KR19980047189A - Oxirane carboxylic acid derivatives and processes for their preparation - Google Patents

Abstract

The present invention relates to (R) (+) - oxiranecarboxylic acid derivatives represented by the following general formula (1), a process for producing the same, and (R) (+) - ethyl 2- (6- Hexyl-2-oxirane-carboxylate.

Description

Oxirane carboxylic acid derivatives and processes for their preparation

The present invention relates to an (R) (+) - oxiranecarboxylic acid derivative represented by the following general formula (1) and a process for producing the same.

In the above formula, A is selected from the radicals represented by the following general formulas (2), (3) and (4).

(Wherein, R ₁ represents a lower alkyl group, R ₂ ~R ₁₀ is hydrogen, halogen, an alkoxy group, a lower alkyl group, a hydroxy group, an alkenyl group, an alkynyl group, represents a cyano group, or amino group, X represents oxygen or sulfur , B each independently represents nitrogen or carbon, and n has a value of 0, 1, or 2.)

In the peripheral tissues of diabetic patients, the glucose uptake is inhibited, glycolysis is inhibited, and the? -Oxidation of the fatty acid is used instead of glucose as an energy source in the body, resulting in hyperglycemia, hyperlipidemia, , Hyperketonemia.

Carnitine Palmitoyl Transperase I (CPT I) is an enzyme that transports higher fatty acids from the cytoplasm to the mitochondrial matrix. The β-oxidation of β-oxidation It is a very important enzyme that acts as a rate step.

Therefore, the inhibitor of CPT I inhibits? -Oxidation of higher fatty acids to increase the utilization of glucose, and exhibits hypoglycemia, hypolipidemia, and hypoketonemia.

The compounds which inhibit CPT I include cormoxylate, chromosyl and etomocyl, all of which have an oxirane carboxylic acid structure as an active site, and the active site of CPT I in the cytoplasm and a stable And it is known that it is effective for the treatment of diabetes by inhibiting the activity of CPT I by forming a covalent bond.

Etomoxir, a representative compound among these oxirane carboxylic acid derivatives, has an ethyl 2- [6- (4-chlorophenoxy) hexyl] -oxirane-2 carboxylate structure of the following formula (5) .

It is known that only (R) (+) - enantiomer among the (R) (+) - and (S) (-) - enantiomers of this compound has the above- Kiorpes, TC et al., J. Biol. Chem., 1984, 259, 9750.], because the process of converting the (R) (+) - enantiomer into the Co A ester in the cell membrane is much easier than the (S) [Agius, L. et al., Biochem. Pharmacol., 1991, 42, 1711.]

In 1989, Martin Krilli et al. (R) (+) - announced a method for selective synthesis of civil engineering sir. According to the method of Crilly et al., The α, β-unsaturated ester (Compound 6) is hydrolyzed to give an α, β-unsaturated acid (Compound 7 ), Which was treated with thionyl chloride to convert it to an acid chloride (Compound 8), and then reduced with sodium borohydride to silica to obtain allyl alcohol (Compound 9). Alternatively, the alpha, beta -unsaturated ester (Compound 6) is reduced with aluminum trihydride to give the compound (Compound 9) directly. The obtained compound (9) is reacted with t-butyl hydroperoxide, titanium isopropoxide and diethyl-L - (+) - tartrate to obtain optically pure (S) (-) - epoxycarbanol 10) was synthesized. This is followed by ruthenium (III) -catalyzed oxidation (RuCl ₃ -NaIO ₄ ) to give the acid compound and reacting with diethylsulfate to give the ethyl ester, ie, (R) (+) - Were synthesized. (Scheme 1)

Scheme 1

However, the above-mentioned method of Martin Kleei et al. Is a method capable of synthesizing only the Corynebacterium syrup at (R) (+) -, so that it is difficult to synthesize various (R) (+) - oxirane carboxylic acid derivatives .

The inventors of the present invention have conducted extensive studies to variously synthesize derivatives having an important structure in the active phase of oxirane carboxylic acid derivatives having a strong inhibitory effect on CPT I. As a result, it has been found that (R) ( +) - oxiranecarboxylic acid. ≪ / RTI >

It is an object of the present invention to provide (R) (+) - oxiranecarboxylic acid derivatives.

Another object of the present invention is to provide a process for producing (R) (+) - oxiranecarboxylic acid derivatives.

Another object of the present invention is to provide (R) (+) - ethyl 2- (6-hydroxy) hexyl-2-oxirane-carboxylate as a synthetic intermediate.

Hereinafter, the present invention will be described in detail.

The present invention relates to (R) (+) - oxiranecarboxylic acid derivatives represented by the following general formula (1), a process for producing the same, and (R) (+) - ethyl 2- (6- Hexyl-2-oxirane-carboxylate.

In the above formula, A is selected from the radicals represented by the following general formulas (2), (3) and (4).

(Wherein, R ₁ represents a lower alkyl group, R ₂ ~R ₁₀ is a hydrogen, a halogen, an alkoxy group, a lower alkyl group, a hydroxy group, an alkenyl group, an alkynyl group, a cyano group, or an amino group, X is oxygen or sulfur , B is each independently nitrogen or carbon, and n has a value of n = 0, 1, or 2.)

The inventors also discovered a novel compound that could be used as an intermediate useful in the synthesis of (R) (+) - oxiranecarboxylic acid derivatives during the study, -Hydroxy) hexyl-2-oxirane-carboxylate.

Various derivatives of the (R) (+) - oxiranecarboxylic acid of the present invention are prepared by the following method.

Step 1

O-benzylation of 6-bromo-1-hexanol (Compound 12) gave 6-benzyloxy-1-bromo-hexane (Compound 13) in high yield. In order to obtain the compound (14) which is an alpha, beta -unsaturated ester in the compound (13), conventionally, an alkylation reaction is carried out with diethylmalonate and the partial hydrolysis is followed by the use of an esenmoseride salt. Because of the reaction, it was economically and temporally inefficient, and the yield was not so good. Thus, in the present invention, an α, β-unsaturated ester (Compound 14) is synthesized by Wittig reaction of Compound (13) and hydrolyzed to obtain 2- (6-benzyloxy) Ene-propionic acid (Compound 15). (Scheme 2)

Schematic 2

Compound (15) obtained in Step 1 and (S) (-) - ethylpyrrolinate as a subtitle are subjected to an amidation reaction using DEPC and triethylamine to obtain a compound (16). The compound (16) thus obtained can be hydrolyzed to obtain the compound (17) in quantitative yield. Bromo succinimide in the presence of bromoacetonitrile in a DMF solvent at 0 < 0 > C for 2 hours and at room temperature for 24 hours to obtain the desired bromo lactone compound (compound 18). ≪ / RTI > (Scheme 3)

Scheme 3

Step 3

(S) (-) - Methyl-2-hydroxy-2- (6-benzyloxy) hexyl-3-hydroxypropionate was obtained by acid hydrolysis of the bromoractone (Compound 18) Bromo-propionate (Compound 19). When concentrated hydrochloric acid is used in the hydrolysis, the desired compound (19) can not be obtained. Since the isomer thereof is obtained as a side reaction, it is preferable to reflux with a 6N hydrochloric acid aqueous solution for 12 hours. (R) (+) - ethyl-2- (6-hydroxy) hexyl-2-oxirane-carboxylate (Compound 20) was obtained by carrying out base- ). The esterification reaction can be carried out by using ethanol as a solvent in the base treatment. (Scheme 4)

Scheme 4

Step 4

Carboxylate (Compound 20) obtained in the above (R) (+) - ethyl-2- (6-hydroxyoxy) 1) can be prepared (Scheme 5).

Scheme 5

(S) (-) - ethyl proprionate as an azeotropic agent in order to synthesize the (R) (+) - enantiomer of the oxirane carboxylic acid derivatives as described above (R (R) (+) - oxirane carboxylic acid derivative can be synthesized, and the conventional technique was a production method which could not be synthesized except for the (R) (+) - Various derivatives of carboxylic acids can be synthesized, and these derivatives can be used as new diabetes therapeutic agents.

Example 1: 6-Benzyloxy-1-bromo-hexane (13)

60% NaH (883.2 mg, 22.08 mmol) was added, and the mixture was purged with argon gas, suspended in 20 ml of anhydrous THF, and a solution of 6-bromo-1-hexanol (compound 12, 4 g, 22.08 mmol) in anhydrous THF . Benzyl bromide (3.78 g, 22.08 mmol) was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was distilled under reduced pressure and diluted with 800ml ethyl acetate and 100ml of water and salt water (brine) the organic layer (20ml × 2) and the column washed with anhydrous MgSo ₄ dried, filtered, evaporated under reduced pressure Purification by chromatography (ethyl acetate: n- hexane = 1: 5) to obtain 5.6 g (93%) of a colorless oil, 6-benzyloxy-1-bromo-hexane (Compound 13).

IR (neat) 3300, 3040, 2950, 2880, 1460, 1100 cm < ^-1 >.

^{1 H-NMR (CDCl3, 400MHz} ) δ 7.38-7.24 (m, 5H) 4.50 (s, 2H),

3.47 (t, 2H, J = 3.6 Hz), 1.85 (qt, 2H, J = 7.2 Hz)

1.61 (qt, 2H, J = 6.8 Hz) 1.47-1.38 (m, 4H).

MS, m / e 271 (M ^< ^{+ &} gt ^; ).

Example 2: Ethyl 2- (6-benzyloxy) hexyl-2-en-propionate (14)

Triethylphosphonoacetate (3.66 ml, 18.44 mmol) and 10 ml of DME were added to a suspension of 60% NaH (738 mg, 18.44 mmol) in anhydrous dimethoxyethane (DME) at room temperature under argon gas atmosphere and stirred for 1 hour . 20 ml of a solution of 6-benzyloxy-1-bromo-hexane (compound 13, 5 g, 18.44 mmol) in DME was added to the reaction mixture, and the mixture was refluxed for 10 hours. After cooling the reaction mixture, 60% NaH (738 mg, 18.44 mmol) After putting it at 0 ° C once, the temperature was brought to room temperature, 10 ml of 95% paraformaldehyde (618 mg) in DME was added, and the mixture was stirred for 1 hour. The reaction mixture was evaporated under reduced pressure to remove DME. The organic layer was washed with saturated brine, dried over anhydrous MgSO ₄ , filtered, evaporated under reduced pressure and purified by column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain 4.01 g (75%) of ethyl 2- (6-benzyloxy) hexyl-2-en-propionate (Compound 14) as a colorless oil.

IR (neat) 2950, 2880, 1720, 1200, 1160, 1100 cm ^-1 .

_{^{1 H-NMR (CDCl 3,}} 400MHz) δ 7.37-7.26 (m, 5H), 6.12 (s, 1H), 5.50 (s, 1H),

2H), 4.19 (q, 2H, J = 7.2 Hz), 3.46 (t, 2H, J = 6.8 Hz)

2H), 2.28 (t, 2H, J = 7.4 Hz), 1.62 (qt, 2H, J = 6.8 Hz), 1.46

1.40-1.31 (m, 4H), 1.28 (t, 3H, J = 7.2 Hz).

MS, m / e 290 (M ^< ^{+ &} gt ^; ). _{HRMS calcd for C 18 H 26 O} 3 290.1882, fonud 290.1881.

Example 3: 2- (6-Benzyloxy) hexyl-2-en-propionic acid (15)

85% KOH (681 mg, 10.32 mmol) was added to a solution of ethyl 2- (6-benzyloxy) hexyl-2-en-propionate (compound 14, 2 g, 6.88 mmol) in 50% methanol Lt; / RTI >

The reaction mixture was evaporated under reduced pressure, acidified with 7% hydrochloric acid (10 ml), extracted with ethyl acetate (3 × 100 ml), washed with brine (2 × 10), dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure to give 2 - (6-benzyloxy) hexyl-2-en-propionic acid (Compound 15) 1.8 g (100%) was quantitatively obtained.

IR (neat) 3000, 2950, 2880, 1700, 1640, 1460, 1100 cm ^-1 .

_{^{1 H-NMR (CDCl 3,}} 300MHz) δ 7.35-7.24 (m, 5H), 6.27 (s, 1H), 5.63 (s, 1H),

2H), 3.46 (t, 2H, J = 6.6 Hz), 2.29 (t, 2H, J = 7.35 Hz)

1.61 (qt, 2H, J = 6.6 Hz), 1.48 (qt, 2H, J = 6.4 Hz), 1.37-1.28 (m, 4H).

MS, m / e 262 (M ^< ^{+ &} gt ^; ). HRMS calcd for C ₁₆ H ₂₂ O ₃ 262.1569, foung 262.1573.

Example 4: (S) (-) - Ethyl N- (6-benzyloxy) hexyl-acryloyl-proprionate (16)

(S) - (-) - ethyl proprinate (969 mg, 6.77 mmol) was dissolved in 50 ml of anhydrous DMF After argon substitution, DEPC (1.1 ml, 6.77 mmol) and triethylamine (0.94 ml, 6.77 mmol) were added at 0 ° C and stirred for 2 hours. The reaction solution was diluted and the diluted hydrochloric acid (2 × 10ml), saturated NaHCO ₃ (2 × 10ml), water (5 × 10ml), brine (2 × 10ml) to clean and anhydrous MgSO ₄ ethyl acetate (3 × 100ml) After filtration and evaporation under reduced pressure, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1: 1) to thereby give a colorless oil, (S) (-) - ethyl- N- (6-benzyloxy) hexyl- Propionate (Compound 16), 1.98 g (83%).

_{[α] D = -35.66 (c} 0.54, CHCl 3).

IR (neat) 2960, 1740, 1660, 1640, 1450, 1200, 1100 cm ^-1 .

_{^{1 H-NMR (CDCl 3,}} 400MHz) δ 7.30-7.21 (m, 5H), 5.19 (s, 1H), 5.16 (s, 1H),

4.43 (s, 2H), 4.45-4. 41 (m, 1H), 4.13 (q, 2H, J = 7.06 Hz)

2H), 3.39 (t, 2H, J = 6.8 Hz), 2.25 (t, 2H, J = 7.8 Hz)

1.98-1.79 (m, 4H), 1.58-1.50 (m, 2H), 1.44-1.37 (m, 2H)

1.36-1.28 (m, 4H), 1.21 (t, 3H, J = 7.2 Hz).

MS, m / e 388 (M ^< + & gt ^; +1). HRMS calcd for C ₂₃ H ₃₃ O ₄ N ₁ 387.2410, found 387.2406.

Example 5: (s) (-) - N- (6-Benzyloxy) hexyl-acryloyl-proline (17)

(Compound 16, 1.78 g, 4.58 mmol) was added to 50 mL of 50% methanol and 85% KOH (435 mg, 6.87 mmol) was added to (S) (-) - ethyl N- (6-benzyloxy) hexyl- acryloyl- mmol) was added and the mixture was stirred under reflux for 10 hours. The removal by distillation under reduced pressure, methanol and aqueous 7% hydrochloric acid (2 × 10ml) and washed with acidification and ethyl acetate (3 × 100ml) extracted with water (2 × 10ml), brine (2 × 10ml), the anhydrous MgSO ₄ , Filtered and evaporated under reduced pressure to give 1.65 g (100%) of (S) (-) - N- (benzyloxy) hexyl-acryloyl-proline (Compound 17) as a colorless oil.

_{[α] D = -75.50 (c} 1.34, CHCl 3).

IR (neat) 3300, 2950, 1740, 1720, 1600, 1460, 1280, 1180 cm ^-1 .

_{^{1 H-NMR (CDCl 3,}} 400MHz) δ 7.37-7.21 (m, 5H), 5.31 (s, 1H), 5.24 (s, 1H),

2H), 3.64-3.56 (m, 2H), 4.65 (s, 2H)

J = 6.6 Hz), 2.31 (t, 2H, J = 7.4 Hz), 2.09-1.88 (m, 4H)

1.64-1.57 (m, 2H), 1.49-1.42 (m, 2H), 1.40-1.34 (m, 4H).

MS, m / e 360 (M ^< + & gt ^; +1).

Example 6: Bromolactone (18)

(Compound 17, 1.6 g, 4.45 mmol) was added, and after the substitution with argon, DMF (20 ml) was added to dry DMF (20 ml) A solution of N-bromosuccinimide (1.58 g, 8.9 mmol) in anhydrous DMF (20 ml) was added, and the mixture was stirred at 0 ° C for 2 hours and at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (3 x 100 ml), washed with saturated NaHCO ₃ (2 x 15 ml), water (5 x 10 ml), brine (2 x 15 ml), dried over anhydrous MgSO ₄ , filtered, Chromatography (ethyl acetate: n-hexane = 1: 2) afforded 1.7 g (87%) of a colorless oil, bromoractone (Compound 18).

[?] _D = -66.91 (c 0.965, EtOH).

IR (neat) 2950, 1760, 1680, 1460, 1360 cm ^-1 .

_{^{1 H-NMR (CDCl 3,}} 400MHz) δ 7.29-7.21 (m, 5H), 4.45-4.43 (m, 1H), 4.41 (s, 2H),

3.80 (d, 1H, J = 11.2 Hz), 3.67-3.62 (m, 2H), 3.53

3.37 (t, 2H, J = 6.4 Hz), 2.43-2.40 (m, 2H), 2.11-1.86 (m, 4H)

1.72-1.64 (m, 2H), 1.54-1.48 (m, 2H), 1.32-1.21 (m, 4H).

MS, m / e 437 (M ^< ^{+ &} gt ^; ). HRMS calcd for C ₂₁ H ₂₈ O ₄ N ₁ Br ⁷⁹ 437.1202, found 437.1212.

Example 7: (S) (-) - Methyl 2-hydroxy-2- (6-hydroxy) hexyl-3-bromo-propionate (19)

The reaction mixture was extracted with ethyl acetate (2 x 50 ml), washed with brine (2 x 5 ml), dried over anhydrous MgSO 4 (2 x 5 ml) _The crude product was purified by column chromatography (ethyl acetate: n-hexane = 1: 2) to give 132 mg of a pale yellow oil, which was then reacted immediately with CH ₂ N ₂ at 0 ° C, (90%, 2 steps) of (S) (-) - methyl 2-hydroxy-2- (6-hydroxy) hexyl-3-bromo-propionate (Compound 19).

_{[α] D = -3.12 (c} 1.115, CHCl 3).

IR (neat) 3450, 2950, 1740, 1440, 1200 cm ^-1 .

¹ H-NMR (CDCl ₃ , 300 MHz)? 3.83 (s, 3H), 3.66 (d, 1H, J = 10.23 Hz)

J = 6.33), 3.47 (d, 1H, J = 10.23), 1.87-1.64 (m, 2H), 3.63 (t, 2H,

1.57-1.51 (m, 4H), 1.37-1.13 (m, 4H).

¹³ C-NMR (CDCl ₃ , 100 MHz)? 23.84, 25.40, 29.21, 32.48, 37.27, 39.65, 53.19, 62.81, 77.24, 173.98.

MS, m / e 283 (M ^< ^{+ &} gt ^; ).

Example 8: (R) (+) - Ethyl 2- (6-hydroxy) hexyl-2-oxiranecarboxylate (20)

(Compound 19, 130 mg, 1.459 mmol) was dissolved in 5 ml of anhydrous ethanol, to which was added anhydrous K ₂ (2-hydroxy-2- CO ₃ (63.4 mg, 0.459 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure to remove the ethanol, extracted with ethyl acetate (50 ml), washed with brine (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated under reduced pressure, and subjected to column chromatography (ethyl acetate: 1) to obtain 97 mg (98%) of (R) (+) - ethyl 2- (6-hydroxy) hexyl-2-oxirane- carboxylate (Compound 20) as a colorless oil.

_{[α] D = + 10.60 (} c 0.515, CHCl 3).

IR (neat) 3450, 2950, 1740 cm < ^{-1 &} gt ;.

¹ H-NMR (CDCl ₃ , 300 MHz)? 4.23 (dq, 2H, J = 4.14, 2.94 Hz)

3.64 (t, 2H, J = 6.33 Hz), 3.02 (d, 1H, J = 5.85 Hz)

2.13-2.08 (m, 2H), 1.70-1.36 (m, 8H), 1.29 (t, 3H, J = 7.065Hz).

¹³ C-NMR (CDCl ₃ , 100 MHz)? 14.08, 24.68, 25.44, 29.20, 31.10, 32.52, 51.81, 56.99, 61.56, 62.82, 170.41.

MS, m / e 217 (M ^< + & gt ^; +1). _{HRMS calcd for C 11 H 21 O} 4 (M + +1) 217.1440, found 217.1445.

Example 9: (R) (+) - Ethyl 2- [6- (2-thiophenemethoxy) hexyl] oxirane-

(Compound 20, 17 mg, 0.0787 mmol) and 2-thiophenemethanol (8.98 mg, 0.0787 mmol) were added to the above obtained (R) (+) - ethyl 2- ) In 1 ml of dry methylene chloride was added dimethyl sulfate (0.00744 ml, 0.0787 mmol) at 0 占 폚 and stirred for 5 hours. The reaction solution was evaporated under reduced pressure to remove methylene chloride and the residue was purified by column chromatography (ethyl acetate: n-hexane = 1: 10) to give a colorless oil (R) (+) - ethyl 2- [6- Methoxy) hexyl] oxirane-2-carboxylate (Compound 21) 13.5 (55%).

_{[α] D = + 4.36 (} c 0.275, CHCl 3).

IR (neat) 2950, 2880, 1740, 1460, 1380, 1200, 1100 cm ^-1 .

_{^{1 H-NMR (CDCl 3,}} 300MHz) δ 7.28-7.26 (m, 1H), 6.98-6.94 (m, 2H), 4.65 (s, 2H),

J = 7.08, 3.18 Hz), 3.46 (t, 2H, J = 6.585 Hz), 4.21 (dq, 2H)

(D, 1H, J = 5.85Hz), 2.09-2.01 (m, 2H), 3.06

1.70-1.34 (m, 8H), 1.28 (t, 3H, J = 7.05Hz).

MS, m / e 312 (M < ^{+ &} gt ^; ).

Claims (6)

A compound of the following general formula (1) or a pharmaceutically acceptable salt thereof; In the above formula, A represents a radical represented by the following general formulas (2), (3) and (4) (Wherein, R ₁ represents a lower alkyl group, R ₃ ~R ₁₀ is a hydrogen, a halogen, an alkoxy group, a lower alkyl group, a hydroxy group, an alkenyl group, an alkynyl group, a cyano group, or an amino group, X represents oxygen or sulfur , B each independently represents nitrogen or carbon, and n has a value of n = 0, 1, or 2.) (R) (+) - Ethyl 2- (6-hydroxy) hexyl-2-oxiranecarboxylate (Compound 20). Wherein the oxirane carboxylic acid derivative of the general formula (1) is obtained by subjecting the compound (20) to an ether or ether reaction with A-H. A process for producing an oxiranecarboxylic acid derivative, which comprises hydrolyzing a compound (18) and subjecting the compound to an esterification reaction to obtain a compound (19) and treating the compound (19) with a base. Compound (15) is subjected to an amidation reaction with (S) (-) - ethyl proprinate as an auxiliary agent to give compound (16), which is hydrolyzed to give compound (17) (18) is obtained by imidobromochromating an imidazole compound. Benzylation reaction of compound (12) to obtain compound (13), followed by the Wittig reaction to synthesize compound (14) and hydrolysis thereof to obtain compound (15) Lt; / RTI >