Deuterated phenol derivatives, methods of making and uses thereof

Abstract

The present application relates to deuterated compounds of Compound A or pharmaceutically acceptable salts or stereoisomers thereof, wherein one or more hydrogens in said Compound A are replaced by deuterium, for use in the treatment of diseases related to the central nervous system

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically relates to deuterated phenol derivatives, preparation methods, and uses thereof. Background Art

[0002] CBG (Cannabigerol), first discovered in the 1960s, is a non-psychoactive cannabinoid. CBG interacts with both CB1 and CB2 cannabinoid receptors and has been shown to be an α-2 adrenergic receptor agonist and a 5-hydroxytryptamine 1A receptor antagonist. CBG has a wide range of therapeutic properties, including antimicrobial, anti-inflammatory, neuroprotective, neuropathic pain relief, anti-tumor growth, appetite stimulation, and intraocular pressure reduction. It holds potential for the treatment of neurological disorders, inflammatory bowel disease, and cancer. However, CBG is present in trace amounts in most cannabis plants, with common strains containing less than 1%, resulting in high production costs. Therefore, structural modification of CBG and the development of low-cost processes remain hot topics of research. Summary of the Invention

[0003] One or more embodiments of the present application provide a deuterated compound of Compound A or a pharmaceutically acceptable salt or stereoisomer thereof:

[0004]

[0005] wherein one or more hydrogen atoms in the compound A are replaced by deuterium.

[0006] In one or more embodiments, 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) hydrogen atoms in compound A are replaced by deuterium.

[0007] In one or more embodiments, the deuterated compound is:

[0008]

[0009] One or more embodiments of the present application provide an intermediate for preparing a deuterated compound of compound A, wherein the intermediate is a deuterated compound of the following compound:

[0010]

[0011]

[0012] wherein one or more hydrogen atoms in Compound AI, Compound BI, Compound A-II, and Compound A-III are replaced by deuterium. In one or more embodiments, 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) hydrogen atoms in the intermediates are replaced by deuterium.

[0013] In one or more embodiments, the intermediate is:

[0014]

[0015] One or more embodiments of the present application provide a method of preparing deuterated Compound A, comprising the steps of:

[0016]

[0017] wherein one or more hydrogens in Compound A-III, Compound B-I, and Compound A are replaced with deuterium. In one or more embodiments, 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) hydrogens in the above intermediate are replaced with deuterium.

[0018] In one or more embodiments, the above method of preparation comprises the steps of:

[0019]

[0020] wherein

[0021] Step 1: reacting deuterated Compound A-I and p-toluenesulfonic acid in dichloromethane to obtain Compound B-I;

[0022] Step 2: reacting the Compound B-I’, Compound A-III, and acidic alumina in dichloroethane to obtain deuterated Compound A.

[0023] In one or more embodiments, the above method of preparation comprises the steps of:

[0024]

[0025] Step 1: reacting deuterated lithium aluminum hydride, Compound B-VII in a tetrahydrofuran organic solvent to obtain Compound B-VIII;

[0026] Step 2: reacting Compound B-VIII, Compound A-III, acidic alumina in a dichloroethane organic solvent to obtain deuterated Compound A.

[0027] In one or more embodiments, the above method of preparation comprises the steps of:

[0028]

[0029] Step 1: reacting deuterated lithium aluminum hydride, Compound B-IX in a tetrahydrofuran organic solvent to obtain Compound B-X;

[0030] Step 2: adding phosphorus tribromide dropwise to a dichloromethane solution of Compound B-X to obtain deuterated Compound A-II;

[0031] Step 3: adding n-butylmagnesium bromide dropwise to the deuterated compound A-II and dilithium tetrachlorocuprate in dichloromethane organic solvent to react to obtain compound B-XI;

[0032] Step 4: adding boron tribromide dropwise to a dichloromethane solution of the compound B-XI to obtain a deuterated compound A-III;

[0033] Step 5: reacting the deuterated compound A-III, (E)-3,7-dimethylocta-2,6-dien-1-ol, and acidic alumina in dichloroethane organic solvent to obtain the deuterated compound A.

[0034] In one or more embodiments, the preparation method comprises the following steps:

[0035]

[0036] Deuterated compound A-III, compound B-VIII and acidic alumina are reacted in dichloroethane organic solvent to obtain deuterated compound A.

[0037] In one or more embodiments, the preparation method comprises the following steps:

[0038]

[0039] Step 1: Compound B-II and triethyl phosphoacetate react in a solution of sodium hydride in tetrahydrofuran to obtain compound B-III;

[0040] Step 2: Add diisobutylaluminum hydride dropwise to the tetrahydrofuran solution of the compound B-III to react and obtain compound B-IV;

[0041] Step 3: adding 3,4-dihydro-2H-pyran and p-toluenesulfonic acid dropwise to the dichloromethane solution of the compound B-IV to react to obtain compound BV;

[0042] Step 4: reacting the compound BV with triphenylphosphine in acetonitrile to obtain compound B-VI;

[0043] Step 5: adding lithium bis(trimethylsilyl)amide dropwise to the tetrahydrofuran solution of the compound B-VI for reaction, and then adding deuterated acetone dropwise for reaction to obtain the deuterated compound AI;

[0044] Step 6: reacting the deuterated AI compound with p-toluenesulfonic acid in anhydrous ethanol to obtain compound B-I';

[0045] Step 7: reacting the compound B-I', compound A-III and acidic aluminum oxide in dichloroethane to obtain deuterated compound A.

[0046] One or more embodiments of the present application provide a pharmaceutical composition comprising:

[0047] The deuterated compound of the present application or its pharmaceutically acceptable salt or stereoisomer;

[0048] optionally one or more other active ingredients; and

[0049] Pharmaceutically acceptable carriers and / or excipients.

[0050] One or more embodiments of the present application provide use of the deuterated compound or composition of the present application in the preparation of a drug for treating a disease related to the central nervous system. In one or more embodiments, the disease related to the central nervous system is pain or epilepsy.

[0051] One or more embodiments of the present application provide a deuterated compound or composition of the present application, which is used as a medicine.

[0052] One or more embodiments of the present application provide a deuterated compound or composition of the present application for treating and / or inhibiting a disease related to the central nervous system. In one or more embodiments, the disease related to the central nervous system is pain or epilepsy.

[0053] One or more embodiments of the present application provide a method for treating and / or inhibiting a central nervous system-related disease, comprising administering a deuterated compound or composition of the present application to a subject in need thereof. In one or more embodiments, the central nervous system-related disease is pain or epilepsy. Detailed Description of the Invention

[0055] In one or more embodiments, the compounds of the present application show good therapeutic potential for central nervous system-related diseases such as pain and epilepsy.

[0056] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0057] Deuterium in this application is also called heavy hydrogen, which is an isotope of hydrogen and can be represented by D.

[0058] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the salt of the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the salt of the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0059] "Pharmaceutical composition" refers to a mixture of one or more compounds of the application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0060] "Carrier" refers to a material that does not itself induce the production of antibodies to it, and it does not have a significant stimulating effect on the organisms in which it is present in amounts normally used in a pharmaceutical composition.

[0061] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, and disintegrating agents.

[0062] "Stereoisomers" refers to isomers that have the same molecular formula but different physical properties, such as different melting points, boiling points, and / or solubilities. Stereoisomers include enantiomers (mirror-image nontwist-able isomers) and diastereomers (nonmirror-image nontwist-able isomers). Stereoisomers can be designated as "R" or "S" depending on the orientation of the molecule's atoms in space.

[0063] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group can or can not be present, and the description includes instances where the heterocyclyl is substituted with alkyl, and instances where the heterocyclyl is not substituted with alkyl.

[0064] "THP" means 2-tetrahydropyranyl. DETAILED DESCRIPTION

[0065] Example 1

[0066]

[0067] First Step:

[0068] (E)-6-bromo-3-methylhexadec-2-enoic acid ethyl ester

[0069] ethyl (E)-6-bromo-3-methylhex-2-enoate 1b

[0070]

[0071] To a solution of sodium hydride (1.4 g, 36.0 mmol) in tetrahydrofuran (100 mL) was added triethyl phosphonoacetate (8.1 g, 36.0 mmol) and 5-bromo-2-pentanone 1a (5.0 g, 30.0 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h after the addition was completed. The reaction was quenched by the addition of water (100 mL) at 0 °C. The organic phase was extracted with petroleum ether (100 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the title compound (E)-6-bromo-3-methylhexadec-2-en-1-yl acetate 1b (colorless oil, 5.1 g, yield: 72.0%).

[0072] LC-MS m / z (ESI) = 235.1 [M+1]

[0073] Second step:

[0074] (E)-6-bromo-3-methylhexadec-2-en-1-ol

[0075] (E)-6-bromo-3-methylhexadec-2-en-1-ol 1c

[0076]

[0077] To a solution of sodium hydride (1.4 g, 36.0 mmol) in tetrahydrofuran (100 mL) was added triethyl phosphonoacetate (8.1 g, 36.0 mmol) and 5-bromo-2-pentanone 1a (5.0 g, 30.0 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h after the addition was completed. The reaction was quenched by the addition of water (100 mL) at 0 °C. The organic phase was extracted with petroleum ether (100 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the title compound (E)-6-bromo-3-methylhexadec-2-en-1-yl acetate 1b (colorless oil, 5.1 g, yield: 72.0%).

[0078] LC-MS m / z (ESI) = 175.0 [M-17]

[0079] Third step:

[0080] (E)-2-((6-bromo-3-methylhexadec-2-en-1-yl)oxy)tetrahydro-2H-pyran

[0081] (E)-2-((6-bromo-3-methylhex-2-en-1-yl)oxy)tetrahydro-2H-pyran 1d

[0082]

[0083] 3,4-Dihydro-2H-pyran (2.8 mL, 33.0 mmol) and p-toluenesulfonic acid (0.14 g, 0.83 mmol) were added dropwise to a solution of compound 1c (3.2 g, 16.5 mmol) in dichloromethane (40 mL) at 0°C under nitrogen. The mixture was heated to room temperature and stirred for 1 h. The reaction was complete by TLC. Saturated sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The aqueous phase was extracted with petroleum ether (30 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 20) to give the title compound (E)-2-((6-bromo-3-methylhexadec-2-en-1-yl)oxy)tetrahydro-2H-pyran 1d (yellow oil, 4.3 g, yield: 93.0%).

[0084] 1 H NMR (400MHz, CDCl3) δ5.42-5.36(m,1H),4.64-4.58(m,1H),4.22(dd,J=12.0,6.4Hz,1H),4.01(dd,J=12.0,7.2Hz,1H),3.87(ddd,J=11.2,7.6,3.3H z,1H),3.49(dd,J=11.0,5.2Hz,1H),3.37(t,J=6.7Hz,2H),2.19-2.13(m, 2H),2.02-1.93(m,2H),1.91-1.76(m,2H),1.66(s,3H),1.56-1.45(m,4H).

[0085] Step 4:

[0086] (E)-(4-Methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)hexadec-4-en-1-yl)triphenylphosphonium bromide

[0087] (E)-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)hex-4-en-1-yl)triphenylphosphonium bromide 1e

[0088]

[0089] Compound 1d (3.6 g, 12.0 mmol), triphenylphosphine (5.1 g, 19.0 mmol) and acetonitrile (4 mL) were added sequentially to a reaction flask. The temperature was raised to 80°C under nitrogen and stirred for 16 h. The reaction was detected by TLC. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was added with isopropyl ether (50 mL) and slurried for 30 min. The mixture was filtered with suction and the filter cake was dried to obtain the title compound (E)-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)hexadec-4-en-1-yl)triphenylphosphine bromide 1e (yellow solid, 6.8 g, yield: 99.0%).

[0090] Step 5:

[0091] (E)-2-((3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)oxy)tetrahydro-2H-pyran

[0092] (E)-2-((3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)oxy)tetrahydro-2H-pyran 1f

[0093]

[0094] At -78 ° C, under nitrogen protection, lithium bis(trimethylsilyl)amide (13.0 mL, 12.6 mmol) was added dropwise to a solution of compound 1e (6.8 g, 12.6 mmol) in tetrahydrofuran (90 mL). After the addition was complete, the mixture was stirred and reacted for 0.5 h. Deuterated acetone (0.8 g, 12.6 mmol) was added dropwise, and the temperature was returned to 0 ° C and stirred for 2 h. The reaction was detected by TLC. Water (100 mL) was added to quench the reaction. Petroleum ether (100 mL × 2) extraction, washing with saturated brine (100 mL), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the title compound (E)-2-((3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)oxy)tetrahydro-2H-pyran 1f (colorless oil, 2.6 g, yield: 85.0%).

[0095] Step 6:

[0096] (E)-3-Methyl-7-(methyl-d3)octa-2,6-diene-8,8,8-d3-1-ol

[0097] (E)-3-methyl-7-(methyl-d3)octa-2,6-dien-8,8,8-d3-1-ol 1g

[0098]

[0099] To the reaction flask was added compound 1f (2.6 g, 11.0 mmol), p-toluenesulfonic acid (0.2 g, 1.1 mmol) and anhydrous ethanol (10 mL) successively, stirred at room temperature for 2 h under nitrogen protection; TLC detection until the reaction was completed; concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL) respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 2) to obtain the title compound (E)-3-methyl-7-(methyl-d3)octa-2,6-dien-8,8,8-d3-1-ol 1g (colorless oil, 0.62 g, yield: 36.0%).

[0100] 1 H NMR (400 MHz, DMSO) δ 5.26 (t, J = 6.4 Hz, 1H), 5.08 (t, J = 6.9 Hz, 1H), 4.44 (dd, J = 10.1, 4.9 Hz, 1H), 3.93 (t, J = 5.8 Hz, 2H), 2.07-2.00 (m, 2H), 1.99-1.94 (m, 2H), 1.57 (s, 3H).

[0101] LC-MS m / z (ESI) = 143.20 [M-17]

[0102] Seventh step:

[0103] (E)-2-(3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)-5-pentylbenzene-1,3-diol

[0104] (E)-2-(3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)-5-pentylbenzene-1,3-diol compound 1

[0105]

[0106] Compound 1g (0.6 g, 3.8 mmol), 3,5-dihydroxypentylbenzene 1h (1.0 g, 5.6 mmol), acidic alumina (7.6 g, 75.0 mmol) and dichloroethane (20 mL) were added to the reaction flask in sequence. The temperature was raised to 85°C under nitrogen protection and stirred for 30 min. TLC was used to detect the completion of the reaction. The mixture was cooled to room temperature, filtered, rinsed with ethyl acetate (30 mL×3), and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to obtain the title compound (E)-2-(3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)-5-pentylbenzene-1,3-diol compound 1 (white solid, 0.73 g, yield: 60.0%).

[0107] 1 H NMR (400MHz, DMSO) δ8.85(s,2H),6.08(s,2H),5.17(t,J=5.1Hz,1H),5.05(t,J=6.9Hz,1H),3.12(d,J=7.0Hz,2H),2.32(t,J=7.5Hz,2H),1. 98(dd,J=9.8,5.2Hz,2H),1.91-1.85(m,2H),1.69(s,3H),1.46(dd,J=14.3,7.1Hz,2H),1.26(dt,J=15.1,5.4Hz,4H),0.86(t,J=6.9Hz,3H).

[0108] LC-MS m / z (ESI) = 323.30 [M+1]

[0109] Example 2

[0110]

[0111] first step:

[0112] (E)-3,7-Dimethylocta-2,6-dien-1,1-d2-1-ol

[0113] (E)-3,7-dimethylocta-2,6-dien-1,1-d2-1-ol 2b

[0114]

[0115] Deuterated lithium aluminum hydride (2.3 g, 54.0 mmol) was added portionwise to a solution of (E)-methyl 3,7-dimethylocta-2,6-dienoate (5.0 g, 27.0 mmol) in tetrahydrofuran (50 mL) at -30 °C under nitrogen protection, and the reaction was stirred for 1 h after the addition; TLC detection until the reaction was completed; the reaction was quenched by dropwise addition of water (50 mL), extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 1) to give the title compound 2b (colorless oil, 4.2 g, yield: 97.0%).

[0116] LC-MS m / z (ESI) = 139.2 [M-17]

[0117] Second step:

[0118] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl-1,1-d2)-5-pentylbenzene-1,3-diol

[0119] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl-1,1-d2)-5-pentylbenzene-1,3-diol compound 2

[0120]

[0121] To the reaction bottle, compound 2b (0.8 g, 5.1 mmol), 3,5-dihydroxy pentylbenzene (1.1 g, 6.1 mmol), acidic aluminum oxide (10.0 g, 0.10 mol) and dichloroethane (26 mL) were added in turn, and the reaction was stirred at 85 °C under nitrogen protection for 30 min; TLC detection until the reaction was completed; cooled to room temperature, suction filtered, eluted with ethyl acetate (30 mL*3), and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the title compound 2 (white solid, 0.38 g, yield: 24.0%).

[0122] 1H NMR (400MHz, DMSO) δ8.85(s,2H),6.08(s,2H),5.15(s,1H),5.04(t,J=6.9Hz,1H),2.32(t,J=7.6Hz,2H),1.99(dd,J=14.6,6.9Hz,2H),1.93–1 .83(m,2H),1.69(d,J=1.1Hz,3H),1.60(s,3H),1.52(d,J=9.4Hz,3H),1.46(dd,J=14.7,7.2Hz,2H),1.31–1.22(m,4H),0.85(t,J=7.0Hz,3H).

[0123] LC-MS m / z (ESI) = 319.0 [M+1]

[0124] Example 3

[0125]

[0126] first step:

[0127] (3,5-Dimethoxyphenyl)methane-d2-ol

[0128] (3,5-dimethoxyphenyl)methan-d2-ol 3b

[0129]

[0130] At 0°C under nitrogen, lithium aluminum hydride (2.4 g, 56.0 mmol) was added portionwise to a solution of methyl 3,5-dimethoxybenzoate (5.0 g, 26.0 mmol) in tetrahydrofuran (50 mL). The reaction was stirred for 1 h after the addition was completed. TLC was used to monitor the reaction until completion. Water (50 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3b (colorless oil, 4.3 g, yield: 99.0%).

[0131] LC-MS m / z (ESI) = 171.2 [M+1]

[0132] Step 2:

[0133] 1-(Bromomethyl-d2)-3,5-dimethoxybenzene

[0134] 1-(bromomethyl-d2)-3,5-dimethoxybenzene 3c

[0135]

[0136] Phosphorus tribromide (6.4 g, 23.0 mmol) was added dropwise to a solution of compound 3b (3.8 g, 22.0 mmol) in dichloromethane (50 mL) at 0 °C under nitrogen atmosphere. After the addition was complete, the reaction was stirred for 0.5 h. TLC monitoring showed that the reaction was complete. The reaction was quenched by the addition of water (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3c (white solid, 2.8 g, yield: 54.0%).

[0137] 1 H NMR (400 MHz, DMSO) δ 6.61 (d, J = 2.3 Hz, 2H), 6.44 (t, J = 2.3 Hz, 1H), 3.74 (s, 6H).

[0138] LC-MS m / z (ESI) = 233.5 [M+1]

[0139] Third Step:

[0140] 1,3-Dimethoxy-5-(pentyl-1,1-d2)benzene

[0141] 1,3-dimethoxy-5-(pentyl-1,1-d2)benzene 3d

[0142]

[0143] n-Butyl magnesium bromide (16.0 mL, 14.0 mmol, 1 N) was added dropwise to a solution of compound 3c (3.2 g, 12.0 mmol), lithium copper chloride (14.0 mL, 1.2 mmol, 0.1 N), and dichloromethane (40 mL) at 0 °C under nitrogen atmosphere. After the addition was complete, the reaction was stirred for 15 h at room temperature. TLC monitoring showed that the reaction was complete. The reaction was quenched by the addition of saturated ammonium chloride solution (20 mL). The organic phase was extracted with ethyl acetate (50 mL x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 30) to give the title compound 3d (colorless oil, 1.9 g, yield: 67.8%).

[0144] 1 H NMR (400 MHz, CDCl3) δ 6.35 (d, J = 2.2 Hz, 2H), 6.30 (t, J = 2.2 Hz, 1H), 3.78 (s, 6H), 1.60 (d, J = 7.3 Hz, 2H), 1.31 (dd, J = 8.3, 4.7 Hz, 4H), 0.89 (t, J = 6.8 Hz, 3H).

[0145] LC-MS m / z (ESI) = 211.4 [M+1]

[0146] Step 4:

[0147] 5-(Pentyl-1,1-d2)benzene-1,3-diol

[0148] 5-(pentyl-1,1-d2)benzene-1,3-diol 3e

[0149]

[0150] Boron tribromide (2.6 mL, 27.0 mmol) was added dropwise to a solution of compound 3d (1.9 g, 9.0 mmol) in dichloromethane (30 mL) at 0°C under nitrogen. The mixture was heated to room temperature and stirred for 1.5 h. The reaction was completed by TLC. Saturated sodium bicarbonate solution (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL × 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 2) to give the title compound 3e (white solid, 1.5 g, yield: 90.3%).

[0151] 1 H NMR (400MHz, DMSO) δ9.00 (s, 2H), 6.00 (dt, J = 4.1, 2.1Hz, 3H), 1.49–1.43 (m, 2H), 1.25 (ddd, J = 9.0, 7.1, 4.4Hz, 4H), 0.85 (t, J = 7.0Hz, 3H).

[0152] LC-MS m / z (ESI) = 183.2 [M+1]

[0153] Step 5:

[0154] (E)-2-((3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)oxy)tetrahydro-2H-pyran

[0155] (E)-2-((3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)oxy)tetrahydro-2H-pyran compound 3

[0156]

[0157] Into a reaction flask was added compound 3e (0.4 g, 2.7 mmol), (E)-3,7-dimethylocta-2,6-dien-1-ol (0.5 g, 2.7 mmol), acidic alumina (5.5 g, 55.0 mmol) and dichloroethane (15 mL) successively, and the reaction was stirred at 85 °C for 30 min under nitrogen protection; TLC detection until the reaction was completed; cooled to room temperature, suction filtered, washed with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to obtain the title compound 3 (white solid, 0.24 g, yield: 29.0%).

[0158] 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 6.08 (s, 2H), 5.16 (t, J = 6.5 Hz, 1H), 5.04 (t, J = 6.9 Hz, 1H), 3.12 (d, J = 7.1 Hz, 2H), 1.99 (dd, J = 14.8, 7.0 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H), 1.48 - 1.42 (m, 2H), 1.30 - 1.22 (m, 4H), 0.85 (t, J = 7.0 Hz, 3H).

[0159] LC-MS m / z (ESI) = 319.3 [M+1]

[0160] Example 4

[0161]

[0162] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl-1,1-d2)-5-(pentyl-1,1-d2)benzene-1,3-diol

[0163] (E)-2-(3,7-dimethylocta-2,6-dien-1-yl-1,1-d2)-5-(pentyl-1,1-d2)benzene-1,3-diol

[0164]

[0165] Into a reaction flask was added 5-(pentyl-1,1-d2)benzene-1,3-diol (0.50 g, 2.74 mmol), (E)-3,7-dimethylocta-2,6-dien-1,1-d2-1-ol (0.43 g, 2.74 mmol), acidic alumina (5.60 g, 0.06 mol) and dichloroethane (15 mL) successively, and the reaction was stirred at 85 °C for 30 min under nitrogen protection; TLC detection until the reaction was completed; cooled to room temperature, suction filtered, eluted with ethyl acetate (50 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 1 / 10) to obtain the title compound 4 (white solid, 72 mg, yield: 8.3%).

[0166] 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 6.07 (s, 2H), 5.15 (s, 1H), 5.04 (t, J = 6.3 Hz, 1H), 1.98 (t, J = 7.1 Hz, 2H), 1.93-1.82 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H), 1.45 (t, J = 7.0 Hz, 2H), 1.31-1.21 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H).

[0167] LC-MS m / z (ESI) = 321.5 [M+1]

[0168] Mouse pharmacokinetics

[0169] Six adult healthy ICR mice were divided into two groups (3 mice in each group), one group was given intravenous injection (i.v) of the control compound (CBG) (1 mg / kg), and the other group was given intravenous injection (i.v) of compound 4 (1 mg / kg). Blood samples (0.1 mL) were taken from the orbit before administration (0 h) and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h after administration. All blood samples were anticoagulated with EDTA-K2, then centrifuged at 3500 rpm for 10 min at 5 °C to separate the plasma, which was stored at -20 °C for testing. LC / MS method was established to determine the drug concentration in plasma. Note: The control compound was prepared according to WO2017216362.

[0170] Using the above method, the pharmacokinetics of the test compound was measured as follows:

[0171] AUCall (ng*h / mL) t1 / 2 (h) CL (mL / min / kg) Control Compound 113 0.40 145.1 Compound 4 244 0.99 66.1

[0172] According to the experimental results, the deuterated compound 4 of the present invention showed significantly better pharmacokinetic characteristics than the control compound in mice, indicating that the compound of the present invention will have significantly excellent pharmacokinetic trends.

[0173] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A deuterated compound A or a pharmaceutically acceptable salt thereof, wherein the deuterated compound A is:

2. A method for preparing a deuterated compound A, comprising the following steps: Deuterated compound A-III, compound B-VIII and acidic alumina are reacted in dichloroethane organic solvent to obtain deuterated compound A.

3. Use of the deuterated compound A according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to the central nervous system.

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