JP2005120027A - 5-benzyloxy-1,2,3,4-tetrahydronaphthalene derivative and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve the problems wherein a well-known method for producing an important intermediate is insufficient for a large-scale industrial production in a cost field and an environmental field because an expensive trimethylsilyl cyanide is used in the process, and further a compound of tin which is a heavy metal is used. <P>SOLUTION: The production method for obtaining optically pure 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid through 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile involves using an inexpensive reaction reagent easily made harmless. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a 5-benzyloxy-1,2,3,4-tetrahydronaphthalene derivative useful as a pharmaceutical intermediate and a method for producing the same.

  An amide derivative having a C5a receptor antagonistic action or a salt thereof is described in International Publication (see Patent Document 1). As an important intermediate in the synthesis of 5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide derivatives described in the publication, 5-benzyloxy-1,2,3,4-tetrahydro As naphthalene-1-carboxylic acid (in the following formula, I) and its production method, the following method is disclosed in Preparation Example 6 (quoting Preparation Example 5).

  The method for producing an important intermediate disclosed in the above publication uses an expensive trimethylsilyl cyanide in the process, and further uses a tin compound of a heavy metal. Is inadequate.

  Furthermore, as a separate method, the general description of International Publication No. WO02 / 22556 includes Method 10

However, there is no specific example in which 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, which is an important intermediate, was synthesized using this process.

  In addition, when developing a compound having an asymmetric carbon as a pharmaceutical, if the optically active substance is used, it is expected that its medicinal effect is further improved and toxicity such as side effects is reduced. Therefore, when it is intended to develop a pharmaceutical having an asymmetric carbon, it is extremely important to produce the optically active substance at a low cost, and it is more useful if an optically active intermediate can be used as the synthesis method. is there. However, International Publication No. WO02 / 22556 discloses 5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide derivative having C5a receptor antagonistic activity as an optically active intermediate 5-benzyl. There is no description of synthesis using oxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.

From the above, 5-benzyloxy-1,2, which is an important intermediate in the synthesis of optically active 5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide derivatives having C5a receptor antagonistic activity A more industrial production method of 3,4-tetrahydronaphthalene-1-carboxylic acid is desired, and as a production method of the optically active substance, yield, purity (including optical purity), safety, and simplicity There is an urgent need to establish an efficient manufacturing method suitable for production on an environmentally-oriented industrial mass scale, which is superior in such points.
International Publication WO02 / 22556

  A method for producing 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid useful as an important intermediate disclosed in International Publication No. WO02 / 22556 is an expensive trimethylsilyl cyanate in the process. Since nido is used and also a heavy metal tin compound is used, it is insufficient for industrial production with a large scale in terms of cost and environment.

  Therefore, as a method for producing 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, a production method suitable for industrial production by using an inexpensive and easily detoxifying reagent. The purpose is to provide.

  Furthermore, optically pure 5-benzyloxy-1,2,3,4-tetrahydro, essential for the synthesis of optically active forms of 5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide derivatives. An object is to provide an optically active form of naphthalene-1-carboxylic acid.

  The present inventors are important intermediates of 5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide derivatives having C5a receptor antagonistic activity disclosed in International Publication WO02 / 22556. As a result of intensive studies on a method for producing 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile was obtained. An industrially useful production method is found, and optically active 5-benzyloxy-1,2,2 is obtained by a simple optical resolution method using an optically active amine, preferably an optically active form of 1-phenylethylamine. A method has been established for producing 3,4-tetrahydronaphthalene-1-carboxylic acid inexpensively, safely and efficiently.

That is, the present invention is as follows.
1. A process for producing 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, characterized by passing 5-hydroxy-1-tetralone as a starting material and an intermediate in the following formula .

[Wherein L represents a leaving group for halogen, methanesulfonyloxy or toluenesulfonyloxy. ]
2. A salt is formed with 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid and an optically active amine, and crystals of the salt are precipitated and separated using the difference in solubility of the salt with respect to the solvent. And a method of producing optically active 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid by further treatment with an acid.
3. In (2) above, (R)-(+)-1-phenylethylamine is used as the optically active amine, and (-)-5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid is converted to How to manufacture.
4). 5-benzyloxy-1-chloro-1,2,3,4-tetrahydronaphthalene; 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile; (−)-5-Benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

5-Benzyloxy-1,2,3,4-tetrahydronaphthalene-1-, which is an important intermediate of 5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide derivatives having C5a receptor antagonistic activity By using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile as a method for producing carboxylic acid, no expensive trimethylsilylcyanide is used in the process, and a heavy metal tin is used. Established an inexpensive, safe and efficient production method that does not use compounds.

  Furthermore, by performing simple optical resolution using an optically active amine, it is simple, has good yield and purity (including optical purity), and has an efficiency suitable for production on an environmentally-oriented industrial mass scale. A method for producing a good optically active form of 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid was established.

  In this specification, the definition of each symbol is as follows.

The halogen in L represents chlorine, bromine and iodine.
Manufacturing method 1

[The symbols in the formula are as defined above. ]
Compound (I) of the present invention can be produced from compound (II) through steps 1-5.

  The introduction of the benzyl group in Step 1 is described in Theodora W. Greene, Peter G. M.M. It can be performed by the method described in Wuts edition “PROTECTIVE GROUP IN ORGANIC SYNTHESIS” (John Wiley & Sons, Inc. (1991)). For example, sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide in a solvent that does not inhibit the reaction of benzyl halide In the presence of a base such as triethylamine or pyridine, the reaction is carried out at -20 ° C to the reflux temperature of the solvent. Solvents used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran and dioxane, esters such as acetate, acetone and methyl ethyl ketone. Ketones such as methanol, ethanol such as isopropyl alcohol, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, water and mixed solvents thereof, etc. can do.

  Examples of the reducing agent used in the reduction reaction in Step 2 include lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane and the like. Examples of the solvent used in the reaction include water, methanol, ethanol, propanol, ether, THF, dioxane, acetic acid and the like, or a mixed solvent thereof. Although the reaction temperature varies depending on the solvent, it is usually from −20 ° C. to 80 ° C., and the reaction time varies depending on the reaction temperature, but is usually from 1 hour to 24 hours.

  When L of compound (V) in Step 3 is a chlorine atom, the reaction is usually carried out in an inert solvent or without solvent in the presence of thionyl chloride, methanesulfonyl chloride, paratoluenesulfonyl chloride, triphenylphosphine, and the like. The reaction is carried out at −20 ° C. to 80 ° C. in the presence of an organic base, and examples of the solvent used include methylene chloride, chloroform, carbon tetrachloride, ether, dimethylformamide, and mixed solvents thereof. When L of compound (V) is methanesulfonyloxy or paratoluenesulfonyloxy, the reaction is usually an organic base such as triethylamine in the presence of methanesulfonyl chloride or paratoluenesulfonyl chloride in an inert solvent or without solvent. The reaction is carried out at −20 ° C. to 80 ° C. in the coexistence, and examples of the solvent used include methylene chloride, chloroform, ether, dimethylformamide, and mixed solvents thereof.

  Step 4 is performed at −20 ° C. to the reflux temperature of the solvent in the presence of sodium cyanide, potassium cyanide, tetraethylammonium cyanide, etc. in a solvent that does not inhibit the reaction. Examples of the solvent used in Step 4 include water, methanol, ethanol, propanol, ethyl ether, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, or a mixed solvent thereof.

  Step 5 is carried out from −20 ° C. to the reflux temperature of the solvent in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide or an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., in a solvent that does not inhibit the reaction. Done. Examples of the solvent used in Step 5 include water, methanol, ethanol, propanol, ethylene glycol, ethylene glycol monomethyl ether, dimethyl ether, acetic acid, formic acid, or a mixed solvent thereof.

Manufacturing method 2 (Optical resolution)
The optically active form of 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (I) can be obtained by optical resolution of a racemic mixture. For example, a salt can be formed with an optically active amine, and separation can be performed using the difference in solubility of the salt in the solvent. In this case, in order to preferentially crystallize one of the less soluble salts, it is preferable to cool the reaction solution to a predetermined crystallization temperature to bring it into a supersaturated state.

  The optically active amine is (3S)-(−)-3-aminopyrrolidine, (3R)-(+)-3-aminopyrrolidine, (1R, 2S)-(−)-2-amino-1,2 -Diphenylethanol, (1S, 2R)-(+)-2-amino-1,2-diphenylethanol, (D)-(-)-arginine, (L)-(+)-arginine, (+)-cis 2-benzylaminocyclohexanemethanol, (-)-cis-2-benzylaminocyclohexanemethanol, brucine, cinchonidine, cinchonine, (R) -α-methyl-4-nitrobenzylamine, (S) -α-methyl-4 -Nitrobenzylamine, (R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine, (R)-(+)-1- (p-tolyl) ethylamine, S)-(-)-1- (p-tolyl) ethylamine, (R)-(+)-2-pyrrolidinemethanol, (S)-(+)-2-pyrrolidinemethanol, (1R, 2R)-(- ) -2-Amino-1- (4-nitrophenyl) -1,3-propanediol, (1S, 2S)-(+)-2-amino-1- (4-nitrophenyl) -1,3-propane Examples include diol, and (R)-(+)-1-phenylethylamine is preferable.

  Preferable solvents include alcohols such as methanol, ethanol and isopropyl alcohol, ethyl acetate, hexane, heptane, acetone, acetonitrile, ethyl ether, isopropyl ether, tetrahydrofuran, water or a mixed solvent thereof.

  The preferred crystallization temperature varies depending on the amount of solvent used, the type of solvent, and the dissolution temperature, but is usually in the range of -20 to 80 ° C.

  When crystallizing one of the salts, a very small amount of crystals of the salt to be crystallized can be added as seed crystals to the reaction solution.

  The precipitated salt can be isolated by general techniques such as centrifugation, filtration, and pressure filtration. Furthermore, if necessary, the optical purity can be improved by repeating recrystallization.

  The optically active form of compound (I) can be obtained by following a conventional method such as treatment of the obtained salt with an acid.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

¹ H-NMR was measured at 270 MHz. ^For chemical shift values of ¹ H-NMR, tetramethylsilane (TMS) was used as an internal standard, and relative delta (δ) values were expressed in parts per million (ppm). Coupling constants indicate trivial multiplicity in hertz (Hz) and are expressed as s (singlet), d (doublet), t (triplet), m (multiplet), and the like.

Chemical purity and optical purity were determined using high performance liquid chromatography under the following conditions.
High-performance liquid chromatography column: STR ODS-II (manufactured by Shinwa Kako Co., Ltd., inner diameter: 4.6 mm, column length: 150 mm)
Moving layer: 0.05 mol / L NaClO ₄ (pH 2.5): CH ₃ CN = 4: 7
Flow rate: 1.0 mL / min
Temperature: Room temperature Detection wavelength: 235nm

Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries, Ltd., inner diameter: 4.6 mm, column length: 150 mm)
Moving layer: 0.2 mol / L KH ₂ PO ₄ (pH 2.1): CH ₃ CN = 55: 45
Flow rate: 0.5 mL / min
Temperature: Room temperature Detection wavelength: 220nm

Example 1
To 200 g (1.23 mol) of 5-hydroxy-1-tetralone, 600 mL of dimethylformamide was added and dissolved, and 159.1 g (1.41 mol) of potassium tert-butoxide was added little by little at 5 to 15 ° C. with ice cooling. After that, the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and 243 g (1.41 mol) of benzyl bromide was added dropwise at 5 to 12 ° C., followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ice water, extracted with 1 L of ethyl acetate, washed with water, and dried over magnesium sulfate. The ethyl acetate solution was concentrated under reduced pressure to obtain 327 g (theoretical amount: 310 g) of oily 5-benzyloxy-1-tetralone.

¹ H-NMR (CDCl ₃ ) δ: 2.05-2.20 (2H, m), 2.64 (2H, t, J = 6.6 Hz), 2.97 (2H, t, J = 6. 6 Hz), 5.11 (2H, s), 7.06-7.10 (1 H, m), 7.25 (1 H, t, J = 7.9 Hz), 7.30-7.50 (5 H, m), 7.65-7.70 (1H, m)
Example 2
5-Benzyloxy-1-tetralone (327 g) was dissolved in 2000 mL of methanol, and 32.6 g (0.86 mol) of sodium borohydride was added in small portions at 8-13 ° C. with ice cooling, and then at room temperature for 1 hour. Stir. The reaction mixture was concentrated under reduced pressure, 2 L of water was added to the residue, and the mixture was stirred at room temperature for 30 minutes. After the solidified crystals were collected by filtration, 500 mL of isopropyl alcohol was added, and 1.5 L of n-hexane was added to the solution dissolved by heating to 60 ° C., followed by stirring for 1 hour under ice cooling. The precipitated solid was collected by filtration and then dried by air blowing at 60 ° C. overnight to obtain 237 g of 5-benzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene as slightly yellowish white crystals. The filtrate was concentrated under reduced pressure, isopropyl alcohol / n-hexane = 1/3 (350 ml) was added and ice-cooled. The precipitated solid was collected by filtration and then air-dried at 60 ° C. overnight to give 5-benzyloxy-1-hydroxy. 42.8 g of a second crystal of -1,2,3,4-tetrahydronaphthalene was obtained (total yield from 5-hydroxy-1-tetralone 90%)
Melting point 75-77 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.70-2.05 (4H, m), 2.55-2.70 (1H, m), 2.80-2.92 (1H, m), 4 70-4.80 (1H, m), 5.07 (2H, s), 6.82 (1H, d, J = 7.9 Hz), 7.08 (1H, d, J = 7.9 Hz) 7.18 (1H, t, J = 7.9 Hz), 7.25-7.50 (5H, m)
Example 3
150 g (0.59 mol) of 5-benzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene was dissolved in 450 mL of methylene chloride, and 51 mL (0.708 mol) of thionyl chloride at 5-12 ° C. with ice cooling. Was added dropwise, and the mixture was stirred for 30 minutes under ice-cooling and then for 2.5 hours at room temperature. The reaction mixture is poured into ice water, washed with water and dried over magnesium sulfate, and the methylene chloride solution is concentrated under reduced pressure to give an oily (solidified at room temperature) 5-benzyloxy-1-chloro-1,2,3,4-tetrahydro 163 g of naphthalene (theoretical amount 161 g) was obtained.
Melting point 74 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.80-1.95 (1H, m), 2.00-2.35 (3H, m), 2.45-2.65 (1H, m), 2 .90-3.05 (1H, m), 5.05 (2H, s), 5.29 (1H, t, J = 3.3 Hz), 6.80 (1H, d, J = 7.9 Hz) , 7.00 (1H, d, J = 7.9 Hz), 7.14 (1H, t, J = 7.9 Hz), 7.25-7.50 (5H, m)
Example 4
57.8 g (1.18 mol) of sodium cyanide was added to 480 mL of dimethyl sulfoxide and heated to 65 ° C. to dissolve it, and 163 g of 5-benzyloxy-1-chloro-1,2,3,4-tetrahydronaphthalene and A solution of 160 mL of dimethyl sulfoxide was added dropwise at 62 to 63 ° C, and then stirred at 65 ° C for 4.5 hours. The reaction mixture was poured into ice water, extracted with 800 mL of ethyl acetate, washed with water, and dried over magnesium sulfate. The ethyl acetate solution was concentrated under reduced pressure to obtain 154 g (theoretical amount: 155 g) of oily 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile.
¹ H-NMR (CDCl ₃ ) δ: 1.76-1.92 (1H, m), 1.95-2.15 (3H, m), 2.70-2.90 (2H, m), 3 .97 (1H, t, J = 5.9 Hz), 5.07 (2H, s), 6.83 (1H, d, J = 7.9 Hz), 6.99 (1H, d, J = 7. 9 Hz), 7.17 (1 H, t, J = 7.9 Hz), 7.25-7.45 (5 H, m)
Example 5
To 154 g of 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile was added 144 mL of ethylene glycol, and 60.0 g (0.909 mol) of potassium hydroxide (purity 85%) was stirred at room temperature. After adding a small amount, the mixture was stirred and refluxed for 3 hours. The reaction mixture was poured into ice water and washed three times with 200 mL of ethyl acetate. The aqueous layer was adjusted to pH 1 with 2N-hydrochloric acid, and the precipitated solid was collected by filtration and dried by blowing at 60 ° C. overnight to give 5-benzyloxy- 103 g of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid was obtained (total yield from 5-benzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene 62%).
Melting point 144 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.70-2.05 (3H, m), 2.10-2.25 (1H, m), 2.60-2.90 (2H, m), 3 .84 (1H, t, J = 5.3 Hz), 5.05 (2H, s), 6.79 (1H, d, J = 7.9 Hz), 6.85 (1H, d, J = 7. 9 Hz), 7.11 (1 H, t, J = 7.9 Hz), 7.25-7.50 (5 H, m)
Example 6
(R)-(+)-1- In a solution in which 65 mL of acetone was added to 14.1 g (0.05 mol) of 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid and dissolved by heating. 6.05 g (0.05 mol) of phenylethylamine was added and stirred under ice cooling. The precipitated solid was collected by filtration to obtain 7.7 g of crude crystals having an optical purity of 93.3%. The crude crystals were dissolved in 31 mL of acetone by heating and stirred under ice-cooling. The precipitated solid was collected by filtration and then dried by blowing at 60 ° C. overnight to give (−)-5-benzyloxy-1,2,3. , 4-tetrahydronaphthalene-1-carboxylic acid (R)-(+)-1-phenylethylamine salt 6.80 g (light brown crystals) was obtained (yield 34%).
Optical purity 99.3% e.e. e.
Melting point 87 ° C
Example 7
To 6.5 g (0.0161 mol) of (R)-(+)-1-phenylethylamine salt of (−)-5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid was added ethanol / water. (1/2) 32 mL was added, and a solution of 3.64 g of concentrated hydrochloric acid and 9 mL of ethanol / water (1/2) was added dropwise thereto while stirring at room temperature, followed by stirring at room temperature for 1 hour. The reaction mixture was stirred at 50 ° C. for 1 hour and then ice-cooled for 30 minutes. The precipitated solid was collected by filtration and then dried by blowing at 60 ° C. overnight to give pale brown crystals of (−)-5-benzyloxy-1,2 , 3,4-tetrahydronaphthalene-1-carboxylic acid 4.36 g was obtained (yield 96%).
Melting point 96-97 ° C
Chemical purity 99.6%
Optical purity 99.2% e.e. e.

  5-Benzyloxy-1,2,3,4-tetrahydronaphthalene-1-, which is an important intermediate of 5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide derivatives having C5a receptor antagonistic activity By using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile as a method for producing carboxylic acid, no expensive trimethylsilylcyanide is used in the process, and a heavy metal tin is used. Established an inexpensive, safe and efficient production method that does not use compounds.

  Furthermore, by performing simple optical resolution using an optically active amine, it is simple, has good yield and purity (including optical purity), and has an efficiency suitable for production on an environmentally-oriented industrial mass scale. A method for producing a good optically active form of 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid was established.

Claims (6)

A process for producing 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, characterized by passing 5-hydroxy-1-tetralone as a starting material and an intermediate in the following formula .

[Wherein L represents a leaving group for halogen, methanesulfonyloxy or toluenesulfonyloxy. ] A salt is formed with 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid and an optically active amine, and crystals of the salt are precipitated and separated using the difference in solubility of the salt with respect to the solvent. And a method of producing optically active 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid by further treatment with an acid. (-)-5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, wherein the optically active amine of claim 2 is (R)-(+)-1-phenylethylamine how to. 5-Benzyloxy-1-chloro-1,2,3,4-tetrahydronaphthalene 5-Benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (−)-5-Benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid