf, R, p, q, and s need not be the same in each display position.

Although it does not specifically limit as a highly fluorinated carboxylic acid which has one or more perfluoroalkyl groups which are another raw material, It is a carboxylic acid which has one or more perfluoroalkyl groups as a substituent. . Examples thereof include carboxylic acids having an acyl group such as formula [II] and formula [III]. More specific examples include the following formulas [[VIII], [IX] and the like.

As the reaction 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, fluorocarbon (eg Novec ^™ HFE-7200) ), Perfluorocarbon (for example, Fluorinert ^™ FC-72) and the like. Needless to say, the reaction can be carried out in a mixture, hydrated product, or heterogeneous system.

  Usually these condensation steps are carried out in the presence of a base in order to accelerate the reaction. There is no restriction as a 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.
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.

The highly fluorinated alcohol derivative represented by the formula [I], which is the compound of the present invention obtained as described above, can be used as a reagent for fluorous synthesis per se, but is bonded to the target compound via a linker. If they are bonded, after synthesizing the target product as shown in FIG. 1, it can be cut out at the linker portion. Thereafter, through a procedure for cleaving the highly fluorinated alcohol derivative and the linker, the highly fluorinated alcohol derivative can be efficiently recovered regardless of the structure of the linker, and can be recycled and reused. If the structure of the linker is designed according to the object, it can be used for various reactions.
For example, mention may be made of a method in which a linker containing a carboxyl group and another functional group is esterified with a highly fluorinated alcohol derivative and the other functional group of the linker is used to bind to a synthetic reaction compound. Can do.

リンカーと本発明のアルコール誘導体との結合方法には制限は無く、既知の方法を用いることができる。リンカーとフルオラス合成原料化合物との結合も、合成反応に耐え、合成後の切り出しが容易なものであれば良い。 There is no particular limitation on the structure of the linker, as long as it has a functional group capable of binding to alcohol and a functional group capable of binding to a synthetic reaction compound, but considering the fluorine content necessary for fluorous synthesis, the molecular weight Avoid large ones.
Specific examples include structures represented by formula [X], formula [XI], formula [XII], and the like.

There is no restriction | limiting in the coupling | bonding method of a linker and the alcohol derivative of this invention, A known method can be used. The bond between the linker and the fluorous synthesis raw material compound may be any one that can withstand the synthesis reaction and can be easily cut out after the synthesis.

Fluorous synthesis is performed in each step after the completion of the reaction by solid phase extraction method using silica gel with highly fluorinated surface or reaction solution using perfluorocarbon solvent and organic solvent or water, acidic aqueous solution, or basic aqueous solution. Any method of performing partition extraction and extracting the target product into the perfluorocarbon layer is used, but partition extraction using perfluorocarbon is preferred.
As the perfluorocarbon used for extraction, a known perfluorocarbon solvent can be used. Specific examples include perfluorohexyne, perfluoroheptane, perfluorooctane, Fluorinert ^™ FC72, Fluorinert ^™ FC77, Fluorinert ^™ FC84, Fluorinert ^™ FC87, perfluoromethylhexane, and the like. Particularly preferred are Fluorinert ^™ FC72 and perfluoromethylhexane.

  As the organic solvent, a known organic solvent can be used. Specific examples include dichloromethane, chloroform, benzene, toluene, tetrahydrofuran, diethyl ether, DMF, acetonitrile, ethyl acetate, dimethylformamide, acetone, methyl ethyl ketone, methanol, ethanol, propanol, and the like. In particular, methanol, DMF, toluene, and acetonitrile are preferable.

  The compound in which the compound of the present invention is introduced is easily extracted into the perfluorocarbon layer, and the purification operation is facilitated. Therefore, purification operations at the deprotection and condensation reaction steps in the synthesis of natural products and derivatives thereof can be simplified. In addition, after synthesis of the target compound, the compound of the present invention can be easily removed from the target compound by an appropriate method. For example, when a compound represented by the formula [X] or [XI] is used as the linker, the target compound is highly fluorinated having a linker moiety by a reaction under acidic conditions such as trifluoroacetic acid and trifluoromethanesulfonic acid. Can be excised from the base. Then, by cutting out from the linker by a reaction under basic conditions such as sodium hydroxide and sodium methoxide, the formula [I] (wherein Rf has one or more perfluoroalkyl groups, A highly fluorinated acyl group, R is hydrogen, an alkyl group, an aralkyl group, an aryl group, or a perfluoroalkyl group having 3 to 16 carbon atoms, m is an integer of 0 to 6, and n is 0 An integer of ˜2, p is an integer of 0-6, q is an integer of 1-6, s is an integer of 0-2, and Rf, R, p, q, s are the same in each display position. The highly fluorinated alcohol derivative shown below is regenerated. Since the regenerated compound of the present invention or a derivative thereof is easily extracted into the perfluorocarbon layer, a circulation type fluorous synthesis system that can be recovered and reused can be established.

  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. Fmoc is an abbreviation for 9-fluorenylmethoxycarbonyl group, Gly is a glycine residue, Ala is an alanine residue, Phe is a phenylalanine residue, and Thr is an abbreviation for threonine residue.

[Example 1]
N- (2-aminoethyl) ethanolamine represented by formula [VI] (127 mg, 1.22 mmol) and highly fluorinated carboxylic acid represented by formula [VIII] (3.79 g, 2.44 mmol) ) Was dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (30 mL) and dichloromethane (30 mL), and N, N-diisopropylethylamine (0.85 mL, 4.88 mmol) and PyBOP (1.52 g, 1.5 mL, 2.93 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated to one third, then partitioned and extracted with methanol (100 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (100 mL), and the FC-72 layer was concentrated under reduced pressure. The entire amount of the crude product was dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (30 mL) and methanol (60 mL), a catalytic amount of sodium methoxide was added to this solution, and the mixture was stirred at room temperature for 60 minutes. Ion exchange resin (Amberlite IR-120H ⁺ type) was added to stop the reaction, and after filtration, the filtrate was concentrated, partitioned and extracted with methanol (100 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (100 mL). The FC-72 layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and the formula [I] (wherein Rf was the formula [II], R was H, m was 0, n was 2, 3.29 g (85%) of the compound of the following formula represented by p = 1, q = 2 and s represents 1) was obtained.
MALDI-TOF MASS: Calcd for C ₈₂ H ₅₉ F ₁₀₂ N ₆ O ₇ (M + H ⁺ ): 3177.3, Found: 3176.4.

[Example 2]
A carboxylic acid derivative (199 mg, 0.37 mmol) in which the amino group of the formula [X] is protected with an Fmoc group and the compound 1 (390 mg, 0.12 mmol) synthesized in Example 1 were combined with a fluorocarbon (Novec ^™ HFE-7200) ( 2 mL) and dichloromethane (4 mL), and this solution was dissolved in N, N-diisopropylethylamine (77 μL, 0.44 mmol), PyBOP (223 mg, 0.44 mmol) and N, N-dimethylaminopyridine (1. 5 mg, 12 μmol) was added, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution to one third, it was partitioned and extracted with methanol (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), the FC-72 layer was concentrated under reduced pressure, and the amino group was converted to Fmoc group. The protected compound 2 of the following formula (wherein Rf represents formula [II]) (462 mg) was obtained.

Compound 2 (wherein Rf represents formula [II]) (420 mg) was dissolved in a mixed solvent of perfluorocarbon (Fluorinert ^™ FC-72) (4 mL) and N, N-dimethylformamide (4 mL), and this solution Piperidine (0.4 mL) was added to and stirred at room temperature for 20 minutes. The reaction solution was partitioned and extracted with acetonitrile (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), the FC-72 layer was concentrated under reduced pressure, and amino compound 3 (wherein Rf represents the formula [II]) (390 mg) was obtained.

[Example 3]
Fmoc-Gly-OH (162 mg, 0.54 mmol) and compound 1 of Example 1 (576 mg, 0.18 mmol) were combined with fluorocarbon (Novec ^™ HFE-7200) (2.5 mL), dichloromethane (5 mL) and N, N- It was dissolved in a mixed solvent of dimethylformamide (2 mL), and N, N-diisopropylcarbodiimide (76 mg, 0.60 mmol) and N, N-dimethylaminopyridine (6.6 mg, 54 μmol) were added to this solution, and the mixture was stirred at room temperature for 3 hours. Stir. After the reaction solution was concentrated to one third, it was partitioned and extracted with acetonitrile (40 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (40 mL), the FC-72 layer was concentrated under reduced pressure, and the amino group became an Fmoc group. Protected compound 4 (wherein Rf represents formula [II]) (626 mg) was obtained.

Compound 4 (wherein Rf represents formula [II]) (626 mg) was dissolved in a mixed solvent of perfluorocarbon (Fluorinert ^™ FC-72) (6 mL) and N, N-dimethylformamide (6 mL). Piperidine (0.6 mL) was added to and stirred at room temperature for 60 minutes. The reaction solution was partitioned and extracted with acetonitrile (40 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (40 mL), the FC-72 layer was concentrated under reduced pressure, and amino compound 5 (Rf represents formula [II]) (596 mg) Got.

[Example 4]
A carboxylic acid derivative represented by the formula [XI] (87 mg, 0.36 mmol) was dissolved in N-methylpyrrolidone (2 mL), and a 2 M solution of N, N-diisopropylethylamine in N-methylpyrrolidone (0.18 mL, 0.36 mmol) and N-methylpyrrolidone solution (0.36 mL, 0.36 mmol) of dimethylphosphinothioyl chloride adjusted to 1M was added, and the mixture was stirred at 0 ° C. for 30 minutes, and mixed with dimethylthiophosphinic acid anhydride Was prepared. Further, N-methylpyrrolidone solution of N, N-diisopropylethylamine prepared by adjusting Compound 5 (Rf represents Formula [II]) (596 mg) to fluorocarbon (Novec ^™ HFE-7200) (3 mL), dichloromethane (6 mL) and 2M The above dimethylthiophosphinic acid mixed acid anhydride solution was added to a solution dissolved in (0.18 mL, 0.36 mmol) of mixed solvent, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated to one third, it was partitioned and extracted with acetonitrile (40 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (40 mL), and the FC-72 layer was concentrated under reduced pressure to give compound 6 (wherein Rf represents formula [II]) (640 mg).

[Example 5]
Glutaric anhydride (140 mg, 1.23 mmol) and compound 1 of Example 1 (1.30 g, 0.41 mmol) were dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (13 mL) and dichloromethane (13 mL). Triethylamine (0.34 mL, 2.45 mmol) was added to this solution, and the mixture was stirred at room temperature for 20 hours. Distilled water (5 mL) was added to the reaction mixture, and the mixture was partitioned and extracted with a 2N aqueous hydrochloric acid solution (100 mL), a mixed solution of fluorocarbon (Novec ^™ HFE-7200) and ethyl acetate (100 mL). (Wherein Rf represents formula [II]) (1.38 g) was obtained quantitatively.
MALDI-TOF MASS: Calcd for C ₈₇ H ₆₄ F ₁₀₂ N ₆ NaO ₁₀ (M + Na ⁺ ): 3113.3, Found: 3113.2.

[Example 6]
Pentaerythritol triamine hydrochloride represented by formula [VII] (74.8 mg, 0.31 mmol) and highly fluorinated carboxylic acid represented by formula [IX] (1.09 g, 1.01 mmol) Dissolve in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (10 mL) and methanol (10 mL), and add N, N-diisopropylethylamine (0.16 mL, 0.92 mmol) and 4- (4,6-dimethoxy) to this solution. -1,3,5-triazin-2-yl) -4-methylmorpholine chloride (301 mg, 1.05 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to one third, then partitioned and extracted with acetonitrile (100 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (100 mL), and the FC-72 layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 6: 1), and the formula [I] (wherein Rf was formula [III], R was H, m was 1, n was 0, 816 mg (84%) of the compound of the following formula represented by p = 1, q = 0, and s = 0 were obtained.
¹ H-NMR (CDCl ₃ -CD ₃ OD): δ 1.82-2.01 (6H, m), 2.06-2.29 (6H, m), 2.46-2.88 (18H, m), 2.91-3.06 (6H, m), 3.10-3.20 (2H, m), 3.43-3.56 (6H, m), 3.61-4.08 (6H, m).

[Example 7]
For compound 3 obtained in Example 2 (wherein Rf represents formula [II]) (390 mg), Fmoc-Ala-OH, Fmoc-Phe-OH, and naphthylacetic acid were added according to the schedule shown below. The reaction was carried out sequentially. Each amino acid derivative was used in an amount of 1.5 equivalents, 1.8 equivalents of PyBOP as a condensation reagent, and 1.8 equivalents of N, N-diisopropylethylamine as a base.

The peptide synthesis schedule is shown below.
Condensation reaction: Amino acid and the highly fluorinated derivative of the present invention are dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (2 mL) and dichloromethane (4 mL), and N, N-diisopropylethylamine and PyBOP are added to this solution. And stirred at room temperature for 1 hour. After concentrating the reaction solution to one third, it is partitioned and extracted with acetonitrile (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), and the FC-72 layer is concentrated under reduced pressure.
Deprotection reaction: The substrate was dissolved in a mixed solvent of perfluorocarbon (Fluorinert ^™ FC-72) (4 mL) and N, N-dimethylformamide (4 mL), piperidine (0.4 mL) was added to this solution, and the mixture was stirred at room temperature for 30 minutes. Stir for minutes. The reaction solution is partitioned and extracted with acetonitrile (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), and the FC-72 layer is concentrated under reduced pressure.
To the obtained protected peptide (429 mg) bound to the highly fluorinated derivative of the present invention was added 95% aqueous trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, the residue was partitioned and extracted with a mixed solvent (50 mL) consisting of acetonitrile, ether and methanol and perfluorocarbon (Fluorinert ^™ FC-72) (50 mL), and the organic layer was concentrated under reduced pressure. The obtained residue was recrystallized with a mixed solvent of N, N-dimethylformamide and diethyl ether to obtain 38 mg (8 steps, 83%) of the desired dipeptide derivative 9.
Compound 9; ESI-TOF MASS: Calcd for C ₄₀ H ₄₆ NaO ₁₁ (M + K ⁺ ): 442.1528, Found: 442.1516.

On the other hand, the perfluorocarbon (Fluorinert ^™ FC-72) layer was concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (8 mL) and methanol (4 mL). Sodium methoxide was added and stirred at room temperature for 5 minutes. Ion exchange resin (Amberlite IR-120H ⁺ type) was added to stop the reaction, and after filtration, the filtrate was concentrated, partitioned and extracted with methanol (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), The FC-72 layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and the formula [I] (wherein Rf was the formula [II], m was 0, n was 2, p was 1, 322 mg (9 steps, 90%) of the compound 1 represented by q is 2 and s is 1) was recovered.

[Example 8]
For compound 6 obtained in Example 4 (wherein Rf represents formula [II]) (634 mg), Fmoc-Ala-OH, Fmoc-Thr (tBu) -OH, Naphthyl acetic acid was reacted sequentially. Each amino acid derivative was used in an amount of 1.5 equivalents, 1.8 equivalents of PyBOP as a condensation reagent, and 1.8 equivalents of N, N-diisopropylethylamine as a base.

The peptide synthesis schedule is shown below.
Condensation reaction: Amino acid and the highly fluorinated derivative of the present invention are dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (3 mL) and dichloromethane (6 mL), and N, N-diisopropylethylamine and PyBOP are added to this solution. And stirred at room temperature for 1 hour. After concentrating the reaction solution to one third, it is partitioned and extracted with acetonitrile (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), and the FC-72 layer is concentrated under reduced pressure.
Deprotection reaction: The substrate was dissolved in a mixed solvent of perfluorocarbon (Fluorinert ^™ FC-72) (6 mL) and N, N-dimethylformamide (6 mL), piperidine (0.4 mL) was added to this solution, and the mixture was stirred at room temperature for 30 minutes. Stir for minutes. The reaction solution is partitioned and extracted with acetonitrile (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), and the FC-72 layer is concentrated under reduced pressure.
A 95% aqueous trifluoroacetic acid solution (14 mL) was added to the obtained protected peptide (660 mg) bound to the highly fluorinated derivative of the present invention, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, the residue was partitioned and extracted with acetonitrile (50 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (50 mL), and the acetonitrile layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol: acetic acid = 9: 1: 0.5) to obtain 56 mg (9 steps, 87%) of the desired dipeptide derivative 10.
Compound 10; ESI-TOF MASS: Calcd for C ₄₀ H ₄₆ NaO ₁₁ (M + Na ⁺ ): 381.1421, Found: 384.1379.

On the other hand, the perfluorocarbon (Fluorinert ^™ FC-72) layer was concentrated under reduced pressure, and the entire residue was dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (6 mL) and methanol (6 mL). Sodium methoxide was added and stirred at room temperature for 10 minutes. Ion exchange resin (Amberlite IR-120H ⁺ type) was added to stop the reaction, and after filtration, the filtrate was concentrated, partitioned and extracted with methanol (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), The FC-72 layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and the formula [I] (wherein Rf was the formula [II], m was 0, n was 2, p was 1, 515 mg (10 steps, 91%) of the compound 1 represented by q is 2 and s is 1 was recovered.

[Example 9]
A sugar chain was synthesized using the compound of the present invention.
Compound 11 (212 mg, 0.39 mmol) of the following formula [XIII] and compound 7 obtained in Example 5 (wherein Rf represents formula [II]) (427 mg, 0.13 mmol) were converted to fluorocarbon (Novec ^™ HFE-7200) (2 mL) and dichloromethane (10 mL) were dissolved in a mixed solvent, and PyBOP (203 mg, 0.39 mmol) and N, N-dimethylaminopyridine (47 mg, 0.39 mmol) were added to this solution. Stir for 2 hours. After concentrating the reaction solution to one third, it was partitioned and extracted with methanol (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL), and the FC-72 layer was concentrated under reduced pressure to give a compound of the formula [XIII] 12 (wherein Rf represents formula [II]) (510 mg) was obtained.

Compound 12 (wherein Rf represents formula [II]) (510 mg) was dissolved in THF (7.5 mL), hydrogen fluoride pyridine solution (0.75 mL) was added to this solution, and the mixture was stirred at room temperature for 19 hours. did. The reaction solution was partitioned and extracted with toluene (60 mL), saturated sodium hydrogen carbonate solution (60 mL), and perfluorocarbon (Fluorinert ^™ FC-72) (60 mL). The FC-72 layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 457 mg of compound 13 (wherein Rf represents formula [II]).

Compound 13 (wherein Rf represents formula [II]) (457 mg) and phenyl = 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (165 mg, 0.26 mmol) Was dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (2.5 mL) and dichloromethane (5 mL) under an argon atmosphere, molecular sieves 4A (1.0 g) was added, and the mixture was stirred at room temperature for 2 hours. N-iodosuccinimide (117 mg, 0.52 mmol) and trifluoromethanesulfonic acid (5.0 μL, 52 μmol) were sequentially added, and the mixture was stirred for 1 hour at 0 ° C. The solid was filtered off and washed with ethyl acetate. Is washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium thiosulfate, and a saturated saline solution in this order. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, methanol was added to the residue, and the mixture was partitioned and extracted with perfluorocarbon (Fluorinert ^™ FC-72) (20 mL) The FC-72 layer was concentrated under reduced pressure. Thus, 513 mg of compound 14 (wherein Rf represents formula [II]) was obtained.

Compound 14 was dissolved in a mixed solvent of fluorocarbon (Novec ^™ HFE-7200) (10 mL) and methanol (5 mL), a catalytic amount of sodium methoxide was added to this solution, and the mixture was stirred at room temperature for 1 hour. Ion exchange resin (Amberlite IR-120H ⁺ type) was added to stop the reaction, and after filtration, the filtrate was concentrated, partitioned and extracted with methanol (20 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (20 mL). The layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 71 mg (4 steps, 78%) of the compound 15 of the formula [XIV].
On the other hand, the FC-72 layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the formula [I] (wherein Rf represents the formula [II], R 386 mg (4 steps, 93%) of the compound of the formula [XIV] represented by the formula (XI) is H, m is 0, n is 2, p is 1, q is 2, and s is 1.
Compound 15; ESI-TOF MASS: Calcd for C ₄₀ H ₄₆ NaO ₁₁ (M + Na ⁺ ): 725.2932, Found: 723.2916.

  It is certain that fluorous synthesis using the compounds of the present invention facilitates the production of fine chemicals such as pharmaceuticals, food additives, cosmetics, liquid crystals, electronic materials, polymer monomer functional materials, and medical materials. In particular, the fluorous synthesis using the compounds of the present invention enables efficient regeneration and reuse of highly fluorinated derivatives, which has been difficult in the past, and it is certain that the fluorous synthesis method is made more efficient, Industrial value and its ripple effect are extremely large.

It is a conceptual diagram of the fluorosynthetic method using the compound of this invention.

Claims (6)

The following formula [I]

Wherein Rf is a highly fluorinated acyl group having one or more perfluoroalkyl groups, R is hydrogen, an alkyl group, an aralkyl group, an aryl group, or a C 3-16 perfluoroalkyl group. Any one of the groups, m is an integer of 0-6, n is an integer of 0-2, p is an integer of 0-6, q is an integer of 1-6, s is an integer of 0-2. And Rf, R, p, q, and s need not be the same in each display position.)
A highly fluorinated alcohol derivative represented by:   The highly fluorinated alcohol derivative according to claim 1, wherein m is 0, n is 2, p is 1, q is 2, and s is 1.   The highly fluorinated alcohol derivative according to claim 1, wherein m is 1, n is 0, p is 1 and s is 0. The highly fluorinated alcohol derivative according to claim 2 or 3, wherein Rf is represented by the formula [II] or [III].

  Use of the highly fluorinated alcohol derivative according to any one of claims 1 to 4 as a synthesis reagent.   A method for producing a peptide, sugar chain or glycopeptide using the highly fluorinated alcohol derivative according to any one of claims 1 to 4.

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