Preparation method of ramelteon intermediate and ramelteon

Abstract

The invention discloses a ramelteon intermediate and a preparation method of ramelteon, and belongs to the technical field of medical chemistry. According to the preparation method, 1, 2, 6, 7-tetrahydro-8H-indeno [5, 4-b] furan-8-ketone is taken as an initial raw material, and three steps of reactions are carried out in sequence: 1) a Wittig-Horner reaction is carried out to generate an (E)-type olefinic nitrile intermediate; (2) carrying out asymmetric reduction on the alkene nitrile intermediate by adopting a Cu (II) / Walphos chiral ligand / reducing agent catalytic system to obtain an (S)-type nitrile intermediate with high selectivity; and 3) carrying out catalytic hydrogenation reduction on cyano groups in a continuous flow microreactor, and acidifying to obtain the ramelteon key intermediate with high optical purity. And carrying out propionylation and recrystallization on the intermediate to obtain the final product ramelteon. According to the method, the material loss of traditional chiral resolution is avoided, and the continuous flow hydrogenation technology remarkably improves the production safety and effectively controls the generation of byproducts.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a ramelteline intermediate and a method for preparing ramelteline. Background Technology

[0002] Ramelteon is the first approved highly selective melatonin MT1 / MT2 receptor agonist for the treatment of insomnia with difficulty falling asleep. Its molecular structure contains a tricyclic 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan core with a chiral center; therefore, the efficient and highly selective synthesis of the (S)-enantiomer is both a key factor and a challenge for its industrial production.

[0003] Existing technologies, including WO2006030739, WO2008151170, WO2009056993, Tetrahedron: Asymmetry 2006, 17(2), Org. Process Res. Dev. 2015, 19, 373-377, and J. Org. Chem. 2022, 87, 2129-2135, disclose methods for preparing (S)-2-(1,6,7,8-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine (a key intermediate of ramelteamide) using (E)-2-(1,2,6,7-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile as a raw material in subsequent reduction steps. However, these existing processes have the following significant drawbacks, which severely restrict their industrial application:

[0004] 1. Inefficient chiral control strategies: Existing methods often employ a strategy of first preparing the racemic mixture and then performing chiral resolution to obtain the desired (S)-configuration. This method inherently leads to the loss of at least 50% of non-target enantiomers, and the resolution reagents are expensive and difficult to recover, resulting in poor atom economy and high production costs, making it difficult to meet the needs of large-scale production.

[0005] 2. The restoration process carries safety and quality risks:

[0006] a. Reduction of cyano groups and double bonds: Traditional processes typically employ autoclave-type high-pressure catalytic hydrogenation or metal hydride (e.g., sodium borohydride, lithium aluminum hydride) reduction systems. Autoclave-type high-pressure hydrogenation requires high-pressure hydrogen gas, posing significant safety hazards due to its flammability and explosiveness, and placing stringent requirements on equipment. Metal hydrides, on the other hand, suffer from poor reaction selectivity and uncontrollable, vigorous reactions. For example, patents with publication numbers CN112500380, CN101654445, and CN102321056 use metal hydride reduction systems, such as sodium borohydride and lithium aluminum hydride, for reduction, but the related double bond byproducts are difficult to control, especially those in formulas (I') and (II').

[0007]

[0008] b. Difficulty in controlling impurity formation: Particularly noteworthy is the high likelihood of generating difficult-to-remove byproduct impurities during the reduction process, especially when using metal hydrides, such as the over-reduction impurity shown in equation (I') and the double bond shifting impurity shown in equation (II'). These impurities have structures similar to the target product, making purification and separation extremely difficult, directly impacting the quality and purity of the final product and placing immense pressure on meeting the stringent quality control standards for pharmaceuticals.

[0009] 3. Uncompetitive process yield and cost: Considering the above problems, the total yield of ramelteamide prepared by the existing reported methods from the starting material 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one is only about 57.2%, which has limited economic benefits.

[0010] Therefore, there is a need to develop a new preparation method for rameltein and its key chiral intermediates that is highly atom-economical, has good production safety, can effectively control impurities, and is suitable for industrial scale-up. Summary of the Invention

[0011] The purpose of this invention is to overcome the shortcomings of the prior art and provide a ramelteline intermediate and a method for preparing ramelteline.

[0012] This invention uses Cu II / Walphos ligands asymmetrically reduce the double bond of (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile to directly obtain the S-configuration intermediate, avoiding chiral resolution. The cyano group is reduced by microchannel continuous flow hydrogenation technology, replacing the traditional batch hydrogenation, while more effectively controlling the formation of formulas (I') and (II').

[0013] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0014] In a first aspect, the present invention provides a method for preparing a rameltein intermediate, the synthetic route of which is as follows:

[0015]

[0016] The method includes the following steps:

[0017] Step 1: Using 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one as a raw material, it is reacted with diethyl cyanomethylphosphonate under alkaline conditions to prepare (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile, i.e., intermediate 1;

[0018] Step 2, in Cu II In the presence of a catalytic system of salt, Walphos ligand, and reducing agent, (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile underwent an asymmetric reduction reaction to yield (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile, i.e., intermediate 2;

[0019] Step 3: In a continuous flow microreactor, in the presence of a catalyst and hydrogen, (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile is catalytically hydrogenated and reduced to obtain (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, which is then acidified to obtain its salt, namely the ramelteamide intermediate.

[0020] Further, the alkaline conditions are provided by sodium methoxide, sodium ethoxide, potassium tert-butoxide, or sodium hydride, preferably sodium hydride or sodium methoxide; the molar ratio of the 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, diethyl cyanomethylphosphonate, and sodium methoxide solution is 1:1.2:1.2; the reaction solvent is selected from one or more of toluene, heptane, methanol, tetrahydrofuran, methyl tert-butyl ether, ethanol, or water, preferably toluene; the reaction temperature is 0–10°C.

[0021] The steps for preparing (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile described in step 1 are as follows:

[0022] 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one and toluene were added sequentially to a three-necked flask, stirred, and then cooled. Diethyl cyanomethylphosphonate was then added, and when the temperature dropped to 5°C, a 30% sodium methoxide solution was slowly added dropwise while maintaining the reaction temperature between 0 and 10°C. After the raw materials were completely consumed, the reaction was stopped, and the reaction solution was quenched, separated, washed, filtered, and dried to obtain (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile.

[0023] Further, the Cu mentioned in step 2 II The salt is selected from one of copper nitrate, copper acetate, and copper chloride.

[0024] Further, the chiral ligand in step 2 includes BINAP, BDPP, MeOBIPHEP, Phosferrox, TaniaPhos, MonoPhos, DifluorPhos, PhanePhos, Jo-SPOphos, MandyPhos, JosiPhos, WalPhos, and ChenPhos, with Walphos ligand being preferred. Walphos ligand is selected from one of SL-J005-1, SL-M004-1, SL-J001-2((S)-(+)-1-[(R)-2-(diphenylphosphine)ferrocene]ethyldicyclohexylphosphine.

[0025]

[0026] Furthermore, the reducing agent mentioned in step 2 is selected from one of PMHS (polymethylhydrosiloxane), triethylsilane, and triphenylsilane.

[0027] Further, in step 2, (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile, Cu II The molar ratio of salt, Walphos ligand, reducing agent, and tert-butanol is 1:0.02-0.03:0.02-0.03:4.6:4. The reaction solvent is selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran, or dichloromethane, with tetrahydrofuran being preferred.

[0028] The steps for preparing (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile in step 2 are as follows:

[0029] Cu II Salt and Walphos ligand were placed in a three-necked flask, solvent was added, nitrogen was used for purging, and the mixture was stirred and cooled to 5°C. Reducing agent was added dropwise, and stirring was continued for 10 min. Then (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile and tert-butanol were added. The temperature was maintained at 0-10°C and the reaction was stirred for 50 min. Then the temperature was raised to 30°C and the reaction was stopped after the starting material was completely consumed. The reaction solution was separated, washed, dried, filtered, and recrystallized to obtain (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile.

[0030] Furthermore, the catalyst mentioned in step 3 is selected from one of the supported ruthenium catalyst, supported palladium catalyst, or supported nickel catalyst.

[0031] Preferably, the supported ruthenium catalyst is 5% Ru-Al2O3, 5% Ru-C or 5% Ru-SiO2; the supported palladium catalyst is 5% Pd-C; and the supported nickel catalyst is 30% Ni-SiO2.

[0032] Furthermore, in step 3, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or methanesulfonic acid; the reaction parameters of the continuous flow microreactor are: liquid flow rate 0.1–20 ml / min, hydrogen pressure 0.2–5 MPa, hydrogen flow rate 30–600 sccm, and reaction temperature 30–120 °C.

[0033] Step 3 is as follows:

[0034] (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile was fully dissolved in methanol, and a 7.0 M ammonia-methanol solution was added. After the catalyst was packed into a continuous flow reaction column, the parameters of the continuous flow reactor were set, and the reactants were injected. After the reactants were completely consumed, the product was concentrated under reduced pressure to remove the solvent, and 1,4-dioxane was added to dissolve it. Inorganic or organic acids were slowly added dropwise. After the addition was complete, the product was filtered, washed, and dried to obtain (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine salt.

[0035] Secondly, the present invention provides a method for preparing ramelteinamide, comprising the following steps:

[0036] The rameltein intermediate obtained by the above method is subjected to an acylation reaction with propionyl chloride in a mixed system of alkaline aqueous solution and organic solvent. After the reaction is completed, rameltein is obtained by recrystallization. The solvent used for recrystallization is a mixed solvent of ethanol and water with a volume ratio of ethanol to water of 2:1.

[0037] Furthermore, the organic solvent is selected from aromatic hydrocarbons (e.g., toluene, benzene, etc.), ethers (e.g., isopropyl ether, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, and 2-methyltetrahydrofuran, etc.), halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, etc.), etc. These solvents can be used alone or in mixtures of two or more. Tetrahydrofuran and toluene are preferred.

[0038] The preparation process of rameltein of this invention involves compounds of formulas (I), (II), (III), (IV), and (V) each containing 0.1% or less:

[0039]

[0040] The method of this invention features mild reaction conditions, high yield, and high purity, making it suitable for industrial-scale preparation of high-purity ramelteamide. It improves existing processes by controlling impurities I' and II', reducing their impact on subsequent products. It also avoids the use of high-pressure hydrogenation in a batch reactor, thus improving the safety of industrial production.

[0041] The present invention has the following beneficial effects: (1) The preparation method of rameltein and its intermediate involves the following steps: starting material SM1 undergoes Wittig-Horner reaction, asymmetric reduction of α,β-unsaturated nitrile, and continuous flow catalytic hydrogenation to obtain rameltein intermediate, which is then propionylated to obtain rameltein. The starting material is readily available, the reaction route is simple, and the process is highly operable.

[0042] (2) In step 2 of this preparation method, Cu is used II The method of asymmetric reduction of α,β-unsaturated nitrile structures using salt and Walphos ligands can yield intermediate 2 in high yield and purity, while solving the industrialization problem of low safety when using high-pressure hydrogenation in a batch reactor.

[0043] (3) The preparation method uses continuous flow catalytic hydrogenation reduction of cyano in step 3, which makes the reaction process more stable and controllable, and effectively controls the generation of impurities I' and II', thereby reducing the pressure of subsequent purification, improving the yield of final product on the basis of improving the quality of final product, reducing costs, and enhancing the competitiveness of enterprises. Attached Figure Description

[0044] Figure 1 The final liquid chromatogram of ramelteamide;

[0045] Figure 2 XRD pattern of final product rameltetinamide;

[0046] Figure 3 The 1H NMR spectrum of ramelteinide;

[0047] Figure 4 The carbon NMR spectrum of ramelteinide;

[0048] Figure 5 This is the synthetic route diagram for ramelteinamide. Detailed Implementation

[0049] The present invention will be further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0050] The preparation method of rameltein includes the following steps:

[0051] Step 1: Prepare (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one)acetonitrile, i.e., intermediate 1, using 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl]one as a raw material;

[0052] Step 2, using Cu II The asymmetric reduction of (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile with salt, Walphos ligand, and reducing agent yields (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile, i.e., intermediate 2;

[0053] Step 3: (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile is catalytically reduced in a continuous flow microreactor to obtain (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, and then acidified to obtain its salt, i.e., intermediate 3;

[0054] Step 4: The rameltein intermediate is subjected to aminopropionylation, and the product is recrystallized using an ethanol / heptane system to obtain rameltein.

[0055]

[0056] All raw materials and reagents used in this invention are commercially available.

[0057] Example 1

[0058] (1) Preparation of (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile

[0059] 100g (0.57mol, 1.0eq) of SM1 was added to a 1L three-necked flask, followed by 500ml of toluene. The mixture was then cooled in an ice bath with stirring. 122.03g (0.68mol, 1.2eq) of diethyl cyanomethylphosphonate was added. Once the temperature reached 5℃, 124.05g (0.69mol, 1.2eq) of 30% sodium methoxide solution was slowly added dropwise, maintaining the temperature below 10℃. After the addition was complete, the reaction was continued at 0–10℃. The reaction was stopped when the reactant concentration was less than 1% as monitored by the liquid phase. 500ml of water was slowly added dropwise to quench the reaction. After the addition was complete, the mixture was stirred for 30 min. The mixture was separated, and the organic layer was retained. The organic layer was washed with 500ml x 2 of water, then slurried with 1L of n-heptane for 2 h. After filtration, the filter cake was slurried with 500ml of isopropanol for 2 h, filtered again, and the filter cake was retained and dried to obtain 103g of a white solid, with a yield of 91.0% and a purity of 99%. 1H NMR (300MHz, DMSO-d6) δ = 7.14 (d, J = 8.1Hz, 1H), 6.87 (d, J = 8.1Hz, 1H), 5.79–5.72 (m, 1H), 4 .60(t,J=8.8Hz,2H),3.31(t,J=8.8Hz,2H),3.04–2.93(m,4H)ppm.HRMS(ESI)(m / z):[M+H] + Calculated for C 13 H 12 NO + ,198.0913;found198.09465.

[0060] (2) Preparation of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile

[0061] Weigh 1.84 g (10.14 mmol, 0.02 eq) of anhydrous copper acetate and 6.03 g (10.14 mmol, 0.02 eq) of SL-J001-2 into a three-necked flask. Add 1 L of tetrahydrofuran. After purging with nitrogen, stir and cool to 5 °C. Add 150 g of PMHS (1.55% hydrogen content, 4.6 eq) dropwise. After the addition is complete, continue stirring in an ice bath for 10 min. Then add 100 g (0.51 mol, 1.0 eq) of intermediate 1 and 150.32 g (2.03 mol, 4.0 eq) of tert-butanol. After the addition is complete, continue stirring in an ice bath for 50 min. Then remove the ice bath and heat to 30 °C for 3 h. When the liquid phase monitoring shows that the starting material is <0.1%, stop the reaction. 52 ml of water was added to the reaction solution under ice bath conditions, followed by 25 ml of 1.0 M tetrabutylammonium fluoride. After the addition was complete, stirring was continued until no more bubbles were generated. Then, 500 ml of water was added, the mixture was separated, and the organic layer was retained. The organic layer was washed with 500 ml of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and then recrystallized with 300 ml of ethanol to obtain 85 g of off-white solid, with a yield of 84.1% and an ee of 92%. 1 H NMR (300MHz, DMSO-d6) δ = 6.94 (d, J = 8.0Hz, 1H), 6.59 (d, J = 8.0Hz, 1H), 4.60–4.39 (m, 2H), 3.50–3.39 (m, 1H), 3.30–3 .06(m,2H),2.98–2.83(m,2H),2.81–2.64(m,2H),2.37–2.21(m,1H),1.93–1.78(m,1H)ppm.HRMS(ESI)(m / z):[M+H] + Calculated for C 13H 14 NO + ,200.1070;found 200.1073.

[0062] (3) Preparation of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride

[0063] Weigh 100 g (0.50 mol, 1.0 eq) of intermediate 2 and dissolve it completely in 2630 ml of methanol. Then add 720 ml (5.0 mol, 10.0 eq) of a 7.0 M ammonia methanol solution, bringing the final concentration of the raw material to 0.15 M. Pack a sufficient amount of 5% Ru-SiO2 catalyst into a continuous flow reaction column, adjust the back pressure to 3.0 MPa, maintain a hydrogen flow rate of 400 ml / min and a column temperature of 100 °C, and inject the reactants at a flow rate of 15 ml / min. After the material was completely consumed, the obtained product was concentrated under reduced pressure at 40℃ to remove the solvent. 500 ml of 1,4-dioxane was added to dissolve it, and 41 ml of concentrated hydrochloric acid (0.50 mol, 1.0 eq) was slowly added dropwise. After the addition was completed, the mixture was stirred for 30 min and filtered. The filter cake was washed with 50 ml of 1,4-dioxane and dried to obtain 115 g of white powder, with a yield of 95.6%, purity of 99.8%, and ee of 99.7%. 1 H NMR (300MHz, DMSO-d6) δ = 8.17 (s, 3H), 6.92 (d, J = 8.0Hz, 1H), 6.55 (d, J = 8.1Hz, 1H), 4.61–4.38 (m, 2H), 3.29–3.04(m,3H),2.89–2.63(m,4H),2.29–2.04(m,2H),1.81–1.57(m,2H)ppm.HRMS(ESI)(m / z):[M–Cl - ] + Calculated for C 13 H 18 NO + ,204.1383; found 204.1385.

[0064] (4) Preparation of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)propionamide

[0065] (I) Preparation

[0066] Weigh 41.7 g (1.04 mol, 2.5 eq) of sodium hydroxide into a reaction flask and dissolve it in 250 ml of water at low temperature. After the temperature drops to 20°C, maintain this temperature and add 100.0 g (0.42 mol, 1.0 eq) of intermediate 3 and 500 ml of tetrahydrofuran. Continue cooling to 5°C, then slowly add 57.89 g (0.63 mol, 1.5 eq) of propionyl chloride dropwise, maintaining the temperature below 30°C. After the addition is complete, continue the reaction at 20–30°C for 1 hour until the starting material is completely consumed. Remove the ice bath, add 1 L of water, stir for 2 hours, and then filter, retaining the filter cake. After washing the filter cake with 100 ml of water, retain the filter cake and dry it to obtain 105 g of white solid, with a yield of 97.1%, purity of 99.1%, and ee > 99.9%.

[0067] (II) Purification

[0068] 105g of the above solid was recrystallized using ethanol:water = 2:1 to obtain 101g of white solid, with a yield of 96.2% and a purity of 99.9%, ee > 99.9%. 1 H NMR (300MHz, Chloroform-d) δ = 6.95 (d, J = 7.9Hz, 1H), 6.61 (d, J = 7.9Hz, 1H), 5.50 (s, 1H), 4.65–4.43 (m, 2H), 3.41–3.29 (m, 2H), 3.28–3.03 (m, 3H) ,2.97–2.68(m,2H),2.35–2.23(m,1H),2.17(q,J=7.7Hz,2H),2.07–1.96 (m,1H),1.90–1.74(m,1H),1.72–1.54(m,1H),1.14(t,J=7.6Hz,3H)ppm. 13 C NMR(75MHz,Chloroform-d)δ=174.03,159.66,143.41,136.09,123.68,122.47,107.71,7 1.45,42.47,38.32,33.76,32.02,30.97,30.05,28.87,10.19ppm.HRMS(ESI)(m / z):[M+H] + Calculated for C 16 H 22 NO2 + ,260.1645;found260.1642.

[0069] (III) Analysis Conditions

[0070] (a) Reversed-phase HPLC analysis conditions

[0071] Detector: Ultraviolet detector (210nm)

[0072] Column: Shim-pack Scepter C18-120, 4.6 × 250 mm, 5 μm

[0073] Column temperature: 30℃

[0074] Mobile phase: A: 20mM KH2PO4, 1.5‰ TEA, 1‰ H3PO4 buffer; B: MeOH

[0075] Flow rate: 1.2 ml / min

[0076] Gradient condition:

[0077] Time (min) Phase A Phase B 0.00 60.0 40.0 11.00 60.0 40.0 22.00 45.0 55.0 40.00 45.0 55.0 40.50 60.0 40.0 50.00 60.0 40.0

[0078] (b) Chiral HPLC analysis conditions

[0079] Detector: DAD detector

[0080] Column: CHIRALPAK AD-H, 5μm, 4.6×250mm

[0081] Column temperature: 30℃

[0082] Mobile phase: A: 1‰ diethylamine ethanol solution; B: n-hexane

[0083] Flow rate: 0.8 ml / min

[0084] Gradient condition:

[0085] Time (min) Phase A Phase B 0.00 15.0 85.0 20.00 15.0 85.0

[0086] HPLC chromatogram as shown Figure 1 As shown. From Figure 1 It is evident that the purity of (S)-N-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide is greater than 99.9%, and impurities I and II were not detected.

[0087] Crystal form data such as Figure 2 As shown.

[0088] 1 H NMR data such as Figure 3 As shown.

[0089] 13 C NMR data such as Figure 4 As shown.

[0090] Industrial applicability

[0091] According to the method of the present invention, high-purity optically active amine derivatives as pharmaceuticals can be prepared in a high yield of 68% by using an asymmetric reduction of α,β-unsaturated nitrile and a microchannel continuous flow hydrogenation reaction through a chiral bisphosphine ligand / transition metal catalytic system, thus enabling the industrial supply of high-quality pharmaceutical raw materials.

[0092] Example 2

[0093] The difference from Example 1 is that in step (2), the preparation of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile, SL-J001-ligand is replaced by SL-M004-1, and toluene is used as the solvent. The specific steps are as follows:

[0094] Weigh 2.76 g (15.21 mmol, 0.03 eq) of anhydrous copper acetate and 16.02 g (10.14 mmol, 0.03 eq) of SL-M004-1 into a three-necked flask, add 1 L of toluene, purge with nitrogen, stir and cool to 5 °C, then add 150 g of PMHS (1.55% hydrogen content, 4.6 eq) dropwise. After the addition is complete, continue stirring in an ice bath for 10 min. Then add 100 g (0.51 mol, 1.0 eq) of intermediate 1 and 150.32 g (2.03 mol, 4.0 eq) of tert-butanol. After the addition is complete, continue stirring in an ice bath for 50 min. Then remove the ice bath and heat to 30 °C until the starting materials are completely consumed, then stop the reaction. 52 ml of water was added to the reaction solution under ice bath conditions, followed by the slow addition of 25 ml of 1.0 M tetrabutylammonium fluoride. After the addition was complete, stirring was continued until no more bubbles were generated. Then, 500 ml of water was added, the mixture was separated, and the organic layer was retained. The organic layer was washed with 500 ml of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and then recrystallized with 300 ml of ethanol to obtain 82 g of off-white solid, with a yield of 81.1% and an ee of 94%.

[0095] Example 3

[0096] The difference from Example 1 is that in step (3) (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride, the 5% Ru-SiO2 catalyst is replaced with 5% Pd-C. The specific steps are as follows:

[0097] Weigh 100 g (0.50 mol, 1.0 eq) of intermediate 2 and dissolve it completely in 2630 ml of methanol. Then add 720 ml (5.0 mol, 10.0 eq) of a 7.0 M ammonia methanol solution, bringing the final concentration of the raw material to 0.15 M. Pack a sufficient amount of 5% Pd-C catalyst into a continuous flow reaction column, adjust the back pressure to 3.0 MPa, maintain a hydrogen flow rate of 400 ml / min and a column temperature of 100 °C, and inject the reactants at a flow rate of 15 ml / min. After the material was completely consumed, the obtained product was concentrated under reduced pressure at 40℃ to remove the solvent. 500 ml of 1,4-dioxane was added to dissolve it, and 41 ml of concentrated hydrochloric acid (0.50 mol, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 min and filtered. The filter cake was washed with 50 ml of 1,4-dioxane and dried to obtain intermediate 3 110 g, with a yield of 91.4%, purity of 98.2%, and ee of 99.0%.

[0098] Example 4

[0099] The difference from Example 1 is that in step (3) (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride, the 5% Ru-SiO2 catalyst is replaced with 30% Ni-SiO2. The specific steps are as follows:

[0100] Weigh 100 g (0.50 mol, 1.0 eq) of intermediate 2 and dissolve it completely in 2630 ml of methanol. Then add 720 ml (5.0 mol, 10.0 eq) of a 7.0 M ammonia methanol solution, bringing the final concentration of the raw material to 0.15 M. Pack a sufficient amount of 30% Ni-SiO2 catalyst into a continuous flow reaction column, adjust the back pressure to 4.0 MPa, maintain a hydrogen flow rate of 400 ml / min and a column temperature of 100 °C, and inject the reactants at a flow rate of 15 ml / min. After the material was completely consumed, the obtained product was concentrated under reduced pressure at 40℃ to remove the solvent. 500 ml of 1,4-dioxane was added to dissolve it, and 41 ml of concentrated hydrochloric acid (0.50 mol, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 min and filtered. The filter cake was washed with 50 ml of 1,4-dioxane and dried to obtain intermediate 3113 g, with a yield of 93.9%, purity of 97.6%, and ee of 98.6%.

[0101] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. However, the above description is merely a specific embodiment of the present invention, and the technical features of the present invention are not limited thereto. Any other embodiments derived by those skilled in the art without departing from the technical solution of the present invention should be covered within the patent scope of the present invention.

Claims

1. A method for preparing a rameltein intermediate, characterized in that, The synthesis route is as follows: The method includes the following steps: Step 1: Using 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one as a raw material, it is reacted with diethyl cyanomethylphosphonate under alkaline conditions to prepare (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile, i.e., intermediate 1; Step 2, in Cu II In the presence of a catalytic system of salt, Walphos ligand, and reducing agent, (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile underwent an asymmetric reduction reaction to yield (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile, i.e., intermediate 2; Step 3: In a continuous flow microreactor, in the presence of a catalyst and hydrogen, (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile is catalytically hydrogenated and reduced to obtain (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, which is then acidified to obtain its salt, i.e., intermediate 3.

2. The method for preparing the rameltein intermediate according to claim 1, characterized in that, In step 1, the alkaline conditions are provided by sodium methoxide, the molar ratio of 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, diethyl cyanomethylphosphonate, and sodium methoxide solution is 1:1.2:1.2, the reaction solvent is toluene, and the reaction temperature is 0-10℃.

3. The method for preparing the rameltein intermediate according to claim 1, characterized in that, Cu in step 2 II The salt is selected from one of copper nitrate, copper acetate, or copper chloride.

4. The method for preparing the rameltein intermediate according to claim 1, characterized in that, The Walphos ligand mentioned in step 2 is selected from one of SL-J005-1, SL-M004-1 or SL-J001-2.

5. The method for preparing the rameltein intermediate according to claim 1, characterized in that, The reducing agent mentioned in step 2 is selected from PMHS, triethylsilane, or triphenylsilane.

6. The method for preparing the rameltein intermediate according to claim 1, characterized in that, In step 2, (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile, Cu II The molar ratio of salt, Walphos ligand, reducing agent, and tert-butanol is 1:0.02-0.03:0.02-0.03:4.6:4, and the reaction solvent is selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran, or dichloromethane.

7. The method for preparing the rameltein intermediate according to claim 1, characterized in that, The catalyst mentioned in step 3 is selected from one of the supported ruthenium catalyst, supported palladium catalyst, or supported nickel catalyst.

8. The method for preparing the rameltein intermediate according to claim 7, characterized in that, The supported ruthenium catalyst is 5% Ru-Al2O3, 5% Ru-C or 5% Ru-SiO2; the supported palladium catalyst is 5% Pd-C; and the supported nickel catalyst is 30% Ni-SiO2.

9. The method for preparing the rameltein intermediate according to claim 1, characterized in that, In step 3, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or methanesulfonic acid; the reaction parameters of the continuous flow microreactor are: liquid flow rate 0.1-20 ml / min, hydrogen pressure 0.2-5 MPa, hydrogen flow rate 30-600 sccm, and reaction temperature 30-120℃.

10. A method for preparing rameltein, characterized in that, The method includes the following steps: acylation reaction of the rameltein amine intermediate obtained by the method according to any one of claims 1-9 with propionyl chloride in a mixed system of alkaline aqueous solution and organic solvent, and recrystallization after the reaction to obtain rameltein amine; wherein the solvent used for recrystallization is a mixed solvent of ethanol and water, with a volume ratio of ethanol to water of 2:1.

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