Preparation method of tetrahydro-1-naphthylamine and derivatives thereof

Abstract

The invention relates to a preparation method of tetrahydro-1-naphthylamine and a derivative thereof. Specifically, the invention relates to a preparation method of (1S, 4S)-4-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-amine, and the method comprises the step of reacting a compound C-1 under the condition of (R)-2-methyl-CBS-oxazolidine to form a compound D-1. The method is simple to operate and suitable for industrial production. # imgabs0 #

Description

A preparation method of tetrahydro-1-naphthylamine and its derivatives Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing tetrahydro-1-naphthylamine and its derivatives. Background Art

[0002] Chiral amines are structural components or fragments of numerous important biologically active compounds. 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 a method of using (S)-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester as a starting material, obtaining (1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester under chiral reducing agent conditions, and then etherifying and deprotecting to obtain the target product.

[0004] Summary of the Invention

[0005] The present disclosure provides a method for preparing a compound represented by formula I or a salt thereof,

[0006] The method comprises the steps of reacting the compound represented by formula C under (R)-2-methyl-CBS-oxazaborolidine conditions to form the compound represented by formula D,

[0007] Among them, R 1 Selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy is substituted, n is 0, 1, 2 or 3, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the alkyl or cycloalkyl is optionally substituted by one or more selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted with a cycloalkyl group.

[0008] 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 numbers. In some embodiments, the molar ratio of (R)-2-methyl-CBS-oxazaborolidine to the compound of Formula C in the method is 1:10.

[0009] In some embodiments, the process of reacting the compound shown in Formula C to form the compound shown in Formula D further contains a reducing agent, and the reducing agent is selected from but not limited to borane. In some embodiments, the amount of borane used in the method is 0.5 to 1 equivalents (eq.) of the molar amount of the compound shown in Formula C, including but not limited to 0.5 equivalents, 0.6 equivalents, 0.7 equivalents, 0.8 equivalents, 0.9 equivalents, 1.0 equivalents or any value between two numbers. In some embodiments, the amount of borane used in the method is 0.8 to 1 equivalents (eq.) of the molar amount of the compound shown in Formula C.

[0010] In other embodiments, the solvent used in the reaction of the compound shown in Formula C is selected from but not limited to toluene or tetrahydrofuran. In some embodiments, the solvent used in the reaction of the compound shown in Formula C is tetrahydrofuran.

[0011] On the other hand, the reaction temperature of the compound represented by Formula C is -10 to 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 numbers.

[0012] Furthermore, 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 conditions to form a compound of Formula C,

[0013] where R 1 and n are as defined above.

[0014] In some embodiments, the oxidant is selected from, but not limited to, potassium permanganate or sodium hypochlorite. In some embodiments, the compound of formula B in the method reacts under potassium permanganate conditions to form the compound of formula C. In some embodiments, the reaction temperature of 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 numbers.

[0015] In some embodiments, the solvent used in the reaction of the compound of Formula B is acetone. In other embodiments, the amount of the oxidant used in the method is 1 to 6 equivalents (eq.) of the molar amount of the compound of Formula B, including but not limited to 1 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, or any value between two numbers.

[0016] Other embodiments provide methods for preparing a compound of Formula I or a salt thereof, further comprising the step of reacting a compound of Formula A with phthalic anhydride to form a compound of Formula B.

[0017] where R 1 and n are as defined above.

[0018] In some embodiments, the molar ratio of the compound of 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 numbers. In some embodiments, the molar ratio of the compound of formula A to phthalic anhydride in the method is 1:1.

[0019] In other embodiments, the solvent used in the reaction of the compound represented by Formula A is toluene.

[0020] In some embodiments, the method comprises the following steps:

[0021] a) the compound represented by formula A reacts with phthalic anhydride to form a compound represented by formula B,

[0022] b) the compound represented by formula B reacts under oxidizing conditions to form a compound represented by formula C,

[0023] c) the compound represented by formula C reacts under (R)-2-methyl-CBS-oxazaborolidine conditions to form a compound represented by formula D,

[0024] where R 1 and n are as defined above.

[0025] In other embodiments, the compound represented by Formula I in the method is a compound represented by Formula I-1,

[0026] The method comprises the steps of reacting compound C-1 under (R)-2-methyl-CBS-oxazaborolidine conditions to form compound D-1

[0027] In some embodiments, the method for preparing the compound of formula I-1 comprises the step of reacting compound B-1 with an oxidizing agent such as potassium permanganate to form compound C-1.

[0028] In other embodiments, the method for preparing the compound of formula I-1 comprises the step of forming compound B-1 by reacting compound A-1 with phthalic anhydride.

[0029] In some embodiments, the method for preparing the compound of formula I-1 comprises the following steps:

[0030] a) Compound A-1 reacts with phthalic anhydride to form Compound B-1,

[0031] b) Compound B-1 reacts with an oxidizing agent to form Compound C-1,

[0032] c) Compound C-1 reacts under (R)-2-methyl-CBS-oxazaborolidine conditions to form Compound D-1,

[0033] In some embodiments, in step a), compound A-1 is reacted with phthalic anhydride under heating conditions to form compound B-1.

[0034] In some embodiments, in step a), compound A-1 is reacted with phthalic anhydride in the presence of triethylamine to form compound B-1.

[0035] In some embodiments, step b) Compound B-1 is reacted under potassium permanganate conditions to form Compound C-1.

[0036] In some embodiments, 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.

[0037] Furthermore, the method for preparing the compound of formula I-1 further comprises the steps of reacting compound D-1 with ethane halide to form a compound of formula E-1, followed by deprotection of compound E-1 to form a compound of formula I-1 or a salt thereof.

[0038] In some embodiments, the ethyl halide in the method is selected from ethyl iodide or ethyl bromide. In other embodiments, compound D-1 is reacted with an ethyl halide such as ethyl iodide under silver oxide conditions to form compound E-1.

[0039] In some embodiments, compound E-1 is reacted under methylamine conditions to form a compound of formula I-1. Th Ed.TWGreene&P.GM Wuts, and the relevant contents are introduced into this text for illustration.

[0040] The present disclosure also provides a compound represented by formula D or a pharmaceutically acceptable salt thereof,

[0041] Among them, R 1 Selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 The moiety is substituted by an alkoxy group, and n is 0, 1, 2 or 3.

[0042] In some embodiments, the compound represented by formula D is compound D-1,

[0043] The present disclosure also provides a compound represented by formula C or a pharmaceutically acceptable salt thereof,

[0044] Among them, R 1 Selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 The moiety is substituted by an alkoxy group, and n is 0, 1, 2 or 3.

[0045] In some embodiments, the compound represented by formula C is compound C-1,

[0046] The present disclosure also provides a method for preparing compound AA, which comprises the steps of preparing the compound represented by formula I as described above,

[0047] In some embodiments, the method for preparing compound AA further comprises the step of reacting a compound of formula I-1 with compound F to form compound AA.

[0048] Relevant experimental operations can be found in WO2019062804, and the relevant content is introduced into this text for illustration.

[0049] On the other hand, the preparation method disclosed herein further comprises one or more steps of filtration, concentration, purification by column chromatography and drying.

[0050] The terms "form" and "convert" in this disclosure do not necessarily imply a single-step conversion reaction between two substrates; they may be a single-step or multi-step reaction between two substrates. If an intermediate contains a protecting group, the intermediate is subjected to a one-step removal of the protecting group and then reacted with the corresponding substrate to obtain the corresponding target product.

[0051] The numerical values ​​in this disclosure are instrumental measurements and are subject to a certain degree of error. Generally speaking, within a reasonable error range of plus or minus 10%. The context in which the numerical value is used must be considered. For example, the particle size of an active ingredient, where the error after measurement does not exceed plus or minus 10%, may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0052] The pharmaceutically acceptable salts of the compounds described in this disclosure, or their salts, may be selected from inorganic or organic salts. These include "acid" addition salts and "base" addition salts. For example, salts formed by acid-base reactions with basic groups (amino groups), wherein the acid comprises an organic acid or an inorganic acid. In some embodiments, the salt of the compound of Formula I is an oxalate.

[0053] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0054] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl. Alkyl groups can be optionally substituted or unsubstituted.

[0055] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups can be optionally substituted or unsubstituted.

[0056] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 6 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment.

[0057] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0058] The term "cyano" refers to -CN.

[0059] The term "amino" refers to -NH2.

[0060] The term "nitro" refers to -NO2.

[0061] The term "oxo" refers to a =0 substituent.

[0062] When the functional groups disclosed herein are substituted, the substituents are preferably one or more of the following groups, such as halogen, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl. DETAILED DESCRIPTION

[0063] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0064] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0065] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectroscopy (MS). NMR shifts (δ) are given in units of 10-6 (ppm).

[0066] NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the solvent was deuterated chloroform (CDCl3).

[0067] MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0068] HPLC column: YMC-Pack ODS-A (3 μm, 4.6 mm x 150 mm)

[0069] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0070] Embodiment 1:

[0071] Step 1 Preparation of (S)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione

[0072] To a 1 L flask, add raw material 1 (100.0 g, 1.0 eq.) and phthalic anhydride (100.0 g, 1.0 eq.), raise the temperature to about 140°C, and keep the reaction. The reaction is completed by HPLC detection, and the temperature is slowly lowered; crystallize with isopropanol (600 mL, 6.0 V), filter and dry to obtain 166.0 g of an off-white solid with a yield of 88.3% and a purity of 98.8%.

[0073] 1 HNMR (400MHz, DMSO-d6): δ7.84-7.89(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).

[0074] LCMS (ESI): m / z 278 [M+1] +

[0075] Step 2: Preparation of (S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione

[0076] 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; potassium permanganate (170.6 g, 5.0 eq.) was added at 0-10 °C; after addition, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction was completed by HPLC detection; EA (1000 mL, 16.7 V) was added, and water (1000 mL, 16.7V), and quench the reaction with a saturated aqueous sodium thiosulfate solution under an ice bath; filter, and rinse the filter cake with EA; the obtained filtrate is separated, and the organic phase is washed once with 1000 mL of water; the organic phase is dried over anhydrous sodium sulfate; filtered and concentrated to obtain a crude product; EA (180 mL, 3.0V) and petroleum ether (540 mL, 9.0V) are added to the crude product, slurried, filtered, and dried in vacuo to obtain product 4 as an off-white solid (48.5 g) with a yield of 77.0% and a purity of 98.4%.

[0077] 1HNMR (400MHz, DMSO-d6): δ7.87-7.95(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).

[0078] LCMS (ESI): m / z 292 [M+1] + .

[0079] Step 3) Preparation of 2-((1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione

[0080] 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 stirred to dissolve. 1 M borane / tetrahydrofuran (176 mL, 0.54 eq.) was added dropwise under an ice bath. After the addition was complete, the reaction was kept at around 0°C and the reaction was completed by HPLC. 20 mL of acetic acid was slowly added to quench the reaction. EA (500 mL) and water (500 mL) were added, and the mixture was extracted and separated. The aqueous phase was back-extracted with EA (300 mL). The combined organic phases were washed once with 300 mL of water and then once with 300 mL of 5% sodium bicarbonate. The organic phases were separated and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain 93.7 g of product 5 as an off-white solid with a yield of 97.9%. The yield of the product was 93.6% by HPLC (diastereomer content was 2.6%).

[0081] 1 HNMR (400MHz, DMSO-d6): δ7.86-7.89(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,1 H),5.38-5.42(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).

[0082] LCMS (ESI): m / z 276[M-17] + (EM=293).

[0083] Step 4) Preparation of 2-((1S,4S)-4-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione

[0084] 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.), dichloromethane (832 mL, 10.0 V) were added to the reaction flask in sequence, and finally iodoethane (398.5 g, 9.0 eq.) was added. The external temperature was raised to 40 ° C for reaction; the raw material was controlled to be less than 1.0% by HPLC. ; Cool to room temperature, filter with diatomaceous earth, rinse the filter cake with dichloromethane (249 mL, 3V), and concentrate the filtrate to dryness; add ethyl acetate (832 mL, 10V) and slurry at room temperature, filter, and rinse the filter cake with ethyl acetate (249 mL, 3V); wash the filtrate twice with purified water (416 mL*2, 5V*2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain 92.8 g of crude product with a purity of 93.6%. The crude product is directly used in the next step.

[0085] 1 HNMR (400MHz, CDCl3): δ7.81-7.85(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) ),5.56-5.60(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).

[0086] LCMS (ESI): m / z 276[M-45] + (EM=321).

[0087] Step 5) Preparation of (1S,4S)-4-ethoxy-1,2,3,4-tetrahydro-1-naphthylamine

[0088] Compound 6 (80.0 g) and methanol (640 mL, 8 V) were added to a 1 L three-necked flask, heated to 50°C, and stirred to dissolve. A 30% aqueous methylamine solution (411.5 g) was added and the reaction was stirred, maintaining an internal temperature of 45-55°C for 20-24 hours. The reaction was complete. The mixture was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by column chromatography afforded compound 7 (37.7 g, off-white solid) with an HPLC purity of 98.6%, a chiral purity of 99.7%, and a two-step yield of 80.6%.

[0089] 1H NMR (400MHz, DMSO-d6): δ7.46(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).

[0090] LCMS (ESI): m / z 192 [M+H] + .

Claims

1. A method for preparing a compound of formula I or a salt thereof, The method includes the step of reacting the compound shown by formula C under the condition of (R)-2-methyl-CBS-oxazaborolidine to form the compound shown by formula D. Among them, R 1 selected from halogen, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy being optionally substituted by one or more groups selected from halogen, oxo, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, n being 0, 1, 2 or 3, R 2 being selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, the alkyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.

2. The method according to claim 1, wherein the molar ratio of (R)-2-methyl-CBS-oxazaborolidine to the compound of formula C is 1:10 to 1:1, preferably 1:

10.

3. The method according to claim 1 or 2, further comprising reacting the compound of formula B under oxidizing conditions to form the compound of formula C, where R 1 and n are as defined in claim 1.

4. The method according to claim 3, wherein the oxidant is selected from potassium permanganate or sodium hypochlorite.

5. The method according to any one of claims 1-4, further comprising the step of reacting the compound of formula A with phthalic anhydride to form the compound of formula B, where R 1 and n are as defined in claim 1.

6. The method according to any one of claims 1-5, comprising the following steps: a) reacting the compound of formula A with phthalic anhydride to form the compound of formula B, b) reacting the compound of formula B under oxidizing conditions to form the compound of formula C, c) The compound shown by formula C reacts under the condition of (R)-2-methyl-CBS-oxazaborolidine to form the compound shown by formula D, where R 1 and n are as defined in claim 1.

7. The method according to any one of claims 1-6, wherein the compound of formula I is the compound of formula I-1, The method includes the step of reacting compound C-1 under (R)-2-methyl-CBS-oxazaborolidine conditions to form compound D-1 8. The method according to claim 7 further comprises the step of reacting compound D-1 with chloroethane to form compound E-1, and then deprotecting compound E-1 to form the compound of formula I-1.

9. A compound of formula D or a pharmaceutically acceptable salt thereof, Among them, R 1 Selected from halogen, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted by one or more substituents selected from halogen, oxo, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, and n is 0, 1, 2 or 3.

10. A compound of formula C or a pharmaceutically acceptable salt thereof, Among them, R 1 Selected from halogen, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy being optionally substituted by one or more substituents selected from halogen, oxo, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, and n is 0, 1, 2 or 3.

11. A method for preparing compound AA, the method comprising the method steps recited in any one of claims 1-8,

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