CN115260185A - Deuterated derivatives of corydaline and stepholidine and preparation method thereof - Google Patents

Deuterated derivatives of corydaline and stepholidine and preparation method thereof Download PDF

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CN115260185A
CN115260185A CN202210923366.0A CN202210923366A CN115260185A CN 115260185 A CN115260185 A CN 115260185A CN 202210923366 A CN202210923366 A CN 202210923366A CN 115260185 A CN115260185 A CN 115260185A
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benzyloxy
methoxy
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杨征
付健民
王尧德
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The disclosure relates to deuterated compounds having the structure shown in the formula, wherein R is 1 And R 2 Independently selected from H and C (Y) 4 ) 3 ，Y 1 、Y 2 、Y 3 And Y 4 Independently selected from H or D, and at least one hydrogen in the compounds shown is replaced by deuterium. The disclosure also relates to methods of making and uses of the compounds.

Description

Deuterated derivatives of corydaline and stepholidine and preparation method thereof
Technical Field
The invention relates to deuterated derivatives of corydaline and stepholidine, a preparation method thereof and application thereof in treating diseases.
Background
Many current drugs have poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major cause of candidate drug failure in clinical trials. While formulation techniques and prodrug strategies may be employed in some cases to improve certain ADME properties, these approaches generally fail to address the fundamental ADME issues that exist with many drugs and drug candidates.
A potentially attractive strategy for improving the metabolic properties of drugs is deuterium modification. In this approach, there are attempts to slow CYP-mediated drug metabolism or reduce undesirable metabolite formation by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Deuterium forms a stronger bond with carbon than hydrogen. In selected cases, the increased bond strength imparted by deuterium can positively affect ADME properties of a drug, creating the potential for improved efficacy, safety, and/or tolerability. Meanwhile, since deuterium is substantially the same size and shape as hydrogen, compared to the original chemical entity containing only hydrogen, replacement of hydrogen with deuterium is not expected to affect the biochemical potency and selectivity of the drug.
Disclosure of Invention
In one aspect, the present invention provides a deuterated compound having a structure represented by formula I below:
Figure BDA0003778601520000021
wherein R is 1 And R 2 Independently selected from H and C (Y) 4 ) 3 ，Y 1 、Y 2 、Y 3 And Y 4 Independently selected from H or D, and at least one hydrogen in the compounds shown is replaced by deuterium.
In one embodiment, R 1 Is H and R 2 Is CH 3 Or CD 3 Or R is 1 Is CH 3 And R 2 Is H or CD 3 。
In one embodiment, the compound contains 1-8 deuterations.
In one embodiment, the compound is selected from:
Figure BDA0003778601520000022
Figure BDA0003778601520000031
Figure BDA0003778601520000041
in another aspect, the present invention relates to a pharmaceutical composition comprising the deuterated compound described above.
In another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of schizophrenia, anxiety, depression, schizoaffective disorder, autism, gilles de la tourette syndrome, attention deficit syndrome, pain (including neuropathic or vascular pain), insomnia, bacterial infection, viral infection.
Detailed Description
The following is a detailed description provided to assist those skilled in the art in carrying out the invention. Modifications and variations of the embodiments described herein may be made by those of ordinary skill in the art without departing from the spirit or scope of the disclosure.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure (e.g., in the case of a group comprising more than one carbon atom, each number of carbon atoms falling within that range is provided). The present disclosure also contemplates that the upper and lower limits of these smaller ranges may independently be included in the smaller ranges, but are limited by any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those limits are also included in the disclosure.
The following terminology is used to describe the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.
As used herein in the specification and claims, the term "pharmaceutically acceptable" with respect to a substance used herein refers to a substance that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use when the substance is used in a pharmaceutical composition.
As used herein in the specification and claims, the terms "treat," "treating," and "therapy" refer to the alleviation of a disease or disorder and/or at least one of its attendant symptoms.
It will be appreciated that some variation in the abundance of natural isotopes occurs in the synthetic compounds, depending on the source of the chemical materials used in the synthesis. Thus, the preparation of ivagato will inherently contain a small amount of deuterated isotopologues (isotopologues). Despite this variation, the concentration of naturally abundant stable hydrogen and carbon isotopes is small and unimportant compared to the degree of substitution of stable isotopes by the compounds of the invention. See, e.g., wada, E et al, seikagaku,1994, 66; gannes, LZ et al, comp Biochem Physiol Mol Integr Physiol,1998, 119.
Both "D" and "D" refer to deuterium. "stereoisomers" refers to both enantiomers and diastereomers.
"substituted" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
In the compounds of the present invention, any atom not specifically labeled as a specific isotope is intended to mean any stable isotope of the atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen in its natural abundance isotopic composition. Also unless otherwise indicated, when a position is specifically designated as "D" or "deuterium", that position is understood to have deuterium at an abundance that is at least 3000 times as great as the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% incorporation of deuterium).
The invention also provides salts of the compounds of the invention. Salts of the compounds of the present invention are formed between an acid and a basic group of the compound (e.g., an amino functional group), or between a base and an acidic group of the compound (e.g., a carboxyl functional group). According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.
Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, and organic acids such as p-toluenesulfonic, salicylic, tartaric, acid tartaric, ascorbic, maleic, benzenesulfonic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, p-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acids, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, decanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
The medicaments of the invention are prepared in a known manner and in suitable dosages, using the usual solid or liquid excipients or diluents and the usual pharmaceutical industrial adjuvants corresponding to the type of application desired. Preferred preparations include administration forms suitable for oral use. Such administration forms include, for example, tablets, troches, film tablets, dragees, capsules, pills, powders, solutions, aerosols, or suspensions or sustained release forms.
The following examples are given to illustrate the present invention in more detail, but are not to be construed as limiting the scope of the present invention.
Preparation examples
Preparation of example 1
Synthesis of Compounds 01-0Q and 01-0H
Figure BDA0003778601520000071
Synthesis scheme 1
Figure BDA0003778601520000072
Experimental part
1. 2- (3-bromo-4-hydroxyphenyl) acetic acid methyl ester
Figure BDA0003778601520000081
Under nitrogen, liquid bromine (3.30mL, 64.41mmol) was added portionwise to a solution of methyl 2- (4-hydroxyphenyl) acetate (10.00g, 60.18mmol) in dichloromethane at 0 ℃ and stirred for 0.5 h. The reaction was allowed to return to room temperature and stirring was continued for 2 hours. The reaction solution was evaporated to dryness under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (3X 100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give methyl 2- (3-bromo-4-hydroxyphenyl) acetate (14.7g, 99%) as a pale yellow oil. The product was used directly in the next reaction without further purification. MS ESI calculated value C 9 H 9 BrO 3 [M-H] - 243.0,245.0, found experimentally 243.1,245.1; 1 H NMR(400MHz,DMSO-d 6 )δ10.15(s,1H),7.39(d,J＝2.1Hz,1H),7.09-7.06(m,1H),6.90(d,J＝8.3Hz,1H),3.61(s,3H),3.58(s,2H)。
2. 3 2- (3-bromo-4- (methoxy-d) phenyl) acetic acid methyl ester
Figure BDA0003778601520000082
Deuterated iodomethane (19.52g, 134.66mmol) was added to a suspension of methyl 2- (3-bromo-4-hydroxyphenyl) acetate (30.00g, 122.41mmol) and potassium carbonate (25.38g, 183.65mmol) in acetone (300 mL) at room temperature under nitrogen. The reaction was stirred at 60 ℃ for 16 hours. The organic solvent was evaporated under reduced pressure. The residue was diluted with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 500 mL), dried over anhydrous sodium sulfate and filtered. Evaporating the filtrate under reduced pressure to dryness to obtain light yellow oily 2- (3-bromo-4- (methoxy-d) 3 ) Phenyl) acetic acidMethyl ester (32.00g, 99%). The product was used in the next reaction without further purification. MS ESI calculated value C 10 H 8 D 3 BrO 3 [M+H] + 262.0,264.0, found experimentally 262.0,264.0; 1 H NMR(400MHz,DMSO-d 6 )δ7.50(d,J＝2.1Hz,1H),7.26-7.24(m,1H),7.06(d,J＝8.4Hz,1H),3.64(s,2H),3.62(s,3H)。
3. 3 2- (3-hydroxy-4- (methoxy-d) phenyl) acetic acid
Figure BDA0003778601520000091
Bis (8-quinolinic acid) copper (II) (2.01g, 5.72mmol) was added to 2- (3-bromo-4- (methoxy-d) 3 ) Phenyl) methyl acetate (10.00g, 38.15mmol) in 30% aqueous sodium hydroxide (60 mL). The reaction was stirred at 120 ℃ for 16 hours under nitrogen. The reaction solution was cooled to room temperature and then neutralized with concentrated hydrochloric acid. The reaction solution was filtered, the filtrate was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate (3 × 500 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give yellow 2- (3-hydroxy-4- (methoxy-d) 3 ) Phenyl) acetic acid (6.60g, 93%) as a solid. The product was used directly in the next reaction without further purification. MS ESI calculated value C 9 H 7 D 3 O 4 [M-H] - 184.1, found experimentally 184.1; 1 H NMR(400MHz,CDCl 3 )δ6.89(d,J＝2.1Hz,1H),6.83(d,J＝8.2Hz,1H),6.82-6.76(m,1H),5.63(s,1H),3.58(s,2H)。
4. 3 8-hydroxy-7- (methoxy-d) isochroman-3-one
Figure BDA0003778601520000092
Phenylboronic acid (48.06g, 394.16mmol) was added to 2- (3-hydroxy-4- (methoxy-d) at room temperature under nitrogen 3 ) Phenyl) acetic acid (36.50g, 197.09mmol) in toluene (750 mL). The reaction is carried out at 110 DEG CStirred for 1 hour. Paraformaldehyde (33.20g, 1.11mol) was added in portions to the above mixture at 100 ℃. The reaction was stirred at 100 ℃ for 16 hours. The uncooled mixture was directly filtered, the filtrate was evaporated to dryness under reduced pressure, and water (750 mL) was added. After refluxing for 2 hours, the mixture was cooled to room temperature and extracted with dichloromethane (3 × 500 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (3 × 400 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was stirred in a solution of ether (300 mL) for 16 h. Filtering, drying the filter cake to obtain yellow 8-hydroxy-7- (methoxyl-d) 3 ) Isochroman-3-one (28.00g, 72%) as a solid. MS ESI calculated value C 10 H 7 D 3 O 4 [M-H] - 196.1, 196.1 found experimentally; 1 H NMR(400MHz,DMSO-d 6 )δ9.17(s,1H),6.92(d,J＝8.1Hz,1H),6.71(d,J＝8.1Hz,1H),5.32(s,2H),3.70-3.61(m,2H)。
5. 3 8- (benzyloxy) -7- (methoxy-d) isochroman-3-one
Figure BDA0003778601520000101
Benzyl bromide (29.14g, 170.36mmol) was added to 8-hydroxy-7- (methoxy-d) at room temperature under nitrogen protection 3 ) Isochroman-3-one (28.00g, 141.98mmol) and potassium carbonate (29.43g, 212.95mmol) in a suspension of acetone (280 mL). The reaction was stirred at 60 ℃ for 16 hours. The reaction was cooled to room temperature and filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (3/1 by volume). The product-containing fractions were evaporated to dryness under reduced pressure to give white 8- (benzyloxy) -7- (methoxy-d 3 ) Isochroman-3-one (36.0 g, 88%) as a solid. MS ESI calculated value C 17 H 13 D 3 O 4 [M-H] - 286.1, 286.1 by experimental measurement; 1 H NMR(400MHz,CDCl 3 )δ7.44-7.33(m,5H),6.96-6.88(m,2H),5.13(s,2H),5.09(s,2H),3.59(s,2H)。
6.(E) -1- (benzyloxy) -2-methoxy-4- (2-nitrovinyl) benzene
Figure BDA0003778601520000102
Ammonium acetate (12.73g, 165.1mmol) was added to a solution of 4- (benzyloxy) -3-methoxybenzaldehyde (40.0 g, 165.1mmol) in nitromethane (330 mL) at room temperature. The reaction was stirred at 55 ℃ for 16 hours under nitrogen. The reaction solution was evaporated to dryness under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (3X 500 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (3 × 500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give (E) -1- (benzyloxy) -2-methoxy-4- (2-nitrovinyl) benzene (30.0 g, 64%) as a dark yellow solid. The product was used directly in the next reaction without further purification. MS ESI calculated value C 16 H 15 NO 4 [M+H] + 286.1, found experimentally 286.2; 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝13.6Hz,1H),7.54(d,J＝13.6Hz,1H),7.48-7.34(m,5H),7.14-7.11(m,1H),7.05(d,J＝2.1Hz,1H),6.95(d,J＝8.3Hz,1H),5.25(s,2H),3.96(s,3H)。
7. 2- (4- (benzyloxy) -3-methoxyphenyl) ethan-1-amine
Figure BDA0003778601520000111
A solution of (E) -1- (benzyloxy) -2-methoxy-4- (2-nitrovinyl) benzene (20.00g, 70.1mmol) in tetrahydrofuran (40 mL) was added to a suspension of lithium aluminum tetrahydride (13.30g, 350.4 mmol) in tetrahydrofuran (60 mL) at 0 deg.C under nitrogen. The reaction was stirred at 0 ℃ for 1 hour, then at room temperature for 0.5 hour, and then at 60 ℃ for 16 hours. The reaction solution was cooled to 0 ℃, water (13.30 mL) was added dropwise, and then a 15% aqueous NaOH solution (13.30 mL) and water (40 mL) were slowly added in this order. The reaction was allowed to return to room temperature and stirring was continued for 0.5 hour. The reaction mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give 2- (4- (benzyloxy) -3-methoxyphenyl) ethan-1-amine (14 g, crude) as a dark yellow oil. The product was not further purified and,directly used for the next reaction. MS ESI calculated value C 16 H 19 NO 2 [M+H] + 258.1, 258.1 by experimental measurement; 1 H NMR(400MHz,DMSO-d 6 )δ7.47-7.34(m,5H),6.96(d,J＝8.1Hz,1H),6.88(d,J＝2.0Hz,1H),6.74-6.71(m,1H),5.06(s,2H),3.78(s,3H),2.95-2.92(m,2H),2.76-2.72(m,2H)。
8. 3 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) phenyl) -N- (4- (benzyloxy) -3-methoxy Phenethyl) acetamide
Figure BDA0003778601520000121
2- (4- (benzyloxy) -3-methoxyphenyl) ethan-1-amine (3.36g, 13.05mmol) was added to 8- (benzyloxy) -7- (methoxy-d at room temperature 3 ) Isochroman-3-one (2.50g, 8.70mmol) in ethanol (30 mL). The reaction was stirred at 85 ℃ for 16 hours under nitrogen. The reaction solution was evaporated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel eluting with petroleum ether/(ethyl acetate: ethanol (3:1 by volume)) (2/1). The fractions containing the product were collected and evaporated to dryness under reduced pressure to give pure white 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d 3 ) Phenyl) -N- (4- (benzyloxy) -3-methoxyphenethyl) acetamide (3.1g, 65%) as a solid. MS ESI calculated value C 33 H 32 D 3 NO 6 [M+H] + 545.3, found 545.4; 1 H NMR(400MHz,DMSO-d 6 )δ8.21-8.17(m,1H),7.53-7.47(m,2H),7.47-7.30(m,9H),6.98-6.94(m,2H),6.92(d,J＝8.2Hz,1H),6.82(d,J＝2.0Hz,1H),6.66(dd,J＝8.2,2.0Hz,1H),5.04(s,2H),4.93(s,2H),4.54(d,J＝5.8Hz,2H),3.75(s,3H),3.51(s,2H),3.31-3.23(m,2H),2.67-2.60(m,2H)。
9. 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3-methoxyphenethyl) amino) -2-oxoethyl) -3- (methyl) 3 Oxy-d) acetic acid benzyl ester
Figure BDA0003778601520000122
Acetyl chloride (0.35mL, 4.51mmol) was added to 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) at 0 deg.C under nitrogen 3 ) Phenyl) -N- (4- (benzyloxy) -3-methoxyphenethyl) acetamide (1.80g, 3.31mmol) and 4-dimethylaminopyridine (0.61g, 4.96mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (30 mL) and hydrochloric acid (5mL, 1N) at room temperature. The mixture was extracted with dichloromethane (2 × 100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (3 × 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/(ethyl acetate: ethanol (3:1 by volume)) (2/1). The product-containing fractions were evaporated to dryness under reduced pressure to give yellow 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3-methoxyphenethyl) amino) -2-oxoethyl) -3- (methoxy-d 3 ) Benzyl acetate (1.85g, 95%) as a solid. MS ESI calculated value C 35 H 34 D 3 NO 7 [M+H] + 587.3, 587.5; 1 H NMR(400MHz,DMSO-d 6 )δ7.93-7.90(m,1H),7.46-7.29(m,10H),7.06(d,J＝8.5Hz,1H),6.99(d,J＝8.5Hz,1H),6.92(d,J＝8.2Hz,1H),6.82(d,J＝2.0Hz,1H),6.67-6.64(m,1H),5.10(s,2H),5.04(s,2H),4.95(s,2H),3.75(s,3H),3.43(s,2H),3.28-3.23(m,2H),2.64(t,J＝7.3Hz,2H),1.93(s,3H)。
10. 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl) methyl) -3- 3 (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000131
Phosphorus oxychloride (2.86mL, 18.65mmol) was added to 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3-methoxyphenethyl) amino) -2-oxoethyl) -3- (methoxy-d-ethyl) at room temperature under nitrogen 3 ) Benzyl acetate (3.00g, 5.11mmol) in acetonitrile (50 mL). The reaction was stirred at 85 ℃ for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. Dissolve the residue with dichloromethane (200 mL) and dissolve with saturated aqueous sodium bicarbonate (200 mL) and saturated aqueous sodium chloride (3X 100 mL), respectivelyWashed and the organic phase dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/(ethyl acetate: ethanol (3:1 by volume)) (1/1). Collecting the product-containing fractions, and evaporating under reduced pressure to dryness to obtain yellow 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Benzyl acetate (2.19g, 75%) as a solid. MS ESI calculated value C 35 H 32 D 3 NO 6 [M+H] + 569.3, found experimentally 569.4; 1 H NMR(400MHz,DMSO-d 6 )δ7.43-7.30(m,10H),7.22(s,1H),6.97(d,J＝8.5Hz,1H),6.90(s,1H),6.86(d,J＝8.5Hz,1H),5.10(s,2H),5.04(s,2H),4.94(s,2H),4.01-3.98(m,2H),3.81(s,3H),3.49(t,J＝7.5Hz,2H),2.57-2.55(m,2H),1.90(s,3H)。
11. 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) - 3 3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000141
Triethylamine (6.00mL, 43.17mmol) was added to anhydrous formic acid (15.00mL, 397.61mmol) at 0 deg.C under nitrogen. Then 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.80g, 3.17mmol) and chloro { [ (1R, 2R) - (-) -2-amino-1,2-diphenylethyl](4-Toluenesulfonyl) amino } (P-isopropyltoluene) ruthenium (II) (RuCl [ (R, R) -Tsdpen](p-cymene), 0.72g, 1.13mmol) in N, N-dimethylformamide (18 mL) was added to the above mixture at 0 ℃. The reaction was stirred at room temperature for 24 hours. The reaction solution was adjusted to pH 8 with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/(ethyl acetate: ethanol (3:1 by volume)) (1/1). The fractions containing the product were collected and evaporated to dryness under reduced pressure to give a pale yellow oil, 2-(benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.24g, 68%). MS ESI calculated value C 35 H 34 D 3 NO 6 [M+H] + 571.3, found by experiments 571.4; 1 H NMR(400MHz,CDCl 3 )δ7.51-7.29(m,10H),7.03-6.93(m,2H),6.64(s,1H),6.57(s,1H),5.28(d,J＝11.6Hz,1H),5.17(d,J＝11.6Hz,1H),5.08-5.06(m,4H),4.10-4.05(m,1H),3.88(s,3H),3.30-3.22(m,1H),3.15-3.07(m,1H),3.05-3.01(m,1H),2.96-2.90(m,1H),2.84-2.78(m,2H),1.97(s,3H)。
12.(2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) - 3 3- (methoxy-d) phenyl) methanol
Figure BDA0003778601520000151
Sodium hydroxide (480.0mg, 12.00mmol) and water (4.00 mL) were added to 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3- (methoxy-d at room temperature 3 ) Benzyl acetate (1.24g, 2.17mmol) in ethanol (10 mL). The reaction was stirred at room temperature for 1 hour. Water (40 mL) was added to the above mixture and stirring was continued for 15 minutes. The reaction solution was filtered, and the filter cake was washed with n-hexane (30 mL) and ether (50 mL). The filter cake in air drying, obtained dark gray (2- (phenylsulfonyl) -6- ((7- (phenylsulfonyl) -6-methoxy-1,2,3,4-four hydrogen isoquinoline-1-yl) methyl) -3- (methoxy-d) 3 ) Phenyl) methanol (0.96g, 84%) as a solid. MS ESI calculated value C 33 H 32 D 3 NO 5 [M+H] + 529.3, found experimentally 529.4; 1 H NMR(400MHz,CDCl 3 )δ7.60-7.53(m,2H),7.53-7.47(m,2H),7.45-7.37(m,5H),7.36-7.31(m,1H),6.96-6.85(m,2H),6.83(s,1H),6.64(s,1H),5.26-5.15(m,2H),5.13(d,J＝10.7Hz,1H),5.06(d,J＝10.7Hz,1H),4.88(d,J＝11.6Hz,1H),4.46(d,J＝11.7Hz,1H),4.09-4.01(m,1H),3.91(s,3H),3.12-3.00(m,2H),2.96-2.87(m,2H),2.85-2.73(m,1H),2.66-2.57(m,1H)。
13 and 14. 3 2,9-bis (benzyloxy)Yl) -3-methoxy-10- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-iso Quinoline [3,2-a]Isoquinoline derivatives
Figure BDA0003778601520000152
Under nitrogen protection, thionyl chloride (0.79mL, 10.89mmol) was added to (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3- (methoxy-d) at 0 deg.C 3 ) Phenyl) methanol (0.96g, 1.82mmol) in dichloromethane (15 mL). The reaction was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution (30 mL) was added to the above mixture at 0 ℃ and stirred for another 1 hour. The reaction mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel eluting with dichloromethane/methanol (15/1). The product containing fractions were collected and evaporated to dryness under reduced pressure to afford pale yellow 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13,13a-tetrahydro-6H-isoquinoline [3,2-a]Isoquinoline (0.84g, 90.5%) as a solid. MS ESI calculated value C 33 H 30 D 3 NO 4 [M+H] + 511.3, found experimentally 511.4; 1 H NMR(400MHz,CDCl 3 )δ7.53-7.45(m,4H),7.45-7.30(m,6H),6.88-6.84(m,2H),6.76(s,1H),6.66(s,1H),5.16(s,2H),5.11(d,J＝11.1Hz,1H),5.01(d,J＝11.1Hz,1H),4.26-4.17(m,1H),3.90(s,3H),3.49-3.40(m,2H),3.23-3.03(m,3H),2.81-2.51(m,3H)。
15. 3 3-methoxy-10- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline- 2,9-diol
Figure BDA0003778601520000161
At room temperature, adding Pd (OH) 2 /C (0.40g, 2.85mmol) and methanol (3 mL) was added to 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13,13a-tetrahydro-6H-isoquinoline [3,2-a]Isoquinoline derivatives(0.80g, 1.57mmol) in ethyl acetate (12 mL). The reaction solution was replaced with hydrogen gas 3 times, and stirred at room temperature for 16 hours. The reaction was filtered and the filter cake was rinsed with ethyl acetate (3 × 20 mL). The filtrate was evaporated to dryness under reduced pressure to give 3-methoxy-10- (methoxy-d) as a pink color 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.40g, 77%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.2, found 331.1 experimentally.
16.(R) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquine Quinoline-2,9-diolAnd 3 (S) -3-methoxy-10- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Different from each other Quinoline-2,9-diols
Figure BDA0003778601520000171
The racemic product (0.5 g) was separated by chiral high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane: dichloromethane =3:1 (plus 10mM ammonia methanol solution); mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 10% B13 min; detection wavelength: 254/220nm; retention time 1:6.595 min; retention time 2:10.793 min.) the pre-peak was collected and evaporated to dryness under reduced pressure to give pink (R) -or (S) 3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.16g, 40%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.17, found experimentally 331.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.70(s,1H),6.64(s,1H),6.59(d,J＝8.3Hz,1H),4.01(d,J＝15.7Hz,1H),3.75(s,3H),3.38-3.34(m,1H),3.30-3.23(m,1H),3.20-3.12(m,1H),3.11-3.04(m,1H),2.96-2.85(m,1H),2.70-2.41(m,3H)；α＝+305(c＝0.2in MeOH)；ee>99％；D 3 ＝99.48％。
collecting the final peak, evaporating under reduced pressure to obtain pink (S) -or (R) -3-methoxy-10- (methoxy-d) 3 )-5,8,13,13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.16g, 41%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.17, 331.15; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.79(d,J＝8.2Hz,1H),6.70(s,1H),6.65(s,1H),6.59(d,J＝8.3Hz,1H),4.01(d,J＝15.7Hz,1H),3.75(s,3H),3.38-3.34(m,1H),3.30-3.22(m,1H),3.21-3.12(m,1H),3.12-3.04(m,1H),2.98-2.85(m,1H),2.63-2.40(m,3H)；α＝-308.5(c＝0.2in MeOH)；ee>99％；D 3 ＝99.55％。
preparation of example 2
Synthesis of Compounds 02-0Q and 02-0H
Figure BDA0003778601520000181
Synthetic scheme 2
Figure BDA0003778601520000182
Experimental part
1. 8-hydroxy-7-methoxyisochroman-3-one
Figure BDA0003778601520000191
Starting from 2- (3-hydroxy-4-methoxyphenyl) acetic acid (30.0g, 164.68mmol), phenylboronic acid (40.16g, 329.35mmol) and paraformaldehyde (27.23g, 907.67mmol), the experimental procedure in step 4 of preparation example 1 was carried out to give 8-hydroxy-7-methoxyisochrom-3-one (22.8g, 71%) as a white solid. MS ESI calculated value C 10 H 10 O 4 [M-H]193.1, determined experimentally; 1 H NMR(400MHz,DMSO-d 6 )δ9.16(s,1H),6.93(d,J＝8.2Hz,1H),6.72-6.70(m,1H),5.32(s,2H),3.80(s,3H),3.66(s,2H)。
2. 8- (benzyloxy) -7-methoxyisochroman-3-one
Figure BDA0003778601520000192
Starting from 8-hydroxy-7-methoxyisochroman-3-one (22.80g, 117.41mmol) and benzyl bromide (24.10 g, 140.90mmol), the procedure of step 5 in preparation example 1 was followed to give 8- (benzyloxy) -7-methoxyisochroman-3-one (30.0 g, 90%) as a white solid. MS ESI calculated value C 17 H 16 O 4 [M+H] + 285.1, found experimentally 285.2; 1 H NMR(400MHz,DMSO-d 6 )δ7.46-7.32(m,5H),7.08(d,J＝8.3Hz,1H),7.01(d,J＝8.3Hz,1H),5.19(s,2H),5.01(s,2H),3.87(s,3H),3.67(s,2H)。
3. 3 4- (benzyloxy) -3- (methoxy-d) benzaldehyde
Figure BDA0003778601520000193
Deuterated iodomethane (48.90g, 337.35mmol) was added dropwise to a suspension of 4- (benzyloxy) -3-hydroxybenzaldehyde (70.00g, 306.69mmol) and potassium carbonate (63.58g, 460.03mmol) in acetone (700.00 mL) under nitrogen. The reaction was stirred at 60 ℃ overnight. The reaction solution was filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (2 × 500 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 400 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give 4- (benzyloxy) -3- (methoxy-d) white 3 ) Benzaldehyde (68.0 g, 90%) as a solid. MS ESI calculated value C 15 H 11 D 3 O 3 [M+H] + 246.1, found 246.2 experimentally; 1 HNMR(400MHz,CDCl 3 )δ9.84(s,1H),7.48-7.41(m,3H),7.40-7.37(m,3H),7.35-7.29(m,1H),6.99(d,J＝8.2Hz,1H),5.25(s,2H)。
4.(E) -1- (benzyloxy) -2- (methoxy-d 3 ) -4- (2-nitrovinyl) benzene
Figure BDA0003778601520000201
With 4- (benzyloxy) -3- (methoxy-d 3 ) Benzaldehyde (46.0g, 187.53mmol), nitromethane (375 mL) and ammonium acetate (14.46g, 187.53mmol) as starting materials, according to the experimental procedure of step 6 in preparation example 1, yellow (E) -1- (benzyloxy) -2- (methoxy-d) was obtained 3 ) -4- (2-nitrovinyl) benzene (35.0 g, 64.7%) as a solid. 1 H NMR(300MHz,CDCl 3 )δ7.97(d,J＝13.6Hz,1H),7.56-7.51(m,1H),7.49-7.31(m,5H),7.14-7.11(m,1H),7.05(d,J＝2.0Hz,1H),6.95(d,J＝8.3Hz,1H),5.25(s,2H)。
5. 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethan-1-amines
Figure BDA0003778601520000202
With (E) -1- (benzyloxy) -2- (methoxy-d 3 ) Starting from (42.00g, 145.67mmol) of (2-nitrovinyl) benzene and (27.64g, 728.36mmol) lithium tetrahydridoaluminum, according to the experimental procedure of step 7 of preparation example 1, brown 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethan-1-amine (35.0 g, crude) oil. MS ESI calculated value C 16 H 16 D 3 NO 2 [M+H] + 261.16, 261.2; 1 H NMR(300MHz,CDCl 3 )δ7.48-7.44(m,2H),7.42-7.30(m,3H),6.84(d,J＝8.1Hz,1H),6.77(d,J＝2.0Hz,1H),6.71-6.68(m,1H),5.16(s,2H),2.97(t,J＝6.8Hz,2H),2.71(t,J＝6.8Hz,2H)。
6. 3 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxyphenyl) -N- (4- (benzyloxy) -3- (methoxy-d) Phenethyl) acetamide
Figure BDA0003778601520000211
With 8- (benzyloxy) -7-methoxyisochroman-3-one (1.70g, 5.98mmol) and 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethan-1-amine (1.84g, 7.07mmol) as starting material was subjected to the experimental procedure of step 8 of preparation example 1 to give 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methyl ester as yellow pigmentOxyphenyl) -N- (4- (benzyloxy) -3- (methoxy-d 3 ) Phenethyl) acetamide (2.80g, 85.9%) as an oil. MS ESI calculated value C 33 H 32 D 3 NO 6 [M+H] + 545.3, found 545.4 experimentally; 1 HNMR(400MHz,CDCl 3 )δ7.50-7.45(m,5H),7.41-7.31(m,5H),6.95(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),6.77(d,J＝8.2Hz,1H),6.68(d,J＝2.0Hz,1H),6.50-6.48(m,1H),6.11(s,1H),5.14(s,2H),5.09(s,2H),4.62(s,2H),3.91(s,3H),3.53(s,2H),3.47-3.42(m,2H),2.68(t,J＝6.9Hz,2H)。
7. 3 3 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) phenethyl-d) amino) -2-oxoethyl ester 3-methoxybenzyl acetate radical
Figure BDA0003778601520000212
With 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxy phenyl) -N- (4- (benzyloxy) -3- (methoxy-d 3 ) Phenethyl) acetamide (2.80g, 5.14mmol) and acetyl chloride (605.31mg, 7.71mmol) as starting materials according to the experimental procedure of step 9 of preparation example 1 to give pale yellow 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) 3 ) Phenylethyl-d 3 ) Amino) -2-oxoethyl) -3-methoxybenzyl acetate (2.54g, 84.2%) as a solid. MS ESI calculated value C 35 H 34 D 3 NO 7 [M+H] + 587.28, found experimentally 587.3; 1 HNMR(400MHz,CDCl 3 )δ7.50-7.41(m,4H),7.41-7.30(m,6H),6.93-6.89(m,2H),6.76(d,J＝8.2Hz,1H),6.65(d,J＝2.0Hz,1H),6.49-6.46(m,1H),5.42(s,1H),5.14-5.10(m,4H),5.05(s,2H),3.91(s,3H),3.55(s,2H),3.45-3.41(m,2H),2.66(t,J＝7.0Hz,2H),1.95(s,3H)。
8. 3 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -3,4-dihydroisoquinolin-1-yl) methyl) - 3-methoxybenzyl acetate
Figure BDA0003778601520000221
With 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) 3 ) Phenylethyl-d 3 ) Amino) -2-oxyethyl) -3-methoxybenzyl acetate (2.54g, 4.33mmol) and phosphorus oxychloride (2.42mL, 15.79mmol) were used as starting materials to give 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) as a yellow color according to the experimental procedure of the 10 th step in preparation example 1 3 ) -3,4-dihydroisoquinolin-1-yl) methyl) -3-methoxybenzyl acetate (1.95g, 79%) as a solid. MS ESI calculated value C 35 H 32 D 3 NO 6 [M+H] + 569.3, found experimentally 569.4; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.44(m,2H),7.42-7.36(m,2H),7.36-7.30(m,6H),6.96(s,1H),6.82(d,J＝2.6Hz,2H),6.71(s,1H),5.21(s,2H),5.06(s,2H),5.01(s,2H),4.00-3.96(m,2H),3.88(s,3H),3.72(t,J＝7.6Hz,2H),2.70-2.65(m,2H),1.96(s,3H)。
9. 3 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl) methane 3-methoxybenzyl acetate radical
Figure BDA0003778601520000222
To 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -3,4-dihydroisoquinolin-1-yl) methyl) -3-methoxybenzyl acetate (0.95g, 1.67mmol) in methanol (18 mL) was added sodium borohydride (94.80mg, 2.51mmol) at room temperature. After stirring at room temperature for 1 hour, sodium borohydride (20mg, 0.53mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched by addition of ice water (100 mL) and extracted with dichloromethane (3X 100 mL). The extract was washed with saturated aqueous sodium chloride (2X 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give yellow 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3-methoxybenzyl acetate (0.87g, 91%) as a solid. MS ESI calculated value C 35 H 34 D 3 NO 6 [M+H] + 571.3, found by experiments 571.4; 1 HNMR(400MHz,CDCl 3 )δ7.51-7.44(m,4H),7.43-7.30(m,6H),7.01-6.95(m,2H),6.63(s,2H),5.31(d,J＝11.5Hz,1H),5.17(d,J＝11.5Hz,1H),5.09(s,4H),4.03-4.01(m,1H),3.92(s,3H),3.27-3.21(m,1H),3.12-3.08(m,1H),3.01-2.95(m,1H),2.90-2.82(m,1H),2.81-2.77(m,2H),1.97(s,3H)。
10. 3 (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl) Methyl) -3-methoxyphenyl) methanol
Figure BDA0003778601520000231
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3-methoxybenzyl acetate (0.87g, 1.52mmol) and sodium hydroxide (0.36g, 9.00mmol) were used as starting materials to obtain an off-white color (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) according to the experimental procedure of step 12 of preparation example 1 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3-methoxyphenyl) methanol (0.74g, 91.8%) as a solid. MS ESI calculated value C 33 H 32 D 3 NO 5 [M+H] + 529.3, found experimentally 529.4; 1 H NMR(400MHz,CDCl 3 )δ7.60-7.54(m,2H),7.52-7.46(m,2H),7.43-7.39(m,4H),7.37-7.30(m,2H),6.90(d,J＝1.2Hz,2H),6.81(s,1H),6.63(s,1H),5.24-5.15(m,2H),5.15-5.03(m,2H),4.88(d,J＝11.6Hz,1H),4.47(d,J＝11.6Hz,1H),4.11-4.05(m,1H),3.90(s,3H),3.08-3.04(m,2H),2.98-2.87(m,2H),2.84-2.74(m,1H),2.67-2.59(m,1H)。
11 and 12. 3 2,9-bis (benzyloxy) -10-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-iso Quinolyl [3,2-a]Isoquinoline derivatives
Figure BDA0003778601520000232
With (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) 1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3-methoxyphenyl) methanol (0.92g, 1.74mmol) and thionyl chloride (1.24g, 10.44mmol) as starting materials according to the experimental procedures of steps 13 and 14 of preparation example 1 to give 2,9-Bis (benzyloxy) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline (0.84g, 95%) as a solid. MS ESI calculated value C 33 H 30 D 3 NO 4 [M+H] + 511.3, found experimentally 511.4; 1 H NMR(400MHz,CDCl 3 )δ7.52-7.48(m,4H),7.44-7.31(m,6H),6.89-6.83(m,2H),6.77(s,1H),6.65(s,1H),5.17(s,2H),5.11(d,J＝11.1Hz,1H),5.01(d,J＝11.1Hz,1H),4.26-4.20(m,1H),3.90(s,3H),3.48-3.42(m,2H),3.20-3.05(m,3H),2.82-2.53(m,3H)。
13. 3 10-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline- 2,9 diol
Figure BDA0003778601520000241
With 2,9-bis (benzyloxy) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13,13a-tetrahydro-6H-iso quinolyl [3,2-a]Isoquinoline (0.78g, 1.53mmol) as a starting material was subjected to the experimental procedure of step 15 of preparation example 1 to give 10-methoxy-3- (methoxy-d) as a pink color 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.36g, 71%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.2, found in experiments 331.2.
14.(R) -and (S) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13,13a-tetrahydro-6H-isoquinolinyl [3,2- a]Isoquinoline-2,9-diol
Figure BDA0003778601520000242
The racemic product (0.35 g) was separated by manual high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane: dichloromethane =3:1 (plus 10mM ammonia in methanol solution); mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 20% B10 min; detection wavelength: 254/220nm; retention time 1.725 min; retention time 2:8.332 minCollecting peak, evaporating under reduced pressure to obtain pink (R) -or (S) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.13g, 37%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.17, found experimentally 331.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.65(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.7Hz,1H),3.76(s,3H),3.36-3.34(m,1H),3.28-3.23(m,1H),3.20-3.12(m,1H),3.11-3.04(m,1H),2.96-2.86(m,1H),2.63-2.41(m,3H).α＝+300.5(c＝0.2in MeOH)；ee>99％；D 3 ＝99.58％。
collecting the final peak, vacuum evaporating to dryness to obtain pink (S) -or (R) 10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.13g, 37%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.17, found experimentally 331.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.65(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.7Hz,1H),3.76(s,3H),3.36-3.34(m,1H),3.28-3.23(m,1H),3.20-3.12(m,1H),3.11-3.05(m,1H),2.96-2.87(m,1H),2.63-2.42(m,3H).α＝-300(c＝0.2in MeOH)；ee>99％；D 3 ＝99.60％。
preparation of example 3
Synthesis of Compounds 03-0Q and 03-0H
Figure BDA0003778601520000251
Synthetic scheme 3
Figure BDA0003778601520000252
Experimental part
1. 2- (4- (benzyloxy) -3-methoxyphenyl) ethane-1,1-d 2 -1-amine hydrochloride
Figure BDA0003778601520000261
BF is carried out at 0 ℃ under the protection of nitrogen 3 .Et 2 A solution of O (85.00mL, 598.88mmol) and 2- (4- (benzyloxy) -3-methoxyphenyl) acetonitrile (10.00g, 39.48mmol) in tetrahydrofuran (150 mL) was slowly added dropwise to a suspension of sodium borodeuteride (25.00g, 597.31mmol) in tetrahydrofuran (100 mL). The reaction solution was stirred at room temperature for 1 hour, and then at 60 ℃ for 2 hours. After cooling to room temperature, the reaction was quenched with 20% aqueous HCl (130 mL) and water (400 mL) at 0 ℃. The mixture was extracted with ethyl acetate (2 × 300 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give white 2- (4- (benzyloxy) -3-methoxyphenyl) ethane-1,1-d 2 1-amine hydrochloride (11.0 g, 94%) as a solid. The product was used directly in the next reaction without further purification. MS ESI calculated value C 16 H 18 D 2 ClNO 2 [M+H-HCl+ACN] + 301.2, and 301.2 is measured by experiments; 1 H NMR(400MHz,DMSO-d 6 )δ7.69(brs,3H),7.46-7.37(m,4H),7.36-7.30(m,1H),6.98(d,J＝8.2Hz,1H),6.89(d,J＝2.0Hz,1H),6.75-6.73(m,1H),5.06(s,2H),3.79(s,3H),2.77(s,2H)。
2. 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxyphenyl) -N- (2- (4- (benzyloxy) -3-methoxybenzene 2 Yl) ethyl-1,1-d) acetamide
Figure BDA0003778601520000262
N, N-diisopropylethylamine (6.55g, 50.71mmol) was added to 2- (4- (benzyloxy) -3-methoxyphenyl) ethane-1,1-d at room temperature under nitrogen protection 2 -1-amine hydrochloride (3.00g, 10.14mmol) and 8- (benzyloxy) -7-methoxyisochroman-3-one (2.15g, 7.57mmol) in ethanol (40 mL). The reaction solution was stirred at 85 ℃ for 2 days. The reaction solution was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/(ethyl acetate: ethanol (volume ratio)3:1)) (2/1). The product containing fractions were collected and evaporated to dryness under reduced pressure to give yellow 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxyphenyl) -N- (2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Acetamide (3.7g, 90%) as an oil. MS ESI calculated value C 33 H 33 D 2 NO 6 [M+H] + 544.3, 544.2; 1 H NMR(400MHz,CDCl 3 )δ7.51-7.47(m,2H),7.46-7.42(m,2H),7.42-7.30(m,5H),6.95(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),6.78(d,J＝8.1Hz,1H),6.69(d,J＝2.0Hz,1H),6.50-6.48(m,1H),6.06(s,1H),5.14(s,2H),5.09(s,2H),4.62(s,2H),3.91(s,3H),3.87(s,3H),3.53(s,2H),2.67(s,2H)。
3. 2 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d) amino) -2- Oxyethyl) methoxybenzyl acetate
Figure BDA0003778601520000271
With 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxyphenyl) -N- (2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Acetamide (3.70g, 6.81mmol) and acetyl chloride (0.80g, 10.21mmol) as starting materials gave, by the experimental procedure of step 9 of preparation example 1, off-white 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Amino) -2-oxyethyl) methoxybenzyl acetate (3.70g, 93%) as a solid. MS ESI calculated value C 35 H 35 D 2 NO 7 [M+H] + 586.3, 586.2; 1 H NMR(400MHz,CDCl 3 )δ7.48-7.41(m,4H),7.41-7.31(m,6H),6.94-6.87(m,2H),6.76(d,J＝8.3Hz,1H),6.66(d,J＝2.0Hz,1H),6.49-6.46(m,1H),5.40(s,1H),5.15-5.10(m,4H),5.05(s,2H),3.91(s,3H),3.86(s,3H),3.54(s,2H),2.65(s,2H),1.95(s,3H)。
4. 2 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl-3,3-d) methyl 3-methoxybenzyl acetate radical
Figure BDA0003778601520000272
With 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Amino) -2-oxyethyl) methoxybenzyl acetate (3.50g, 5.98mmol) and phosphorus oxychloride (3.50mL, 37.55mmol) as starting materials were subjected to the experimental procedure of step 10 of preparation example 1 to give 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl-3,3-d as pink color 2 ) Methyl) -3-methoxybenzyl acetate (2.90g, 85%) as a solid. MS ESI calculated value C 35 H 33 D 2 NO 6 [M+H] + 568.3, found 568.1 experimentally; 1 H NMR(400MHz,CDCl 3 )δ7.51-7.43(m,2H),7.43-7.26(m,8H),6.97(s,1H),6.87-6.78(m,2H),6.72(s,1H),5.21(s,2H),5.06(s,2H),5.01(s,2H),3.98(s,2H),3.93(s,3H),3.88(s,3H),2.66(s,2H),1.96(s,3H)。
5. 2 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) Methyl) -3-methoxybenzyl acetate
Figure BDA0003778601520000281
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinoline-1-yl-3,3-d 2 ) Methyl) -3-methoxybenzyl acetate (1.40g, 2.47mmol) and sodium borohydride (0.112g, 2.96mmol) were used as starting materials, and experimental operation in step 9 of preparation example 2 was carried out to give red 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxybenzyl acetate (1.38g, 98%) was semisolid. MS ESI calculated value C 35 H 35 D 2 NO 6 [M+H] + 570.27, 570.25; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.45(m,4H),7.44-7.32(m,5H),7.32-7.29(m,1H),7.02-6.94(m,2H),6.64(s,2H),5.36-5.29(m,1H),5.18(d,J＝11.6Hz,1H),5.12-5.07(m,4H),4.03-3.98(m,1H),3.92(s,3H),3.89(s,3H),3.13-3.06(m,1H),2.89-2.80(m,1H),2.76(s,2H),1.97(s,3H)。
6. 2 (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) Methyl) -3-methoxyphenyl) methanol
Figure BDA0003778601520000282
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxybenzyl acetate (1.40g, 2.46mmol) and sodium hydroxide (0.40g, 10.00mmol) were used as starting materials, and according to the experimental procedure of step 12 of preparation example 1, pink (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d was obtained 2 ) Methyl) -3-methoxyphenyl) methanol (1.26g, 97%) as a solid. MS ESI calculated value C 33 H 33 D 2 NO 5 [M+H] + 528.3, found experimentally 528.3; 1 H NMR(400MHz,CDCl 3 )δ7.60-7.55(m,2H),7.53-7.48(m,2H),7.44-7.37(m,4H),7.37-7.30(m,2H),6.95-6.87(m,2H),6.83(s,1H),6.64(s,1H),5.20(d,J＝3.1Hz,2H),5.15-5.02(m,2H),4.88(d,J＝11.6Hz,1H),4.46(d,J＝11.6Hz,1H),4.06-4.01(m,1H),3.91(s,3H),3.90(s,3H),3.08-3.01(m,1H),2.96-2.85(m,1H),2.78(d,J＝16.1Hz,1H),2.60(d,J＝16.1Hz,1H)。
7 and 8.2,9-bis (benzyloxy) -3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a] 2 Isoquinoline-6,6-d
Figure BDA0003778601520000291
To obtain ((2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) 2 ) Methyl) -3-methoxyphenyl) methanol (1.26g, 2.39mmol) and thionyl chloride (1.04mL, 8.74mmol) as starting materials according to the experimental procedures at steps 13 and 14 of preparation example 1 to give orange 2,9-bis (benzyloxy) -3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a ] that is a mixture of]Isoquinoline-6,6-d 2 (1.10 g, 90%) semisolid. MS ESI calculated value C 33 H 31 D 2 NO 4 [M+H] + 510.3, found by experiment 510.3; 1 H NMR(400MHz,CDCl 3 )δ7.52-7.46(m,4H),7.45-7.31(m,6H),6.89-6.83(m,2H),6.77(s,1H),6.66(s,1H),5.17(s,2H),5.11(d,J＝11.1Hz,1H),5.01(d,J＝11.2Hz,1H),4.26-4.22(m,1H),3.90(2s,6H),3.52-3.39(m,2H),3.16-3.07(m,2H),2.82-2.60(m,2H)。
9. 2 3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d-2,9- Diols
Figure BDA0003778601520000301
Using 2,9-bis (benzyloxy) -3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolino [3,2-a]Isoquinoline-6,6-d 2 (0.98g, 1.92mmol) as a starting material, according to the experimental procedure of step 15 of preparation example 1, pink 3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a)]Isoquinoline-6,6-d 2 -2,9-diol (0.45g, 71%) as a solid. MS ESI calculated value C 19 H 19 D 2 NO 4 [M+H] + 330.16, 330.20 was experimentally determined.
10. 2 (R) -3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d- 2,9 diolAnd(S) -3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 - 2,9 diol
Figure BDA0003778601520000302
The racemic product (0.5 g) was separated by chiral high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane: dichloromethane =3:1 (plus 10mM ammonia methanol solution); mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 10% B24 min; detection wavelength: 254/220nm; retention time 1.7.013 min; retention time 2.323 min.) the pre-peak collection was evaporated to dryness under reduced pressure to give pink (R) -or (S) 3,10-dimethoxy-5, 8,13,13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.2g, 41%) as a solid. MS ESI calculated value C 19 H 19 D 2 NO 4 [M+H] + 330.16, found experimentally 330.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.6Hz,1H),3.76(s,3H),3.74(s,3H),3.37-3.34(m,1H),3.26(d,J＝15.7Hz,1H),3.19-3.12(m,1H),2.89(d,J＝15.6Hz,1H),2.61-2.53(m,2H)；α＝+300.5(c＝0.2in MeOH)；ee>99％；D 2 ＝99.25％。
collecting the rear peak, vacuum evaporating to dryness to obtain pink (S) -or (R) 3,10-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.2g, 41%) as a solid. MS ESI calculated value C 19 H 19 D 2 NO 4 [M+H] + 330.16, 330.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.64(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.6Hz,1H),3.76(s,3H),3.74(s,3H),3.37-3.34(m,1H),3.26(d,J＝15.7Hz,1H),3.19-3.12(m,1H),2.89(d,J＝15.6Hz,1H),2.61-2.53(m,2H)；α＝-301(c＝0.2in MeOH)；ee>99％；D 2 ＝98.61％。
preparation of example 4
Synthesis of Compounds 04-0Q and 04-0H
Figure BDA0003778601520000311
Synthesis scheme 4
Figure BDA0003778601520000312
Experimental part
1. 3 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) phenyl) -N- (4- (benzyloxy) -3- (methoxy-d) 3 Yl-d) phenethylacetamide
Figure BDA0003778601520000321
With 8- (benzyloxy) -7- (methoxy-d 3 ) Isochroman-3-one (2.15g, 7.483mmol) and 2- (4- (benzyloxy) -3-methoxyphenyl) ethane-1,1-d 2 Starting from (E) -1-amine hydrochloride (3.00g, 10.11mmol), according to the experimental procedure of step 2 in preparation example 3, off-white 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) was obtained 3 ) Phenyl) -N- (4- (benzyloxy) -3- (methoxy-d 3 ) Phenethylacetamide (3.70g, 67%) as a solid. MS ESI calculated value C 33 H 29 D 6 NO 6 [M+H] + 548.3, 548.3 measured by experiments; 1 H NMR(400MHz,CDCl 3 )δ7.52-7.46(m,2H),7.45-7.42(m,2H),7.42-7.35(m,4H),7.35-7.29(m,2H),6.95(d,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),6.77(d,J＝8.1Hz,1H),6.68(d,J＝2.0Hz,1H),6.50-6.48(m,1H),6.09-6.01(m,1H),5.14(s,2H),5.09(s,2H),4.62(s,2H),3.52(s,2H),3.47-3.42(m,2H),2.68(t,J＝6.9Hz,2H)。
2. 3 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) phenethyl) amino) -2-oxyethyl) - 3 3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000322
With 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d 3 ) Phenyl) -N- (4- (benzyloxy) -3- (methoxy-d 3 ) Phenethylacetamide (3.70g, 6.76mmol) and acetyl chloride (0.79g, 10.13mmol) as starting materials gave, by the experimental procedure of step 9 of preparation example 1,2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) as white color 3 ) Phenylethyl) amino) -2-oxoethyl) -3- (methoxy-d 3 ) Benzyl acetate (3.70g, 93%) as a solid. MS ESI calculated value C 35 H 31 D 6 NO 7 [M+H] + 590.29, found experimentally 590.30; 1 H NMR(400MHz,CDCl 3 )δ7.47-7.41(m,4H),7.40-7.30(m,6H),6.95-6.87(m,2H),6.76(d,J＝8.1Hz,1H),6.65(d,J＝2.0Hz,1H),6.48(dd,J＝8.1,2.0Hz,1H),5.42(t,J＝5.7Hz,1H),5.14-5.10(m,4H),5.05(s,2H),3.54(s,2H),3.45-3.41(m,2H),2.66(t,J＝7.0Hz,2H),1.95(s,3H)。
3. 3 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -3,4-dihydroisoquinolin-1-yl) methyl) - 3 3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000331
With 2- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) 3 ) Phenylethyl) amino) -2-oxoethyl) -3- (methoxy-d 3 ) Benzyl acetate (3.00g, 5.09mmol) and phosphorus oxychloride (2.85mL, 18.56mmol) as starting materials gave, by following the experimental procedure of step 10 of preparation example 1,2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) as a yellow color 3 ) -3,4-dihydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.95g, 79%) as a solid. MS ESI calculated value C 35 H 29 D 6 NO 6 [M+H] + 572.3, found experimentally 572.3; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.44(m,2H),7.43-7.36(m,2H),7.35-7.30(m,6H),6.96(s,1H),6.84-6.80(m,2H),6.71(s,1H),5.21(s,2H),5.06(s,2H),5.01(s,2H),3.98-3.94(m,2H),3.77-3.67(m,2H),2.67(t,J＝7.6Hz,2H),1.96(s,3H)。
4. 3 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl) methane 3 3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000332
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -3,4-dihydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.05g, 1.84mmol) and sodium borohydride (83.38mg, 2.20mmol) as starting materials, according to the experimental procedure of step 9 in preparation example 2, yellow 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) was obtained 3 ) -1,2,3,4-tetrahydroisoquinoline-1-yl) methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.00g, 95%) as an oil. MS ESI calculated value C 35 H 31 D 6 NO 6 [M+H] + 574.3, found experimentally 574.2; 1 H NMR(300MHz,CDCl 3 )δ7.53-7.45(m,4H),7.44-7.31(m,6H),7.03-6.93(m,2H),6.69-6.59(m,2H),5.37-5.28(m,1H),5.23-5.14(m,1H),5.13-5.05(m,4H),4.04-3.95(m,1H),3.30-3.17(m,1H),3.15-3.02(m,1H),3.00-2.90(m,1H),2.88-2.81(m,1H),2.80-2.72(m,2H),1.97(s,3H)。
5. 3 (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl 3 3- (methoxy-d) phenyl) methanol
Figure BDA0003778601520000341
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.00g, 1.74mmol) and sodium hydroxide (0.40g, 10.00mmol) as starting materials, according to the experimental procedure of step 12 of preparation example 1, gave (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) as a pale pink color 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Phenyl) methanol (0.89g, 96%) as a solid. MS ESI calculated value C 33 H 29 D 6 NO 4 [M+H] + 532.29, found experimentally 532.40; 1 H NMR(400MHz,CDCl 3 )δ7.61-7.54(m,2H),7.53-7.46(m,2H),7.44-7.38(m,4H),7.37-7.30(m,2H),6.94-6.90(m,2H),6.82(s,1H),6.63(s,1H),5.25-5.16(m,2H),5.16-5.03(m,2H),4.88(d,J＝11.6Hz,1H),4.46(d,J＝11.6Hz,1H),4.05-4.02(m,1H),3.10-3.01(m,2H),2.97-2.87(m,2H),2.86-2.74(m,1H),2.67-2.56(m,1H)。
6 and 7. 3 2,9-bis (benzyloxy) -3,10-bis (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline derivatives
Figure BDA0003778601520000342
With (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -3- (methoxy-d 3 ) Phenyl) methanol (0.87g, 1.64mmol) and thionyl chloride (0.71mL, 5.99mmol) were used as starting materials to obtain 2,9-bis (benzyloxy) -3,10-bis (methoxy-d) in red by the experimental procedures of steps 13 and 14 of preparation example 1 3 ) -5,8,13,13a-tetrahydro-6H-iso quinolyl [3,2-a]Isoquinoline (0.76g, 90%) semisolid. MS ESI calculated value C 33 H 27 D 6 NO 4 [M+H] + 514.3, 514.3 measured by experiment; 1 H NMR(400MHz,CDCl 3 )δ7.55-7.46(m,4H),7.44-7.31(m,6H),6.89-6.83(m,2H),6.77(s,1H),6.65(s,1H),5.17(s,2H),5.11(d,J＝11.2Hz,1H),5.00(d,J＝11.2Hz,1H),4.22(d,J＝15.8Hz,1H),3.52-3.39(m,2H),3.19-3.06(m,3H),2.82-2.50(m,3H)。
8. 3 3,10-bis (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-bis Alcohol(s)
Figure BDA0003778601520000351
The compound is prepared from 2,9-bis (benzyloxy) -3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline (0.76g, 1.48mmol) as a starting material was subjected to the experimental procedure of step 15 of preparation example 1 to give 3,10-bis (methoxy-d) as a pink color 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.36g, 73%) as a solid. MS ESI calculated value C 19 H 15 D 6 NO 4 [M+H] + 334.2, found 334.1 experimentally.
9.(R) -and (S) -3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquine Quinoline-2,9-diol
Figure BDA0003778601520000352
Racemic product (0.36 g) was purified by chiral high Performance liquid chromatographySeparation was carried out under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane (plus 8mM ammonia methanol solution); mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 50% for B13 minutes; detection wavelength: 254/220nm; retention time 1:5.014 minutes; retention time 2:10.199 minutes; pre-peak collection was evaporated to dryness under reduced pressure to give pink (R) -or (S) -3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.15g, 41%) as a solid. MS ESI calculated value C 19 H 15 D 6 NO 4 [M+H] + 334.18, found experimentally 334.15; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.7Hz,1H),3.38-3.34(m,1H),3.30-3.22(m,1H),3.20-3.12(m,1H),3.11-3.04(m,1H),2.96-2.85(m,1H),2.64-2.40(m,3H)；α＝+291.5(c＝0.2in MeOH)；ee>99％；D 6 ＝99.78％。
collecting the tail peak, evaporating to dryness under reduced pressure to obtain pink (S) -or (R) -3,10-bis (methoxyl-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,9-diol (0.17g, 46%) as a solid. MS ESI calculated value C 19 H 15 D 6 NO 4 [M+H] + 334.18, found experimentally 334.15; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.7Hz,1H),3.38-3.34(m,1H),3.29-3.22(m,1H),3.20-3.12(m,1H),3.11-3.04(m,1H),2.96-2.85(m,1H),2.64-2.41(m,3H)；a＝-287.5(c＝0.2in MeOH)；ee>99％；D 6 ＝99.80％。
preparation of example 5
Synthesis of Compounds 05-0Q and 05-0H
Figure BDA0003778601520000361
Synthesis scheme 5
Figure BDA0003778601520000362
Experimental part
1. 3 (4- (benzyloxy) -3- (methoxy-d) phenyl) methanol
Figure BDA0003778601520000371
Sodium borohydride (3.85g, 101.76mmol) was added portionwise to 4- (benzyloxy) -3- (methoxy-d) at 0 ℃ under nitrogen 3 ) Benzaldehyde (20.8g, 84.79mmol) in methanol (200 mL). The reaction solution was stirred at 0 ℃ for 0.5 hour, then returned to room temperature, and then stirred for 2 hours. The reaction was cooled to 0 ℃ and quenched with ice water (200 mL) at 0 ℃. The organic solvent was removed under reduced pressure. The remaining mixture was extracted with ethyl acetate (2 × 400 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 400 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (6/1 by volume). The product-containing fractions were collected and evaporated to dryness under reduced pressure to give white (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) methanol (18.8g, 90%) as a solid. MS ESI calculated value C 15 H 13 D 3 O 3 [M+Na] + 270.1, 270.2 by experimental measurement; 1 H NMR(400MHz,DMSO-d 6 )δ7.48-7.36(m,4H),7.35-7.29(m,1H),7.00-6.93(m,2H),6.81-6.78(m,1H),5.09-5.05(m,3H),4.42(d,J＝5.7Hz,2H)。
2. 4- (benzyloxy) -3- (methoxy-d 3 ) Methanesulfonic acid benzyl ester
Figure BDA0003778601520000372
Methanesulfonyl chloride (8.73mL, 76.23mmol) was added dropwise to (4- (benzyloxy) -3- (methoxy-d) at 0 deg.C under nitrogen 3 ) Phenyl) methanol (18.60g, 75.21mmol) and triethylamine (31.36mL, 309.9mmol) in dichloromethane (200 mL). The reaction was stirred at room temperature for 2 hours. The reaction was cooled to 0 ℃ and quenched with ice water (100 mL) at 0 ℃. Is provided withAfter the organic phase was separated, the remaining mixture was extracted with dichloromethane (2 × 200 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give yellow 4- (benzyloxy) -3- (methoxy-d 3 ) Benzyl methanesulfonate (18.0 g, crude) as a solid. The product was used directly in the next reaction without further purification.
3. 3 2- (4- (benzyloxy) -3- (methoxy-d) phenyl) acetonitrile
Figure BDA0003778601520000381
Sodium cyanide (3.00g, 61.21mmol) was added to 4- (benzyloxy) -3- (methoxy-d 3 ) Benzyl methanesulfonate (18.0 g, 55.32mmol) in N, N-dimethylformamide (180 mL). The reaction was stirred at room temperature for 16 hours. To the above mixture was added aqueous sodium hydroxide (1M, 180mL). The reaction was stirred for a further 15 minutes and diluted with water (500 mL). The mixture was extracted with ethyl acetate (2 × 400 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2 × 400 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (volume ratio 5/1). The product-containing fractions were collected and evaporated to dryness under reduced pressure to give off-white 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) acetonitrile (9.0 g, 63%) as a solid. 1 H NMR(400MHz,CDCl 3 )δ7.49-7.43(m,2H),7.42-7.37(m,2H),7.36-7.31(m,1H),6.91-6.84(m,2H),6.81(dd,J＝8.2,2.2Hz,1H),5.18(s,2H),3.70(s,2H)。
4. 3 2 2- (4- (benzyloxy) -3- (methoxy-d) phenyl) ethane-1,1-d-1-amine hydrochloride
Figure BDA0003778601520000382
With 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) acetonitrile (1.00g, 3.90mmol) and sodium borodeuteride (2.45g, 58.52mmol) as starting materialsPreparation example 3 Experimental procedure in step 1 gave white 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethane-1,1-d 2 1-amine hydrochloride (1.20 g, crude) as a solid. MS ESI calculated value C 16 H 15 D 5 ClNO 2 [M+H-HCl] + 263.2, found experimentally 263.3; 1 H NMR(400MHz,DMSO-d 6 )δ7.68(brs,3H),7.47-7.37(m,4H),7.36-7.30(m,1H),6.98(d,J＝8.2Hz,1H),6.89(d,J＝2.0Hz,1H),6.74(dd,J＝8.2,2.0Hz,1H),5.07(s,2H),2.78(s,2H)。
5. 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxyphenyl) -N- (2- (4- (benzyloxy) -3- (methoxy-) 3 2 d) Phenyl) ethyl-1,1-d) acetamide
Figure BDA0003778601520000391
With 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethane-1,1-d 2 Starting from (E) -1-amine hydrochloride (1.00g, 3.35mmol) and 8- (benzyloxy) -7-methoxyisochroman-3-one (0.72g, 2.53mmol), the experimental procedure of step 2 of preparation example 3 gave 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxyphenyl) -N- (2- (4- (benzyloxy) -3- (methoxy-d) as a yellow color 3 ) Phenyl) ethyl-1,1-d 2 ) Acetamide (1.40g, 77%) as an oil. MS ESI calculated value C 33 H 30 D 5 NO 6 [M+H] + 547.28, found experimentally 547.30; 1 H NMR(400MHz，CDCl 3 )δ7.52-7.42(m,5H),7.41-7.31(m,5H),6.95(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),6.77(d,J＝8.1Hz,1H),6.68(d,J＝2.0Hz,1H),6.49(dd,J＝8.1,2.0Hz,1H),6.10(s,1H),5.14(s,2H),5.09(s,2H),4.63(s,2H),3.91(s,3H),3.53(s,2H),2.67(s,2H)。
6. 3 2 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3- (methoxy-d) phenyl) ethyl-1,1-d) ammonia 2-Oxoethyl) -3-methoxybenzyl acetate
Figure BDA0003778601520000392
By 2- (3- (benzyloxy) -2- (hydroxymethyl) -4-methoxyphenyl) -N- (2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethyl-1,1-d 2 ) Acetamide (2.50g, 4.57mmol) and acetyl chloride (0.49mL, 6.24mmol) as starting materials gave, following the experimental procedure of step 9 of preparation example 1, yellow 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethyl-1,1-d 2 ) Amino) -2-oxoethyl) -3-methoxybenzyl acetate (2.54g, 84%) as an oil. MS ESI calculated value C 35 H 32 D 5 NO 7 [M+H] + 589.3, found 589.3 experimentally; 1 H NMR(400MHz,CDCl 3 )δ7.49-7.41(m,4H),7.41-7.30(m,6H),6.94-6.87(m,2H),6.76(d,J＝8.2Hz,1H),6.65(d,J＝2.0Hz,1H),6.48(dd,J＝8.1,2.1Hz,1H),5.14-5.10(m,4H),5.05(d,J＝2.2Hz,2H),3.91(s,3H),3.54(s,2H),2.66(d,J＝5.7Hz,2H),1.95(s,3H)。
7. 3 2 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -3,4-dihydroisoquinolin-1-yl-3,3-d) Methyl) -3-methoxybenzyl acetate
Figure BDA0003778601520000401
With 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethyl-1,1-d 2 ) Amino) -2-oxyethyl) -3-methoxybenzyl acetate (2.00g, 3.40mmol) and phosphorus oxychloride (1.90mL, 12.39mmol) were used as starting materials to afford 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) as an orange color by the experimental procedure of step 10 of preparation example 1 3 ) -3,4-dihydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxybenzyl acetate (1.40g, 72%) as a solid. MS ESI calculated value C 35 H 30 D 5 NO 6 [M+H] + 571.3, found by experiments 571.3; 1 H NMR(400MHz,CDCl 3 )δ7.51-7.44(m,2H),7.42-7.36(m,2H),7.36-7.29(m,6H),6.96(s,1H),6.86-6.78(m,2H),6.71(d,J＝0.9Hz,1H),5.21(s,2H),5.06(s,2H),5.01(s,2H),3.96(d,J＝8.8Hz,2H),3.88(s,3H),2.66(s,2H),1.96(s,3H)。
8. 3 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl-3, 2 3-d) methyl) -3-methoxybenzyl acetate
Figure BDA0003778601520000402
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -3,4-dihydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxybenzyl acetate (1.00g, 1.75mmol) and sodium borohydride (99.4mg, 2.63mmol) were used as starting materials, and experimental work-up at step 9 of preparation example 2 gave 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) as a yellow color 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxybenzyl acetate (0.90g, 90%) as an oil. MS ESI calculated value C 35 H 32 D 5 NO 6 [M+H] + 573.3, found experimentally 573.4; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.41(m,5H),7.41-7.30(m,5H),7.02-6.94(m,2H),6.63(s,1H),6.55(s,1H),5.27(d,J＝11.6Hz,1H),5.16(d,J＝11.6Hz,1H),5.08(s,2H),5.05(s,2H),4.11-4.08(m,1H),3.92(s,3H),3.11(dd,J＝14.1,4.9Hz,1H),2.94(s,2H),2.81(s,2H),1.96(s,3H)。
9. 3 (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl-3, 2 3-d) methyl) -3-methoxyphenyl) methanol
Figure BDA0003778601520000411
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxybenzyl acetate (1.08g, 1.89mmol) and sodium hydroxide (0.40g, 10.00mmol) were used as starting materials, and experimental procedures according to step 12 of preparation example 1 gave (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) as a pink color 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxyphenyl) methanol (0.94g4%) solid. MS ESI calculated value C 33 H 30 D 5 NO 5 [M+H] + 531.3, 531.3 by experiment; 1 H NMR(400MHz,CDCl 3 )δ7.60-7.54(m,2H),7.52-7.48(m,2H),7.41(m,4H),7.37-7.30(m,2H),6.96-6.87(m,2H),6.82(s,1H),6.63(s,1H),5.26-5.16(m,2H),5.15-5.02(m,2H),4.88(d,J＝11.5Hz,1H),4.46(d,J＝11.6Hz,1H),4.08-4.01(m,1H),3.90(d,J＝1.2Hz,3H),3.09-3.05(m,1H),2.96-2.86(m,1H),2.78(d,J＝16.2Hz,1H),2.60(d,J＝16.0Hz,1H)。
10 and 11. 3 2,9-bis (benzyloxy) -10-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-iso 2 Quinolyl [3,2-a]Isoquinoline-6,6-d
Figure BDA0003778601520000412
With (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3-methoxyphenyl) methanol (0.94g, 1.77mmol) and thionyl chloride (0.77mL, 6.48mmol) as starting materials according to the experimental procedures of steps 13 and 14 of preparation example 1 to give pale yellow 2,9-bis (benzyloxy) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 (0.84g, 95%) solid. MS ESI calculated value C 33 H 28 D 5 NO 4 [M+H] + 513.3, and 513.3 is measured by an experiment; 1 H NMR(400MHz,CDCl 3 )δ7.53-7.45(m,4H),7.45-7.31(m,6H),6.89-6.83(m,2H),6.76(s,1H),6.65(s,1H),5.17(s,2H),5.11(d,J＝11.1Hz,1H),5.01(d,J＝11.1Hz,1H),4.22(d,J＝15.8Hz,1H),3.90(s,3H),3.53-3.38(m,2H),3.18-3.05(m,2H),2.83-2.59(m,2H)。
12 3 10-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline- 2 6,6-d-2,9-diol
Figure BDA0003778601520000421
With 2,9-bis (benzyloxy) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 (0.56g, 1.09mmol) as a starting material, according to the experimental procedure of the 15 th step in preparation example 1, 10-methoxy-3- (methoxy-d) was obtained as pink 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.31g, 84%) as a solid. MS ESI calculated value C 19 H 16 D 5 NO 4 [M+H] + 333.2, 333.2 found experimentally.
13.(R) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquine 2 3 Quinoline-6,6-d-2,9-diol and (S) -10-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3, 2 2-a]isoquinoline-6,6-d-2,9-diol
Figure BDA0003778601520000422
The racemic product (0.32 g) was isolated by chiral high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane (plus 0.5%2M ammonia in methanol), mobile phase B: ethanol; flow rate: 16mL/min; isocratic: 50% B for 18 minutes; detection wavelength: 254/220nm; retention time 1:6.47 minutes; retention time 2:10.958 minutes.) the pre-peak collection was evaporated to dryness under reduced pressure to give (R) -or (S) -10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.14g, 44%) solids. MS ESI calculated value C 19 H 16 D 5 NO 4 [M+H] + 333.18, found experimentally 333.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.57(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.6Hz,1H),3.76(s,3H),3.33-3.30(m,1H),3.30-3.14(m,2H),2.89(d,J＝15.6Hz,1H),2.59-2.51(m,2H)；α＝+284.5(c＝0.2in MeOH)；ee>99％；D 5 ＝99.22％。
collecting the final peak, evaporating to dryness under reduced pressure to obtain pink(S) -or (R) 10-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.14g, 45%) solids. MS ESI calculated value C 19 H 16 D 5 NO 4 [M+H] + 333.18, found experimentally 333.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.6Hz,1H),3.76(s,3H),3.33-3.30(m,1H),3.27-3.22(m,1H),3.17-3.13(m,1H),2.89(d,J＝15.6Hz,1H),2.59-2.52(m,2H)；α＝-295.5(c＝0.2in MeOH)；ee>99％；D 5 ＝99.43％。
preparation of example 6
Synthesis of Compounds 06-0Q and 06-0H
Figure BDA0003778601520000431
Synthesis scheme 6
Figure BDA0003778601520000441
Experimental part
1. 3 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) phenyl) -N- (2- (4- (benzyloxy) -3-methoxy 2 Phenylphenyl) ethyl-1,1-d) acetamide
Figure BDA0003778601520000442
With 2- (4- (benzyloxy) -3-methoxyphenyl) ethane-1,1-d 2 -1-amine hydrochloride (3.00g, 10.14mmol) and 8- (benzyloxy) -7- (methoxy-d 3 ) Isochroman-3-one (2.15g, 7.48mmol) as a starting material according to the experimental procedure of the 2 nd step in preparation example 3 gave white 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) 3 ) Phenyl) -N- (2- (4- (benzyloxy) -3 methoxyphenyl) ethyl-1,1-d 2 ) Acetamide (3.1g, 56%) as an oil. MS ESI calculated value C 33 H 30 D 5 NO 6 [M+H] + 547.3, experimental determination 547.3; 1 H NMR(400MHz,CDCl 3 )δ7.52-7.31(m,10H),6.94(d,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),6.77(d,J＝8.1Hz,1H),6.68(d,J＝2.1Hz,1H),6.51-6.47(m,1H),6.06(s,1H),5.13(s,2H),5.09(s,2H),4.62(s,2H),3.86(s,3H),3.52(s,2H),2.67(s,2H)。
2. 2 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d) amino) -2- 3 Oxyethyl) -3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000451
With 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) 3 ) Phenyl) -N- (2- (4- (benzyloxy) -3 methoxyphenyl) ethyl-1,1-d 2 ) Acetamide (3.10g, 5.67mmol) and acetyl chloride (0.67g, 8.51mmol) as starting materials, as in the 9 th step of preparation example 1, off-white 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Amino) -2-oxoethyl) -3- (methoxy-d 3 ) Benzyl acetate (2.86g, 86%) as a solid. MS ESI calculated value C 35 H 32 D 5 NO 7 [M+H] + 589.3, found 589.3 experimentally; 1 H NMR(400MHz,CDCl 3 )δ7.48-7.41(m,4H),7.40-7.31(m,6H),6.95-6.86(m,2H),6.76(d,J＝8.1Hz,1H),6.66(d,J＝2.0Hz,1H),6.50-6.47(m,1H),5.43-5.38(m,1H),5.14-5.10(m,4H),5.05(s,2H),3.86(s,3H),3.54(s,2H),2.65(s,2H),1.95(s,3H)。
3. 2 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl-3,3-d) methyl 3 3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000452
With 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Amino) -2-oxoethyl) -3- (methoxy-d 3 ) Benzyl acetate (2.66g, 4.52mmol) and phosphorus oxychloride (2.53mL, 16.48mmol) as starting materials gave, according to the experimental procedure of step 10 of preparation example 1, yellow 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.70g, 66%) as a solid. MS ESI calculated value C 35 H 30 D 5 NO 6 [M+H] + 571.3, found by experiments 571.3; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.44(m,2H),7.42-7.36(m,2H),7.35-7.30(m,6H),6.97(s,1H),6.85-6.77(m,2H),6.72(s,1H),5.21(s,2H),5.06(s,2H),5.01(s,2H),3.99(s,2H),3.93(s,3H),2.67(s,2H),1.96(s,3H)。
4. 2 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) 3 Methyl) -3 (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000461
To obtain 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinoline-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.00g, 1.75mmol) and sodium borohydride (79.55mg, 2.10mmol) as starting materials, according to the experimental procedure of step 9 of preparation example 2, yellow 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d was obtained 2 ) Methyl) -3 (methoxy-d 3 ) Benzyl acetate (0.92g, 92%) as an oil. MS ESI calculated value C 35 H 32 D 5 NO 6 [M+H] + 573.3, found experimentally 573.3; 1 H NMR(300MHz,CDCl 3 )δ7.52-7.44(m,4H),7.43-7.30(m,6H),7.02-6.92(m,2H),6.64(d,J＝3.3Hz,2H),5.32(d,J＝11.5Hz,1H),5.18(d,J＝11.6Hz,1H),5.12-5.07(m,4H),4.02-3.98(m,1H),3.89(s,3H),3.12-3.06(m,1H),2.88-2.79(m,1H),2.76(s,2H),1.97(s,3H)。
5. 2 (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) 3 Methyl) -3- (methoxy-d) phenyl) methanol
Figure BDA0003778601520000462
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3 (methoxy-d 3 ) Benzyl acetate (0.92g, 1.61mmol) and sodium hydroxide (0.37g, 9.25mmol) as starting materials, according to the experimental procedure of step 12 of preparation example 1, pink (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) 2 ) Methyl) -3- (methoxy-d 3 ) Phenyl) methanol (0.78g, 92%) as a solid. MS ESI calculated value C 33 H 30 D 5 NO 5 [M+H] + 531.3, 531.2 by experiment; 1 H NMR(400MHz,CDCl 3 )δ7.60-7.54(m,2H),7.53-7.47(m,2H),7.44-7.37(m,4H),7.37-7.30(m,2H),6.96-6.86(m,2H),6.82(s,1H),6.64(s,1H),5.25-5.16(m,2H),5.15-5.03(m,2H),4.88(d,J＝11.6Hz,1H),4.46(d,J＝11.5Hz,1H),4.06-4.01(m,1H),3.91(s,3H),3.07-3.01(m,1H),2.95-2.87(m,1H),2.78(d,J＝16.1Hz,1H),2.60(d,J＝16.0Hz,1H)。
6 and 7. 3 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquine 2 Morpholinyl [3,2-a]Isoquinoline-6,6-d
Figure BDA0003778601520000471
To obtain (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) 2 ) Methyl) -3- (methoxy-d 3 ) Phenyl) methanol (0.78g, 1.47mmol) and thionyl chloride (0.64mL, 5.38mmol) as starting materials according to the experimental procedures of steps 13 and 14 of preparation example 1 gave brown 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 (0.62g, 82%) semi-solid. MS ESI calculated value C 33 H 28 D 5 NO 4 [M+H] + 513.3, and 513.3 is measured by an experiment; 1 H NMR(400MHz,CDCl 3 )δ7.60-7.55(m,2H),7.53-7.48(m,2H),7.44-7.38(m,4H),7.37-7.30(m,2H),6.95-6.87(m,2H),6.83(s,1H),6.64(s,1H),5.20(d,J＝3.1Hz,2H),5.15-5.02(m,2H),4.88(d,J＝11.6Hz,1H),4.46(d,J＝11.6Hz,1H),4.06-4.01(m,1H),3.90(s,3H),3.46-3.40(m,2H),3.13-3.09(m,2H),2.78(d,J＝16.1Hz,1H),2.60(d,J＝16.1Hz,1H)。
8. 3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline- 2 6,6-d-2,9-diol
Figure BDA0003778601520000472
With 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 (0.62g, 1.21mmol) was used as a starting material, and experimental operation in the 15 th step of preparation example 1 was carried out to give 3-methoxy-10- (methoxy-d) as pink 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.29g, 72%) as a solid. MS ESI calculated value C 19 H 16 D 5 NO 4 [M+H] + 333.2, 333.2 found experimentally.
9. 3 (R) -and (S) -3-methoxy-10- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2- 2 a]Isoquinoline-6,6-d-2,9-diol
Figure BDA0003778601520000481
The racemic product (0.27 g) was isolated by chiral high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane (plus 0.5%2M ammonia in methanol), mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 50% B12 min; detection wavelength: 254/220nm; retention time 1:3.158 min; retention time 2:8.062 min.) the pre-peak collection was evaporated to dryness under reduced pressure to give (R) -or (S) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.13g, 46%) as a solid. MS ESI calculated value C 19 H 16 D 5 NO 4 [M+H] + 333.18, found experimentally 333.15; 1 H NMR(400MHz,DMSO-d 6 )δ8.67(s,1H),8.57(s,1H),6.78(d,J＝8.2Hz,1H),6.70(s,1H),6.64(s,1H),6.59(d,J＝8.2Hz,1H),4.01(d,J＝15.7Hz,1H),3.74(s,3H),3.38-3.22(m,2H),3.20-3.11(m,1H),2.89(d,J＝15.8Hz,1H),2.64-2.53(m,2H)；α＝+282(c＝0.2in MeOH)；ee>99％；D 5 ＝99.37％。
collecting the later peak, pressurizing and evaporating to dryness to obtain pink (S) -or (R) 3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.13g, 45%) as a solid. MS ESI calculated value C 19 H 16 D 5 NO 4 [M+H] + 333.18, found experimentally 333.15; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.70(s,1H),6.64(s,1H),6.58(d,J＝8.2Hz,1H),4.01(d,J＝15.7Hz,1H),3.74(s,3H),3.39-3.23(m,2H),3.21-3.13(m,1H),2.90(d,J＝15.7Hz,1H),2.64-2.54(m,2H)；α＝-297.5(c＝0.2in MeOH)；ee>99％；D 5 ＝99.36％。
preparation of example 7
Synthesis of Compounds 07-0Q and 07-0H
Figure BDA0003778601520000482
Synthesis scheme 7
Figure BDA0003778601520000491
Experimental part
1. 3 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) phenyl) -N- (2- (4- (benzyloxy) -3- (methyl) 3 2 Oxy-d) phenyl) ethyl-1,1-d) acetamide
Figure BDA0003778601520000492
With 8- (benzyloxy) -7- (methoxy-d 3 ) Isochroman-3-one (2.00g, 6.96mmol) and 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethane-1,1-d 2 Starting from (2.19g, 8.35mmol) the procedure of preparation example 1, step 8, gave 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) as a yellow color 3 ) Phenyl) -N- (2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethyl-1,1-d 2 ) Acetamide (2.64g, 69%) as an oil. MS ESI calculated value C 33 H 27 D 8 NO 6 [M+H] + 550.3, found experimentally 550.3; 1 H NMR(400MHz,CDCl 3 )δ7.51-7.47(m,2H),7.46-7.43(m,2H),7.42-7.30(m,6H),6.97-6.93(m,1H),6.88-6.85(m,1H),6.81-6.73(m,1H),6.69-6.67(m,1H),6.51-6.47(m,1H),6.08(s,1H),5.14(s,2H),5.09(s,2H),4.64-4.60(m,2H),3.52(s,2H),2.67(s,2H)。
2. 3 2 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3- (methoxy-d) phenyl) ethyl-1,1-d) ammonia 3 2-Oxoethyl) -3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000501
With 2- (3- (benzyloxy) -2- (hydroxymethyl) -4- (methoxy-d) 3 ) Phenyl) -N- (2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethyl-1,1-d 2 ) Acetamide (2.66g, 4.84mmol) and acetyl chloride (0.52mL, 6.60mmol) as starting materials gave off-white 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3- (methoxy-d) following the experimental procedure of step 9 of preparation example 1 3 ) Phenyl) ethyl-1,1-d 2 ) Amino) -2-oxoethyl) -3- (methoxy-d 3 ) Benzyl acetate (2.50g, 87%) is semi-solid. MS ESI calculated value C 35 H 29 D 8 NO 7 [M+H] + 592.3, found experimentally 592.3; 1 HNMR(400MHz,CDCl 3 )δ7.48-7.41(m,5H),7.41-7.30(m,5H),6.94-6.86(m,2H),6.76(d,J＝8.2Hz,1H),6.65(d,J＝2.0Hz,1H),6.49-6.45(m,1H),5.14-5.10(m,4H),5.05(s,2H),3.54(s,2H),2.65(s,2H),1.95(s,3H)。
3. 3 2 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -3,4-dihydroisoquinolin-1-yl-3,3-d) 3 Methyl) -3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000502
With 2- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethyl-1,1-d 2 ) Amino) -2-oxoethyl) -3- (methoxy-d 3 ) Benzyl acetate (2.30g, 3.89mmol) and phosphorus oxychloride (2.17mL, 14.18mmol) as starting materials gave, according to the experimental procedure of step 10 of preparation example 1, orange 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -3,4-dihydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Benzyl acetate (1.05g, 47%) as a solid. MS ESI calculated value C 35 H 27 D 8 NO 6 [M+H] + 574.3, found experimentally 574.3; 1 H NMR(400MHz,CDCl 3 )δ7.52-7.44(m,3H),7.43-7.30(m,7H),6.98-6.94(m,1H),6.85-6.79(m,2H),6.71(s,1H),5.21(s,2H),5.06(s,2H),5.01(s,2H),3.97(s,2H),2.66(s,2H),1.96(s,3H)。
4. 3 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl-3, 2 3 3-d) methyl) -3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000511
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -3,4-dihydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Benzyl acetate (0.90g, 1.57mmol) and sodium borohydride (89.02mg, 2.35mmol) as starting materials gave, following the experimental procedure of step 9 of preparation example 2, yellow 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolineQuinolin-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Benzyl acetate (0.71g, 79%) as an oil. MS ESI calculated value C 35 H 29 D 8 NO 6 [M+H] + 576.3, 576.2; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.45(m,4H),7.44-7.30(m,6H),7.01-6.94(m,2H),6.66-6.62(m,2H),5.35-5.29(m,2H),5.17(d,J＝11.5Hz,1H),5.11-5.09(m,4H),4.02-3.97(m,1H),3.12-3.05(m,1H),2.87-2.80(m,1H),2.76(s,2H),1.97(s,3H)。
5. 3 (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl-3, 2 3 3-d) methyl) -3- (methoxy-d) phenyl) methanol
Figure BDA0003778601520000512
With 2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Benzyl acetate (0.71g, 1.24mmol) and sodium hydroxide (0.30g, 7.50mmol) as starting materials gave off-white (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) following the experimental procedure of step 12 of preparation example 1 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Phenyl) methanol (0.61g, 92%) as a solid. MS ESI calculated value C 33 H 27 D 8 NO 5 [M+H] + 534.3, 534.4; 1 H NMR(400MHz,CDCl 3 )δ7.61-7.56(m,2H),7.54-7.47(m,2H),7.43-7.38(m,4H),7.37-7.30(m,2H),6.95-6.87(m,2H),6.82(s,1H),6.63(s,1H),5.26-5.15(m,2H),5.15-5.02(m,2H),4.88(d,J＝11.6Hz,1H),4.46(d,J＝11.6Hz,1H),4.05-4.01(m,1H),3.06-3.02(m,1H),2.93-2.89(m,1H),2.78(d,J＝16.1Hz,1H),2.60(d,J＝16.0Hz,1H)。
6 and 7. 3 2,9-bis (benzyloxy) -3,10-bis (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl 2 [3,2-a]Isoquinoline-6,6-d
Figure BDA0003778601520000521
With (2- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d 2 ) Methyl) -3- (methoxy-d 3 ) Phenyl) methanol (0.61g, 1.14mmol) and thionyl chloride (0.50mL, 4.18mmol) as starting materials gave, according to the experimental procedures of steps 13 and 14 of preparation example 1, yellow 2,9-bis (benzyloxy) -3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 (0.51g, 88%) oil. MS ESI calculated value C 33 H 25 D 8 NO 4 [M+H] + 516.3, 516.3 is measured by experiments; 1 H NMR(400MHz,CDCl 3 )δ7.51-7.47(m,4H),7.44-7.31(m,6H),6.89-6.82(m,2H),6.76(s,1H),6.65(s,1H),5.16(s,2H),5.11(d,J＝11.1Hz,1H),5.00(d,J＝11.2Hz,1H),4.23-4.19(m,1H),3.48-3.41(m,2H),3.11(d,J＝15.9Hz,2H),2.77-2.64(m,2H)。
8. 3 2 3,10-bis (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d- 2,9 diol
Figure BDA0003778601520000522
The compound is prepared from 2,9-bis (benzyloxy) -3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 (0.47g, 0.91mmol) as a starting material, following the experimental procedure of step 15 of preparation example 1 gave light orange 3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 -2,9-diol (0.24g, 77%) as a solid. MS ESI calculated value C 19 H 13 D 8 NO 4 [M+H] + 336.2, found 336.3 experimentally.
9. 3 (R) -and (S) -3,10-bis (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquine 2 Quinoline-6,6-d-2,9-diol
Figure BDA0003778601520000531
The racemic product (0.24 g) was isolated by chiral high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane (plus 0.5% ammonia in methanol; 2M; min; mobile phase B: ethanol; flow rate: 18mL/min; isocratic: 50% B25 min; detection wavelength: 254/220nm; retention time 1:8.916 min; retention time 2:16.952 min.) the pre-peak collection was evaporated to dryness under reduced pressure to give orange (R) -or (S) -3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 2,9-diol (0.10g, 43%) as a solid. MS ESI calculated value C 19 H 13 D 8 NO 4 [M+H] + 336.20, 336.15; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.6Hz,1H),3.36-3.30(m,1H),3.30-3.22(m,1H),3.18-3.13(m,1H),2.89(d,J＝15.6Hz,1H),2.61-2.53(m,2H)；α＝+274.5(c＝0.2in MeOH)；ee>99％；D 8 ＝99.55％。
collecting the later peak, evaporating under reduced pressure to dryness to obtain orange (S) -or (R) 3,10-bis (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d 2 2,9-diol (0.10g, 43%) as a solid. MS ESI calculated value C 19 H 13 D 8 NO 4 [M+H] + 336.20, 336.15; 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.56(s,1H),6.78(d,J＝8.2Hz,1H),6.69(s,1H),6.63(s,1H),6.58(d,J＝8.3Hz,1H),4.00(d,J＝15.6Hz,1H),3.33-3.30(m,1H),3.29-3.22(m,1H),3.19-3.13(m,1H),2.89(d,J＝15.6Hz,1H),2.61-2.52(m,2H)；α＝-301.5(c＝0.2in MeOH)；ee>99％；D 8 ＝99.68％.
preparation of example 8
Synthesis of Compounds 08-0Q and 08-0H
Figure BDA0003778601520000541
Scheme 8
Figure BDA0003778601520000542
Experimental part
1. 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-1-d) methyl 3 3- (methoxy-d) acetic acid benzyl ester
Figure BDA0003778601520000551
To produce [2- (benzyloxy) -6- [ [7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl ] compound]Methyl radical]-3- (methoxy-d) 3 ) Phenyl radical]Methyl acetate (0.35g, 0.09mmol) and boron sodium deuteride (30.94mg, 0.11mmol) as starting materials, according to the preparation example 2 in the 9 th step of the experimental operation to obtain brown 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-four hydrogen isoquinoline-1-yl-1-d) methyl) -3- (methoxy-d 3 ) Benzyl acetate (0.24g, 68%) as a solid. MS ESI calculated value C 35 H 33 D 4 NO 6 [M+H] + 572.29, 572.15 was experimentally determined.
2.(2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-1-d) methyl 3 3- (methoxy-d) phenyl) methanol
Figure BDA0003778601520000552
To obtain 2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-1-d) methyl) -3- (methoxy-d 3 ) Benzyl acetate (0.24g, 0.42mmol) and sodium hydroxide (56.00mg, 1.40mmol) as starting materials, according to the experimental procedure of step 12 of preparation example 1, white (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-1-d) methyl) -3- (methoxy-d 3 ) Phenyl) methanol (0.27g, 96%) as a solid. MS ESI calculated value C 33 H 31 D 4 NO 5 [M+H] + 530.28, 530.15; 1 H NMR(300MHz,CDCl 3 )δ7.58-7.52(m,2H),7.52-7.48(m,2H),7.45-7.37(m,6H),6.91-6.87(m,2H),6.80(s,1H),6.63(s,1H),5.21-5.18(m,2H),5.12(d,J＝10.8Hz,1H),5.05(d,J＝10.7Hz,1H),4.87(d,J＝11.6Hz,1H),4.47(d,J＝11.6Hz,1H),3.91(s,3H),3.10-2.87(m,2H),2.74-2.85(m,2H),2.72-2.58(m,2H)。
3 and 4. 3 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquine Morpholinyl [3,2-a]Isoquinoline-13 a-d
Figure BDA0003778601520000561
To prepare (2- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-1-d) methyl) -3- (methoxy-d) 3 ) Phenyl) methanol (0.27g, 0.51mmol) and thionyl chloride (0.21mL, 2.90mmol) as starting materials according to the experimental procedures of steps 13 and 14 of preparation example 1 to give brown 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-13 a-d (0.22g, 85%) as a solid. MS ESI calculated value C 33 H 29 D 4 NO 4 [M+H] + 512.27, 512.15; 1 H NMR(400MHz,CDCl 3 )δ7.51-7.45(m,3H),7.44-7.30(m,7H),6.88-6.84(m,2H),6.76(s,1H),6.66(s,1H),5.32(s,2H),5.16(s,2H),5.10(d,J＝11.2Hz,1H),5.00(d,J＝11.2Hz,1H),4.23-4.19(m,1H),3.90(s,3H),3.46-3.42(m,1H),3.13-3.08(m,2H),2.75-2.58(m,2H)。
5. 3 3-methoxy-10- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline- 13a-d-2,9-diol
Figure BDA0003778601520000562
Concentrated hydrochloric acid (0.50 mL) was added dropwise to 2,9-bis (benzyloxy) -3-methoxy-10- (methoxy-d) at 0 ℃ under nitrogen blanket 3 ) -5,8,13,13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-13 a-d (0.20g, 0.39mmol) in ethanol (2 mL). The reaction solution was stirred at 80 ℃ for 16 hours. The reaction was diluted with water (20 mL) and extracted with dichloromethane (3X 20 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was separated using a preparative liquid phase under the following conditions: preparing a column: XBridge Prep C18 OBD Column,19x150mm,5 μm; mobile phase A, water (plus 10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 20mL/min; gradient: 30% b to 60% b 6 minutes; detection wavelength: 210/254nm; retention time: 5.53 minutes. Collecting the product-containing fractions, and evaporating under reduced pressure to obtain pink 3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-13 a-d-2,9-diol (16.8mg, 13%) as a solid. MS ESI calculated value C 19 H 17 D 4 NO 4 [M+H] + 332.17, found experimentally 332.10; 1 H NMR(300MHz,DMSO-d 6 )δ8.67(s,1H),8.56(s,1H),6.79(d,J＝8.2Hz,1H),6.70(s,1H),6.65(s,1H),6.59(d,J＝8.2Hz,1H),4.01(d,J＝15.8Hz,1H),3.75(s,3H),3.40-3.25(m,1H),3.18-3.08(m,2H),2.97-2.82(m,1H),2.62-2.48(m,3H)；D 4 ＝99.67％。
6.(R) -and (S) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13,13a-tetrahydro-6H-isoquinolinyl [3,2- a]Isoquinoline-13 a-d-2,9-diol
Figure BDA0003778601520000571
The racemic product (16.8 mg) was isolated by manual high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane: dichloromethane =3:1 (plus 0.5%2M ammonia in methanol), mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 50: 7 min; detection wavelength: 254/220nm; retention time 1.107 min; retention time 2.066 min.) Pre-peak collection was evaporated to dryness under reduced pressure to give pink (R) -or (S) -3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-13 a-d-2,9Diol (4.2mg, 25%) as a solid. MS ESI calculated value C 19 H 17 D 4 NO 4 [M+H] + 332.17, found experimentally 332.10; 1 HNMR(400MHz,DMSO-d 6 )δ8.67(s,1H),8.56(s,1H),6.79(d,J＝8.2Hz,1H),6.70(s,1H),6.64(s,1H),6.59(d,J＝8.2Hz,1H),4.01(d,J＝15.8Hz,1H),3.74(s,3H),3.40-3.26(m,1H),3.17-3.08(m,2H),2.97-2.82(m,1H),2.65-2.40(m,3H)；ee>99％。
collecting the final peak, evaporating under reduced pressure to obtain pink (S) -or (R) 3-methoxy-10- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-13 a-d-2,9-diol (4.3mg, 26%) as a solid. MS ESI calculated value C 19 H 17 D 4 NO 4 [M+H] + 332.17, found experimentally 332.10; 1 H NMR(400MHz,DMSO-d 6 )δ8.67(s,1H),8.56(s,1H),6.79(d,J＝8.2Hz,1H),6.70(s,1H),6.64(s,1H),6.59(d,J＝8.2Hz,1H),4.01(d,J＝15.8Hz,1H),3.74(s,3H),3.40-3.20(m,1H),3.18-3.10(m,2H),2.97-2.82(m,1H),2.65-2.40(m,3H)；ee>99％。
preparation of example 9
Synthesis of Compounds 09-0Q and 09-0H
Figure BDA0003778601520000581
Synthesis scheme 9
Figure BDA0003778601520000582
Experimental part
1. 2- (4- (benzyloxy) -3-bromophenyl) acetic acid methyl ester
Figure BDA0003778601520000583
Starting from methyl 2- (3-bromo-4-hydroxyphenyl) acetate (29.20g, 119.15mmol) and benzyl bromide (22.51g, 131.61mmo), the experimental procedure of step 2 of preparation example 1 was conducted to obtain white 2- (4- (benzyloxyl) methyl acetateYl) -3-bromophenyl) acetic acid methyl ester (35.4g, 89%) as a solid. MS ESI calculated value C 16 H 15 BrO 3 [M+NH 3 +H] + 352.02,354.02, found experimentally 352.15,354.15; 1 HNMR(300MHz,CDCl 3 )δ7.55-7.48(m,3H),7.45-7.30(m,3H),7.17(dd,J＝8.4,2.2Hz,1H),6.91(d,J＝8.4Hz,1H),5.17(s,2H),3.72(s,3H),3.56(s,2H)。
2. 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid
Figure BDA0003778601520000584
Starting from methyl 2- (4- (benzyloxy) -3-bromophenyl) acetate (15.70g, 46.84mmol) and copper (II) bis (8-quinolinate) (2.47g, 7.02mmol), the experimental procedure of step 3 in preparation example 1 gave 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid (4 g, 33%) as a brown solid. MS ESI calculated value C 15 H 14 O 4 [M-H] - 257.09, found 257.05 experimentally; 1 H NMR(400MHz,CDCl 3 )δ7.47-7.34(m,5H),7.00-6.87(m,2H),6.77(dd,J＝8.2,2.1Hz,1H),5.68(s,1H),5.12(s,2H),3.59(s,2H)。
3. 7- (benzyloxy) -8-hydroxyisochroman-3-one
Figure BDA0003778601520000591
Starting from 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid (4.00g, 15.49mmol), phenylboronic acid (2.83g, 23.21mmol) and paraformaldehyde (3.64g, 121.33mmol), the procedure in step 4 of preparation example 1 gave 7- (benzyloxy) -8-hydroxyisochroman-3-one (3.52g, 84%) as a brown solid. MS ESI calculated value C 16 H 14 O 4 [M-H] - 269.09, 269.20 was experimentally determined.
4. 7- (benzyloxy) -8-methoxyisochroman-3-one
Figure BDA0003778601520000592
Starting from 7- (benzyloxy) -8-hydroxyisochroman-3-one ((3.5g, 12.85mmol) and iodomethane (2.02g, 14.23mmol), the experimental procedure of step 5 of preparation example 1 gave brown 7- (benzyloxy) -8-methoxyisochroman-3-one (1.5g, 40%) as a solid MS ESI calculated for C 17 H 16 O 4 [M+H] + 285.10, found experimentally 285.20; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.23(m,5H),6.96(d,J＝8.2Hz,1H),6.88-6.86(m,1H),5.43(s,2H),5.15(s,2H),3.94(s,3H),3.64(d,J＝0.8Hz,2H)。
5. 3 2- (4- (benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (4- (benzyloxy) -3- (methoxy-d) Phenethyl) acetamide
Figure BDA0003778601520000601
With 7- (benzyloxy) -8-methoxyisochroman-3-one (0.61g, 2.15mmol) and 2- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenyl) ethan-1-amine (0.60g, 2.31mmol) as starting material was subjected to the experimental procedure of step 8 of preparation example 1 to give off-white 2- (4- (benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (4- (benzyloxy) -3- (methoxy-d) 3 ) Phenethyl) acetamide (0.93g, 74%) as a solid. MS ESI calculated value C 33 H 32 D 3 NO 6 [M+H] + 545.27, 545.30; 1 H NMR(300MHz,CDCl 3 )δ7.51-7.25(m,11H),6.93-6.81(m,2H),6.78(d,J＝8.1Hz,1H),6.68(d,J＝2.0Hz,1H),6.50(dd,J＝8.1,2.0Hz,1H),5.96(br s,1H),5.15(d,J＝4.6Hz,4H),4.70(s,2H),3.96(s,3H),3.52(s,2H),3.48-3.46(m,2H),2.70(t,J＝6.8Hz,2H)。
6. 3 3- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) phenethyl) amino) -2-oxyethyl) - 2-methoxybenzyl acetate
Figure BDA0003778601520000602
With 2- (4- (benzyloxy) -2- (hydroxy)Methyl) -3-methoxyphenyl) -N- (4- (benzyloxy) -3- (methoxy-d 3 ) Phenethyl) acetamide (0.93g, 1.71mmol) and acetyl chloride (0.20g, 2.56mmol) as starting materials, according to the experimental procedure of step 9 of preparation example 1, off-white 3- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) 3 ) Phenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate (1.02g, 96%) as a solid. MS ESI calculated value C 35 H 34 D 3 NO 7 [M+H] + 587.28, found experimentally 587.10; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.31(m,10H),6.92(d,J＝8.5Hz,1H),6.86(d,J＝8.5Hz,1H),6.76(d,J＝8.2Hz,1H),6.66(d,J＝2.0Hz,1H),6.48(dd,J＝8.1,2.1Hz,1H),5.48-5.46(m,1H),5.18(s,2H),5.13(s,4H),3.91(s,3H),3.56(s,2H),3.46-3.44(m,2H),2.68(t,J＝6.9Hz,2H),2.02(s,3H)。
7. 3 3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -3,4-dihydroisoquinolin-1-yl) methyl) - 2-Methoxyacetic acid benzyl ester
Figure BDA0003778601520000611
With 3- (benzyloxy) -6- (2- ((4- (benzyloxy) -3- (methoxy-d) 3 ) Phenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate (0.9g, 1.53mmol) and phosphorus oxychloride (0.86mL, 9.20mmol) as starting materials according to the experimental procedure of step 10 in preparation example 1, yellow 3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -3,4-dihydroisoquinolin-1-yl) methyl) -benzyl 2-methoxyacetate (0.62g, 58%) as a solid. MS ESI calculated value C 35 H 32 D 3 NO 6 [M+H] + 569.27, found experimentally 569.20; 1 H NMR(300MHz,CDCl 3 )δ7.47-7.29(m,10H),6.97(s,1H),6.83(d,J＝8.5Hz,1H),6.72(d,J＝9.4Hz,2H),5.25(s,2H),5.08(s,2H),4.99(s,2H),4.03(s,2H),3.91(s,3H),3.72(t,J＝7.6Hz,2H),2.69(t,J＝7.7Hz,2H),2.03(s,3H)。
8. 3 3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl 2-Methoxyacetic acid benzyl ester
Figure BDA0003778601520000612
With 3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -3,4-dihydroisoquinolin-1-yl) methyl) -2-methoxy benzyl acetate (0.57g, 1.00mmol) and sodium borohydride (56.88mg, 1.50mmol) as starting materials gave, according to the experimental procedure in preparation example 2, 3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) as an off-white color 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -benzyl 2-methoxyacetate (0.32g, 55%) as a solid. MS ESI calculated value C 35 H 34 D 3 NO 6 [M+H] + 571.28, found experimentally 571.10; 1 H NMR(300MHz,CDCl 3 )δ7.51-7.27(m,10H),7.00-6.92(m,2H),6.63-6.60(m,2H),5.39-5.29(m,1H),5.21(d,J＝11.5Hz,1H),5.14(s,2H),5.07(s,2H),4.06-4.04(m,1H),3.94(s,3H),3.20-3.15(m,2H),3.06-2.76(m,4H),2.06(s,3H)。
9. 3 (3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl 2-methoxyphenyl) -2-yl) -methanol
Figure BDA0003778601520000621
With 3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxyacetic acid benzyl ester (0.27g, 0.46mmol) and sodium hydroxide (0.95mL, 2.79mmol, 3N) as starting materials gave white (3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) according to the experimental procedure of the 12 th step in preparation example 1 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxyphenyl) methanol (0.27g, 99%) as a solid. MS ESI calculated value C 33 H 32 D 3 NO 5 [M+H] + 529.27, found experimentally 529.20; 1 H NMR(300MHz,CDCl 3 )δ7.50-7.30(m,10H),6.91(d,J＝8.4Hz,1H),6.88-6.78(m,2H),6.62(s,1H),5.20-5.15(m,4H),4.86(d,J＝11.5Hz,1H),4.48(d,J＝11.5Hz,1H),4.04-4.01(m,1H),3.97(s,3H),3.60-3.80(m,2H),3.12-2.98(m,2H),2.97-2.71(m,3H),2.68-2.55(m,1H)。
3 10 and 11.2,10-bis (benzyloxy) -9-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-iso Quinolyl [3,2-a]Isoquinoline derivatives
Figure BDA0003778601520000622
With (3- (benzyloxy) -6- ((7- (benzyloxy) -6- (methoxy-d) 3 ) -1,2,3,4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxyphenyl) methanol (0.22g, 0.41mmol) and thionyl chloride (0.30g, 2.49mmol) were used as starting materials to obtain yellow 2,10-bis (benzyloxy) -9-methoxy-3- (methoxy-d) according to the experimental procedures of the 13 th and 14 th steps of preparation example 1 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline (0.17g, 80%) as an oil. MS ESI calculated value C 33 H 30 D 3 NO 4 [M+H] + 511.26, 511.40 was experimentally determined.
12. 3 9-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline- 2,10 diol
Figure BDA0003778601520000631
With 2,10-bis (benzyloxy) -9-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline (0.17g, 0.03mmol) as a starting material was subjected to the experimental procedure of step 14 of preparation example 1 to give off-white 9-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,10-diol (60mg, 55%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.17, 331.25 was experimentally determined.
3 13. (R) -and (S) -9-methoxy-3- (methoxy-d) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2- a]Isoquinoline-2,10-diol
Figure BDA0003778601520000632
The racemic product (60 mg) was separated by chiral high performance liquid chromatography under the following conditions (column: CHIRAL ART cell lose-SB,2x25cm,5 μm; mobile phase A: n-hexane (plus 10mM ammonia methanol solution); mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 50% B10.5 min; detection wavelength: 254/220nm; retention time 1.367 min; retention time 2.524 min. Peeak collection was evaporated to dryness under reduced pressure to give (R) -or (S) -9-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,10-diol (22.9mg, 38%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.17, found experimentally 331.10; 1 H NMR(300MHz,DMSO-d 6 )δ9.06(s,1H),8.66(s,1H),6.77-6.61(m,4H),4.04(d,J＝15.8Hz,1H),3.73(s,3H),3.39-3.34(m,2H),3.19-3.06(m,2H),2.96-2.82(m,1H),2.59-2.41(m,3H)；α＝+268.3(c＝0.1in MeOH)；ee＝98.2％；D 3 ＝99.14％.
collecting the final peak, evaporating under reduced pressure to obtain pink (S) -or (R) 9-methoxy-3- (methoxy-d) 3 ) -5,8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-2,10-diol (22.0 mg, 36%) as a solid. MS ESI calculated value C 19 H 18 D 3 NO 4 [M+H] + 331.17, 331.10; 1 H NMR(300MHz,DMSO-d 6 )δ9.06(s,1H),8.66(s,1H),6.77-6.61(m,4H),4.04(d,J＝15.8Hz,1H),3.73(s,3H),3.39-3.34(m,2H),3.19-3.06(m,2H),2.96-2.82(m,1H),2.59-2.41(m,3H)；a＝-265.7(c＝0.1in MeOH)；ee＝95.1％；D 3 ＝99.24％。
preparation of example 10
Synthesis of Compounds 10-0Q and 10-0H
Figure BDA0003778601520000641
Synthesis scheme 10
Figure BDA0003778601520000642
Experimental part
1. 2- (4- (benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (2- (4- (benzyloxy) -3-methoxybenzene 2 Yl) ethyl-1,1-d) acetamide
Figure BDA0003778601520000643
With 7- (benzyloxy) -8-methoxyisochroman-3-one (0.70g, 2.46mmol) and 2- [4- (benzyloxy) -3-methoxyphenyl](1,1-d 2 ) Ethylamine hydrochloride (0.75g, 2.54mmol) as the starting material, according to the experimental procedure of step 2 of preparation example 3, gave off-white 2- (4- (benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Acetamide (0.82g, 59%) as a solid. MS ESI calculated value C 33 H 33 D 2 NO 6 [M+H] + 544.26, found experimentally 544.01; 1 H NMR(300MHz,CDCl 3 )δ7.49-7.30(m,11H),6.92-6.82(m,2H),6.78(d,J＝8.2Hz,1H),6.69(d,J＝2.0Hz,1H),6.50(dd,J＝8.1,2.0Hz,1H),5.93(s,1H),5.15(s,2H),5.14(s,2H),4.71(s,2H),3.96(s,3H),3.86(s,3H),3.53(s,2H),2.69(s,2H)。
2. 2 3- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d) amino) -2- Oxyethyl) -2-methoxybenzyl acetate
Figure BDA0003778601520000651
With 2- (4- (benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Acetamide (0.82g, 1.40mmol) and acetyl chloride (0.16g, 2.10mmol) as starting materials, according to the experimental procedure of step 9 of preparation example 1, off-white 3- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d was obtained 2 ) Amino) -2-oxoethyl) -2-methoxybenzyl acetate (0.81g, 99%) as a solid. MS ESI calculated value C 35 H 35 D 2 NO 7 [M+H] + 586.27, found experimentally 586.20; 1 H NMR(400MHz,CDCl 3 )δ7.50-7.27(m,10H),6.92(d,J＝8.5Hz,1H),6.86(d,J＝8.4Hz,1H),6.76(d,J＝8.1Hz,1H),6.66(d,J＝2.0Hz,1H),6.49(dd,J＝8.1,2.0Hz,1H),5.46(s,1H),5.18(s,2H),5.15-5.12(m,4H),3.91(s,3H),3.85(s,3H),3.56(s,2H),2.67(s,2H),2.02(s,3H)。
3. 2 3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl-3,3-d) methyl 2-Methoxyacetic acid benzyl ester
Figure BDA0003778601520000652
With 3- (benzyloxy) -6- (2- ((2- (4- (benzyloxy) -3-methoxyphenyl) ethyl-1,1-d 2 ) Amino) -2-oxyethyl) -2-methoxybenzyl acetate (0.81g, 1.38mmol) and phosphorus oxychloride (0.77mL, 8.29mmol) were used as starting materials to obtain yellow 3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinolin-1-yl-3,3-d according to the experimental operation of the 10 th step in preparation example 1 2 ) Methyl) -2-methoxy-acetic acid benzyl ester (0.50g, 64%) as a solid. MS ESI calculated value C 35 H 33 D 2 NO 6 [M+H] + 568.26, found experimentally 568.30; 1 H NMR(400MHz,CDCl 3 )δ7.49-7.31(m,6H),7.32-7.24(m,4H),6.98(s,1H),6.84(d,J＝8.5Hz,1H),6.78-6.70(m,2H),5.26(s,2H),5.10(s,2H),5.01(s,2H),4.00(s,2H),3.92(2s,6H),2.66(s,2H),2.04(s,3H)。
4. 2 3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) Methyl) -2-methoxybenzyl acetate
Figure BDA0003778601520000661
To obtain 3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-3,4-dihydroisoquinoline-1-yl)-3,3-d 2 ) Benzyl methyl) -2-methoxyacetate (0.50g, 0.91mmol) and sodium borohydride (41.19mg, 1.08mmol) were used as starting materials, and the procedure of 9 th step in preparation example 2 was followed to give 3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d as red color 2 ) Methyl) -2-methoxybenzyl acetate (0.30g, 58%) is semisolid. MS ESI calculated value C 35 H 35 D 2 NO 6 [M+H] + 570.27, found experimentally 570.25; 1 H NMR(300MHz,CDCl 3 )δ7.46-7.25(m,10H),7.00-6.91(m,2H),6.63(s,1H),6.39(s,1H),5.15-4.94(m,6H),4.22-4.12(m,1H),3.92(s,3H),3.87(s,3H),3.11(br s,2H),2.90-2.86(m,2H),2.04(s,3H)。
5. 2 (3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) Methyl) -2-methoxyphenyl) methanol
Figure BDA0003778601520000662
3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-yl-3,3-d 2 ) Methyl) -2-methoxybenzyl acetate (0.30g, 0.53mmol) and sodium hydroxide (0.13g, 3.18mmol) were used as starting materials to obtain (3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) as pink in the experimental operation at step 12 of preparation example 1 2 ) Methyl) -2-methoxyphenyl) methanol (0.20g, 72%) as a solid. MS ESI calculated value C 33 H 33 D 2 NO 5 [M+H] - 528.26, found experimentally 528.40; 1 H NMR(400MHz,CDCl 3 )δ7.53-7.26(m,10H),6.90(d,J＝8.4Hz,1H),6.87-6.78(m,2H),6.63(s,1H),5.20-5.15(m,4H),4.86(d,J＝11.6Hz,1H),4.48(d,J＝11.5Hz,1H),4.03-4.00(m,1H),3.97(s,3H),3.90(s,3H),3.05-3.01(m,1H),2.92-2.89(m,1H),2.77(d,J＝16.1Hz,,1H),2.59(d,J＝16.1Hz,1H)。
6 and 7.2,10-bis (benzyloxy) -3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a] 2 Isoquinoline-6,6-d
Figure BDA0003778601520000671
To prepare (3- (benzyloxy) -6- ((7- (benzyloxy) -6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl-3,3-d) 2 ) Methyl) -2-methoxyphenyl) methanol (0.23g, 0.43mmol) and thionyl chloride (0.31g, 2.61mmol) were used as starting materials to obtain 2,10-bis (benzyloxy) -3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a ] orange by following the experimental procedures of steps 13 and 14 of preparation example 1]Isoquinoline-6,6-d 2 (0.18g, 81%) solid. MS ESI calculated value C 33 H 31 D 2 NO 4 [M+H] + 510.25, found experimentally 510.40; 1 H NMR(400MHz,CDCl 3 )δ7.49-7.43(m,4H),7.45-7.29(m,6H),6.86-6.80(m,2H),6.76(s,1H),6.67(s,1H),5.17-5.14(m,4H),4.27(d,J＝15.9Hz,1H),3.92(2s,6H),3.56-3.54(m,2H),3.13-3.10(m,2H),2.72-2.69(m,2H)。
8. 2 3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]Isoquinoline-6,6-d-2,10- Diols
Figure BDA0003778601520000672
Using 2,10-bis (benzyloxy) -3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolino [3,2-a]Isoquinoline-6,6-d 2 (0.18g, 0.35mmol) was used as a starting material to obtain 3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a ] in pink according to the experimental procedure of step 15 of preparation example 1]Isoquinoline-6,6-d 2 -2,10-diol (90mg, 77%) as a solid. MS ESI calculated value C 19 H 19 D 2 NO 4 [M+H] + 330.16, 330.30 was experimentally determined.
9. (R) -and (S) -3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a]The content of the isoquinoline-6 is as follows, 2 6-d-2,10-diol
Figure BDA0003778601520000681
The racemic product (0.09 g) was separated by chiral high performance liquid chromatography under the following conditions (column: CHIRAL ART cell-SB, 2x25cm,5 μm; mobile phase A: n-hexane: dichloromethane =3:1 (plus 10mM ammonia methanol solution); mobile phase B: ethanol; flow rate: 20mL/min; isocratic: 10% B24 min; detection wavelength: 254/220nm; retention time 1.7.013 min; retention time 2.323 min; pre-peak collection, reduced pressure evaporation to dryness to obtain pink (R) -or (S) -3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolinyl [3,2-a)]Isoquinoline-6,6-d 2 -2,10-diol (22.2mg, 25%) as a solid. MS ESI calculated value C 19 H 19 D 2 NO 4 [M+H] + 330.16, found experimentally 330.00; 1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),8.64(s,1H),6.72-6.63(m,4H),4.02(d,J＝15.6Hz,1H),3.73(s,3H),3.71(s,3H),3.37-3.31(m,1H),3.16-3.09(m,1H),2.91-2.85(m,1H),2.53-2.50(m,3H)；α＝+299.3(c＝0.1in MeOH)；ee>99％；D 2 ＝99.13％。
collecting the rear peak, vacuum evaporating to dryness to obtain pink (S) -or (R) 3,9-dimethoxy-5, 8,13, 13a-tetrahydro-6H-isoquinolyl [3,2-a]Isoquinoline-6,6-d 2 -2,10-diol (21.1mg, 23%) as a solid. MS ESI calculated value C 19 H 19 D 2 NO 4 [M+H] + 330.16, 330.00; 1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),8.64(s,1H),6.72-6.63(m,4H),4.02(d,J＝15.3Hz,1H),3.73(s,3H),3.71(s,3H),3.37-3.31(m,1H),3.16-3.09(m,1H),2.91-2.85(m,1H),2.58-2.50(m,3H)；α＝-282.3(c＝0.1in MeOH)；ee＝96.5％；D 2 ＝99.16％。
analytical examples
Each compound prepared above is subjected to D 1 、D 2L 、D 4 And 5HT 2A Ligand binding assays for receptors and assays for receptor agonistic and inhibitory activity. The non-deuterated compounds levo-Stepholidine (l-stephilicine, l-SPD, 21-0) and levo-aureovioline (l-Scoulerine, l-SLR, 22-0) were used as controls in the assay.
Analytical example 1.5HT 2A Radioligand binding assay protocol
1. Experimental material and instrument and equipment
Reagent Brand Goods number
5-hydroxytryptamine 5HT 2A (human) film PerkinElmer ES-313-M400UA
3 H-ketanserin hydrochloride PerkinElmer NET791250UC
Mianserin hydrochloride sigma M2525
ULTIMA GOLD Perkin Elmer 77-16061
Polyethylenimine (PEI), branched Sigma 408727
Tris-base Sigma 77-86-1
CaCl 2 Sigma C5670
L-ascorbic acid Tianjin Guangfu 50-81-7
Consumable material Brand Goods number
1.1mL of 96-hole round-bottom deep-hole plate Perkin Elmer P-DW-11-C
384-hole round bottom plate Corning 3657
UNIFILTER-96GF/B filter plate PerkinElmer 6005177
Centrifuge tube (15mL, 50mL) BD 352096,352070
Sample adding groove JET BIOFIL LTT001050
Tray JET BIOFIL LTT001050
Instrument Brand Goods number
Vortex mixer IKA MS3 basic
Electric heating constant temperature incubator Shanghai yi heng DHP-9032
Micro-plate vibrating screen VWR 12620-928
TopCount PerkinElmer NTX
Universal Harvester Perkin Elmer UNIFILTER-96
2. Experimental methods
1) To each well of a 96-deep well plate, 100. Mu.L of reaction buffer was added.
2) Add 5. Mu.L of diluted compounds (1% DMSO) to each well in 96-well plates.
3) Add 300. Mu.L of membrane buffer mix to each well: add 1.5. Mu.L of membrane protein and 298.5. Mu.L of buffer to each well and shake for 5min at 600 rpm.
4) Adding 100. Mu.L of the reaction buffer and [2 ] 3 H]And (3) adding a mixed solution of ketanserin hydrochloride (the final concentration is 2 nM) into the reaction system, shaking at 600rpm for 5min, and incubating at 27 ℃ for 1h.
5) 0.5% PEI pretreatment UNIFILTER-96GF/B plates, 150. Mu.L of 0.5% PEI per well, incubation for 1 hour at 4 ℃.
6) UNIFILTER-96GF/B plates were washed 2 times with Universal Harvester, 50mL each time.
7) The reaction system was transferred to a UNIFILTER-96GF/B plate using a Universal Harvester, 900. Mu.L of the washing solution was added to each well to wash the GF/B plate 4 times, and the washed UNIFILTER-96GF/B plate was dried in an oven at 55 ℃ for 10min.
8) Add 40. Mu.L of ULTIMA GOLD scintillation fluid per well using the TopCount reading.
Analytical example 2.D 1 Radioligand binding assays
Experimental protocol
1. Experimental material and instrument and equipment
Figure BDA0003778601520000701
Figure BDA0003778601520000711
Consumable material Brand Goods number
1.1mL of 96-hole round-bottom deep-hole plate Perkin Elmer P-DW-11-C
384-hole round bottom plate Corning 3657
UNIFILTER-96GF/B filter plate PerkinElmer 6005177
Centrifuge tube (15mL, 50mL) BD 352096,352070
Sample adding groove JET BIOFIL LTT001050
Tray JET BIOFIL LTT001050
Instrument for measuring the position of a moving object Brand Goods number
Vortex mixer IKA MS3 basic
Electric heating constant temperature incubator Shanghai yi heng DHP-9032
Micro-plate vibrating screen VWR 12620-928
TopCount PerkinElmer NTX
Universal Harvester Perkin Elmer UNIFILTER-96
2 Experimental methods
1) To each well of a 96-deep well plate, 100. Mu.L of reaction buffer was added.
2) Add 5. Mu.L of diluted compounds (1% DMSO) to each well in 96-well plates.
3) Add 300. Mu.L of membrane buffer mix to each well: mu.L of membrane protein and 299. Mu.L of buffer were added to each well and shaken at 600rpm for 5min.
4) Adding 100. Mu.L of the reaction buffer and [2 ] 3 H]SCH 23390 (final concentration 0.25 nM) was added to the reaction mixture, shaken at 600rpm for 5min and incubated at 27 ℃ for 1h.
5) 0.5% PEI pretreatment UNIFILTER-96GF/B plates, 150. Mu.L of 0.5% PEI per well, 1 hour incubation at 4 ℃.
6) UNIFILTER-96GF/B plates were washed 2 times with Universal Harvester, 50mL each time.
7) The reaction system was transferred to a UNIFILTER-96GF/B plate using a Universal Harvester, 900. Mu.L of the washing solution was added to each well to wash the GF/B plate 4 times, and the washed UNIFILTER-96GF/B plate was dried in an oven at 55 ℃ for 10min.
8) Add 40. Mu.L of ULTIMA GOLD scintillation fluid per well using the TopCount reading.
Analytical example 3.D 2L Radioligand binding assays
Experimental protocol
1. Experimental material and instrument and equipment
Reagent Brand Goods number
[ 3 H]-Methospilon (Methylpiperone) PerkinElmer NET856250UC
Haloperidol Sigma H1512-5G
D 2L Film Pharmaron In house
ULTIMA GOLD Perkin Elmer 77-16061
Polyethyleneimine (PEI), branched Sigma 408727
Tris-base Sigma 77-86-1
MgCl 2 Sigma 7786-30-3
NaCl Sigma 7647-14-5
EDTA Invitrogen 15575-038
Protease inhibitor mixture tablet Roche 4693132001
Pierce (TM) BCA protein assay kit Thermo 23227
Consumable material Brand Goods number
1.1mL of 96-hole round-bottom deep-hole plate Perkin Elmer P-DW-11-C
384-hole round bottom plate Corning 3657
UNIFILTER-96GF/C filter plate PerkinElmer 6005174
Centrifuge tube (15mL, 50mL) BD 352096,352070
Sample adding groove JET BIOFIL LTT001050
Tray JET BIOFIL LTT001050
Instrument for measuring the position of a moving object Brand Goods number
Electric heating constant temperature incubator Shanghai-heng DHP-9032
Micro-plate vibrating screen VWR 12620-928
Universal Harvester Perkin Elmer UNIFILTER-96
CO 2 Culture box Thermo 371
Electric liquid transfer device Thermo /
Desk type centrifuge Eppendorf 5702
Electric heating constant temperature water tank JINGHONG DKB-8A
Glass tissue homogenizer Nanjing jade changed glass instrument 50mL
High-speed dispersion machine IKA T18
Multi-template enzyme-labeling instrument PerkinElmer Victor Nivo 35
Small-sized high-speed centrifugal machine Eppendorf 5810R
Low-temperature high-speed centrifuge SORVALL LYNX4000
Vortex mixer IKA MS3 basic
TopCount PerkinElmer NTX
2 method of experiment
1) To each well of a 96-deep well plate, 100. Mu.L of reaction buffer was added.
2) Add 5. Mu.L of diluted compounds (1% DMSO) to each well in 96-well plates.
3) Add 300. Mu.L of membrane buffer mix to each well: mu.L of membrane protein and 290. Mu.L of buffer were added to each well and shaken at 600rpm for 5min.
4) Adding 100. Mu.L of the reaction buffer and [2 ] 3 H]And adding a mixed solution of-Methospirone (the final concentration is 0.5 nM) into the reaction system, shaking at 600rpm for 5min, and incubating at 27 ℃ for 1h.
5) 0.5% PEI pretreatment UNIFILTER-96GF/C plates, 150. Mu.L of 0.5% PEI per well, incubation for 1 hour at 4 ℃.
6) UNIFILTER-96GF/C plates were washed 2 times with Universal Harvester, 50mL each time.
7) The reaction system was transferred to a UNIFILTER-96GF/C plate using a Universal Harvester, 900. Mu.L of the washing solution was added to each well to wash the GF/C plate 4 times, and the washed UNIFILTER-96GF/C plate was dried in an oven at 55 ℃ for 10min.
8) 40 μ L of ULTIMA GOLD scintillant was added to each well using a TopCount reading.
Analytical example 4.D 4 Radioligand binding assays
Experimental protocol
1. Experimental material and instrument and equipment
Figure BDA0003778601520000741
Figure BDA0003778601520000742
Figure BDA0003778601520000751
Instrument for measuring the position of a moving object Brand Goods number
Electric heating constant temperature incubator Shanghai yi heng DHP-9032
Micro-plate vibrating screen VWR 12620-928
Universal Harvester Perkin Elmer UNIFILTER-96
CO 2 Culture box Thermo 371
Electric liquid transfer device Thermo /
Desk type centrifuge Eppendorf 5702
Electric heating constant temperature water tank JINGHONG DKB-8A
Glass tissue homogenizer Nanjing jade changed glass instrument 50mL
High-speed dispersion machine IKA T18
Multi-template enzyme-labeling instrument PerkinElmer Victor Nivo 35
Small-sized high-speed centrifugal machine Eppendorf 5810R
Low-temperature high-speed centrifuge SORVALL LYNX4000
Vortex mixer IKA MS3 basic
TopCount PerkinElmer NTX
2 method of experiment
1) To each well of a 96-deep well plate, 100. Mu.L of reaction buffer was added.
2) Add 5. Mu.L of diluted compounds (1% DMSO) to each well in 96-well plates.
3) Add 300. Mu.L of membrane buffer mix to each well: mu.L of membrane protein and 290. Mu.L of buffer were added to each well and shaken at 600rpm for 5min.
4) Adding 100. Mu.L of the reaction buffer and [2 ] 3 H]And adding a mixed solution of-Methospirone (the final concentration is 1.5 nM) into the reaction system, shaking at 600rpm for 5min, and incubating at 27 ℃ for 1h.
5) 0.5% PEI pretreatment UNIFILTER-96GF/C plates, 150. Mu.L of 0.5% PEI per well, 1 hour incubation at 4 ℃.
6) UNIFILTER-96GF/C plates were washed 2 times with Universal Harvester, 50mL each time.
7) The reaction system was transferred to a UNIFILTER-96GF/C plate using a Universal Harvester, 900. Mu.L of the washing solution was added to each well to wash the GF/C plate 4 times, and the washed UNIFILTER-96GF/C plate was dried in an oven at 55 ℃ for 10min.
8) Add 40. Mu.L of ULTIMA GOLD scintillation fluid per well using the TopCount reading.
The results of the above receptor binding assay are shown in table 1 below.
TABLE 1 Compound pair D 1 、D 2L 、D 4 And 5HT 2A Affinity (IC) of the receptor 50 ,nM)
Compound (I) D 1 D 2L D 4 5HT 2A
21-0(l-SPD) 0.62 49.99 835.16 6880.55
22-0(l-SLR) 5.37 47.46 151.36 >10000
01-0H 6.19 48.61 129.3 >10000
02-0H 3.64 49.3 84.97 >10000
03-0H 15.08 54.36 113.32 >10000
04-0H 8.12 53.92 103.76 >10000
05-0H 7.9 60.41 103.55 >10000
06-0H 12.17 48.14 79.02 >10000
07-0Q No measurement No measurement No measurement No measurement
07-0H 11.64 49.01 95.78 >10000
08-0Q No measurement No measurement Without measurement No measurement
08-0H 5.02 52.63 117.3 >10000
09-0H 2.72 59.05 888.09 5238.16
10-0Q 1358 43389 >100000 47593.26
10-0H 0.41 61.1 1044.31 5427.82
Analytical example 5.5 HT 2A Receptor calcium flux assay
Experimental protocol
1. Experimental material and instrument and equipment
Reagent Brand Goods number
Flp-In-CHO-5HT 2A Stable cell lines Pharmaron -
Fetal bovine serum Gibco 10999141
Dialyzing FBS ThermoFisher Scientific 30067334
Penicillin-streptomycesPlain, liquid Gibco 15140122
Ham's F-12K Hyclone SH30526.01
1X TrypLE Express Enzyme, phenol Red free ThermoFisher Scientific 12604021
Component A calcium ion probe Molecular Devices R8191
Hygromycin B Gold solution Invivogen ant-hg-5
HBSS, calcium, magnesium, phenol red free Gibco 14025076
HEPES Gibco 15630080
FLIPR calcium 6 analysis kit Molecular Devices R8191
Consumable material Brand Goods number
384-orifice plate Corning 3764
Echo-qualified 384-well polypropylene microplate, transparent, flat bottom LABCYTE PP-0200
384-well plate Corning 3657
384-hole flipr tetra pipetting tip Molecular Devices 9000-0764
96-well conical bottom PP Plt natural RNase-free/Dnase plate ThermoFisher 249944
Figure BDA0003778601520000771
Figure BDA0003778601520000781
2. Experimental methods
2.1 Compounds EC 50 Determination of value
1)Flp-In-CHO-5HT 2A Cell lines were cultured in complete medium (Ham's F-12K +10% FBS +1x penicillin-streptomycin + 600. Mu.g/mL hygromycin B) at 37 ℃,5% CO 2 And (5) culturing.
2) After TrypLE digestion, cells were resuspended in inoculation medium (Ham's F-12K +10% dialyzed FBS) and plated in 384 well cell culture plates, 10,000 cells per well, at 37 deg.C, 5% CO 2 The culture was carried out overnight.
3) Freeze-thawing 20 Xcomponent A to room temperature, diluting it with assay buffer to 2 Xworking concentration containing 5mM probenecid, and standing at room temperature for use.
4) The 384-well cell culture plate was removed and allowed to stand at room temperature for 10min. The medium was removed and 20. Mu.L of assay buffer was added to each well followed by 20. Mu.L of 2X fraction A containing 5mM probenecid to each assay well, centrifuged at 200g at RT for 3-5 seconds and incubated at 37 ℃ for 2 hours.
5) Preparing a 5X positive control compound and a working solution of a compound to be detected, and placing the working solutions at room temperature for later use.
6) The cell culture plate was taken out and allowed to stand at room temperature for 10 minutes.
7) 10 μ L of compound working solution diluted in step 5) was added to each experimental well using FLIPR Tetra and data was collected.
2.1 Compound IC 50 Determination of value
1)Flp-In-CHO-5HT 2A The cell lines were cultured in complete medium (Ham's F-12K +10% FBS +1x penicillin-streptomycin + 600. Mu.g/mL hygromycin B) at 37 ℃,5% CO 2 And (5) culturing.
2) After TrypLE digestion, cells were resuspended in inoculation medium (Ham's F-12K +10% dialysis FBS) and plated in 384 well cell culture plates, 10,000 cells per well, at 37 ℃,5% CO 2 The culture was carried out overnight.
3) Freeze-thawing 20X fraction A to room temperature, diluting it with assay buffer to 2X working concentration containing 5mM probenecid, and standing at room temperature for use.
4) The 384-well cell culture plate was removed and allowed to stand at room temperature for 10min. The medium was removed and 20. Mu.L of assay buffer was added to each well followed by 20. Mu.L of 2X fraction A containing 5mM probenecid to each assay well, centrifuged at 200g at RT for 3-5 seconds and incubated at 37 ℃ for 2 hours.
5) And preparing 6X positive control compound and working solution of the compound to be detected.
6) Taking out the cell culture plate and standing for 10 minutes at room temperature; add 10. Mu.L of the 6 Xcompound working solution from step 5) to the corresponding experimental wells of 384 well cell culture plates and incubate for 30 min at room temperature.
7) 5HT was diluted to 6 μm with assay buffer and left at room temperature until use.
8) 10 μ L of 5HT diluted in step 7) was added to each experimental well using FLIPR Tetra and data collected.
Analytical example 6.D 1 Receptor calcium flux assay
Experimental protocol
1. Experimental material and instrument and equipment
Figure BDA0003778601520000791
Consumable material Brand Goods number
384-orifice plate Corning 3764
Echo-qualified 384-well polypropylene microplate, transparent, flat bottom LABCYTE PP-0200
384-well plate Corning 3657
384-well flipr tetra pipette tip Molecular Devices 9000-0764
96-well conical bottom PP Plt natural RNase-free/Dnase plate ThermoFisher 249944
Instrument for measuring the position of a moving object Brand Goods number
FLIPR Molecular Devices FLIPR Tetra
Personal pipettor Apricot Designs IPPAZMS-384-125(3)
Countess TM II automatic cell counter Invitrogen AMQAX1000
Centrifugal machine Eppendorf 5424R
CO 2 Culture box ThermoFisher 371
Biological safety cabinet (II level) ThermoFisher 1389
2. Experimental methods
2.1 Compounds EC 50 Determination of value
1)Flp-In-CHO-GAN15-D 1 Clone #25 cell line was cultured in complete medium (Ham's F-12K +10% FBS +1x penicillin-streptomycin + 600. Mu.g/mL hygromycin B + 800. Mu.g/mL G418) at 37 ℃,5% CO 2 And (5) culturing.
2) After TrypLE digestion, cells were resuspended in inoculation medium (Ham's F-12K +10% FBS) and plated in 384 well cell culture plates at 6,500 cells/well at 37 ℃ 5% CO 2 The culture was carried out overnight.
3) Freeze-thawing 20X fraction A to room temperature, diluting it with assay buffer to 2X working concentration containing 5mM probenecid, and standing at room temperature for use.
4) The 384-well cell culture plate was removed and allowed to stand at room temperature for 10min. The medium was removed and 20. Mu.L of assay buffer was added to each well followed by 20. Mu.L of 2X fraction A containing 5mM probenecid to each assay well, centrifuged at 200g at RT for 3-5 seconds and incubated at 37 ℃ for 2 hours.
5) Preparing a 5X positive control compound and a working solution of a compound to be tested, and placing the working solutions at room temperature for later use.
6) The cell culture plate was taken out and allowed to stand at room temperature for 10 minutes.
7) mu.L of compound working solution diluted in step 5) was added to each experimental well using FLIPR Tetra and data collected.
2.1 Compound IC 50 Determination of value
1)Flp-In-CHO-GAN15-D 1 Clone #25 cell line was cultured in complete medium (Ham's F-12K +10% FBS +1x penicillin-streptomycin + 600. Mu.g/mL hygromycin B + 800. Mu.g/mL G418) at 37 ℃,5% CO 2 Culturing in that respect.
2) After TrypLE digestion, cells were resuspended in inoculation medium (Ham's F-12K +10% FBS) and plated in 384 well cell culture plates at 6,500 cells/well at 37 ℃ 5% CO 2 The culture was carried out overnight.
3) Freeze-thawing 20X fraction A to room temperature, diluting it with assay buffer to 2X working concentration containing 5mM probenecid, and standing at room temperature for use.
4) The 384-well cell culture plate was removed and allowed to stand at room temperature for 10 minutes. The medium was removed and 20. Mu.L of assay buffer was added to each well followed by 20. Mu.L of 2X fraction A containing 5mM probenecid to each assay well, centrifuged at 200g at RT for 3-5 seconds, and incubated at 37 ℃ for 2 hours.
5) And preparing 6X positive control compound and working solution of the compound to be tested.
6) The cell culture plate was taken out and left to stand at room temperature for 10 minutes, and 10. Mu.L of the 6X compound working solution in step 5) was added to the corresponding experimental wells of the 384-well cell culture plate, and incubated at room temperature for 30 minutes.
7) Dopamine was diluted to 30n μm with assay buffer and left at room temperature until needed.
8) Data were collected by adding 10 μ L of dopamine diluted in step 7) to each experimental well using FLIPR Tetra.
Analytical example 7.D 2L Receptor cAMP protocol
1. Experimental material and instrument and equipment
Reagent Brand Goods number
Flp-In-CHO-D 2L Stable cell lines Pharmaron -
Fetal bovine serum, 500mL Gibco 10999141
Ham's F-12K (Kaighn's) culture medium Hyclone SH30526.01
Penicillin-streptomycin, liquids Gibco 15140122
Hygromycin B Gold Invivogen ant-hg-5
Forskolin,10mg Selleck S2449
BSA stabilizer 7.5%,50mL Perkin Elmer CR84-100
IBMX Sigma I5879
HEPES,1M,100mL Gibco 15630080
Figure BDA0003778601520000821
Instrument for measuring the position of a moving object Brand Goods number
EnVision Perkin Elmer Envison 2105
Countess TM II automatic cell counter Invitrogen AMQAX1000
Centrifugal machine Eppendorf 5424R
CO 2 Culture box ThermoFisher 371
Biological safety cabinet (II level) ThermoFisher 1389
2. Experimental method
2.1 Compounds EC 50 Determination of value
1) Flp-In-CHO-D 2L The cell line was cultured in complete medium (Ham's F K +10% FBS + penicillin-streptomycin + 800. Mu.g/mL hygromycin B) at 37 ℃ 5% CO 2 And (4) culturing.
2) After TrypLE digestion, cells were resuspended in complete medium and plated in 384 well cell plates, 8,000 cells per well, at 37 ℃,5% co 2 The culture was carried out overnight.
3) A working solution of the compound was prepared using the assay buffer (1 XHBSS containing 0.1% BSA, 2mM HEPES, 500. Mu.M IBMX).
4) The medium was removed from the 384-well plates and 15. Mu.L of assay buffer and 2.5. Mu.L of compound working solution were added to each well, followed by incubation at 37 ℃ for 10 minutes.
5) 8 Xforskolin (8. Mu.M) was prepared in assay buffer, 2.5. Mu.L of the prepared forskolin solution was added to each well, and the 384 well plates were incubated at 37 ℃ for 30 minutes.
6) Eu-cAMP tracer and Ulight-anti-cAMP were formulated according to kit instructions, and 10. Mu.L Eu-cAMP tracer and 10. Mu.L Ulight-anti-cAMP were added to each experimental well, respectively.
7) The reaction plate was centrifuged at 200g for 30 seconds at room temperature and then left standing at 25 ℃ for 1 hour, and then data were collected by Envision.
2.2 Compound IC 50 Determination of value
1) Flp-In-CHO-D 2L The cell lines were cultured in complete medium (Ham's F K +10% FBS + penicillin-streptomycin + 800. Mu.g/mL hygromycin B) at 37 ℃ 5% CO 2 And (5) culturing.
2) After the digestion treatment of the trypLE,resuspending the cells in complete medium, plating 384 well cell culture plates, 8,000 cells per well, 5% CO at 37% 2 The culture was carried out overnight.
3) A working solution of the compound was prepared using the assay buffer (1 XHBSS containing 0.1% BSA, 2mM HEPES, 500. Mu.M IBMX).
4) The medium was removed from the 384-well plates and 15. Mu.L of assay buffer and 2.5. Mu.L of compound working solution were added to each well, followed by incubation at 37 ℃ for 10 minutes.
5) A mixture of 8 Xforskolin (8. Mu.M) and dopamine (80 nM) was prepared in assay buffer, 2.5. Mu.L of the above prepared mixture was added to each well, and the 384 well plates were incubated at 37 ℃ for 30 minutes.
6) Eu-cAMP tracer and Ulight-anti-cAMP were formulated according to kit instructions, and 10. Mu.L Eu-cAMP tracer and 10. Mu.L Ulight-anti-cAMP were added to each experimental well, respectively.
7) The reaction plate was centrifuged at 200g at room temperature for 30 seconds and allowed to stand at 25 ℃ for 1 hour, and then data was collected by Envision.
Analytical example 8.D 4 Receptor cAMP protocol
1. Experimental material and instrument and equipment
Figure BDA0003778601520000831
Figure BDA0003778601520000841
Figure BDA0003778601520000842
Instrument for measuring the position of a moving object Brand Goods number
EnVision Perkin Elmer Envison 2105
Countess TM II automatic cell counter Invitrogen AMQAX1000
Centrifugal machine Eppendorf 5424R
CO 2 Culture box ThermoFisher 371
Biological safety cabinet (II level) ThermoFisher 1389
2. Experimental methods
2.1 Compounds EC 50 Determination of value
1) Flp-In-CHO-D 4 The cell lines were cultured in complete medium (Ham's F K +10% FBS +1x penicillin-streptomycin + 800. Mu.g/mL hygromycin B) at 37 ℃ 5% CO 2 And (5) culturing.
2) After TrypLE digestion, cells were resuspended in complete medium and plated in 384 well cell plates, 8,000 cells per well, at 37 ℃,5% co 2 The culture was carried out overnight.
3) A working solution of the compound was prepared using the assay buffer (1 XHBSS containing 0.1% BSA, 2mM HEPES, 500. Mu.M IBMX).
4) The medium was removed from the 384-well plates and 15. Mu.L of assay buffer and 2.5. Mu.L of compound working solution were added to each well, followed by incubation at 37 ℃ for 10 minutes.
5) 8 Xforskolin (16. Mu.M) was prepared in assay buffer, 2.5. Mu.L of the prepared forskolin solution was added to each well, and the 384 well plates were incubated at 37 ℃ for 30 minutes.
6) Eu-cAMP tracer and Ulight-anti-cAMP were configured according to kit instructions, and 10. Mu.L Eu-cAMP tracer and 10. Mu.L Ulight-anti-cAMP were added to each assay well, respectively.
7) The reaction plate was centrifuged at 200g at room temperature for 30 seconds and allowed to stand at 25 ℃ for 1 hour, and then data was collected by Envision.
2.2 Compound IC 50 Determination of value
1) Culturing the Flp-In-CHO-D4 cell line In complete medium (Ham's F K +10% FBS +1x penicillin-streptomycin + 800. Mu.g/mL hygromycin B) at 37 ℃,5% CO 2 And (5) culturing.
2) After TrypLE digestion, cells were resuspended in complete medium and plated in 384 well cell plates, 8,000 cells per well, at 37 ℃,5% co 2 The culture was carried out overnight.
3) A working solution of the compound was prepared using the assay buffer (1 XHBSS containing 0.1% BSA, 2mM HEPES, 500. Mu.M IBMX).
4) The medium was removed from the 384-well plates and 15. Mu.L of assay buffer and 2.5. Mu.L of compound working solution were added to each well, followed by incubation at 37 ℃ for 10 minutes.
5) A mixture of 8 Xforskolin (16. Mu.M) and dopamine (320 nM) was prepared in assay buffer, 2.5. Mu.L of the above prepared mixture was added to each well, and the 384 well plates were incubated at 37 ℃ for 30 minutes.
6) Eu-cAMP tracer and Ulight-anti-cAMP were configured according to kit instructions, and 10. Mu.L Eu-cAMP tracer and 10. Mu.L Ulight-anti-cAMP were added to each assay well, respectively.
7) The reaction plate was centrifuged at 200g at room temperature for 30 seconds and allowed to stand at 25 ℃ for 1 hour, and then data was collected by Envision.
The results of the above analytical tests are shown in table 2 below.
TABLE 2 Compound Pair D 1 、D 2L 、D 4 And 5HT 2A Agonistic and inhibitory Activity of receptors (nM)
Figure BDA0003778601520000851
Figure BDA0003778601520000861
It should be understood that the detailed examples and embodiments described herein are given by way of illustration only and are not to be construed as limiting the present disclosure. Various modifications or changes will occur to those skilled in the art in light thereof and are included within the spirit and scope of the present disclosure and are to be considered as included within the scope of the appended claims. Further, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments disclosed herein. Such equivalents are intended to be encompassed by the following claims.

Claims (7)

1. A deuterated compound having a structure represented by formula I:
Figure FDA0003778601510000011
wherein R is 1 And R 2 Independently selected from H and C (Y) 4 ) 3 ，Y 1 、Y 2 、Y 3 And Y 4 Independently selected from H or D, and at least one hydrogen in the compounds shown is replaced by deuterium.
2. The deuterated compound of claim 1, wherein R is 1 Is H and R 2 Is CH 3 Or CD 3 Or R is 1 Is CH 3 And R 2 Is H or CD 3 。
3. The deuterated compound of claim 1, wherein said compound comprises 1-8 deuterations.
4. The deuterated compound of claim 1 or 2, wherein the compound is selected from the group consisting of:
Figure FDA0003778601510000012
Figure FDA0003778601510000021
Figure FDA0003778601510000031
5. a pharmaceutical composition comprising a compound of any one of claims 1-4.
6. Use of a compound according to any one of claims 1-4 in the manufacture of a medicament for treating schizophrenia, anxiety, depression, schizoaffective disorder, autism, gilles de la tourette syndrome, attention deficit syndrome, pain, insomnia, bacterial infection, viral infection in a subject.
7. The use of claim 6, wherein the pain is neuropathic pain or vascular pain.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1900075A (en) * 2006-07-26 2007-01-24 中国科学院上海药物研究所 Tetrahydro-proto-berberine compounds, their preparing method, composition and use
CN107936008A (en) * 2016-10-13 2018-04-20 泰州华元医药科技有限公司 Deuterated compound and its medical usage

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1900075A (en) * 2006-07-26 2007-01-24 中国科学院上海药物研究所 Tetrahydro-proto-berberine compounds, their preparing method, composition and use
CN107936008A (en) * 2016-10-13 2018-04-20 泰州华元医药科技有限公司 Deuterated compound and its medical usage

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Title
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