WO2021210920A1 - Method for producing ramelteon, and intermediate compound used for same - Google Patents

Abstract

The present invention provides: a novel method for producing Ramelteon; and an intermediate compound used for the production method. The production method according to the present invention is cost-effective, and can be used to produce Ramelteon under relatively mild conditions.

Description

Method for preparing ramelteon and intermediate compound used in such method

This application claims priority based on Korean Patent Application No. 10-2020-0046248 filed on April 16, 2020, and all contents disclosed in the specification and drawings of the application are incorporated herein by reference.

The present invention relates to a method for producing a ramelteon. The present invention also relates to novel intermediate compounds for use in the preparation of ramelteon.

Ramelteon is a medicinal ingredient approved for the treatment of chronic insomnia. Most of the Ramelteon processes are chiral reduction by metal catalysts of double bonds. A typical process is as follows, and so far, it is known that the chiral reduction process using such a metal catalyst is the most effective process.

However, the chiral reduction method using the metal catalyst is a process that requires a high-pressure hydrogen reaction of about 50 atmospheres, and has a disadvantage in that it may be limited in mass production process.

In addition, PCT patent WO2008/151170 discloses a method of optically resolving a non-optically active amine compound using chiral amine or chiral acid without chiral reduction as in the following process.

However, in the case of the above method, in addition to the R-isomer obtained in the resolution process, the loss of the S-isomer having the opposite optical activity is inevitable, so the economic feasibility is inferior compared to the existing patented process using the chiral reduction process.

Therefore, the problem to be solved by the present invention is to provide a method for manufacturing ramelteon that is economical and can be performed under mild conditions. Another problem to be solved by the present invention is to provide an intermediate compound that can be used for the preparation of ramelteon.

In order to solve the above problems, the present invention provides a method for producing a ramelteon (ramelteon), characterized in that using the (R) -isomer of the following formula (1).

[Formula 1]

In particular, the present invention is a racemic compound of Formula 1 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-carboxylic acid by optical resolution (optical resolution) of Formula 1 ( R) - obtaining the isomer.

Preferably, the preparation method of the present invention provides a preparation method characterized in that the (S)-isomer of Formula 1 is recovered, racemized, and reused.

The production method of the present invention can not only react under mild conditions, but also economical production can be possible by performing chiral separation at the beginning of the production step. In addition, the production method of the present invention is economical by using the (S)-isomer of formula (1) again. The compound of Formula 1 of the present invention has a very high acidity of H, which is connected to the carbon atom to which the COOH group is connected, so that there is no need to use a relatively strong base in the racemization process, and consequently, there is a significant risk of impurities occurring during the racemization process. as low as

Preferably, in the preparation method of the present invention, the optical splitting is performed by forming a chiral amine salt, and as a chiral amine, (S)-phenylethylamine, L-(-)- α-Amino-ε-caprolactam hydrochloride, (S)-(-)-1-Amino-2-propanol, L-Aspartic acid, (S)-N-Benzyl-1-(1-naphthyl)ethylamine hydrochloride, (+ )-Bis[(R)-1-phenylethyl]amine hydrochloride, (+)-Cinchonine, (R)-α-Methyl-4-nitrobenzylamine hydrochloride or (S)-(-)-1-(2-Naphthyl)ethylamine This can be used. More preferably, the chiral amine is (S)-phenylethylamine.

That is, the preparation method of the present invention uses the difference in solubility between the (S)-isomer chiral amine salt and (R)-isomer chiral amine salt produced by reacting the compound of Formula 1 with a chiral amine to separate them, and then (S)- The isomer chiral amine salt is racemized again to obtain a compound of formula (1).

Therefore, preferably, the ramelteon production method of the present invention is a racemic compound 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-carboxylic acid optical resolution (optical resolution) to obtain a (R)-isomer of Formula 1 and racemizing the separated (S)-isomer of Formula 1 again to obtain a compound of Formula 1, wherein the obtained compound of Formula 1 is used in the manufacturing method of the invention. This can be expressed as a reaction equation as follows.

[Scheme 1]

In one aspect of the present invention, the preparation method of the present invention includes the step of re-using the chiral amine salt of the (S)-isomer of Formula 1 recovered during the optical resolution process by racemizing it.

In one aspect of the present invention, the chiral amine salt of the (S)-isomer of Formula 1 is racemized under a base, and the base includes sodium hydroxide (NaOH), potassium hydroxide (KOH), and potassium tert-butoxide (KOtBu). , NaOMe (sodium methoxide) or a mixture thereof may be used.

In one aspect of the present invention, the production method of the present invention is a racemic compound 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-carboxylic acid optical resolution (optical resolution) to obtain an (R)-isomer of Formula 1; re-racemizing the separated (S)-isomer of Formula 1 to obtain a compound of Formula 1; and a process of preparing the compound of Formula 3 as the (S)-isomer of Formula 1 prepared by Scheme 1. This reaction is shown in Scheme 2 below.

[Formula 1]

[Formula 3]

[Scheme 2]

In one aspect of the present invention, in the preparation method of the present invention, the compound of Formula 3 is (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8 -yl)ethan-1-amine (TIFEA) or a salt thereof comprises the step of preparing, and then further reacting with propionyl chloride to prepare the target compound of the present invention, ramelteon.

In one aspect of the present invention, the preparation method of the present invention includes the steps represented by Scheme 3 as follows.

[Scheme 3]

In one aspect of the present invention, the TIFEA compound or a salt thereof used in Scheme 3 may be prepared from TIFM using, for example, the method shown in Scheme 4 below.

[Scheme 4]

In one embodiment of the present invention, the compound of Formula 1 can be prepared by reacting 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-carbonitrile (TIFN) with a base. In addition, as the base, NaOH (sodium hydroxide), KOH (potassium hydroxide), LiOH (lithium hydroxide), Ba(OH) ₂ (Barium Hydroxide) or a mixture thereof may be used. For example, it may be prepared as in Scheme 5 below using NaOH.

[Scheme 5]

In one aspect of the present invention, 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-carbonitrile (TIFN) is prepared using methods known in the art. can be manufactured. For example, in the preparation method of the present invention, TIFN is prepared by the method shown in Scheme 6 below.

[Scheme 6]

The present invention also provides a compound of Formula 1, which can be usefully used in the preparation of ramelteon.

[Formula 1]

The present invention also provides (R)-isomeric forms and/or (S)-isomeric forms of the compound of Formula 1 above. According to the preparation method of the present invention, these isomerically pure compounds can be usefully used in the preparation of ramelteon.

The isomeric compounds referred to in the present invention exist as isomerically pure compounds. For example, substantially free of other stereoisomers (eg, at least 80% ee, at least 85% ee, at least 90% ee, at least 95% ee, at least 97% ee, or at least 99% ee). do.

The present invention also provides a chiral amine salt compound of the following formula (2), which can be usefully used in the preparation of ramelteon.

[Formula 2]

The chiral amine salt is (S)-phenylethylamine, L-(-)-α-Amino-ε-caprolactam hydrochloride, (S)-(-)-1-Amino-2-propanol, L-Aspartic acid, (S )-N-Benzyl-1-(1-naphthyl)ethylamine hydrochloride, (+)-Bis[(R)-1-phenylethyl]amine hydrochloride, (+)-Cinchonine, (R)-α-Methyl-4-nitrobenzylamine It is formed from hydrochloride or (S)-(-)-1-(2-Naphthyl)ethylamine.

In one aspect of the present invention, the present invention also provides an (R)-isomer compound represented by the following formula (3). The compound of Formula 3 below may be usefully used in the preparation of ramelteon.

[Formula 3]

The production method of the present invention can be used again by racemizing the (S)-isomer that is not used after optical resolution, and the yield improvement can be expected because the process is simple. In addition, the production method of the present invention can be carried out under relatively mild conditions.

Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art to which the present invention pertains.

Compound TIFO preparation (NaBH ₄ )

Sodium borohydride (43.4 g, 1.15 mol) was added to a solution of the compound TIF (manufactured by Reliable Chem, China, 200 g, 1.15 mmol) in ethanol (900 mL) and tetrahydrofuran (300 mL) and stirred at 70 °C for 2 hours. When the reaction is complete, it is cooled to 5-10 ℃, and concentrated hydrochloric acid (113 g, 1.15 mol) is added. The reaction was diluted with water (1.6 L) and extracted with dichloromethane (800 mL, 400 mL). The combined organic layer was washed with a saturated aqueous sodium bicarbonate solution (600 mL), dried over magnesium sulfate, and then concentrated by filtration. Toluene (200 mL) was added to the concentrated residue, the temperature was raised to 78~83 ℃, and heptane (1.6 L) was added. The reaction mass was cooled slowly to 3-6 °C, and the resulting crystals were filtered to obtain compound TIFO (198 g, 1.12 mol).

Preparation of compound TIFCl (PCl ₃ )

Pyridine (4.19 g, 53.0 mmol) and dichloromethane (933 mL) were added to the compound TIFO (189 g, 1.06 mol) and cooled to -15 ~ -10 ℃. Phosphorous trichloride (87.3 g, 636 mmol) was slowly added, and the mixture was further stirred at -15 to -10 °C for 6 hours. When the reaction was completed, sodium carbonate (5wt.% in water, 1.87 L) was slowly added and the temperature was raised to room temperature, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (373 mL), and the combined organic layer was treated with magnesium sulfate to obtain the compound TIFCl (crude quant.).

Preparation of compound TIFN (NaCN)

Sodium cyanide (104 g, 2.12 mol) was added to a solution of the compound TIFCl and dimethyl sulfoxide (1.03 L) at room temperature, and the temperature was raised to 30-35 ℃ and stirred for 4 hours. When the reaction was completed, it was diluted with water (2.06 L) and extracted with ethyl acetate (824 mL, 412 mL). The combined organic layer was washed with sodium chloride (26wt.% in water, 1.03 L x 2) and treated with magnesium sulfate to obtain a compound TIFN (crude quant.).

Compound TIFC preparation (base, e.g. NaOH)

Sodium hydroxide (127 g, 3.18 mol) was added to a mixture of the compound TIFN, water (970 mL), and dimethyl sulfoxide (39 mL), and the mixture was stirred at 100-102 °C for 16 hours. When the reaction was completed, it was cooled to room temperature and washed with methyl tert -butyl ether (388 mL x 2). Activated carbon (29 g) was added to the obtained aqueous layer, stirred for 30 minutes, and then filtered. The filtrate was acidified by adding hydrochloric acid (353 g, 3.58 mol), and the resulting crystal was filtered to obtain the compound TIFC (146 g, 0.715 mol).

Preparation of compound (R)-TIFC·(S)-PEA salt (Resolution)

Acetone (3.5 L) was added to the compound TIFC (145 g, 0.710 mol), and the temperature was raised to 50-55 °C. (S)-Phenylethyl amine (86.0 g, 0.71 mol) was added, stirred for 30 minutes, and then slowly cooled to 5-10 °C. The precipitated solid was filtered, and the crystallization process was repeated by adding acetone (2.0 L) to the filtered solid. The precipitated solid was filtered and dried to obtain compound (R)-TIFC·(S)-PEA salt (89.5 g, 0.275 mol, optical purity > 98.5%).

Compound (R)-TIFC preparation (de-salting)

Water (312 mL), dichloromethane (520 mL), tetrahydrofuran (144 mL), and hydrochloric acid (100 g) were added to compound (R)-TIFC·(S)-PEA salt (166 g, 0.509 mol) for 30 minutes stirred for a while. After standing, the organic layer was separated and treated with magnesium sulfate to obtain compound (R)-TIFC (103 g, 0.503 mol).

Compound TIFC Preparation (Racemize) (Base, eg NaOH)

The filtrate of the above resolution process was collected and concentrated, and water (810 mL) and sodium hydroxide (59.7 g, 1.49 mol) were added and stirred for 30 minutes. The aqueous solution was washed with methyl tert -butyl ether (324 mL) and stirred. Cool the reaction and wash with methyl tert -butyl ether (230 mL x 2). The aqueous layer was treated with activated carbon (15.0 g) and acidified to recover compound TIFC (89.1 g, 0.436 mol).

Compound TIFM preparation (LAH)

A solution of compound (R)-TIFC (102 g, 0.499 mol) and tetrahydrofuran (510 mL) was slowly added to a mixture of lithium aluminum hydride (37.9 g, 0.999 mol) and tetrahydrofuran (510 mL) and heated at 65 to 68 °C for 3 stirred for hours. When the reaction is complete, cool and add water (40 mL), 15% sodium hydroxide (aqueous solution, 40 mL), and water (120 mL) in this order. The reaction was stirred for 6 hours and the resulting solid was filtered. The filtrate was concentrated, dichloromethane (510 mL) was added to the concentrated residue, washed with a dilute aqueous hydrochloric acid solution, and treated with magnesium sulfate to obtain a compound TIFM (crude quant.).

Preparation of compound TIFMM (MsCl)

A mixture of the compound TIFM, Et ₃ N (75.7 g, 0.748 mol), and dichloromethane (475 mL) was cooled to 0-5 °C, and methanesulfonyl chloride (74.3 g, 0.649 mol) was slowly added thereto. When the input was completed, the reaction was stirred at 5-10 °C for 30 minutes, heated to room temperature, and stirred for an additional 2 hours. When the reaction was completed, it was cooled again to 0-5 °C, and water (475 mL) was slowly added thereto. After stirring the mixture for 30 minutes, the organic layer was separated. The aqueous layer was further extracted with dichloromethane (190 mL) and combined with the previous organic layer. The combined organic layer was treated with magnesium sulfate to obtain a compound TIFMM (crude quant.).

Compound TIFA preparation (NaCN)

Sodium cyanide (48.9 g, 0.998 mol) was added to a solution of the compound TIFMM and dimethyl sulfoxide (670 mL), and the temperature was raised to 55 ~ 60 ℃ and stirred. When the reaction was completed, it was diluted with water (1.40 L) and extracted with ethyl acetate (540 mL, 270 mL). The combined organic layer was washed with sodium chloride (26wt.% in water, 670 mL x 2) and treated with magnesium sulfate to obtain a compound TIFA (crude quant.).

Preparation of compound TIFEA (NaBH ₄ and BF ₃ )

0-5 solution of compound TIFA and tetrahydrofuran (500 mL) Cool to ℃ and add sodium borohydride (22.7 g, 0.600 mol). 10 to 15 reactants The temperature was raised to ℃ and boron trifluoride tetrahydrofuran complex (112 g, 0.801 mol) was added for 30 minutes. When the input is completed, stir at the same temperature for 30 minutes and then 60~65 The temperature was raised to ℃ and further stirred for 12 hours. When the reaction was completed, 5% hydrochloric acid (aqueous solution, 110 mL) was added and stirred at 60-65 °C for 8 hours. Then, 30% sodium hydroxide (aqueous solution, 320 mL) was added, and the mixture was further stirred for 12 hours and then cooled to room temperature. Then, the organic layer was separated and concentrated. Toluene (1.0 L) was added to the concentrated residue and washed with sodium chloride (26wt.% in water, 300 mL). After adding hydrochloric acid (167 g, 1.70 mol) to the obtained organic layer, the mixture was stirred for 30 minutes and concentrated. Acetone (400 mL) was added to the concentrated residue, and after heating and stirring, it was cooled. The resulting solid was filtered, and ethanol (50 mL) and methyl tert- butyl ether (500 mL) were added to the filtered solid. The reaction product was warmed and stirred, cooled, and the resulting solid was filtered to obtain the compound TIFEA (102 g, 0.425 mol).

Manufactured by Ramelteon (Propionyl chloride)

Tetrahydrofuran (225 mL) and water (315 mL) were added to the compound TIFEA (90.0 g, 0.375 mol), and 30% sodium hydroxide (aqueous solution, 85.0 mL, 0.848 mol) was added. The reaction solution was cooled to 10 ~ 15 ℃, propionyl chloride (40.0 g, 0.432 mol) was slowly added. When the input was completed, the mixture was further stirred at 15-25 °C for 1 hour. After adding water (720 mL) to the reaction solution, it was cooled to 0-5 °C, and the resulting solid was filtered. The obtained solid was recrystallized and purified in a mixed solvent of ethanol and water to obtain Ramelteon (87.6 g, 0.338 mol).

Claims (14)

1. A compound of Formula 1 below.

   [Formula 1]

   
2. The compound of claim 1 , wherein the compound is in the (R)-isomeric form.
3. The compound of claim 1 , wherein the compound is in the (S)-isomeric form.
4. A chiral amine salt compound of Formula 2 below.

   [Formula 2]

   
5. 5. The method of claim 4, wherein the chiral amine is (S)-phenylethylamine, L-(-)-α-Amino-ε-caprolactam hydrochloride, ( S )-(-)-1-Amino-2- propanol, L-Aspartic acid, ( S) - N -Benzyl-1- (1-naphthyl) ethylamine hydrochloride, (+) - Bis [(R) -1-phenylethyl] amine hydrochloride, (+) - Cinchonine, (R )-α-Methyl-4-nitrobenzylamine hydrochloride or ( S )-(-)-1-(2-Naphthyl)ethylamine.
6. (R)-isomer compound of formula (3).

   [Formula 3]

   
7. A method for producing a ramelteon, characterized in that using the (R)-isomer of the following formula (1).

   [Formula 1]

   
8. According to claim 7, wherein the method is a racemic compound 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-carboxylic acid by optical resolution (optical resolution) of Formula 1 (R) -A method of preparation comprising the step of obtaining an isomer.
9. The method of claim 8, wherein the optical resolution is performed by forming a chiral amine salt.
10. The method of claim 9, wherein the chiral amine is (S)-phenylethylamine, L-(-)-α-Amino-ε-caprolactam hydrochloride, ( S )-(-)-1-Amino-2- propanol, L-Aspartic acid, ( S) - N -Benzyl-1- (1-naphthyl) ethylamine hydrochloride, (+) - Bis [(R) -1-phenylethyl] amine hydrochloride, (+) - Cinchonine, (R )-α-Methyl-4-nitrobenzylamine hydrochloride or ( S )-(-)-1-(2-Naphthyl)ethylamine.
11. The method according to claim 9, wherein the method uses the chiral amine salt of the (S)-isomer of formula (1) recovered during the optical resolution process by racemization and reuse.
12. The method according to claim 11, wherein the racemization is carried out under a base.
13. The method according to claim 12, wherein the base is sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium tert-butoxide (KOtBu), sodium methoxide (NaOMe), or a mixture thereof.
14. The method according to any one of claims 7 to 13, wherein the method comprises preparing the compound of formula (3) as the (S)-isomer of formula (1).

    [Formula 1]

    

    [Formula 3]