JP3121656B2 - Optically active glycidol derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active glycidol derivative and a method for producing the same. The optically active glycidol derivative of the present invention is an optically active drug,
In particular, it is highly useful as an important and highly versatile raw material for glycerin derivatives.

[0002]

2. Description of the Related Art Many optically active epichlorohydrin and glycidol derivatives are already known, but these compounds have high reactivity at the 3-position and can be converted into the following derivatives. If so, they are often not suitable as raw materials. For example, development of a glycidol derivative which has a protecting group which is stable under any of oxidizing, alkaline or acidic conditions and which can be removed under mild conditions has been desired.

As a method for synthesizing optically active epichlorohydrin and glycidol derivatives, Chem. Rev., 19
91, 91 , 437, 1) Chemical synthesis from mannitol, 2) Chemical synthesis from L-serine, 3) Sharpless oxidation of allyl alcohol, 4) Resolution of racemic glycidol ester by lipase, 5) Resolution of 1-chloro-3-benzyloxy-2-propyl acetate by lipase, 6) Resolution of 2,3-dichloro-1-propanol by enzyme, 7) 1-Tosyloxy-3-allyloxy-2-propyl acetate A method such as splitting with lipase is known. However, these synthesizing methods are not always sufficient in terms of stability, optical purity, economy, etc., and each has various problems.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found an inexpensive method for synthesizing an optically active glycidol derivative, and have completed the present invention. That is, the present invention relates to a method of preparing a racemic or optically pure 1-halogeno-3- (4-methoxyphenyloxy) -2-propanol represented by the general formula (3) and vinyl acetate in an organic solvent using lipase as a catalyst. (R) -1-halogeno-represented by the general formula (2),
Method for producing 3- (4-methoxyphenyloxy) -2-propyl acetate and (S) -1-halogeno-3- (4-methoxyphenyloxy) -2-propanol represented by general formula (1), and (R) -1-halogeno-3- (4-methoxyphenyloxy) -2-propyl acetate represented by the general formula (2) and the general formula (1)
(S) -1-halogeno-3- (4-methoxyphenyloxy) -2-propanol represented by the formula: wherein each is reacted with an alkali in an organic solvent. (R) -O- (4-methoxyphenyloxy)
Glycidol or (S) -O- (4-) represented by the formula (5)
It is intended to provide a method for producing (methoxyphenyloxy) glycidol.

[0005]

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(Wherein X represents a halogen atom such as iodine, bromine or chlorine, and Ac represents an acetyl group.) The starting material for the optically active O- (4-methoxyphenyloxy) glycidol obtained in the present invention is: (S) represented by the general formula (1)
-1-halogeno-3- (4-methoxyphenyloxy)
2-propanol and (R) -1-halogeno-3- (4-methoxyphenyloxy) -2-propyl acetate represented by the general formula (2) are novel compounds.

The aryl ether moiety of the optically active O- (4-methoxyphenyloxy) glycidol obtained in the present invention can be used under various reaction conditions as described in Tetrahedron Lett., 1985, 26 , 6291. And stable
Moreover, since it is a protecting group which can be removed under mild conditions, the optically active O-
The usefulness of (4-methoxyphenyloxy) glycidol is high.

The racemic or low-optical purity 1-halogeno-3- (4) represented by the general formula (3) to be used as a raw material of the present invention.
-Methoxyphenyloxy) -2-propanol is obtained by reacting racemic epichlorohydrin represented by the formula (6) with 4-methoxyphenol in the presence of tetramethylammonium chloride as shown in the following reaction formula. And then reacting with an alkali such as sodium hydroxide in ether to obtain the racemic O represented by the formula (7).
Obtaining-(4-methoxyphenyloxy) glycidol;
The glycidol derivative can be easily obtained by further reacting the glycidol derivative with lithium halide and acetic acid in a solvent such as tetrahydrofuran.

[0009]

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The thus obtained racemic or 1-halogeno-3- having a low optical purity represented by the general formula (3)
Reaction of (4-methoxyphenyloxy) -2-propanol with vinyl acetate in an organic solvent using lipase as a catalyst provides a high rate of change and a high selectivity to the (R) -1 represented by the general formula (2). -Halogeno-3- (4-methoxyphenyloxy) -2-propyl acetate and (S) -1-halogeno-3- (4-methoxyphenyloxy) -2-propanol represented by the general formula (1) are obtained. be able to. The lipase used here is preferably a lipase derived from a microorganism, and the organic solvent is preferably an ether hydrocarbon, a halogenated hydrocarbon, an alkenyl acetate, an aromatic hydrocarbon or a mixture thereof.

The reaction result in this step is 1-halogeno-3
-(4-methoxyphenyloxy) -2-propanol can be arbitrarily changed depending on conditions such as the type of halogen, the type and amount of lipase, the amount of vinyl acetate, the type of solvent, and the temperature. You can choose. For example, methylene chloride is selected as a solvent, chlorine is used as a halogen, and lipase PS (Pseud
omonas sp., Amano Pharmaceutical Co., Ltd.)
At 27 ° C. for 100 hours, (R) -1-halogeno-3- (4-methoxyphenyloxy) -2-propyl acetate having an optical purity of 97% ee is obtained in a yield of 80% (relative to the theoretical yield). When t-butyl methyl ether is used as a solvent, the reaction rate is increased, so that the reaction time can be shortened.

The thus obtained (R) -1-halogeno-3- (4-methoxyphenyloxy) -2-propyl acetate represented by the general formula (2) and the general formula (1)
(S) -1-halogeno-3- (4-methoxyphenyloxy) -2-propanol represented by the following formula:
That is, by reacting each with an alkali such as sodium hydroxide in an organic solvent such as tetrahydrofuran, the corresponding (R) -O- (4-methoxyphenyloxy) glycidol represented by the formula (4) or (S) -O- (4-methoxyphenyloxy) glycidol represented by the formula (5) is obtained. Further, (R) and (S) -O- (4-methoxyphenyloxy) glycidol having low optical purity can be easily purified by recrystallization with an appropriate organic solvent, and (R) -O having high optical purity can be easily purified. -(4-methoxyphenyloxy) glycidol and (S) -O- (4
It is possible to obtain (-methoxyphenyloxy) glycidol, which further enhances the utility of the present invention.

[0013]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

Example 1 Racemic 1-chloro-3- (4-methoxyphenyloxy) -2-propanol (hereinafter referred to as formula (3a))
1.05 g (4.86 mmol) of (±) -3a), 500 mg of lipase PS and 1 ml (10.8 mmol) of vinyl acetate were added to 50 ml of methylene chloride, followed by stirring at room temperature for 100 hours. Lipase PS
After filtration through a celite pad, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column (70 g). (S) -1-chloro-3- (4-methoxyphenyloxy) -2-propanol (hereinafter referred to as (S) -1a) represented by the formula (1a) from the outlet of hexane-ethyl acetate (3: 1). 570 mg (54.3%) and (R) represented by the formula (2a).
-1-chloro-3- (4-methoxyphenyloxy)-
500 mg (39.9%) of 2-propyl acetate (hereinafter abbreviated as (R) -2a) was obtained.

[0015]

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(S) -1a: optical purity 75% ee [CHIRALCE
L OD, i-propanol-hexane (3:17 (v /
v))) (R) -2a: optical purity 96.7% ee [CHIRALCEL OD, i-
Propanol-hexane (1:49 (v / v))] [α] _D ³⁰ = + 26.0 ° (c 1.03, methanol) Example 2 Racemic 1-iodo-3- represented by formula (3b) (4-methoxyphenyloxy) -2-propanol (hereinafter, referred to as
(Abbreviated as (±) -3b), and according to a method similar to Example 1, (S) -1-iodo-3- (4-methoxyphenyloxy)-represented by the optically active formula (1b). 2-propanol (hereinafter abbreviated as (S) -1b) and (R) -1-iodo-3- (4-methoxyphenyloxy) -2-propyl acetate (hereinafter referred to as (2b)) R)
−2b).

[0017]

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(S) -1b: optical purity 96.7 % ee [CHIRALCEL OD, i-propanol-hexane (3:17 (v / v))] [α] _D ²⁷ = + 0.73 ° (c 1.29, methanol) mp: 78-79 ° C. IR ^{_{(film) ν max: 3438cm -1 1 H}} -NMR (CDCl 3) δ: 2.65 (br s, 1H, exchangeable with D ₂ O), 3.4
1 (m, 2H), 3.77 (s, 3H), 3.99 (m, 3H), 6.84 (s, 4H) ms (m / z): 308 (M ⁺ ), 124 (100%) High-resolution mass spectrometry: Calculated for C ₁₀ H ₁₃ O ₃ I 307.9910, found
307.9912 (R) -2b : optical purity 96% ee [CHIRALCEL OD, i-propanol-
Hexane (1:49 (v / v))] [α] ^{_{D 29 = + 14.9 ° (c}} 1.03, methanol) IR ^{_{(film) ν max: 1743cm -1 1 H}} -NMR (CDCl 3) δ: 2.12 ( s, 3H), 3.47 (dd, J = 5.5,5.3Hz,
2H), 3.77 (s, 3H), 4.10 (dd, J = 5.1,5.0Hz, 3H), 5.06 (quin
t, J = 5.1Hz, 1H) , 6.84 (s, 4H) ms (m / z): 350 (M +), 93 (100%) High resolution mass spectrometry: C ₁₂ H ₁₅ O ₄ Calculated I 350.0015 , Measured values
349.9984 Example 3 Racemic 1-bromo-3- (4-methoxyphenyloxy) -2-propanol represented by the formula (3c)
(Abbreviated as (±) -3c), and according to the method according to Example 1, (S) -1-bromo-3- (4-methoxyphenyloxy)-represented by the optically active formula (1c). 2-propanol (hereinafter abbreviated as (S) -1c) and (R) -1-bromo-3- (4-methoxyphenyloxy) -2-propyl acetate (hereinafter referred to as (2c)) R)
−2c).

[0019]

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(S) -1c: optical purity 98.2 % ee [CHIRALCEL OD, i-propanol-hexane ( 3:17 (v / v))] [α] _D ²⁷ = −0.19 ° (c 1.04, methanol) melting point : 59 ° C. IR ^{_{(film) ν max: 3440cm -1 1 H}} -NMR (CDCl 3) δ: 3.13 (br s, 1H, exchangeable with D ₂ O), 3.5
8 (dd, J = 5.5,4.9Hz, 2H), 3.75 (s, 3H), 4.06 (dd, J = 5.6,4.2
Hz, 2H), 3.9-4.3 (m, 1H), 6.83 (s, 4H) ms (m / z): 262, 260 (M ⁺ ), 124 (100%) High-resolution mass spectrometry: C ₁₀ H ₁₃ O ₃ Br Calculated 260.0048 ( ⁷⁹ Br),
262.0029 ⁽⁸¹ Br) Found ^{260.0045 (79 Br), 262.0013 (} 81 Br) (R) -2c: Optical purity 96% ee [CHIRALCEL OD, i-propanol -
Hexane (1:49 (v / v))] IR ^{_{(film) ν max: 1744cm -1 1 H}} -NMR (CDCl 3) δ: 2.12 (s, 3H), 3.64 (m, 2H), 3.76 (s, Three
H), 4.22 (dd, J = 5.4,4.4Hz, 2H), 5.29 (quint, J = 5.1Hz, 1
H), 6.84 (s, 4H) ms (m / z): 304, 302 (M ⁺ ), 124 (100%) High-resolution mass spectrometry: Calculated value of C ₁₂ H ₁₅ O ₄ Br 302.0154 ( ⁷⁹ Br),
304.0135 ⁽⁸¹ Br) Found ^{302.0135 (79 Br), 304.0131 (} 81 Br) Example 4 (±) -3a~3c 0.4mmol and, whereas 2 moles of various shown in Table 1 of vinyl acetate and 50mg Lipase was added to 5 ml of the solvent shown in Table 1 and the conditions of Example 1 were changed at 27 ° C. for 100 hours.
The reaction is carried out according to the method described in (1).
1c and (R) -2a to 2c were obtained. The results are summarized in Table 1.

[0021]

[Table 1]

Note) * 1: Lipase OF [Candida cylindracea, Meito Sangyo Co., Ltd.] MY [Candida cylindracea, Meito Sangyo Co., Ltd.] AK [Pseudomonas sp., Amano Pharmaceutical Co., Ltd.] PS [ Pseudomonas sp., Manufactured by Amano Pharmaceutical Co., Ltd.] AY [Candida rugosa, manufactured by Amano Pharmaceutical Co., Ltd.] WAKO [Porcine pancreas, manufactured by Wako Pure Chemical Co., Ltd.] * 2: Optical purity manufactured by Daicel Chemical Industries, Ltd. CHIRALCEL OD
Was determined using * 3: A raw material with an optical purity of 75% ee was used.

Example 5 3.5 g (16 mmol) of (±) -3a, 1.6 g of lipase PS and 3.2 ml (35.2 mmol) of vinyl acetate were added to 160 ml of methylene chloride, and the mixture was stirred at room temperature for 18 days. After the lipase PS was filtered through a celite pad, the filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column (150 g). 1.61 g (46.4%) of (S) -1a from the outlet of hexane-ethyl acetate (5: 1)
And 1.87 g (45.3%) of (R) -2a. (S) -1a: optical purity 97% ee [CHIRALCEL OD, i-propanol-hexane (3:17 (v / v))] (R) -2a: optical purity 93% ee [CHIRALCEL OD, i-propanol- Hexane (1:49 (v / v))] Example 6 (R) -2a (optical purity 96.7% ee) 352 mg (1.36 mmol)
Was dissolved in 5 ml of tetrahydrofuran, 218 mg (5.46 mmol) of sodium hydroxide was added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with water and extracted with ether. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to give 240 mg of (R) -O- (4-methoxyphenyloxy) represented by the above formula (4) as colorless crystals. ) Glycidol (hereinafter abbreviated as (R) -4)
I got 93.6% yield. Optical purity 93.6% ee [CHIRALCEL OD, hexane-i-propanol (10: 1 (v / v))] [α] _D ²⁹ = -12.6 ° (c 1.01, methanol) Melting point: 43-44 ° C. R) -4 was recrystallized from ethanol-hexane to obtain (R) -4 having an optical purity of ≧ 99% ee. Melting point: 44 ° C [α] _D ³⁰ = -11.4 ° (c 1.06, methanol)

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields investigated (Int. Cl. ⁷ , DB name) C12P 41/00 BIOSIS (DIALOG) CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. (S) -1-halogeno-3- (4-methoxyphenyloxy) -2-propanol represented by the general formula (1). Embedded image (In the formula, X represents a halogen atom.) 2. (R) -1-halogeno-3- (4-methoxyphenyloxy) -2-propyl acetate represented by the general formula (2). Embedded image (In the formula, X represents a halogen atom and Ac represents an acetyl group.) 3. A reaction of 1-halogeno-3- (4-methoxyphenyloxy) -2-propanol represented by the general formula (3) with low optical purity and vinyl acetate in an organic solvent using lipase as a catalyst. (R) -1-halogeno- represented by the general formula (2)
3- (4-methoxyphenyloxy) -2-propyl acetate and (S) -1- represented by the general formula (1)
Halogeno-3- (4-methoxyphenyloxy) -2-
A method for producing propanol. Embedded image (In the formula, X represents a halogen atom.) 4. The (R) -1-halogeno-3- (4-methoxyphenyloxy) -2-propyl acetate represented by the general formula (2) obtained by the production method according to claim 3 and a general formula (S) -1-halogeno-3- represented by (1)
(R) -O- (4-methoxyphenyloxy) glycidol represented by the formula (4), wherein (4-methoxyphenyloxy) -2-propanol is reacted with an alkali in an organic solvent. Or a method for producing (S) -O- (4-methoxyphenyloxy) glycidol represented by the formula (5). Embedded image 5. The method according to claim 3, wherein a lipase derived from a microorganism is used as the lipase. 6. The process according to claim 3, wherein the organic solvent is an ether hydrocarbon, a halogenated hydrocarbon, an alkenyl acetate, an aromatic hydrocarbon or a mixture thereof.