Preparation method of ramelteon

Abstract

The invention discloses a preparation method of ramelteon. The preparation method comprises the following steps: 1, reacting tetrahydrofuran, sodium hydroxide and diethyl cyanomethylphosphonate to prepare a ylide solution, and dropwise adding the ylide solution into a solution of an initial raw material 1 to prepare an intermediate 1; 2, reducing the intermediate 1 through sodium borohydride under the action of nickel chloride and di-tert-butyl dicarbonate to obtain an intermediate 2; 3, performing hydrochloric acid deprotection on the intermediate 2 in a methanol solution to obtain an intermediate 3; 4, preparing an intermediate 4 through chiral resolution and recrystallization; 4, the intermediate 4 is subjected to propionylation under the alkaline condition, and ramelteon is obtained. According to the method, the intermediate 3 is resolved by using the organic acid which is low in price and easy to obtain in the market. The resolution process is simple, convenient and safe to operate and suitable for industrial production, the prepared ramelteon is high in yield and high in optical purity, and the market competitiveness of the ramelteon is enhanced.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical manufacturing, in particular to a method for preparing ramelteon. Background Art

[0002]

[0003] Ramelteon (RozeremTM), with a specification of 8 mg and a maximum recommended daily dose of 8 mg, is chemically named (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl 1-propionamide, and contains a chiral center. The molecular formula is: C 16 H 21 NO2, molecular weight: 259.34, is readily soluble in organic solvents such as methanol, ethanol, 1-octanol, acetonitrile, and dimethyl sulfoxide, and very slightly soluble in water. It is a melatonin receptor agonist developed by Takeda Pharmaceuticals of Japan. It was approved for marketing by the US FDA on July 22, 2005, as an oral hypnotic drug under the trade name Rozerem. It was launched in Japan in 2008 and is not yet available in the EU or China. It is also the first melatonin receptor agonist used clinically to treat insomnia, primarily for the treatment of difficulty falling asleep, and also has demonstrated efficacy for chronic and short-term insomnia. Ramelteon is the first prescription insomnia treatment with a novel mechanism of action in nearly 35 years.

[0004] The main structure of ramelteonide is the indenofuranethylamine part, followed by the propionylation part. According to literature reports, the difference in its synthesis process lies in the construction of the indenofuranethylamine and propionylation parts. There are mainly the following methods:

[0005] Synthesis Method 1: Japanese Patent JP 11140073 reports the asymmetric reduction of (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine hydrochloride using Ru2Cl4[(R)-BINAP]2NEt3 as a chiral catalyst under a hydrogen pressure of 100 atm to obtain (S)-2-(1,6,7,8-tetrahydro-2H(1,2,6,7-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethanamine hydrochloride with an ee value of 88.88%. The product was recrystallized twice from a mixed solvent of methanol and acetone to obtain a product with an ee value of 100%. The total yield of the reduction and recrystallization was 68%. The reaction formula is as follows:

[0006]

[0007] Synthesis Method 2: Patent CN106588840 uses 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one as the starting material. Ramelteon is obtained through a Wittig-Horner reaction, followed by reduction, amino protection, amino deprotection under acidic conditions, hydrogenation, chiral resolution, and propionylation. This process involves six complex steps, using S-ibuprofen as the resolving agent. The purity and yield of this resolution range from 28-34%. Summary of the Invention

[0008] In response to the shortcomings of the prior art, the present invention provides a method for preparing ramelteon. This method provides a mild reaction, high yield, and high-optical-purity ramelteon preparation method. It also avoids the use of expensive chiral homogeneous ruthenium catalysts and eliminates the need for high-pressure hydrogenation, thus avoiding the high requirements for production equipment and safety issues encountered in actual production.

[0009] The present invention provides the following technical solutions:

[0010] 1. A method for preparing ramelteon, characterized in that it is carried out according to the following steps:

[0011] 1) Tetrahydrofuran, sodium hydroxide, and diethyl cyanomethylphosphonate are reacted in sequence to prepare a ylide solution, which is then added dropwise to a tetrahydrofuran solution of the starting material 1 to prepare intermediate 1. After completion of the reaction, water is added to quench the reaction, the mixture is filtered, and the filter cake is dried to obtain intermediate 1;

[0012]

[0013] The mass ratio of the starting material 1: sodium hydroxide: diethyl cyanomethylphosphonate is 1:1.5:2.0;

[0014] 2) Intermediate 1 is reduced with sodium borohydride in the presence of nickel chloride and di-tert-butyl dicarbonate in methanol to obtain intermediate 2;

[0015]

[0016] The mass ratio of the intermediate 1: nickel chloride: di-tert-butyl dicarbonate: sodium borohydride is 1:1.5:1:2; the nickel chloride is anhydrous nickel chloride;

[0017] 3) Intermediate 2 is deprotected with hydrochloric acid in methanol solution to obtain intermediate 3;

[0018]

[0019] The mass volume ratio of the intermediate 1:methanol:hydrochloric acid is 1:8:3;

[0020] 4) Intermediate 3 reacts with a chiral resolution agent and then is purified by recrystallization solvent to obtain intermediate 4;

[0021]

[0022] The mass ratio of the intermediate 3 to the chiral resolution agent is 1:0.22-0.44;

[0023] The recrystallization solvent is methanol, ethanol, or isopropanol;

[0024] 5) intermediate 4 is propionylated under alkaline conditions to obtain ramelteon;

[0025]

[0026] The alkaline reagent is sodium hydroxide, potassium hydroxide, or potassium carbonate;

[0027] The mass ratio of the intermediate 4: alkaline reagent: propionic anhydride is 1:1.27:0.52;

[0028] The hydrochloric acid in step (3) has a content of 20%-36%.

[0029] The chiral resolution reagent in step (4) is D-lactic acid.

[0030] The mass ratio of the intermediate 3 in step (4) to the chiral resolution reagent is 1:0.33.

[0031] The recrystallization solvent in step (4) is methanol.

[0032] The volume mass ratio of the intermediate in step (4) to the recrystallization solvent in step (3) is 1:5-15.

[0033] The volume-to-mass ratio of the intermediate 3 in step (4) to the recrystallization solvent is 1:10.

[0034] The ramelteon prepared by the method is used for improving product yield and optical purity.

[0035] In order to improve the optical purity of the product, the present invention focuses on the selection of the process of the resolution step, and screens a large number of chiral resolution reagents, such as D-lactic acid, L-(-)-dibenzoyltartaric acid, L-(-)-di-p-toluoyltartaric acid, L-(-)-camphorsulfonic acid and other organic acids, among which D-lactic acid has the best resolution effect. The ratio of the intermediate 3 in step (4): the chiral resolution reagent and the solvent for recrystallization are further screened to obtain the intermediate 4 with higher optical purity and yield.

[0036] Compared with the prior art, the preparation method of ramelteon disclosed in the present invention has the following beneficial effects:

[0037] (1) The preparation method of ramelteon improves the yield of the resolution (up to 48%, while most literature reports are 28-34%, and a few reports have a yield of about 30%, but the operation is more complicated, and the process is more dangerous and complicated) by using the preferred optically pure organic acid D-lactic acid in step 4, thereby enhancing the market competitiveness of the product.

[0038] (2) The impurity content of ramelteon is effectively controlled, with the single impurity controlled below 0.2%, the total impurity controlled at 0.33%, the optical purity being 100%, and the resolution yield being above 48%. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the optical purity spectrum of ramelteon in Example 1;

[0040] Figure 2 is the H NMR spectrum of ramelteon of Example 1;

[0041] Figure 3 This is the NMR carbon spectrum of ramelteon of Example 1. DETAILED DESCRIPTION

[0042] To make the purpose, technical solutions and advantages of this application clearer, the technical solutions of this application will be clearly and completely described below in conjunction with the specific embodiments of this application. Obviously, the embodiments described are only a part of the embodiments of this application, rather than all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of this application. The raw materials and reagents used in the present invention are all commercially available.

[0043] Example 1

[0044] 1) Add 375ml of THF and 112.5g of sodium hydroxide to the reaction flask. Turn on the stirring, control the temperature at 25-35°C and slowly add 150.0g of diethyl cyanomethyl phosphate. After the addition is completed, control the temperature at 25-35°C and react for 1 hour to obtain a clarified ylide reagent. Dissolve 75.0g of the starting material 1 in 375ml of THF, cool to 0-10°C, control the temperature at 0-10°C and start adding the ylide reagent dropwise. After the addition is complete, stir at 0-10°C for 1h. Add 375ml of water to the system at a temperature below 25°C to quench the reaction, filter the precipitated solid, rinse the filter cake with a large amount of water, and bake the material at 50°C to constant weight to obtain 82.5g of the intermediate 1 as a white solid, with a yield of 96.67% and a purity of 99.621%.

[0045] 2) Add 82.5g of compound intermediate 1 to the reaction flask, then add 533ml of methanol, move the reaction to an ice-salt bath, cool to 0°C, add 123.75g of nickel chloride, then add 82.5g of di-tert-butyl dicarbonate, and slowly add 165g of sodium borohydride in batches while controlling the temperature below 10°C. The reaction is exothermic and produces gas, and the reaction solution quickly turns black. After the addition of sodium borohydride, ventilate three times under a N2 device, and the reaction is slowly warmed to room temperature for 12 hours. The reaction is complete. Add ethyl acetate (666mL) and water (333mL), then filter with diatomaceous earth, wash the filter cake with ethyl acetate (666mL), collect all the filtrate, add saturated brine (33mL) to separate the organic layer, wash twice with water (333mL), and dry and concentrate the organic layer to obtain a yellow oil. Without purification, proceed directly to the next step.

[0046] 3) Add HCl (247.5 mL) to a three-necked flask. In another flask, dissolve Intermediate 2 from the previous step in methanol (660 mL). Add the resulting mixture to the HCl in an ice-water bath, maintaining the temperature below 25°C, and react for half an hour. Add water and ethyl acetate (950 mL), separate the aqueous layer, and concentrate it to yield 53.33 g of Intermediate 3 as a pale yellow solid. Proceed directly to the next step without purification.

[0047] 4) Weigh 10g of Intermediate 3 and dissolve it in 20ml of methanol. Weigh 3.3g of D-lactic acid and dissolve it in 80ml of methanol. Heat the methanol solution of D-lactic acid to 60-65°C and begin adding the methanol solution of Intermediate 3 dropwise. Stir at 60-65°C for 2 hours, then cool to 0-10°C and keep warm for 2 hours. Filter with suction, rinse the filter cake with a small amount of methanol, and bake at 50°C to constant weight. The resulting solid is recrystallized from 100ml of methanol and baked at 50°C to constant weight to obtain 6.93g of Intermediate 4 as a white solid. Yield: 48%, purity: 99.3%, chiral purity: 99.3%.

[0048] 5) In a reaction flask, 6.93 g of intermediate 4, 25 ml of water, and 25 ml of tetrahydrofuran were weighed and cooled to 0-10°C. 8.80 g of solid sodium hydroxide was added while slowly controlling the temperature at 0-10°C. After the addition was complete, 3.60 g of propionic anhydride was added while continuing to control the temperature at 0-10°C. The reaction was continued for 1 hour. After the reaction was warmed to room temperature, 20 ml of dichloromethane was added while stirring continuously. The liquids were separated, the aqueous phase was discarded, and the dichloromethane phase was washed with saturated ammonium chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 6.03 g of the finished product, ramelteon, as a white solid. Yield: 98.5%, purity: 99.9%, optical purity: 100%. 1HNMR (600MHz, CDCl3) δ6.97(d,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),5.50(s,1H),4.60-4.51(m,2H),3.37-3.03(m,5H),2.91(dt,J=14.5,7.2Hz, 1H),2.84-2.70(m,1H),2.39-2.24(m,1H),2.18(t,J=7.6Hz,2H),2.10- 1.96(m,1H),1.8-1.81(m,1H),1.70-1.57(m,1H),1.15(t,J=7.6Hz,3H). 13 CNMR (600MHz, CDCl3) δ173.69,159.39,143.11,135.80,123.40,122.18,107.44,71.17,42.20,38.04,33.50,31.74,30.69,29.77,28.59,9.89.

[0049] Ramelteon prepared according to the above formula and process has an optical purity of 100%, a resolution yield of 48%, and an overall yield of 45.7%. It is suitable for treating most insomnia patients and has a low cost, making it suitable for widespread production and preparation to enhance the competitiveness of enterprises.

[0050] The following is an example of preparing the finished product ramelteon from intermediate 3.

[0051] Example 2

[0052] 1) Weigh 10g of Intermediate 3 and dissolve it in 20ml of methanol. Weigh 2.2g of D-lactic acid and dissolve it in 80ml of methanol. Heat the methanol solution of D-lactic acid to 60-65°C and begin adding the methanol solution of Intermediate 3 dropwise. Stir at 60-65°C for 2 hours, then cool to 0-10°C and hold at this temperature for 2 hours. Filter with suction, rinse the filter cake with a small amount of methanol, and bake at 50°C to constant weight. The resulting solid is recrystallized from 100ml of methanol and baked at 50°C to constant weight to obtain 4.62g of Intermediate 4 as a white solid. Yield: 32.0%, purity: 99.1%, chiral purity: 99.0%.

[0053] 2) In a reaction flask, 4.62 g of intermediate 4, 18 ml of water, and 18 ml of tetrahydrofuran were weighed and cooled to 0-10°C. 5.87 g of solid sodium hydroxide was added while slowly controlling the temperature at 0-10°C. After the addition was complete, 2.40 g of propionic anhydride was added while continuing to control the temperature at 0-10°C. The reaction was continued for 1 hour. After the reaction was warmed to room temperature, 14 ml of dichloromethane was added while stirring continuously. The liquids were separated, the aqueous phase was discarded, and the dichloromethane phase was washed with saturated ammonium chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 3.81 g of the finished product, ramelteon, as a white solid. Yield: 93.5%, purity: 99.4%, optical purity: 100%.

[0054] Ramelteon prepared according to the above formula and process has an optical purity of 100%, a resolution yield of 32.0%, and a total yield of 28.9%.

[0055] Example 3

[0056] 1) Weigh 10g of Intermediate 3 and dissolve it in 20ml of methanol. Weigh 4.4g of D-lactic acid and dissolve it in 80ml of methanol. Heat the methanol solution of D-lactic acid to 60-65°C and begin adding the methanol solution of Intermediate 3 dropwise. Stir at 60-65°C for 2 hours, then cool to 0-10°C and hold at this temperature for 2 hours. Filter with suction, rinse the filter cake with a small amount of methanol, and bake at 50°C to constant weight. The resulting solid is recrystallized from 100ml of methanol and baked at 50°C to constant weight to obtain 7.2g of Intermediate 4 as a white solid. Yield: 50%, purity: 99.3%, chiral purity: 89.0%.

[0057] 2) In a reaction flask, 7.2 g of intermediate 4, 28 ml of water, and 28 ml of tetrahydrofuran were weighed and cooled to 0-10°C. 9.14 g of solid sodium hydroxide was added slowly at 0-10°C. After the addition was complete, 3.74 g of propionic anhydride was added while continuing to control the temperature at 0-10°C. The reaction was continued for 1 hour. After the reaction was warmed to room temperature, 22 ml of dichloromethane was added with continuous stirring. The phases were separated, the aqueous phase was discarded, and the dichloromethane phase was washed with saturated ammonium chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 5.62 g of the finished product, ramelteon, as a white solid. The yield was 94%, the purity was 99.4%, and the optical purity was 96%.

[0058] The yield of chiral resolution using 0.44 mass ratio of D-lactic acid can reach 50%, but the optical purity of the resolved product is 89.0%, the optical purity of the final product is 96%, and the total yield of the route is 45.4%.

[0059] Example 4

[0060] 1) Weigh 10g of Intermediate 3 and dissolve it in 20ml of methanol. Weigh 3.3g of D-lactic acid and dissolve it in 80ml of methanol. Warm the methanol solution of D-lactic acid to 60-65°C and begin adding the methanol solution of Intermediate 3 dropwise. Stir at 60-65°C for 2 hours, then cool to 0-10°C and hold at this temperature for 2 hours. Filter with suction, rinse the filter cake with a small amount of methanol, and bake at 50°C to constant weight. The resulting solid is recrystallized from 50ml of methanol and baked at 50°C to constant weight to obtain 6.93g of Intermediate 4 as a white solid. Yield: 48%, purity: 99.2%, chiral purity: 93%.

[0061] 2) In a reaction flask, 6.93 g of intermediate 4, 27 ml of water, and 27 ml of tetrahydrofuran were weighed and cooled to 0-10°C. 8.80 g of solid sodium hydroxide was added while slowly controlling the temperature at 0-10°C. After the addition was complete, 3.60 g of propionic anhydride was added while continuing to control the temperature at 0-10°C. The reaction was continued for 1 hour. After the reaction was warmed to room temperature, 22 ml of dichloromethane was added while stirring continuously. The liquids were separated, the aqueous phase was discarded, and the dichloromethane phase was washed with saturated ammonium chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 5.94 g of the finished product, ramelteon, as a white solid. Yield: 97%, purity: 99.4%, optical purity: 95.2%.

[0062] The use of 5 vol methanol in chiral resolution gave a higher yield of 48%, but the optical purity of intermediate 4 was only 93%. The optical purity of the final product was 95.2%, and the total yield of the route was 45.0%.

[0063] Example 5

[0064] 1) Weigh 10g of Intermediate 3 and dissolve it in 20ml of methanol. Weigh 3.3g of D-lactic acid and dissolve it in 80ml of methanol. Warm the methanol solution of D-lactic acid to 60-65°C and begin adding the methanol solution of Intermediate 3 dropwise. Stir at 60-65°C for 2 hours, then cool to 0-10°C and hold for 2 hours. Filter with suction, rinse the filter cake with a small amount of methanol, and bake at 50°C to constant weight. The resulting solid is recrystallized from 150ml of methanol and baked at 50°C to constant weight to obtain 3.18g of Intermediate 4 as a white solid. Yield: 22%, purity: 99.8%, chiral purity: 100%.

[0065] 2) In a reaction flask, 3.18 g of intermediate 4, 12 ml of water, and 12 ml of tetrahydrofuran were weighed and cooled to 0-10°C. 4.04 g of solid sodium hydroxide was added slowly at 0-10°C. After the addition was complete, 1.65 g of propionic anhydride was added while continuing to control the temperature at 0-10°C. The reaction was continued for 1 hour. After the reaction was warmed to room temperature, 10 ml of dichloromethane was added with continuous stirring. The liquids were separated, the aqueous phase was discarded, and the dichloromethane phase was washed with saturated ammonium chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2.67 g of the finished product, ramelteon, as a white solid. Yield: 95%, purity: 99.9%, optical purity: 100%.

[0066] In the chiral separation, 15 vol of methanol intermediate 4 has an optical purity of 100%. If the optical purity of the final product is still 100%, the yield of the intermediate separation is only 22%, and the total yield of the route is only 20%.

[0067] Comparative Example

[0068] 1) Weigh 10g of intermediate 3 and dissolve it in 20ml of methanol. Weigh 9.13g of S-ibuprofen and dissolve it in 80ml of methanol. Heat the methanol solution of S-ibuprofen to 60-65°C and begin adding the methanol solution of intermediate 3 dropwise. Stir at 60-65°C for 2 hours, then cool to 0-10°C and keep warm for 2 hours. Filter with suction, rinse the filter cake with a small amount of methanol, and bake at 50°C to constant weight. The resulting solid is recrystallized from 100ml of methanol and baked at 50°C to constant weight to obtain 4.20g of a white solid. Yield: 20.82%, purity: 99.3%, chiral purity: 88.05%.

[0069] 2) In a reaction flask, 4.20 g of intermediate 4, 16 ml of water, and 16 ml of tetrahydrofuran were weighed and cooled to 0-10°C. 5.26 g of solid sodium hydroxide was added while slowly controlling the temperature at 0-10°C. After the addition was complete, 2.15 g of propionic anhydride was added while continuing to control the temperature at 0-10°C. The reaction was continued for 1 hour. After the reaction was warmed to room temperature, 14 ml of dichloromethane was added while stirring continuously. The liquids were separated, the aqueous phase was discarded, and the dichloromethane phase was washed with saturated ammonium chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2.55 g of the finished product, ramelteon, as a white solid. Yield: 96%, purity: 99.8%, optical purity: 93%.

[0070] In the chiral resolution, S-ibuprofen was used as the resolving agent, and the obtained intermediate 4 had an optical purity of 88.05% and a yield of 20.82%. The optical purity of the final product was only 93%, and the total yield of the route was only 19.3%, which was significantly different from the quality and yield of the route using D-lactic acid as the resolving agent.

[0071] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A preparation method of ramelteon, characterized in that Follow these steps: 1) Tetrahydrofuran, sodium hydroxide, and diethyl cyanomethylphosphonate are reacted in sequence to prepare a ylide solution, which is then added dropwise to a tetrahydrofuran solution of the starting material 1 to prepare intermediate 1. After completion of the reaction, water is added to quench the reaction, the mixture is filtered, and the filter cake is dried to obtain intermediate 1; Described starting material 1: The mass ratio of sodium hydroxide: diethyl cyanomethylphosphonate is 1:1.5:2.0; 2) Intermediate 1 is reduced with sodium borohydride in the presence of nickel chloride and di-tert-butyl dicarbonate in methanol to obtain intermediate 2; The mass ratio of the intermediate 1: nickel chloride: di-tert-butyl dicarbonate: sodium borohydride is 1:1.5:1:2; The nickel chloride is anhydrous nickel chloride; 3) Intermediate 2 is deprotected with hydrochloric acid in methanol solution to obtain intermediate 3; The mass volume ratio of the intermediate 1:methanol:hydrochloric acid is 1:8:3; 4) Intermediate 3 reacts with a chiral resolution agent and then is purified by recrystallization solvent to obtain intermediate 4; The mass ratio of the intermediate 3 to the chiral resolution agent is 1:0.22-0.44; The recrystallization solvent is methanol, ethanol, or isopropanol; 5) intermediate 4 is propionylated under alkaline conditions to obtain ramelteon; The alkaline reagent is sodium hydroxide, potassium hydroxide, or potassium carbonate; The mass ratio of the intermediate 4: alkaline reagent: propionic anhydride is 1:1.27:0.

52.

2. The preparation method according to claim 1, characterized in that The hydrochloric acid in step (3) has a content of 20%-36%.

3. The preparation method according to claim 1, characterized in that The chiral resolution reagent in step (4) is D-lactic acid.

4. The preparation method according to claim 1, characterized in that The mass ratio of the intermediate 3 in step (4) to the chiral resolution reagent is 1:0.

33.

5. The preparation method according to claim 1, characterized in that The recrystallization solvent in step (4) is methanol.

6. The preparation method according to claim 1, characterized in that The volume mass ratio of the intermediate in step (4) to the recrystallization solvent in step (3) is 1:5-15.

7. The preparation method according to claim 6, characterized in that The volume-to-mass ratio of the intermediate 3 in step (4) to the recrystallization solvent is 1:

10.

8. Use of ramelteon prepared by the method according to claim 1 in improving product yield and optical purity.

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