Preparation method and application of (S)-3-hydroxy-3-(2-thienyl)-propionate compound

Abstract

The invention discloses a duloxetine hydrochloride key intermediate synthesis method, which comprises: in a hydrogen atmosphere, under the action of a compound represented by a formula V, carrying out an asymmetric catalytic hydrogenation reaction on a compound represented by a formula I to obtain a compound represented by a formula II, the method has the advantages of mild reaction conditions, simple operation, high catalytic efficiency, high yield, high product purity and high ee value, and is very suitable for industrialization.

Description

Technical Field

[0001] This invention relates to a method for preparing (S)-3-hydroxy-3-(2-thienyl)-propionate compound and its use in the synthesis of duloxetine or its intermediates. Background Technology

[0002] (S)-3-hydroxy-3-(2-thienyl)-propionate (compound II) is an important intermediate of duloxetine, which can be obtained from 3-oxo-3-(2-thienyl)-propionate (compound I) via an asymmetric catalytic hydrogenation step in the presence of a chiral catalyst. The equation for this reaction is shown below:

[0003]

[0004] US8293899B2 discloses a method for reducing compound I to compound II in the presence of a ruthenium catalyst with sulfonamides and aromatics as ligands. The literature "Indan-f-amphox: PNN ligands applicable to iridium-catalyzed asymmetric hydrogenation of β-aryl-β-keto esters" (Chin.J.Org.Chem.2020,40,997-1002) discloses a method for reducing compound I to compound II in the presence of an Ir(III)-indan-f-amphox catalyst. CN109776610B and CN108101785B respectively disclose methods for reducing compound I to compound II in the presence of an iridium catalyst with a chiral PNN ligand having a phenylethylamine skeleton.

[0005] The reported asymmetric catalytic hydrogenation reaction for the preparation of (S)-3-hydroxy-3-(2-thienyl)-propionate still faces problems such as difficulty in obtaining catalysts, poor catalyst stability, low catalytic efficiency, or low product purity.

[0006] In view of the above-mentioned problems, it is necessary to develop a more efficient, readily available, more stable, and more industrially suitable asymmetric hydrogenation method for the preparative (S)-3-hydroxy-3-(2-thienyl)-propionate ester compounds. Summary of the Invention

[0007] This invention provides a method for preparing a compound of formula II, comprising the following steps: in a hydrogen atmosphere, under the action of a compound of formula V, a compound of formula I undergoes an asymmetric catalytic hydrogenation reaction to obtain a compound of formula II. The structural formulas of formulas I, II, and V are shown below:

[0008]

[0009]

[0010] R 1 C 1-5 alkyl;

[0011] Ar is a phenyl group that is optionally substituted with one or more substituents, each substituent being independently selected from halogens, C... 1-5 Alkyl, C 1-5 Alkyloxy;

[0012] R 2 Each is independently hydrogen, halogen, or C 1-5 alkyl;

[0013] R 3 Each is independently hydrogen or C 1-3 Alkyloxy;

[0014] X + It can be an inorganic or organic cation.

[0015] The chiral catalyst can be purchased or prepared by methods known in the prior art, such as those disclosed in CN101391960A and EP0945457B1.

[0016] In some implementations, the R 1 The derivatives are methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, and tert-butyl; preferably, R... 1 It is methyl or ethyl.

[0017] In some embodiments, each of the Ars is independently 3,5-di-tert-butyl-4-methoxyphenyl, p-methylphenyl, p-tert-butylphenyl, dimethylphenyl, or phenyl; more preferably, each of the Ars is independently dimethylphenyl, p-methylphenyl, or phenyl; most preferably, the Ar is phenyl.

[0018] In some implementations, the R 2 Each is independently a hydrogen, methyl, or fluorine atom; preferably, the R 2 Each is independently hydrogen or methyl; more preferably, the R 2 It is hydrogen.

[0019] In some implementations, the R 3 Each is independently hydrogen or methoxy; preferably, the R 3 It is hydrogen.

[0020] In some implementations, the X + for Where R 4 Each independently is hydrogen, C 1-5 Alkyl; preferably, R 4Each can be hydrogen, methyl, ethyl, or isopropyl.

[0021] In some embodiments, the compound of formula V is a compound of formula VI:

[0022]

[0023] In some embodiments, the amount of compound V is 1 / 1000-1 / 100000 of the molar amount of compound I, more preferably 1 / 4000-1 / 20000, and most preferably 1 / 5000-1 / 10000.

[0024] In some embodiments, the reaction solvent for the asymmetric catalytic hydrogenation step is C. 1-4 alcohol solvents, C 6-8 Alkane solvents, toluene, ethyl acetate, preferably C 1-4 The alcohol solvent is more preferably methanol, ethanol, or isopropanol, and even more preferably ethanol or isopropanol.

[0025] In some embodiments, the volume of reaction solvent required per gram of compound I in the asymmetric catalytic hydrogenation step is 1-10 ml; preferably, the volume of reaction solvent required per gram of compound I in the asymmetric catalytic hydrogenation step is 2-5 ml.

[0026] In some embodiments, the hydrogen pressure in the asymmetric catalytic hydrogenation step is preferably 2-20 MPa, more preferably 2-10 MPa, even more preferably 3-5 MPa, and most preferably 3-4 MPa.

[0027] In some embodiments, the reaction temperature of the asymmetric catalytic hydrogenation step is preferably 20-100°C, more preferably 40-80°C, and most preferably 50-80°C.

[0028] This invention also provides a method for preparing a compound of formula III, comprising the following steps:

[0029] (1) Compound of Formula II was obtained by reduction using the above-mentioned asymmetric catalytic hydrogenation method;

[0030] (2) The compound of formula II prepared in step (1) is reacted with methylamine to generate compound of formula III.

[0031] In some embodiments, the mixture prepared in step (1) is used directly to react with methylamine.

[0032] The present invention also provides a method for preparing a compound of formula IV, comprising the following steps: reducing the compound of formula III obtained by the above preparation method to obtain the compound of formula IV.

[0033] Compound of Formula IV can be reacted with 1-fluoronaphthalene via a condensation reaction to produce duloxetine and its salts. This condensation reaction can be performed using methods known in the art, such as the method reported in CN101012219A.

[0034] The present invention also provides an application of the above preparation method in the preparation of duloxetine or its salts.

[0035] The reaction formula of the method of the present invention is as follows:

[0036]

[0037] Terminology and Explanation:

[0038] X + It refers to positively charged cations, not just cations with a single positive charge.

[0039] "Optional" or "optionally" means that the event or scenario described thereafter may or may not occur, and the description includes the situation when the event or scenario occurs and the situation when the event or scenario does not occur. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted, and the description includes substituted alkyl groups and alkyl groups without substituents.

[0040] Unless otherwise specified, “a” or “an” in this invention shall be understood as “one or more”.

[0041] "The mixture prepared in step (1) is used directly to react with methylamine" means that the mixture is used directly to react with methylamine without any purification treatment after the chemical reaction. Common purification methods include, but are not limited to, concentration, extraction, distillation, column chromatography, washing, recrystallization, salt formation, and esterification.

[0042] Complexes are molecules or ions with different properties from the original components, formed by a certain number of ligands (anions or molecules) bonded to a central ion (or neutral atom) through coordinate bonds. They are also called coordination compounds.

[0043] A ligand is a substance or ion that provides a lone pair of electrons when a coordinate bond is formed.

[0044] Alkyl refers to an alkyl group optionally substituted with one or more substituents, wherein each substituent is independent and includes, but is not limited to, C14. 1-5 Alkyl groups, halogens.

[0045] Dimethylphenyl is p-xylyl, o-xylyl, or m-xylyl.

[0046] S / C refers to the molar ratio of substrate to catalyst. Unless otherwise specified, the substrate in this invention refers to compound of formula I, namely 3-oxo-3-(2-thienyl)-propionate.

[0047] In Example (b) and Comparative Example, the product / starting ratio and yield were determined quantitatively using the external standard method; the starting material refers to compound of formula I, namely 3-oxo-3-(2-thienyl)-propionate.

[0048] The purity in the examples was determined using reversed-phase chromatography, and the value included the amount of the product and its enantiomers.

[0049] In the examples, the ee value was determined using a chiral chromatographic column.

[0050] The conversion rate in the comparative example is the TLC result.

[0051] In existing methods, the molar ratio (S / C) of the substrate to the catalyst is always 1000. A method for the asymmetric hydrogenation of Formula I compounds using even smaller amounts of catalyst has not yet been disclosed.

[0052] When using BINAP and MeO-BIPHEP as ligands to catalyze the reaction, we found that the reaction had low conversion, low yield, many byproducts, and low ee value, indicating that BINAP and MeO-BIPHEP are not good ligands for this reaction.

[0053] The asymmetric synthesis method for (S)-3-hydroxy-3-(2-thienyl)-propionate esters provided by this invention features mild reaction conditions, simple operation, high catalytic efficiency, high yield, high product purity, and high ee value, making it highly suitable for industrial production. Detailed Implementation

[0054] The following examples illustrate some embodiments and aspects of the invention. It will be apparent to those skilled in the art that various modifications, additions, substitutions, etc., can be made without altering the spirit or scope of the invention, and such modifications and variations are covered by the invention as defined in the appended claims. The invention disclosed herein is further illustrated by the following examples, which should in no way be construed as limiting.

[0055] All raw materials used in the examples are commercially available.

[0056] Step (a): Preparation of 3-oxo-3-(2-thienyl)-propionate (Compound I)

[0057] Add 40g of 2-acetylthiophene, 650mL of toluene, 86g of dimethyl carbonate, and 52g of sodium methoxide sequentially to a three-necked flask. Stir and slowly heat the solution to reflux, maintaining this temperature with stirring for 5-6 hours. After the reaction is complete, cool the solution to 20-25℃. Quench the reaction with dilute hydrochloric acid, allowing the layers to separate. Wash the organic phase twice with water, evaporate the toluene to dryness, and obtain an oily substance. Distill under reduced pressure, controlling the solution temperature at 110-130℃, to distill off methyl 3-oxo-3-(2-thienyl)propionate (75% yield, purity >99%).

[0058] Step (b): Preparation of (S)-3-hydroxy-3-(2-thienyl)-propionate (compound of formula II)

[0059] Example 1:

[0060] Evacuate the hydrogenation reactor to 0.08-0.10 MPa, slowly purge with nitrogen until the pressure inside the reactor reaches 0.09-0.10 MPa, then purge. Repeat this process three times. Add 50g of methyl 3-oxo-3-(2-thienyl)propionate, 250mL of ethanol (V=5), and 90mg of compound of formula VI (CAS RN: 488809-34-3) (S / C=5000) to the hydrogenation reactor in sequence. Then evacuate to 0.10 MPa and purge with hydrogen to 1-1.5 MPa. Repeat this process three times. Subsequently, the hydrogen pressure was increased to 4.0 MPa, and the pressure inside the reactor was maintained at 3.0 MPa-4.0 MPa. The temperature inside the reactor was controlled at 50°C, and the mixture was stirred for 25 hours until the hydrogen pressure inside the reactor no longer decreased within 1-2 hours. After nitrogen purging, the bottom valve of the reactor was opened, and the product was discharged to obtain a hydrogenated liquid containing methyl (S)-3-hydroxy-3-(2-thienyl)-propionate, with a yield of 91% and a remaining raw material content of 4%.

[0061] Examples 2-8:

[0062] The reaction conditions in Examples 2-8 were the same as those in Example 1, except for the reaction temperature, type and amount of reaction solvent, amount of catalyst, and reaction time.

[0063]

[0064] In the table above, V in solvent (V) refers to the volume of the reaction solvent (in mL) being V times the mass of compound I (in g).

[0065] The ee value determination conditions for (S)-3-hydroxy-3-(2-thienyl)-propionate in this step were as follows: chromatographic column: CHIRALPAKIB-3; mobile phase: n-hexane:isopropanol = 85:15 (V / V); diluent: mobile phase; detection wavelength: 220 nm; column temperature: 30 ℃; flow rate: 1.0 mL / min; S configuration retention time: 6.04 min, R configuration retention time: 3.95 min.

[0066] Step (c): Preparation of (S)-3-hydroxy-3-(2-thienyl)-propionylmethylamine (compound of formula III)

[0067] The hydrogenated liquid obtained in step (b) of Example 6 was transferred to a three-necked flask, and sufficient dry methylamine gas was slowly introduced into the vessel. After the amine introduction was completed, the mixture was kept at 30°C with stirring, and the reaction was monitored by TLC. After the reaction was completed, methanol was evaporated, and 250 mL of n-hexane was added to the vessel. The mixture was stirred at 15°C for 2 hours, filtered, and washed with 20 mL of n-hexane to obtain 43 g of compound III (the yield of the two steps (b) and (c) was 86%, the purity was 99.9%, and the ee was 97%).

[0068] The ee value determination conditions for compound III in this step were as follows: chromatographic column: CHIRALPAK IC-3; mobile phase: n-hexane:isopropanol = 90:10 (V / V); diluent: isopropanol; detection wavelength: 230 nm; column temperature: 30 ℃; flow rate: 1.0 mL / min; S configuration retention time: 22.05 min; R configuration retention time: 19.91 min.

[0069] Step (d): Preparation of (S)-3-(methylamino)-1-(2-thienyl)-1-propanol (compound of formula IV)

[0070] The compound of formula III obtained in step (c) was dissolved in tetrahydrofuran, and a reduction reaction was carried out at room temperature. The reaction was monitored by TLC. After the reaction was completed, the tetrahydrofuran was evaporated to dryness, the solid was dissolved in water, extracted with n-butanol, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound IV (ee 99%).

[0071] The ee value determination conditions for compound IV in this step were as follows: chromatographic column: CHIRALPAK IC-3; mobile phase: n-hexane:isopropanol:diethylamine = 80:20:0.1 (V / V / V); diluent: methanol:water = 95:5 (V / V); detection wavelength: 230 nm; column temperature: 30 ℃; flow rate: 1.0 mL / min; S configuration retention time: 8.82 min; R configuration retention time: 6.18 min.

[0072] Comparative Examples 1-5:

[0073] The hydrogenation reactor was evacuated to 0.08-0.10 MPa, and nitrogen was slowly introduced until the internal pressure reached 0.09-0.10 MPa, then the reactor was purged. This process was repeated three times. Methyl 3-oxo-3-(2-thienyl)-propionate, ethanol, and catalyst (S / C = 150) were added sequentially to the reactor. The volume of ethanol (mL) was 10 times the mass (g) of methyl 3-oxo-3-(2-thienyl)-propionate. The reactor was then evacuated to 0.10 MPa, and hydrogen was introduced to 1-1.5 MPa. This process was repeated three times. Subsequently, the hydrogen pressure was increased to 2.5 MPa, maintaining the internal pressure at 2.5-3 MPa. The internal temperature was controlled at 50°C, and the reactor was stirred while maintaining the temperature until the hydrogen pressure no longer decreased within 1-2 hours, indicating the reaction was complete. After nitrogen purging, the bottom valve of the reactor was opened, and the product was discharged to obtain a hydrogenated liquid containing (S)-3-hydroxy-3-(2-thienyl)-propionate.

[0074] The self-made catalyst was prepared according to the method described in the reference (Adv.Synth.Catal.2003,345,261-274).

[0075]

[0076]

Claims

1. A method for preparing a compound of formula II, characterized in that, Includes the following steps: In a hydrogen atmosphere, under the action of compound V, compound I undergoes an asymmetric catalytic hydrogenation reaction to give compound II. The structural formulas of formulas I, II, and V are shown below: R 1 C 1-5 alkyl; Ar is a phenyl group that is optionally substituted with one or more substituents, each substituent being independently selected from halogens, C... 1-5 Alkyl, C 1-5 Alkyloxy; R 2 Each is independently hydrogen, halogen, or C 1-5 alkyl; R 3 Each is independently hydrogen or C 1-3 Alkyloxy; X + It can be an inorganic or organic cation.

2. The method according to claim 1, characterized in that, The R 1 The derivatives are methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, and tert-butyl; preferably, R... 1 It is methyl or ethyl.

3. The method according to any one of claims 1-2, characterized in that, Each of the Ars is independently 3,5-di-tert-butyl-4-methoxyphenyl, p-methylphenyl, p-tert-butylphenyl, dimethylphenyl, or phenyl; more preferably, each of the Ars is independently dimethylphenyl, p-methylphenyl, or phenyl; most preferably, the Ar is phenyl.

4. The method according to any one of claims 1-3, characterized in that, The R 2 Each is independently a hydrogen, methyl, or fluorine atom; preferably, the R 2 Each is independently hydrogen or methyl; more preferably, the R 2 It is hydrogen.

5. The method according to any one of claims 1-4, characterized in that, The R 3 Each is independently hydrogen or methoxy; preferably, the R 3 It is hydrogen.

6. The method according to any one of claims 1-5, characterized in that, The X + for Where R 4 Each independently is hydrogen, C 1-5 Alkyl; preferably, R 4 Each can be hydrogen, methyl, ethyl, or isopropyl.

7. The method according to claim 1, characterized in that, The compound of formula V is a compound of formula VI:

8. The method according to any one of claims 1-7, characterized in that, The amount of compound V is 1 / 1000-1 / 100000 of the molar amount of compound I, more preferably 1 / 4000-1 / 20000, and most preferably 1 / 5000-1 / 10000.

9. The method according to any one of claims 1-8, characterized in that, The reaction solvent for the asymmetric catalytic hydrogenation step is C. 1-4 alcohol solvents, C 6-8 Alkane solvents, toluene, ethyl acetate, preferably C 1-4 The alcohol solvent is preferably methanol, ethanol, or isopropanol, with ethanol or isopropanol being the most preferred.

10. The method according to any one of claims 1-9, characterized in that, The volume of reaction solvent required per gram of compound I in the asymmetric catalytic hydrogenation step is 1-10 ml; preferably, the volume of reaction solvent required per gram of compound I in the asymmetric catalytic hydrogenation step is 2-5 ml.

11. The method according to any one of claims 1-10, characterized in that, The hydrogen pressure in the asymmetric catalytic hydrogenation step is 2-20 MPa, more preferably 2-10 MPa, even more preferably 3-5 MPa, and most preferably 3-4 MPa.

12. The method according to any one of claims 1-11, characterized in that, The reaction temperature of the asymmetric catalytic hydrogenation step is 20-100℃, more preferably 40-80℃, and most preferably 50-80℃.

13. A method for preparing a compound of formula III, characterized in that, Includes the following steps: (1) The method according to any one of claims 1-12 is used to prepare compound II; (2) The compound of formula II obtained in step (1) is reacted with methylamine to generate compound of formula III. The synthetic route is shown below:

14. The method according to claim 13, characterized in that, The mixture prepared in step (1) is used directly to react with methylamine.

15. A method for preparing a compound of formula IV, characterized in that, The process includes the following steps: The method according to claim 13 or 14 yields compound III, which is further reduced to yield compound IV. The synthetic route is shown below:

16. The preparation method according to any one of claims 1-15 is used in the preparation of duloxetine or a salt thereof.

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