Method for preparing tetrahydro-1-naphthylamine and its derivatives

Abstract

The present disclosure relates to a method for preparing tetrahydro-1-naphthylamine and its derivatives. Specifically, the present disclosure relates to a method for preparing (1S,4S)-4-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine, which comprises reacting compound C-1 with (R)-2-methyl-CBS-oxazaborolidine to form compound D-1. The method is simple in operation and suitable for industrial production. JPEG2026501856000042.jpg43170

Description

[Technical Field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to a preparation method for preparing tetrahydro-1-naphthylamine and its derivatives. [Background technology]

[0002] Chiral amines are structural components or fragments of many compounds with important biological activity. For example, (1S,4S)-4-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine is a key intermediate in the synthesis of the MOR agonist (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine.

[0003] WO2017063509 discloses that tert-butyl (S)-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamate is used as a starting material, and tert-butyl (1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamate is obtained under chiral reducing agent conditions, followed by etherification and deprotection to obtain the target product. [ka] . Summary of the Invention

[0004] The present disclosure provides a method for preparing a compound of formula I or a salt thereof: [ka] the method comprises reacting a compound of formula C with (R)-2-methyl-CBS-oxazaborolidine to form a compound of formula D; [ka] Among them, R 1is a halogen, a nitro group, a cyano group, C 1-6 Alkyl group or C 1-6 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl group or C 1-6 alkoxy groups, n is 0, 1, 2, or 3; R 2 is hydrogen, C 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl group, C 1-6 Alkoxy group or C 3-6 It is substituted with one or more cycloalkyl groups.

[0005] In some embodiments, the molar ratio of (R)-2-methyl-CBS-oxazaborolidine to the compound of Formula C in the method is 1:10 to 1:1, including, but not limited to, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or any value between two of them. In some embodiments, the molar ratio of (R)-2-methyl-CBS-oxazaborolidine to the compound of Formula C in the method is 1:10.

[0006] In some embodiments, the process of reacting a compound of Formula C to form a compound of Formula D further includes a reducing agent, and the reducing agent is selected from, but is not limited to, borane. In some embodiments, the method includes a borane dosage of 0.5 to 1 equivalent (eq.) of the molar amount of the compound of Formula C, including, but not limited to, 0.5 eq., 0.6 eq., 0.7 eq., 0.8 eq., 0.9 eq., 1.0 eq., or any value between two of these. In some embodiments, the method includes a borane dosage of 0.8 to 1 equivalent (eq.) of the molar amount of the compound of Formula C.

[0007] In some other embodiments, the solvent used in the reaction of the compound of formula C is selected from, but not limited to, toluene or tetrahydrofuran. In some embodiments, the solvent used in the reaction of the compound of formula C is tetrahydrofuran.

[0008] In another embodiment, the reaction temperature for the compound of Formula C is between -10 and 10°C, including, but not limited to, -10°C, -8°C, -6°C, -4°C, -2°C, 0°C, 2°C, 4°C, 6°C, 8°C, 10°C, or any value between two of these.

[0009] Additionally, some embodiments provide a method for preparing a compound of Formula I or a salt thereof, further comprising reacting a compound of Formula B under oxidizing agent conditions to form a compound of Formula C: [ka] , among which, R 1 and n is as defined above.

[0010] In some embodiments, the oxidizing agent is selected from, but is not limited to, potassium permanganate or sodium hypochlorite. In some embodiments, the method comprises reacting a compound of Formula B under potassium permanganate conditions to form a compound of Formula C. In some embodiments, the reaction temperature for the compound of Formula B is 0 to 30°C, including, but not limited to, 0°C, 6°C, 10°C, 16°C, 20°C, 26°C, 30°C, or any value between two of these.

[0011] In some embodiments, the solvent used in the reaction of the compound of Formula B is acetone. In other embodiments, in the above method, the dosage of the oxidizing agent is 1 to 6 equivalents (eq.) of the molar amount of the compound of Formula B, including, but not limited to, 1 eq., 2 eq., 3 eq., 4 eq., 5 eq., 6 eq., or any value in between.

[0012] Some embodiments provide a method for preparing a compound of Formula I or a salt thereof, further comprising reacting a compound of Formula A with phthalic anhydride to form a compound of Formula B: [ka] , among which, R 1 and n is as defined above.

[0013] In some embodiments, the molar ratio of the compound represented by Formula A to phthalic anhydride in the method is 1:1 to 1:3, including but not limited to 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, or any value between two of them. In some embodiments, the molar ratio of the compound represented by Formula A to phthalic anhydride in the method is 1:1.

[0014] In some other embodiments, the solvent used in the reaction of the compound of Formula A is toluene.

[0015] In some embodiments, the method further comprises: a) reacting a compound of formula A with phthalic anhydride to form a compound of formula B; b) reacting a compound of formula B under oxidizing agent conditions to form a compound of formula C; c) reacting the compound of formula C with (R)-2-methyl-CBS-oxazaborolidine to form a compound of formula D; Including, [ka] , among which, R 1 and n is as defined above.

[0016] In some further embodiments, in the above method, the compound of formula I is a compound of formula I-1: [ka] The method includes reacting compound C-1 under (R)-2-methyl-CBS-oxazaborolidine conditions to form compound D-1. [ka] .

[0017] In some embodiments, the method for preparing a compound of formula I-1 includes forming compound C-1 from compound B-1 under an oxidizing agent such as potassium permanganate. [ka] .

[0018] In some other embodiments, the method for preparing a compound of formula I-1 includes forming compound B-1 from compound A-1 under phthalic anhydride conditions. [ka] .

[0019] In some embodiments, the method for preparing a compound of formula I-1 comprises: a) reacting compound A-1 with phthalic anhydride to form compound B-1; b) reacting compound B-1 under oxidizing agent conditions to form compound C-1; c) reacting compound C-1 under (R)-2-methyl-CBS-oxazaborolidine conditions to form compound D-1; Contains [ka] .

[0020] In some embodiments, in step a), compound A-1 is reacted with phthalic anhydride under heating conditions to form compound B-1.

[0021] In some embodiments, in step a), compound A-1 is reacted with phthalic anhydride under triethylamine conditions to form compound B-1.

[0022] In some embodiments, in step b), compound B-1 is reacted under potassium permanganate conditions to form compound C-1.

[0023] In some embodiments, in step c), compound C-1 is reduced under (R)-2-methyl-CBS-oxazaborolidine conditions to form compound D-1. In some embodiments, the reducing agent used in the reduction of compound C-1 is borane.

[0024] Additionally, the method for preparing a compound of formula I-1 further comprises reacting compound D-1 with haloethane to form a compound of formula E-1, and then deprotecting compound E-1 to form a compound of formula I-1 or a salt thereof. [ka] .

[0025] In some embodiments, in the above method, the haloethane is selected from iodoethane or bromoethane. In other embodiments, compound D-1 is reacted with a haloethane, such as iodoethane, under silver oxide conditions to form compound E-1.

[0026] In some embodiments, compound E-1 is reacted under methylamine conditions to form compound I-1. Related experimental procedures are described in "Protective Groups in Organic Synthesis", 5 Th Reference may be made to Ed. TW Greene & P. ​​GMWuts, the relevant contents of which are incorporated herein by reference.

[0027] The present disclosure further provides a compound of formula D or a pharmaceutically acceptable salt thereof: [ka] , among which, R 1 is a halogen, a nitro group, a cyano group, C 1-6 Alkyl group or C 1-6 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl group or C 1-6 alkoxy groups, and n is 0, 1, 2, or 3.

[0028] In some embodiments, the compound of formula D is compound D-1. [ka] .

[0029] The present disclosure further provides a compound of formula C or a pharmaceutically acceptable salt thereof: [ka] , among which, R 1 is a halogen, a nitro group, a cyano group, C 1-6 Alkyl group or C 1-6 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl group or C 1-6 alkoxy groups, and n is 0, 1, 2, or 3.

[0030] In some embodiments, the compound of formula C is compound C-1 [ka] .

[0031] The present disclosure further provides a method for preparing compound AA, said method comprising the step of preparing a compound of formula I above. [ka] .

[0032] In some embodiments, the method of preparing compound AA further comprises reacting a compound of formula I-1 with compound F to form compound AA. [ka] For relevant experimental procedures, reference may be made to those described in WO2019062804, the relevant contents of which are incorporated herein by reference.

[0033] In another embodiment, the preparation method described herein further comprises one or more of the following operations: filtration, concentration, purification by column chromatography, and drying.

[0034] The terms "formation" and "conversion" used herein do not necessarily mean that the conversion reaction between two substrates is a single-step reaction, but may be a single-step or multi-step reaction between two substrates. When an intermediate contains a protecting group, the intermediate can be reacted with a corresponding substrate after removing the protecting group in one step to obtain the corresponding target product.

[0035] The values ​​in this disclosure are measured by instruments and have a certain degree of error, and generally, ±10% is within a reasonable error range. Of course, the context in which the value is used must be taken into consideration. For example, in the case of the particle size of an active ingredient, the value has an error variation of ±10% or less after measurement, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and preferably ±5%.

[0036] The pharmaceutically acceptable salt of the compound described in the present disclosure or its salts may be selected from inorganic salts or organic salts. "Acid" addition salts and "base" addition salts are included. For example, salts formed by an acid-base reaction with a basic group (amino group), the acid including organic and inorganic acids. In some embodiments, the salt of the compound represented by Formula I is an oxalate salt.

[0037] In the chemical structures of the compounds described in this disclosure, [ka] " bond indicates that no configuration is specified, i.e., if chiral isomers exist in the chemical structure, " [ka] " is a bond that [ka] " or " [ka] " or " [ka] " and " [ka] " may include both of these configurations at the same time.

[0038] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, and isopropyl groups. Alkyl groups can be optionally substituted or unsubstituted.

[0039] The term "alkoxy group" refers to an -O-(alkyl group), where alkyl is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups can be optionally substituted or unsubstituted.

[0040] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains from 3 to 6 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Cycloalkyl groups can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment.

[0041] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0042] The term "cyano" refers to -CN.

[0043] The term "amino group" refers to -NH2.

[0044] The term "nitro group" refers to -NO2.

[0045] The term "oxo" refers to a ═O substituent.

[0046] When the functional groups of the present disclosure are substituted, the substituents are preferably halogen, oxo, nitro, cyano, C 1-6 Alkyl group, C 1-6 Alkoxy group or C 3-6 One or more of the groups such as a cycloalkyl group. DETAILED DESCRIPTION OF THE INVENTION

[0047] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

[0048] Experimental methods for which specific conditions are not specified in the examples of this disclosure generally follow conventional conditions or conditions recommended by raw material or product manufacturers. Reagents for which specific sources are not specified are conventional commercially available reagents.

[0049] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are given in units of 10 −6 (ppm).

[0050] For the NMR measurement, a Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used, and the measurement solvent was deuterated chloroform (CDCl3).

[0051] For MS measurements, a triple quadrupole mass spectrometer, Waters Micromass Quattro micro API, was used, scanning in positive / negative ion mode with a mass scan range of 120-1300.

[0052] HPLC column: YMC-Pack ODS-A (3 μm, 4.6 mm × 150 mm) Yantai Huanghai HSGF254 silica gel plates were used for thin-layer chromatography. The specifications for silica gel plates used in thin-layer chromatography (TLC) were 0.2 mm ± 0.03 mm, and the specifications for separating and purifying products by thin-layer chromatography were 0.4 to 0.5 mm.

[0053] Example 1: Step 1) Preparation of (S)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione [ka] Raw material 1 (100.0 g, 1.0 eq.) and phthalic anhydride (100.0 g, 1.0 eq.) were added to a 1 L flask, the temperature was raised to about 140°C, and the reaction was allowed to proceed while maintaining the temperature. The completion of the reaction was detected by HPLC, and the temperature was gradually lowered. Crystallization was carried out with isopropanol (600 mL, 6.0 V), followed by filtration and drying to obtain 166.0 g of an off-white solid, with a yield of 88.3% and a purity of 98.8%. 1 HNMR(400MHz,DMSO-d6):δ 7.84-7.89(t.,4H),7.12-7.19(m,2H),7.01-7.06(m,1H),6.93-6.94(d,1H),5.36-5. 40(m,1H),2.80-2.87(m,2H),2.24-2.30(m,1H),2.02-2.05(m,2H),1.79-1.83(m,1H). LCMS(ESI):m / z 278[M+1] +

[0054] Step 2) Preparation of (S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione [ka] Compound 3 (60.0 g, 1.0 eq.), water (600 mL, 10.0 V), acetone (1200 mL, 20.0 V), and magnesium sulfate (52.1 g, 2.0 eq.) were added to a 5 L flask, and potassium permanganate (170.6 g, 5.0 eq.) was added at 0-10°C. After addition was complete, the mixture was allowed to warm to room temperature and react overnight. The completion of the reaction was detected by HPLC, and EA (1000 mL, 16.7 V) and water (1000 mL, 16.7 V) were added. The mixture was then saturated in an ice bath. The reaction was quenched with aqueous sodium thiosulfate solution, filtered, and the filter cake was rinsed with EA. The obtained filtrate was separated into layers, and the organic phase was washed once with 1000 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. EA (180 mL, 3.0 V) and petroleum ether (540 mL, 9.0 V) were added to the crude product, which was slurried, filtered, and dried under vacuum to obtain 48.5 g of an off-white solid, product 4, in a yield of 77.0% and a purity of 98.4%. 1 HNMR(400MHz,DMSO-d6):δ 7.87-7.95(t.,5H),7.51-7.55 (m,1H),7.41-7.45(m,1H), 7.24-7.26 (d, 1H), 5.71-5.75 (m, 1H), 2.91-2.95 (m, 1H), 2.71-2.76 (m, 2H), 2.28-2.30 (m, 1H). LCMS(ESI):m / z 292[M+1] + .

[0055] Step 3) Preparation of 2-((1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione [ka] Compound 4 (95.0 g, 1.0 eq.), (R)-2-methyl-CBS-oxazaborolidine (9.0 g, 0.1 eq.), and THF (475.0 mL, 5.0 V) were added to a 1 L reaction flask, and the mixture was stirred to clarify. 1 M borane / tetrahydrofuran (176 mL, 0.54 eq.) was added dropwise in an ice bath. After the addition was complete, the mixture was allowed to warm to about 0°C to react. The completion of the reaction was detected by HPLC, and 20 mL of acetic acid was slowly added dropwise to quench the reaction. EA (500 mL) and water (500 mL) were added, extracted, and the layers were separated. The aqueous phase was back-extracted with EA (300 mL). The organic phases were combined, washed once with 300 mL of water, and once with 300 mL of 5% sodium bicarbonate. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 93.7 g of product 5 as an off-white solid. The yield was 97.9%, and 93.6% of the product (2.6% diastereomers) was detected by HPLC. 1HNMR(400MHz, DMSO-d6):δ 7.86-7.89(m,4H),7.54-7.56(d,1H),7.20-7.24(t,1H),7.08-7.11(t,1H),6.91-6.93(d,1H),5.38-5.4 2(m,2H),4.70-4.73(m,1H),2.31-2.35(m,1H),2.19-2.23(m,1H),2.06-2.19(m,1H),1.71-1.75(m,1H). LCMS(ESI):m / z 276[M-17] + (EM=293).

[0056] Step 4) Preparation of 2-((1S,4S)-4-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione [ka] Compound 5 (83.27 g, 1.0 eq.), silver oxide (131.6 g, 2.0 eq.), 4A powdered molecular sieves (249.8 g, 3.0 wt.), tetrabutylammonium iodide (209.7 g, 2.0 eq.), and dichloromethane (832 mL, 10.0 V) were added to a reaction flask in this order, and finally iodoethane (398.5 g, 9.0 eq.) was added. The external temperature was raised to 40°C to carry out the reaction. In-process control by HPLC showed that the raw materials were less than 1.0%. After cooling to room temperature, The mixture was heated, filtered through diatomaceous earth, the filter cake was rinsed with dichloromethane (249 mL, 3 V), the filtrate was concentrated to dryness, ethyl acetate (832 mL, 10 V) was added, the mixture was slurried at room temperature, filtered, the filter cake was rinsed with ethyl acetate (249 mL, 3 V), the filtrate was washed twice with purified water (416 mL × 2, 5 V × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 92.8 g of crude product with a purity of 93.6%. The crude product was used directly in the next step. 1HNMR(400MHz,CDCl3):δ 7.81-7.85(m,2H),7.71-7.75(m,2H),7.55-7.57(d,1H),7.23-7.26(t,1H),7.11-7.15(t,1H),6.92-6.94(d,1H),5.56-5.6 0(m,1H),4.69-4.72(m,1H),3.71-3.80(m,2H),2.36-2.46(m,2H),2.21-2.26(m,1H),1.85-1.88(m,1H),1.30-1.33(t,3H). LCMS(ESI):m / z 276[M-45] + (EM=321).

[0057] Step 5) Preparation of (1S,4S)-4-ethoxy-1,2,3,4-tetrahydro-1-naphthylamine [ka] Compound 6 (80.0 g) and methanol (640 mL, 8V) were placed in a 1 L three-neck flask and heated to 50 °C with stirring to dissolve. A 30% aqueous solution of methylamine (411.5 g) was added and the reaction was continued with stirring for 20 to 24 h while maintaining the internal temperature at 45-55 °C. The reaction was then completed. The mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography to obtain compound 7 (37.7 g, off-white solid). The HPLC purity was 98.6%, the chiral purity was 99.7%, and the two-step yield was 80.6%. 1H NMR(400MHz,DMSO-d6):δ 7.46(d,J=7.34Hz,1H),7.29(d,J=7.34Hz,1H),7.12-7.26(m,2H),4.37(s,1H),3.83(s,1H),3.60(d,J=6.85Hz,1H),3 .48(d,J=6.85Hz,1H),2.01-2.19(m,2H),1.87(br,2H),1.65-1.75(m,1H),1.39-1.52(m,1H),1.14(d,J=6.97Hz,3H). LCMS(ESI):m / z 192[M+H] + .

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