JP2008231026A - Method for producing fluorinated phosphoric monoester salt and fluorinated phosphoric monoester salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a fluorinated phosphoric monoester which allows the synthesis of the compound with an extremely small number of steps from a readily available raw material in a high yield with an easy isolating operation. <P>SOLUTION: A diaryl phosphate represented by the general formula (1) (wherein Ar and Ar' each represent an aryl group which may have a substituent and includes the case in which Ar and Ar' are chemically bounded to form a cyclic structure; and R represents an alkyl group which may have a substituent) is reacted with a quaternary ammonium fluoride and/or a fluoride of an alkali metal. Thereby, the fluorinated phosphoric monoester salt is obtained. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing a fluorinated phosphoric acid monoester salt and a fluorinated phosphoric acid monoester salt.

Fluorophosphoric acid diester (a) in which a fluorine atom is bonded directly to a phosphorus atom is known as a drug acting on the neurotransmission system.

  For example, a compound in which R in the fluorophosphoric acid diester (a) is an isopropyl group is used as a therapeutic agent for glaucoma called isoflurophosphate.

On the other hand, the fluorinated phosphoric acid monoester salt (c), which is a structurally similar compound to the fluorinated phosphoric acid diester (a), is known only for the substituent in which R has an ethyl group and a tetrahydrofuryl skeleton. (Non-Patent Document 1). This fluorophosphoric acid monoester salt (c) can be synthesized via 0,0, S-thiophosphotriester (b) as shown in the following reaction formula (Non-patent Document 1).

C. Sund, JChattopadhyaya, tetraheadoron ,, 45, 45, 7523 (1989)

  Since the fluorophosphoric diester (a) has low solubility in water, it is considered that the therapeutic agent has low cell permeability and is slow to be absorbed into cells.

  On the other hand, the fluorophosphate monoester salt (c) is considered to be water-soluble because it is in the form of a salt and excellent in cell penetration into the body. In addition, since this fluorophosphate monoester salt is not in the form of a free acid in which a hydroxyl group is bonded to a phosphorus atom, but in the form of a salt, the pH is not so low. Less damage. Therefore, it can be said that the fluorophosphate monoester salt (c) is an important group of compounds suitable for constructing a compound library for pharmaceuticals that act on the neurotransmission system.

  In addition, the fluorinated phosphoric acid monoester salt (c) is a neutral molecule and has a property that it does not react with the organometallic compound because the electron density on the phosphorus atom is high. Therefore, if a chiral substituent is bonded to the alkoxy group or amino group of the fluorophosphate monoester salt (c), it becomes a very promising compound as a new optically active ligand for asymmetric synthesis reaction. .

  In recent years, phosphate has attracted attention as a flame retardant that replaces nitrate, and it is also conceivable to use the fluorophosphate monoester salt (c) as a flame retardant.

  As described above, the fluorinated phosphoric acid monoester salt (c) is a useful compound that is expected to be used in various applications such as pharmaceuticals, organic synthesis, and flame retardants. However, the process for producing a fluorophosphate monoester salt (c) described in Non-Patent Document 1 requires multiple steps to synthesize 0,0, S-thiophosphotriester (b) as a raw material. However, the total yield is low, and only a manufacturing method that is extremely laborious is known.

  The present invention has been made in view of the above-mentioned conventional situation, and can be synthesized from easily available raw materials in very few steps, and can be produced in a high yield and easy to isolate. It is an object to be solved to provide a method and a new fluorophosphate monoester salt.

The method for producing a fluorinated phosphoric acid monoester salt of the present invention is a phosphoric acid diaryl ester represented by the following general formula (1) (where Ar and Ar ′ represent an aryl group which may have a substituent, Ar And Ar ′ are chemically bonded to form a cyclic structure. R represents an alkyl group which may have a substituent.) And a quaternary ammonium fluoride and / or alkali metal fluoride. It reacts with a compound.

  In the method for producing a fluorophosphate monoester salt of the present invention, the diaryl phosphate ester and the quaternary ammonium fluoride and / or alkali metal fluoride which are raw materials are generally commercially available as reagents and are very easily available. It is. In addition, when the diaryl phosphate ester and the fluoride of quaternary ammonium fluoride and / or alkali metal are mixed, the reaction proceeds under mild conditions, and a fluorophosphate monoester salt is obtained in a high yield. be able to.

The reaction mechanism is not necessarily clear, but is considered as follows. That is, fluorine ions first nucleophilically attack the phosphorus element of the phosphoric acid diaryl ester (1), and ArO ^{− which} is easily desorbed is desorbed to form the fluorophosphoric diester (2). Furthermore, ArO ⁻ reacts with water to produce hydroxide ions, which hydrolyze the fluorinated phosphoric acid diester (2) to form the fluorinated phosphoric acid monoester (3). Then, this fluorophosphoric acid monoester is deprived of hydrogen ions by fluorine ions and becomes the target fluorophosphoric acid monoester salt (4).

The reaction solvent in the method for producing a fluorophosphate monoester salt of the present invention is preferably an aprotic polar solvent. This is because, in an aprotic polar solvent, the nucleophilicity of fluorine ions and hydroxide ions is enhanced, and nucleophilic attack on phosphorus element and elimination of ArO ⁻ are facilitated. Examples of the aprotic polar solvent include tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. The inventors have confirmed that a fluorophosphate monoester salt can be obtained in a high yield by using tetrahydrofuran as a reaction solvent.

The fluorophosphoric acid monoester salt can be produced by the following method. That is, the method for producing a fluorophosphoric acid monoester salt of the present invention is a phosphoric acid diaryl ester represented by the following general formula (1) (wherein Ar and Ar ′ represent an aryl group which may have a substituent) , Ar and Ar ′ are chemically bonded to form a cyclic structure. R represents an alkyl group which may have a substituent.) And quaternary ammonium fluoride and / or alkali metal. A reaction step of reacting with the fluoride, a water extraction step of extracting the reaction liquid obtained in the reaction step with water, an organic solvent extraction step of extracting the aqueous layer obtained in the extraction step with an organic solvent, It is characterized by providing.

  The fluorophosphoric monoester salt produced in the reaction step is soluble in water, but more easily dissolved in halogenated hydrocarbons. Therefore, by extracting the fluorinated phosphoric acid monoester salt in the reaction solution obtained in the reaction step with water, and further extracting the aqueous layer with a halogenated hydrocarbon, the target fluorinated phosphoric acid can be obtained very easily. Monoester salts can be isolated.

  The phosphoric acid diaryl ester (1) used as a raw material in the present invention is obtained by converting a commercially available chlorinated phosphoric acid diaryl ester (5) and an aliphatic alcohol (6) into a phosphoric acid ester in the presence of a trialkylamine or pyridine. Therefore, it can be obtained easily and with a high yield (see the following reaction formula).

  However, when Ar and Ar ′ in the phosphoric acid diaryl ester (1) are chemically bonded to form a cyclic structure, oxygen bonded to the phosphorus element of the chlorinated phosphoric acid diaryl ester by a double bond is replaced by selenium. The corresponding phosphoric acid diaryl ester can be obtained in a higher yield by using the acid chloride and finally oxidizing with hydrogen peroxide to form the phosphoric acid diaryl ester. For example, the case of a binaphthyl group is as follows.

  In addition, when an alkali metal fluoride is used as a fluorine source, it is also preferable to add crown ether. This is because the solubility of the alkali metal fluoride can be increased, and the nucleophilicity of the fluorine ions is also increased, so that the reaction is further facilitated.

Hereinafter, embodiments embodying the present invention will be described in detail.
(Example 1)
In Example 1, O-3-phenylbutyl fluorophosphate tetobutylammonium salt (6a) was synthesized by the method shown in the chemical formula below.

<Reaction process>
Phosphate ester with binaphthyl group 5a (480 mg, 1 mmol) in THF solution (4 mL) and tetrabutylammonium fluoride THF solution (1M solution, 1.2 mL, 1.2 mmol)
At 0 ° C., the mixture was stirred at room temperature for 3 hours.
<Water extraction process>
The reaction mixture was concentrated, poured into water and washed with ether.
<Organic solvent extraction process>
Then, the aqueous layer was extracted with methylene chloride, and the organic layer was dried over magnesium sulfate and concentrated to obtain O-3-phenylbutyltetrafluoroammonium phosphate 6a as a yellow oil (331 mg, 70%). The spectrum data is shown below.

IR (neat): 2963, 2876, 2197, 1711, 1603, 1460, 1383, 1280, 1112, 1063, 1029, 1010,930, 909, 765, 731, 702, 641, 552, 499 cm ^-1 ; ¹ H NMR (CDCl ₃ ): 0.92 (t, J = 7.2 Hz, 12H, CH ₂ C H ₃ ), 1.18 (d, J = 7.2 Hz, 3H, CHC H ₃ ), 1.36 (sex, J = 7.3 Hz, 8H , C H ₂ CH ₃ ), 1.53-1.61 (m, 8H, CH ₂ CH ₂ CH ₃ ), 1.84 (q, J = 6.9 Hz, 2H, CHC H ₂ ), 2.88 (sex, J = 7.2 Hz, 1H , C H ), 3.20-3.24 (m, 8H, NC H ₂ ), 3.78-3.87 (m, 2H, OC H ₂ ), 7.05-7.18 (m, 5H, Ar); ¹³ C NMR (CDCl ₃ ): 13.7 (CH ₂ C H ₃ ), 19.7 ( C H ₂ CH ₃ ), 21.9 (CH C H ₃ ), 24.0 ( C H ₂ CH ₂ CH ₃ ), 35.9 (CHCH ₂ C H ₂ ), 39.1 (d, J = 7.2 Hz, CH C H ₂ ), 58.8 (N C H ₂ ), 64.2 (d, J = 4.8 Hz, O C H ₂ ), 125.7, 127.1, 128.3, 147.4 (Ar); ¹⁹ F NMR (CDCl ₃ ):-78.1 (d, J _PF = 920.9 Hz); ³¹ P NMR (CDCl ₃ ):-4.6 (d, J _PF = 920.9 Hz); MS (FAB ⁺ ): m / z: 242: (M ^{+ ], (FAB -): m} / z: 231: [M -];

(Example 2)
In Example 2, O-1-methyl-3-phenylpropyl fluorophosphate tetrabutylammonium salt (6b) was synthesized by the method shown in the chemical formula below.

<Reaction process>
Phosphate ester with binaphthyl group 5b (480 mg, 1 mmol) in THF solution (4 mL) and tetrabutylammonium fluoride THF solution (1M solution,
1.2 mL, 1.2 mmol) was added at 0 ° C. and the mixture was stirred at room temperature for 3 hours.
<Water extraction process>
The reaction mixture was concentrated, poured into water and washed with ether.
<Organic solvent extraction process>
Next, the aqueous layer was extracted with methylene chloride, the organic layer was dried over magnesium sulfate and concentrated, and O-1-methyl-3-phenylpropyl tetrabutylammonium fluorophosphate 6b as a yellow oil (357 mg, 76% )Obtained. The spectrum data is shown below.

IR (neat): 2962, 2875, 2736, 2514, 1945, 1795, 1641, 1603, 1488, 1462, 1267, 1111,1081, 1055, 1028, 989, 920, 884, 806, 749, 701, 592, 554 , 504, 494, 459, 433,412, 403 cm ^-1 ; ¹ H NMR (CDCl ₃ ): 1.00 (t, J = 7.4 Hz, 12H, CH ₂ C H ₃ ), 1.33 (d, J = 6.0 Hz, 3H , CHC H ₃ ), 1.44 (sex, J = 7.3 Hz, 8H, C H ₂ CH ₃ ), 1.61-1.69 (m, 8H, C H ₂ CH ₂ CH ₃ ), 1.74-1.98 (m, 2H, CHC H ₂ ), 2.64-2.72 (m, 1H, CHCH ₂ C H ₂ ), 2.80-2.87 (m, 1H, CHCH ₂ C H ₂ ), 3.29-3.33 (m, 8H, NC H ₂ ), 4.46 (sep , J = 6.6 Hz, 1H, OC H ), 7.12-7.25 (m, 5H, Ar); ¹³ CNMR (CDCl ₃ ): 13.6 (CH ₂ C H ₃ ), 19.6 ( C H ₂ CH ₃ ), 21.8 ( CH C H ₃ ), 23.9 ( C H ₂ CH ₂ CH ₃ ), 31.8 (CHCH ₂ C H ₂ ), 39.1 (d, J = 6.3 Hz, CH C H ₂ ), 58.6 (N C H ₂ ), 72.3 (d, J = 6.3 Hz, O C H), 125.4, 127.0, 128.2, 147.3, 147.4 (Ar); ¹⁹ F NMR (CDCl ₃ ):-78.2 (d, J _PF = 919.1 Hz); ³¹ P NMR ( _{CDCl 3): - 5.2 (d} , J PF = 919.1 Hz); MS (FAB +): m / z: 242: [M +], (FAB -): m / z: 231: [M -];

(Example 3)
In Example 3, O-2-naphthylethyl fluorophosphate tetrabutylammonium salt (6c) was synthesized by the method shown in the chemical formula below.

<Reaction process>
Phosphate ester with phenyl group 5c (194 mg, 0.5 mmol) in THF solution (1 mL) and tetrabutylammonium fluoride THF solution (1M solution,
0.6 mL, 0.6 mmol) was added at 0 ° C. and the mixture was stirred at room temperature for 5 hours.
<Water extraction process>
The reaction mixture was concentrated, poured into water and washed with ether.
<Organic solvent extraction process>
The aqueous layer was then extracted with methylene chloride, and the organic layer was dried over magnesium sulfate and concentrated to give O-2-naphthylethyl tetrafluoroammonium fluorophosphate 6c as a yellow oil (214 mg, 86%). The spectrum data is shown below.

IR (neat): 3052, 2962 , 2875, 2193, 1632, 1601, 1508, 1469, 1382, 1113, 1067, 1038,931, 887, 856, 819, 784, 731, 640, 533, 498, 478 cm - ¹ ; ¹ HNMR (CDCl ₃ ): 0.98 (t, J = 7.4 Hz, 12H, CH ₂ C H ₃ ), 1.18 (d, J = 7.2 Hz, 3H, CHC H ₃ ), 1.40 (sex, J = 7.4 Hz, 8H, C H ₂ CH ₃ ), 1.55-1.63 (m, 8H, C H ₂ CH ₂ CH ₃ ), 3.15 (t, J = 7.4 Hz, 2H, OCH ₂ C H ₂ ), 3.20-3.25 ( m, 8H, NC H ₂ ), 4.27 (dt, J = 7.6 Hz, 7.5 Hz, 2H, OCH ₂ C H ₂ ), 7.38-7.45, 7.70-7.79 (m, 5H, Ar); ¹³ CNMR (CDCl ₃ ): 13.7 (CH ₂ C H ₃ ), 19.7 ( C H ₂ CH ₃ ), 24.0 ( C H ₂ CH ₂ CH ₃ ), 37.4 (d, J = 6.8 Hz, OCH ₂ C H ₂ ), 58.8 (N C H ₂ ), 66.5 (d, J = 5.4 Hz, O C H ₂ ), 125.1, 125.7, 127.3,127.6, 127.7, 127.9, 132.1, 133.6, 136.5 (Ar); ¹⁹ F NMR (CDCl ₃ ):- 78.0 (d, J _PF = 923.2 Hz); ³¹ P NMR (CDCl ₃ ): -5.0 (d, J _PF = 923.2 Hz).

Example 4
In Example 4, O-2-naphthylethyl fluorophosphate tetrabutylammonium salt (6d) was synthesized by the method shown in the chemical formula below.

<Reaction process>
Phosphate ester with binaphthyl group 5d (122 mg, 0.25 mmol) in THF solution (1 mL) and tetrabutylammonium fluoride in THF solution (1M
solution, 0.3 mL, 0.3 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3.5 hours.
<Water extraction process>
The reaction mixture was concentrated, poured into water and washed with ether.
<Organic solvent extraction process>
The aqueous layer was then extracted with methylene chloride, the organic layer was dried over magnesium sulfate, concentrated, and O-[(1R, 2S, 5R) -5-methyl-2- (1-methylethyl) cyclohexyl fluorinated phosphoric acid tetraphosphate. Butyl ammonium salt 6d was obtained as a white solid (81 mg, 68%). The melting point and spectrum data are shown below.

mp: 48-49 ° C; IR (KBr): 2967, 2872, 2733, 2360, 2341, 1645, 1487, 1383, 1281, 1179,1151, 1094, 1078, 1060, 1028, 1000, 931, 884, 825 , 807, 750, 552, 520, 495,453, 413 cm ^-1 ; ¹ H NMR (CDCl ₃ ): 0.70-0.77 (m, 1H), 0.74 d, J = 7.2 Hz, 3H, OCHCH ₂ CHC H ₃ ), 0.79 d, J = 6.8 Hz, 3H, OCHCH ₂ CHCH (C H ₃ ) ₂ ), 0.80 d, J = 7.2 Hz, 3H, OCHCH ₂ CHCH (C H ₃ ) ₂ ), 0.86-1.02 (m, 1H) , 0.94 (t, J = 7.4 Hz, 12H, CH ₂ C H ₃ ), 1.16-1.23 (m, 1H), 1.38 (sex, J = 7.3 Hz, 8H, C H ₂ CH ₃ ), 1.33-1.63 ( m, 4H), 1.53-1.63 (m, 8H, C H ₂ CH ₂ CH ₃ ), 2.25-2.28 (m, 2H), 3.24-3.28 (m, 8H, NC H ₂ ), 3.93-4.01 m, 1H , OC H ); ¹³ C NMR (CDCl ₃ ): 13.6 (CH ₂ C H ₃ ), 15.8, 19.6 ( C H ₂ CH ₃ ), 21.2, 22.1, 22.9, 23.9 ( C H ₂ CH ₂ CH ₃ ), 25.2, 31.4, 34.5, 43.0, 48.8 (d, J = 7.2 Hz), 58.6 (N C H ₂ ), 75.7 (d, J = 6.3 Hz, O C H); ¹⁹ F NMR (CDCl ₃ ): -74.7 (d, J _PF = 919.5 Hz); ³¹ P NMR (CDCl ₃ ): -5.4 (d, J _PF = 919.5 Hz).

(Example 5)
In Example 5, O- (1-methylethenyl) -5-methyl-4-hexenyl fluorophosphate tetrabutylammonium salt (6e) was synthesized by the method shown in the chemical formula below.

<Reaction process>
Phosphoric ester having phenyl group 5e (138 mg, 0.35 mmol) To THF solution (1 mL), tetrabutylammonium fluoride THF solution (1Msolution, 0.42 mL, 4.2 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 4 hours. Stir.
<Water extraction process>
The reaction mixture was concentrated, poured into water and washed with ether.
<Organic solvent extraction process>
The aqueous layer was then extracted with methylene chloride, the organic layer was dried over magnesium sulfate, concentrated, and O-[(1R, 2S, 5R) -5-methyl-2- (1-methylethyl) cyclohexyl fluorinated phosphoric acid tetraphosphate. Butyl ammonium salt 6e was obtained as a white solid (107 mg, 64%). The spectrum data is shown below.

IR (KBr): 2963, 2876, 2360, 1648, 1460,1384, 1275, 1114, 1051, 887, 849, 797, 497, 453, 435, 423 cm ^-1 ; ¹ HNMR (CDCl ₃ ): 1.00 (t , J = 7.4 Hz, 12H, CH ₂ C H ₃ ), 1.44 (sex, J = 7.4 Hz, 8H, C H ₂ CH ₃ ), 1.58 (s, 3H, C H ₃ C = CH ₂ ), 1.61- 1.69 (m, 8H, C H ₂ CH ₂ CH ₃ ), 1.68 (s, 6H, CHC (C H ₃ ) ₂ ), 1.99-2.07 (m, 1H, OCH ₂ CHC H ₂ ), 2.25-2.32 (m , 1H, OCH ₂ CHC H ₂ ), 2.41 (quin, J = 7.0 Hz, 1H, OCH ₂ C H ), 3.29-3.33 (m, 8H, NC H ₂ ), 3.86-3.97 (m, 2H, OC H ₂ ), 4.71-4.76 (m, 1H, C = C H ₂ ), 4.76-4.78 (m, 1H, C = C H ₂ ), 5.04-5.07 (m, 1H, (CH ₃ ) ₂ C = C H ); ¹³ C NMR (CDCl ₃ ): 13.7 (CH ₂ C H ₃ ), 17.9 (( C H ₃ ) ₂ C = CH), 19.7 ( C H ₂ CH ₃ ), 20.1 (CH ₂ = CH C H ₃ ), 24.0 ( C H ₂ CH ₂ CH ₃ ), 25.8 (OCH ₂ CH C H ₂ ), 28.4 (( C H ₃ ) ₂ C = CH), 47.9 (d, J = 7.7 Hz, OCH ₂ C H) , 58.6 (N C H ₂ ), 68.0 (d, J = 5.8 Hz, O C H ₂ ), 111.8 (CH ₃ C = C H ₂ ), 122.5 ((CH ₃ ) ₂ C = C H), 131.9 ( (CH ₃ ) ₂ C = CH), 145.7 (CH ₃ C = CH ₂ ); ¹⁹ F NMR (CDCl ₃ ): -78.7 (d, J _PF = 921.0 Hz); ³¹ P NMR (CDCl ₃ ): -4.7 (d, J _PF = 921.0 Hz) .

  In Examples 1 to 5, tetrabutylammonium fluoride was used as the fluorine ion source, but alkali metal fluorides (sodium fluoride, potassium fluoride, cesium fluoride, and rubidium fluoride) can also be used.

(Example 6)
In Example 6, fluorinated phosphoric acid monoester potassium salt 7 was obtained by the method shown in the following reaction formula using potassium fluoride which is an alkali metal fluoride as a fluorine source.

<Reaction process>
That is, potassium fluoride (58 mg, 1 mmol) and 18-crown-6-ether (132 mg, 0.5 mmol) were added to a phosphate ester 5d (243 mg, 0.5 mmol) THF solution (2.5 mL) having a binaphthyl group at room temperature. And the mixture was heated under reflux for 4 hours to obtain potassium fluorophosphate monoester 7 (conversion rate: 44%). The spectrum data of ³¹ P NMR performed for confirming the structure was as follows. ³¹ P NMR (CDCl ₃ ) -4.66 ( ¹ J _PF = 904.5 Hz).

  The present invention is not limited to the description of the embodiments of the invention. Various modifications may be included in the present invention as long as those skilled in the art can easily conceive without departing from the description of the scope of claims.

Claims (5)

Phosphoric acid diaryl ester represented by the following general formula (1) (where Ar and Ar ′ represent an aryl group which may have a substituent, and Ar and Ar ′ are chemically bonded to form a cyclic structure) In addition, R represents an alkyl group which may have a substituent, and a quaternary ammonium fluoride and / or an alkali metal fluoride is reacted. A method for producing an ester salt.

  The method for producing a fluorophosphate monoester salt according to claim 1, wherein the reaction solvent is an aprotic polar solvent. Phosphoric acid diaryl ester represented by the following general formula (1) (where Ar and Ar ′ represent an aryl group which may have a substituent, and Ar and Ar ′ are chemically bonded to form a cyclic structure) R represents an alkyl group which may have a substituent, and a reaction step of reacting quaternary ammonium fluoride and / or an alkali metal fluoride;
A water extraction step of extracting the reaction solution obtained in the reaction step with water;
An organic solvent extraction step of extracting the aqueous layer obtained in the extraction step with an organic solvent;
The method for producing a fluorinated phosphoric acid monoester salt according to claim 1 or 2.

  The method for producing a fluorinated phosphoric acid monoester salt according to claim 3, wherein the organic solvent used in the organic solvent extraction step is a halogenated hydrocarbon. A fluorophosphate monoester salt represented by the following general formula (4). (Here, M ⁺ represents a cation, and R represents an alkyl group which may have a substituent (excluding an ethyl group and a substituent having a tetrahydrofuryl skeleton)).