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CN113444010A - Preparation method of safinamide related substances - Google Patents

Preparation method of safinamide related substances Download PDF

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Publication number
CN113444010A
CN113444010A CN202010232401.5A CN202010232401A CN113444010A CN 113444010 A CN113444010 A CN 113444010A CN 202010232401 A CN202010232401 A CN 202010232401A CN 113444010 A CN113444010 A CN 113444010A
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CN113444010B (en
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王进家
高剑
刘飞
袁红群
柴雨柱
周莉
王华萍
徐丹
朱春霞
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/367—Halogenated derivatives polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method of a safinamide related substance, which has a synthetic route shown as the following. The raw materials and reagents are cheap and easy to obtain, the reaction operation is simple and convenient, and the synthesis yield is high; the compound of formula 7 has high purity, and can be used as pharmaceutical drug of safinamideOr an impurity control in the preparation.

Description

Preparation method of safinamide related substances
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a safinamide related substance.
Background
Safinamide is used as a monoamine oxidase inhibitor and is clinically used for the adjuvant treatment of the Parkinson's disease accompanied by the ' off-phase phenomenon '. The structural formula of safinamide is as follows:
Figure BDA0002429673850000011
the synthesis of safinamide is often accompanied by the production of the impurity (S) -2- ((3- (3-fluorobenzyl) -4- ((3-fluorobenzyl) oxy) benzyl) amino) propionamide (structure shown in formula 7 below). According to the report of patent document CN101896456A, the impurity has extremely high toxicity to enzymes of cytochrome P450 system.
Figure BDA0002429673850000012
Disclosure of Invention
The invention aims to provide a method for preparing (S) -2- ((3- (3-fluorobenzyl) -4- ((3-fluorobenzyl) oxy) benzyl) amino) propionamide, so as to provide an impurity reference substance with a satisfactory purity and a required purity, and further carry out quality control on a preparation process of safinamide.
In one aspect, the invention provides a process for the preparation of (S) -2- ((3- (3-fluorobenzyl) -4- ((3-fluorobenzyl) oxy) benzyl) amino) propanamide (compound 7) by the following route:
Figure BDA0002429673850000013
wherein X is Br or I; y is Br, Cl or I; the method specifically comprises the following steps:
(1) carrying out Friedel-crafts acylation reaction on the compound shown in the formula 1 and a compound 2 to prepare a compound shown in a formula 3;
(2) carrying out reduction reaction on the compound shown in the formula 3 to prepare a compound shown in a formula 4;
(3) carrying out substitution reaction on the compound shown as the formula 4 and the compound shown as the formula 8 to prepare a compound shown as a formula 5;
(4) formylating the compound shown in the formula 5 to prepare a compound 6;
(5) compound 6 is reacted with L-alaninamide or a salt thereof to produce compound 7.
In some embodiments, X is Br.
In some embodiments, Y is Br.
In some embodiments, X is Br and Y is Br.
In some embodiments, the catalyst of step (1) is AlCl3、FeCl3、ZnCl2Or SnCl4(ii) a Preference is given to AlCl3Or ZnCl2(ii) a More preferably AlCl3. In some embodiments, the reaction solvent of step (1) is dichloromethane, nitromethane, or nitrobenzene; dichloromethane is preferred. In some embodiments, the reaction temperature is from room temperature to reflux temperature; reflux is preferred. In some typical embodiments, step (1) is performed under nitrogen blanket. In some more typical embodiments, the post-treatment of step (1) comprises: spin-drying the reaction solvent, adding water, stirring for crystallization, filtering, pulping the filter cake with ethanol, filtering, and drying.
In some embodiments, the reducing system of step (2) is selected from Et3SiH/BF3·OEt2、Et3SiH/CF3COOH、NaBH4/CF3CO2H or LiAlH4/AlCl3(ii) a Preferably Et3SiH/BF3·OEt2、Et3SiH/CF3COOH or NaBH4/CF3CO2H; more preferably Et3SiH/BF3·OEt2. In some embodiments, the reaction solvent of step (2) is selected fromDichloromethane, acetonitrile or diethyl ether or a mixed solvent thereof; preferably dichloromethane or acetonitrile or a mixed solvent thereof; more preferably a mixed solvent of dichloromethane and acetonitrile; most preferably, the volume ratio is 2: 1 with acetonitrile. In some embodiments, the reaction temperature is from room temperature to reflux temperature; the reflux temperature is preferred. In some typical embodiments, step (2) is performed under nitrogen blanket.
In some embodiments, step (3) is carried out in the presence of an acid-binding agent selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium phosphate, or potassium phosphate; sodium carbonate, potassium carbonate or cesium carbonate are preferred. In some embodiments, the reaction solvent of step (3) is selected from DMF, NMP, DMSO, or ethanol; DMF is preferred. In some embodiments, the reaction temperature is from room temperature to 100 ℃; preferably 55 deg.c. In some typical embodiments, step (3) is carried out in the presence of a catalyst KI.
In some embodiments, the formylation reaction of step (4) is performed under n-BuLi/DMF conditions. In some embodiments, the reaction solvent of step (4) is selected from THF or toluene or a mixed solvent thereof; THF is preferred. In some embodiments, the reaction temperature is from-80 to-50 ℃; preferably-65 to-70 ℃. In some typical embodiments, step (4) is performed under a nitrogen blanket.
In some embodiments, compound 6 is reacted with L-alaninamide hydrochloride in step (5) to produce compound 7.
In some embodiments, step (5) is carried out in the presence of a base selected from triethylamine or diisopropylethylamine and a reducing agent selected from sodium borohydride or sodium cyanoborohydride; the preferred base is triethylamine; a preferred reducing agent is sodium borohydride. In some embodiments, the reaction solvent of step (5) is methanol or ethanol; methanol is preferred. In some embodiments, the reaction temperature is from 0 ℃ to reflux; preferably 10 to 15 ℃.
In another aspect, the present invention provides a compound of the formula,
Figure BDA0002429673850000031
wherein X is Br or I; preferably, X is Br.
In another aspect, the present invention provides a compound of the formula,
Figure BDA0002429673850000032
wherein X is Br or I; preferably, X is Br.
In another aspect, the present invention provides a compound of the formula,
Figure BDA0002429673850000033
wherein X is Br or I; preferably, X is Br.
The invention has the beneficial effects that the invention provides the preparation method of the safinamide related substance shown as the formula 7, the used raw materials and reagents are cheap and easy to obtain, the reaction operation is simple and convenient, and the synthesis yield is high; the compound of formula 7 has high purity, and can be used as impurity reference substance in safinamide bulk drug or preparation.
Detailed Description
The following examples are provided to further illustrate the technical solutions of the present invention, but not to limit the present invention.
The analysis method comprises the following steps:
measuring by high performance liquid chromatography (China pharmacopoeia 2015 edition four parts general Commission 0512), using octadecylsilane chemically bonded silica as filler [ Welch Xtimate C18(4.6mm × 250mm, 5 μm) or column with equivalent efficiency ]; taking 10mmol/L dipotassium hydrogen phosphate buffer solution (taking 1.74g dipotassium hydrogen phosphate, adding 1000ml water for dissolving, adjusting pH value to 6.8 by using phosphoric acid) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out linear gradient elution according to the following table; the flow rate was 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength was 210 nm.
Figure BDA0002429673850000041
Example 1
(1) Synthesis of compound (5-bromo-2-hydroxyphenyl) (3-fluorophenyl) methanone (compound 3, X ═ Br)
Adding AlCl into a reaction bottle3(20g, 81mmol, 1.5equiv) and DCM (60mL), cooling to 0-10 ℃ in an ice-water bath, slowly dropwise adding 4-bromoanisole (10g, 54mmol, 1.0equiv), and stirring for 10min after dropwise adding; slowly adding the compound 2(10.7g, 67.5mmol, 1.25equiv) dropwise under the ice-bath condition, and heating up and refluxing for 6h after the dropwise addition is finished (monitoring the reaction by TLC to be finished). The reaction solution is cooled to room temperature, DCM is removed by concentration, the residue is slowly added with 50mL of ice water under the ice bath condition, stirred and crystallized for 1h, and filtered by suction. Pulping filter cake with hot ethanol at 50 deg.C for 30min, stirring in ice bath for 30min, vacuum filtering, washing with 20mL water, and air drying. 8.5g of product are obtained in the form of a yellow powder with a yield of 53.3%.1H-NMRδ:6.99(d，J＝10.0Hz，1H)，7.49-7.61(m,6H),10.45(s,1H).
(2) Synthesis of Compound 4-bromo-2- (3-fluorobenzyl) phenol (Compound 4, X ═ Br)
The compound prepared in step (1) (8.5g, 28.8mmol, 1.0equiv) and Et3SiH (17.0mL, 103.7mmol, 3.6equiv) was dissolved in a mixed solvent of DCM (50 mL)/acetonitrile (25mL), and BF was slowly added dropwise3·OEt2(6.0mL, 50.0mmol, 1.74equiv), after the addition, the reaction was refluxed for 6h (TLC monitoring reaction was complete). The reaction solution was cooled to room temperature, washed with 100mL of water, extracted with DCM, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (ethyl acetate: n-hexane ═ 1:20), and the qualified fractions were collected to give 4.0g of 4-bromo-2- (3-fluorobenzyl) phenol as a white solid with a yield of 52.4%.1H-NMRδ:3.88(s,1H),6.80(d,J＝5.0Hz,1H),7.27～7.07(m,6H),9.78(s,1H).
(3) Synthesis of Compound 4-bromo-2- (3-fluorobenzyl) -1- (3-fluorobenzyloxy) benzene (Compound 5, X ═ Br)
DMF (50mL), 4-bromo-2- (3-fluorobenzyl) phenol (4.0g, 14.3mmol, 1.0equiv) and potassium carbonate (2.2g, 15.7mmol, 1.1equiv) were added to a reaction flask in this order, and the compound 1-bromomethyl-3-fluorobenzene (2.96g, 15.7mmol, 1.1equiv) was added with stirring at room temperature, and the reaction was heated to 55 ℃ for 1.5h, followed by TLC detection. The reaction solution was cooled to room temperature,100mL of the extract was washed with water, extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (ethyl acetate: n-hexane 1:20) to collect an acceptable fraction, to obtain 5.0g of 4-bromo-2- (3-fluorobenzyl) -1- (3-fluorobenzyloxy) benzene as a white solid, with a yield of 90.0%.1H-NMRδ:3.96(s，1H),5.12(s，1H),7.41～7.36，m，3H),7.30～7.26(m，1H),7.17～7.06(m，3H),7.03～6.97(m，4H).
(4) Synthesis of Compound 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) benzaldehyde (Compound 6)
Adding the product (5.0g, 12.8mmol, 1.0equiv) of the step (3) and dry THF (60mL) into a reaction flask under the protection of nitrogen, cooling to below-65 ℃, slowly dropwise adding n-BuLi tetrahydrofuran solution (1.2equiv), and preserving heat for 1h after dropwise adding. Dry DMF (1.0mL, 1.2equiv) was slowly added dropwise to the system, stirred and reacted for 30min, and the reaction was terminated by TLC. The reaction was quenched with saturated aqueous ammonium chloride, extracted with DCM, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (ethyl acetate: n-hexane 1:20), yielding 2.5g of compound 6 as a white solid in 62.0% yield.1H-NMRδ:4.04(s,1H)，5.26(s,1H),6.97～7.44(m，9H),7.77～7.84(m，2H),9.85(s，1H).
(5) Synthesis of Compound (S) -2- [3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) benzylamino ] propanamide (Compound 7)
MeOH (20mL), L-alaninamide hydrochloride (0.63g, 4.07mmol, 1.1equiv) and triethylamine (0.63mL, 4.07mmol, 1.1equiv) were added to a reaction flask, and after stirring and clearing at room temperature, Compound 6(1.25g, 3.7mmol, 1.0equiv) was added and reacted at room temperature for 1 hour; the temperature is reduced to 10-15 ℃, sodium borohydride (142mg, 3.7mmol, 1.0equiv) is added, and the reaction is carried out for 1 hour after the addition is finished and the room temperature is recovered. Adding 100mL of water into a reaction system to quench the reaction, extracting with DCM (60mL x 3), combining organic phases, drying with anhydrous sodium sulfate, filtering and concentrating, purifying the residue by column chromatography (ethyl acetate: n-hexane ═ 1:1), collecting qualified components, and concentrating under reduced pressure to dryness to obtain the compound 7, wherein the white solid is 960mg, the yield is 63.0%, and the HPLC purity is 98.65%.
MS(ESI)m/z:411.2[M+H]+。

Claims (10)

1. The preparation method of the compound shown in the formula 7 is characterized in that the synthetic route is as follows:
Figure FDA0002429673840000011
wherein X is Br or I; preferably Br; y is Br, Cl or I; preferably Br; preferably, X is Br and Y is Br;
the method specifically comprises the following steps:
(1) carrying out Friedel-crafts acylation reaction on the compound shown in the formula 1 and a compound 2 to prepare a compound shown in a formula 3;
(2) carrying out reduction reaction on the compound shown in the formula 3 to prepare a compound shown in a formula 4;
(3) carrying out substitution reaction on the compound shown as the formula 4 and the compound shown as the formula 8 to prepare a compound shown as a formula 5;
(4) formylating the compound shown in the formula 5 to prepare a compound 6;
(5) compound 6 is reacted with L-alaninamide or a salt thereof to produce compound 7.
2. The preparation method according to claim 1, wherein the catalyst in step (1) is AlCl3、FeCl3、ZnCl2Or SnCl4(ii) a Preference is given to AlCl3Or ZnCl2(ii) a More preferably AlCl3(ii) a The reaction solvent in the step (1) is dichloromethane, nitromethane or nitrobenzene; preferably dichloromethane; the reaction temperature is between room temperature and reflux temperature; preferably refluxing; preferably, step (1) is carried out under nitrogen protection; preferably, the post-treatment of step (1) comprises: spin-drying the reaction solvent, adding water, stirring for crystallization, filtering, pulping the filter cake with ethanol, filtering, and drying.
3. The process according to claim 1, wherein the reducing system of step (2) is Et3SiH/BF3·OEt2、Et3SiH/CF3COOH、NaBH4/CF3CO2H or LiAlH4/AlCl3(ii) a Preferably Et3SiH/BF3·OEt2、Et3SiH/CF3COOH or NaBH4/CF3CO2H; more preferably Et3SiH/BF3·OEt2(ii) a The reaction solvent in the step (2) is selected from dichloromethane, acetonitrile or diethyl ether or a mixed solvent thereof; preferably dichloromethane or acetonitrile or a mixed solvent thereof; more preferably a mixed solvent of dichloromethane and acetonitrile; most preferably, the volume ratio is 2: 1 with acetonitrile; preferably, the reaction temperature is from room temperature to reflux temperature; preferably the reflux temperature; preferably, step (2) is performed under nitrogen protection.
4. The process according to claim 1, wherein the step (3) is carried out in the presence of an acid-binding agent selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium phosphate or potassium phosphate; preferably sodium carbonate, potassium carbonate or cesium carbonate; the reaction solvent in the step (3) is selected from DMF, NMP, DMSO or ethanol; DMF is preferred. Preferably, the reaction temperature is between room temperature and 100 ℃; preferably 55 ℃; preferably, step (3) is carried out in the presence of a catalyst KI.
5. The process according to claim 1, wherein the formylation reaction in the step (4) is carried out under n-BuLi/DMF conditions; the reaction solvent in the step (4) is THF or toluene or a mixed solvent thereof; preferably THF; preferably, the reaction temperature is-80 to-50 ℃; preferably-65 to-70 ℃; preferably, step (4) is performed under nitrogen protection.
6. The process according to claim 1, wherein compound 6 is reacted with L-alaninamide hydrochloride in step (5) to produce compound 7.
7. The production method according to claim 1, characterized in that step (5) is carried out in the presence of a base selected from triethylamine or diisopropylethylamine and a reducing agent selected from sodium borohydride or sodium cyanoborohydride; the preferred base is triethylamine; the preferred reducing agent is sodium borohydride; the reaction solvent in the step (5) is methanol or ethanol; methanol is preferred; the reaction temperature is 0 ℃ to reflux; preferably 10 to 15 ℃.
8. A compound of the formula,
Figure FDA0002429673840000021
wherein X is Br or I; preferably, X is Br.
9. A compound of the formula,
Figure FDA0002429673840000022
wherein X is Br or I; preferably, X is Br.
10. A compound of the formula,
Figure FDA0002429673840000023
wherein X is Br or I; preferably, X is Br.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002089738A2 (en) * 2001-05-08 2002-11-14 Yale University Proteomimetic compounds and methods
CN1636984A (en) * 1999-09-04 2005-07-13 葛兰素集团有限公司 Benzophenones as inhibitors of reverse transcriptase
CN101896456A (en) * 2007-12-11 2010-11-24 纽朗制药有限公司 Process for the production of 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides with high purity degree
CN106365966A (en) * 2015-07-24 2017-02-01 上海医药集团股份有限公司 Preparation method of benzyl aryl ether
WO2020075080A1 (en) * 2018-10-10 2020-04-16 Janssen Biopharma, Inc. Macrocyclic flu endonuclease inhibitors
CN112028754A (en) * 2020-06-17 2020-12-04 浙江美诺华药物化学有限公司 A kind of preparation method of safinamide mesylate intermediate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1636984A (en) * 1999-09-04 2005-07-13 葛兰素集团有限公司 Benzophenones as inhibitors of reverse transcriptase
WO2002089738A2 (en) * 2001-05-08 2002-11-14 Yale University Proteomimetic compounds and methods
CN101896456A (en) * 2007-12-11 2010-11-24 纽朗制药有限公司 Process for the production of 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides with high purity degree
CN106365966A (en) * 2015-07-24 2017-02-01 上海医药集团股份有限公司 Preparation method of benzyl aryl ether
WO2020075080A1 (en) * 2018-10-10 2020-04-16 Janssen Biopharma, Inc. Macrocyclic flu endonuclease inhibitors
CN112028754A (en) * 2020-06-17 2020-12-04 浙江美诺华药物化学有限公司 A kind of preparation method of safinamide mesylate intermediate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MA, XIAO-DONG ETAL: "Synthesis and biological evaluation of (±)-benzhydrol derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY 》, pages 4704 - 4709 *
QUANDT, GABRIELE ETAL: "Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》, pages 3363 - 3378 *

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