CN105461617A - Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine - Google Patents

Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine Download PDF

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CN105461617A
CN105461617A CN201410432628.9A CN201410432628A CN105461617A CN 105461617 A CN105461617 A CN 105461617A CN 201410432628 A CN201410432628 A CN 201410432628A CN 105461617 A CN105461617 A CN 105461617A
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trifluoromethoxy
phenoxy group
acid
hydrogenchloride
benzyl
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陈义朗
王天才
樊后兴
韩硕
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Abstract

The invention discloses a preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine. The preparation method comprises the following steps: 1) synthesizing N-benzyl (or substituted benzyl)-4-[4-(trifluoromethoxy)phenoxyl]pyridinium salt from 4-[4-(trifluoromethoxy)phenoxyl]pyridine and a benzyl group or substituted benzyl halide; 2) reducing the product of the step 1) into N-benzyl (or substituted benzyl)-1,2,3,6-tetrahydro-4-[4-(trifluoromethoxy)phenoxyl]pyridine; 3) reacting the product of the step 2) with acid and a hydrogen source so as to produce 4-[4-(trifluoromethoxy)phenoxyl]pyridin salt; and 4) reacting the product of the step 3) with alkali so as to produce 4-[4-(trifluoromethoxy)phenoxyl]piperidine. The method provided by the invention prepares 4-[4-(trifluoromethoxy)phenoxyl]piperidine from 4-[4-(trifluoromethoxy)phenoxyl]pyridine, is reduced in production cost and improves product yield and purity.

Description

The preparation method of 4-[4-(trifluoromethoxy) phenoxy group] piperidines
Technical field
The present invention relates to organic synthesis field, particularly relate to the preparation method of Delamanid important intermediate 4-[4-(trifluoromethoxy) phenoxy group] piperidines.
Background technology
Deltyba tM(Delamanid) be researched and developed by Otsuka Pharmaceutical Co., Ltd., and in May, 2014 by European Union's approval listing, for the curative of Drug resistant pulmonary tubeculosis disease (MDR-TB) patient that is grown up.Delamanid is a kind of bactericide, has novel mechanism of action, can disturb the metabolism of mycobacterium tuberculosis (MTB) cell walls.This medicine in vitro, in body to all kinds of sensitivity and resistance tuberculosis, particularly to the tubercule bacillus of various multidrug resistance, there is very strong fungicidal activity [PLoSMed, 2006,3:2131 – 2144; Drugs2010; 70 (17): 2201-2214].
The structure of Delamanid is as follows:
The main method [WO2004035547, J.MedChem.2006,49 (26): 7854-7860, WO2008140090, WO2011093529] of current synthesis Delamanid is as follows:
In above-mentioned route, the synthetic route of key intermediate fragment one and fragment two schematically as follows:
As from the foregoing, in synthesis Delamanid process, two fragments all relate to formula I, i.e. 4-[4-(trifluoromethoxy) phenoxy group] piperidines.By literature search, the synthetic method of formula I mainly contains following three kinds:
Method one [patent WO2000046221]:
The method carries out Mesylation by the hydroxyl of N-tertbutyloxycarbonyl-4-hydroxy piperidine, and then under the condition of alkali, carry out Sn2 reaction with 4-trifluoro-methoxy-phenol, acidic conditions Deprotection obtains product.The subject matter of the method is when carrying out Sn2 reaction, and easily generate the eliminative reaction of piperidine alcohols, amplification quantity is especially obvious, and product assay reduces greatly, is unfavorable for that technique is amplified and produces.
Method two [patent CN1360577A]:
The method is reacted by Mitsunobu, and directly by 4-trifluoro-methoxy-phenol and the coupling of N-tertbutyloxycarbonyl-4-hydroxy piperidine, acidic conditions obtains product.The method subject matter has two aspects: produce a large amount of triphenylphosphine in first reaction process, needs column chromatography to remove; It two is that reaction conversion ratio is not high yet.Enforcement prepared by the industry that these two shortcomings limit the method undoubtedly.
Method three [patent US20100152454]:
In the method, starting raw material 4-halogen pyridine is very expensive, needs expensive PtO in subsequent reactions 2carry out catalysis, equipment requirements is very high, easily there is the incomplete impurity of reduction.This impurity is close with product polarity, is difficult to removing.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of a kind of 4-[4-(trifluoromethoxy) phenoxy group] piperidines, and the method not only yield is high, and product is easy to purifying, and simple to operate, is easy to control.
For solving the problems of the technologies described above, the preparation method of 4-of the present invention [4-(trifluoromethoxy) phenoxy group] piperidines, step comprises:
1) 4-[4-(trifluoromethoxy) phenoxy group] pyridine (formula II compound) and benzylic halides or substituted benzyl halide reaction, generate N-benzyl (or substituted benzyl)-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt (formula III compound);
2) N-benzyl (or substituted benzyl)-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt (formula III compound) and reductive agent react, generate N-benzyl (or substituted benzyl)-1,2,3,6-tetrahydrochysene-4-[4-(trifluoromethoxy) phenoxy group] pyridine (formula IV compound);
3) N-benzyl (or substituted benzyl)-1,2,3,6-tetrahydrochysene-4-[4-(trifluoromethoxy) phenoxy group] pyridine (formula IV compound) reacts in the presence of a catalyst with acid and hydrogen source, generates 4-[4-(trifluoromethoxy) phenoxy group] piperidinium salt (formula V compound);
4) 4-[4-(trifluoromethoxy) phenoxy group] piperidinium salt (formula V compound) and alkali reaction, generates 4-[4-(trifluoromethoxy) phenoxy group] piperidines (type I compound).
Reaction scheme following (X represents halogen):
Wherein:
Step 1) in, temperature of reaction is 40 ~ 150 DEG C; Described benzylic halides or substituted benzyl halogenide can be Benzyl Chloride, cylite, p nitrobenzylchloride, combination to any one or a few in methoxybenzyl chloride; Solvent can adopt any one or a few the combination in following solvent: alcohols (as methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol etc.), arene (as toluene, chlorobenzene, dimethylbenzene etc.), ester class (as ethyl acetate, isopropyl acetate, ethyl formate etc.), alkanes (as sherwood oil, normal heptane, normal hexane, hexanaphthene etc.), acetonitrile, tetrahydrofuran (THF), DMF, methyl-sulphoxide.
Step 2) in, temperature of reaction is 0 ~ 40 DEG C; Described reductive agent is selected from any one or a few the combination in metal boride (as sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride etc.), metal alcohol adduct (as the ethanolic soln of sodium, the ethanolic soln etc. of lithium), metal catalyst (as nickel, palladium carbon, platinum carbon etc.), and consumption is 0 ~ 5 times of equivalent of N-benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt; Solvent can use ethers (as ether, methyl tertiary butyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, isopropyl ether etc.), ester class (as ethyl formate, methyl-formiate, ethyl acetate, isopropyl acetate etc.), hydrochloric ether (as methylene dichloride, chloroform etc.), aromatic hydrocarbons (as toluene, chlorobenzene, dimethylbenzene etc.), acetonitrile.
Step 3) in, temperature of reaction is 0 ~ 100 DEG C, preferably 10 ~ 40 DEG C; Described acid can be the non-aqueous solution (a kind of or several arbitrarily combination in the dichloromethane solution of such as, the diethyl ether solution of the aqueous isopropanol of the ethanolic soln of the methanol solution of the ethyl acetate solution of hydrogenchloride, hydrogenchloride, hydrogenchloride, hydrogenchloride, hydrogenchloride, hydrogenchloride) of trifluoroacetic acid, methylsulfonic acid, tosic acid, Phenylsulfonic acid, phenylformic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or hydrogenchloride; Described hydrogen source can use hydrogen or ammonium formiate; Described catalyzer can be any one or a few the combination in Raney's nickel, thunder Buddhist nun cobalt, palladium-carbon catalyst, platinum dioxide, ruthenium complexe; Solvent can use alcohols (as methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, the trimethyl carbinol etc.), ester class (as ethyl formate, methyl-formiate, ethyl acetate, isopropyl acetate etc.), hydrochloric ether (as methylene dichloride, chloroform etc.), aromatic hydrocarbons (as toluene, chlorobenzene, dimethylbenzene etc.).
Step 4) in, described alkali can use mineral alkali or subsalt and their aqueous solution.Such as, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammoniacal liquor, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus etc.
Compared with the existing preparation method of 4-[4-(trifluoromethoxy) phenoxy group] piperidines, preparation method of the present invention has the following advantages and beneficial effect:
1. raw material is cheap, and cost is low;
2. easy and simple to handle, low for equipment requirements, be easy to suitability for industrialized production;
3. yield is high, and product is easy to purifying.Yield and the content of 4-[4-(trifluoromethoxy) phenoxy group] piperidine product obtained by method of the present invention are obviously better than existing method.
Embodiment
Understanding more specifically for having technology contents of the present invention, feature and effect, below in conjunction with specific embodiment, technical scheme of the present invention being set forth in detail.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted concrete reaction conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.The method preparation that the Chinese patent that 4-[4-(trifluoromethoxy) phenoxy group] pyridine [formula II compound] is CN101675044B according to Authorization Notice No. is recorded, or directly buy from the market, other starting material are commercial product.
In all embodiments, thermometer does not correct; 1h-NMR VarianMercury400 nuclear magnetic resonance analyser record, chemical shift represents with δ (ppm); GC is Shimadzu system; Mass spectrum Agilent6120LC-MS LC-MS instrument measures, content HPLC external standard method.
The preparation of embodiment 1N-benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt (formula III compound)
In reactor, add formula II compound 2500g, sherwood oil 6L successively, open stirring, add cylite 1676.0g, be warming up to back flow reaction 16h, TLC (methylene dichloride: methyl alcohol=10:1) monitors raw material and disappears, and stops heating.Be cooled to 15-25 DEG C with ice-water bath, have a large amount of sticky oil thing to separate out, leave standstill, topple over supernatant liquid, residue oily matter separates out solid, and dry, obtain solid 3700.0g, yield is 90.0%, and purity is 98.4%.
1hNMR (500MHz, chloroform) δ: 8.89-8.9 (d, 2H), 7.65-7.66 (d, 2H), 7.49-7.51 (m, 2H), 7.38-7.41 (m, 3H), 7.18-7.21 (d, 2H), 6.98-6.98 (d, 2H), 6.15 (s, 2H).
13CNMR(125MHz，CDCl 3)δ：165.13，154.38，150.02-149.64，142.72，138.31，129.31，129.02，128.45，123.80，121.93，118.77，118.58，62.80。
ESI-LR:347.1[M+H] +。
The preparation of embodiment 2N-benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt (formula III compound)
In reaction flask, add formula II compound 100g, toluene 300ml successively, open stirring, add cylite 70.0g, be warming up to back flow reaction 4h, TLC (methylene dichloride: methyl alcohol=10:1) monitors raw material and disappears, and stops heating.Cooling, has a large amount of sticky oil thing to separate out, and leaves standstill, topples over supernatant liquid, and residue oily matter stirring and crystallizing, suction filtration, dries, obtain solid 151.0g, yield 95.0%, purity 99.2%.
ESI-LR:347.1[M+H] +。
The preparation of embodiment 3N-benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt (formula III compound)
In reaction flask, add formula II compound 100g, toluene 300mL successively, open stirring, add Benzyl Chloride 52.5g, be warming up to backflow.After back flow reaction 4h, it is complete that TLC (methylene dichloride: methyl alcohol=10:1) monitors raw material reaction, stops heating.Cooling, has a large amount of sticky oil thing to separate out, topples over supernatant liquid, and residue oily matter stirring and crystallizing, suction filtration, dries, obtain solid 111.2g, yield 70.0%, purity 96.6%.
ESI-LR:347.1[M+H] +。
Embodiment 4N-is to the preparation of nitrobenzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt (formula III compound)
In reaction flask, add formula II compound 100g, toluene 300mL successively, open stirring, add nitrobenzyl chlorine 71.6g, be warming up to backflow.After back flow reaction 4h, TLC (methylene dichloride: methyl alcohol=10:1) monitors raw material and disappears, and stops heating.Cooling, has a large amount of sticky oil thing to separate out, topples over supernatant liquid, and residue oily matter stirring and crystallizing, suction filtration, dries, obtain solid 130.5g, yield 74.5%, purity 97.1%.
1HNMR(500MHz，CDCl 3)δ：8.90(d，J＝7.4Hz，2H)，8.09(d，J＝7.5Hz，2H)，7.66(d，J＝7.4Hz，2H)，7.42(d，J＝7.5Hz，2H)，7.19(d，J＝7.5Hz，2H)，6.97(d，J＝7.5Hz，2H)，6.21(s，2H)。
ESI-LR：392.1[M+H] +。
The preparation of embodiment 5N-benzyl-1,2,3,6-tetrahydrochysene-4-[4-(trifluoromethoxy) phenoxy group] pyridine (formula IV compound)
Add formula III compound 3000.0g, methylene dichloride 18L in reactor successively, stir, be cooled to 0 ~ 15 DEG C with ice-water bath, in system, slowly add sodium borohydride 1065.0g.Hierarchy of control temperature is less than 40 DEG C, drips acetic acid 5040.0g in system, complete, and reaction solution is slowly added in mixture of ice and water by room temperature reaction 10h, control temperature 0-15 DEG C, stirs 0.5h, separatory.Aqueous phase dichloromethane extraction, merges organic phase, washing, and saturated common salt is washed, and organic phase concentrating under reduced pressure, obtains dope, adds methyl alcohol heating for dissolving, and cooling leaves standstill crystallization, obtains product 2197.5g.Yield 90.0%, purity 97.5%.
1HNMR(500MHz，CDCl 3)δ：7.308-7.362(m,4H)，7.250-7.281(m,1H)，7.146-7.168(d,2H)，7.018-7.040(d,2H)，4.825-4.833(d,1H)，3.622(s,2H)，3.022-3.029(m,2H)，2.673-2.701(m,2H)，2.348(m,2H)。
13CNMR(125MHz，CDCl 3)δ：153.29，149.81，149.30，138.23，128.81，127.95，126.55，124.51，29.91，120.84，119.80，108.84，62.10，52.25，50.69，28.55。
ESI-LR：350.1[M+H] +。
The preparation of embodiment 6N-benzyl-1,2,3,6-tetrahydrochysene-4-[4-(trifluoromethoxy) phenoxy group] pyridine (formula IV compound)
Add formula III compound 100.0g, methylene dichloride 1L in reaction flask successively, stir, be cooled to 0 ~ 15 DEG C with ice-water bath, in system, slowly add sodium borohydride 40.0g.Hierarchy of control temperature is less than 40 DEG C, drips trifluoroacetic acid 320.0g in system, complete, and reaction solution is slowly added in mixture of ice and water by room temperature reaction 6h, control temperature 0-15 DEG C, stirs, separatory after leaving standstill.Aqueous phase dichloromethane extraction, merges organic phase, washing, and saturated common salt is washed, and organic phase concentrating under reduced pressure, obtains dope, adds methyl alcohol heating for dissolving, and cooling leaves standstill crystallization, obtains product 61g.Yield 75.0%, purity 95.9%.
ESI-LR：350.1[M+H] +。
The preparation of embodiment 7N-benzyl-1,2,3,6-tetrahydrochysene-4-[4-(trifluoromethoxy) phenoxy group] pyridine (formula IV compound)
Add formula III compound 100.0g, tetrahydrofuran (THF) 1L in reaction flask successively, stir, be cooled to 0 ~ 15 DEG C with ice-water bath, in system, slowly add sodium borohydride 40.0g.Hierarchy of control temperature is less than 40 DEG C, drips acetic acid 170.0g in system, complete, and room temperature reaction 6h steams most of tetrahydrofuran (THF), adds methylene dichloride, stirring and dissolving, is added to by solution in mixture of ice and water, control temperature 0-15 DEG C, stirs, separatory after leaving standstill.Aqueous phase dichloromethane extraction, merges organic phase, washing, and saturated common salt is washed, and organic phase concentrating under reduced pressure, obtains dope, adds methyl alcohol heating for dissolving, and cooling leaves standstill crystallization, obtains product 81.0g.Yield 99.0%, purity 96.1%.
ESI-LR:350.1[M+H] +。
The preparation of embodiment 84-[4-(trifluoromethoxy) phenoxy group] piperidinium salt (formula V compound)
In reactor, add formula IV compound 2000g, methyl alcohol 10L, acetic acid 349g, 10% palladium/carbon 100g (moisture 50%) successively, open and stir, 20-40 DEG C of hydrogenation reaction, GC monitors formula IV compound and is less than 0.1%, stopped reaction.Filter, filtrate is concentrated into dry, obtains concentrate 1900g.Add ethyl acetate heating for dissolving.Subcooling leaves standstill crystallization, and filter, filter cake ethyl acetate is washed, vacuum-drying, obtains off-white color solid 1565.0g, yield 85.0%, purity 99.43%.
1HNMR(500MHz，CDCl 3)δ：7.119-7.128(d,2H)，6.895-6.942(d,2H)，4.387-4.399(m,1H)，3.179-3.185(m,2H)，2.732-2.799(m,2H)，2.015(s,3H)，1.986-2.115(m,2H)，1.675-1.702(m,2H)，1.532(s,1H)。
ESI-LR：262.1[M+H] +。
The preparation of embodiment 94-[4-(trifluoromethoxy) phenoxy group] piperidinium salt (formula V compound)
In reaction flask, add formula IV compound 10g, methyl alcohol 100mL, acetic acid 2.0g, platinum dioxide 0.5g successively, stir, 10-30 DEG C, hydrogenation reaction, GC monitors formula IV compound and is less than 0.1%, stopped reaction.Filter, filtrate is concentrated into dry, obtains crude product.Add ethyl acetate heating for dissolving.Subcooling leaves standstill crystallization, and filter, filter cake ethyl acetate is washed, vacuum-drying, obtains off-white color solid 8.7g, yield 94.5%, purity 98.5%.
ESI-LR：262.1[M+H] +。
The preparation of embodiment 104-[4-(trifluoromethoxy) phenoxy group] piperidines (type I compound)
4-[4-(trifluoromethoxy) phenoxy group] Piperidineacetic acid salt (formula V compound) 1160g, water 2L is added in reaction flask, open and stir, ice bath is cooled to less than 10 DEG C, add the aqueous solution (1L) of sodium hydroxide (144.5g), warm <15 DEG C in adition process, add a large amount of solid to separate out, continued to stir 1h.Filter, filter cake washes with water, oven drying, obtains white solid 932.0g, yield: 99.0%.Purity 99.2%, content 99.6%.
1HNMR(500MHz，CDCl 3)δ：7.099-7.122(d,2H)，6.870-6.902(d,2H)，4.287-4.329(m,1H)，3.099-3.154(m,2H)，2.677-2.740(m,2H)，1.953-2.014(m,2H)，1.605-1.692(m,2H)，1.428(s,1H)。
ESI-LR：262.1[M+H] +。
13CNMR(125MHz，CDCl 3)δ：155.977，142.745，122.260，124.384，121.846，119.297，116.887，74.196，43.910，32.398。
Elementary composition (measured value): C:55.01, H:5.38, N:5.55.
The preparation of embodiment 114-[4-(trifluoromethoxy) phenoxy group] piperidines (type I compound)
4-[4-(trifluoromethoxy) phenoxy group] Piperidineacetic acid salt (formula V compound) 100g, water 200mL is added in 5L reaction flask, open and stir, ice bath is cooled to less than 10 DEG C, add the aqueous solution 200mL of sodium carbonate 35.0g, warm <15 DEG C in adition process, add a large amount of solid to separate out, continued to stir 1h.Filter, filter cake washes with water, oven drying, obtains white solid 73.1g, yield 90.0%, purity 99.0%, content 99.0%.
ESI-LR：262.1[M+H] +。
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various change and amendment to the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

  1. The preparation method of 1.4-[4-(trifluoromethoxy) phenoxy group] piperidines, it is characterized in that, step comprises:
    1) 4-[4-(trifluoromethoxy) phenoxy group] pyridine and benzylic halides or substituted benzyl halide reaction, generates N-benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt or N-substituted benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt;
    2) step 1) product and reductive agent react, generate N-benzyl-1,2,3,6-tetrahydrochysene-4-[4-(trifluoromethoxy) phenoxy group] pyridine or N-substituted benzyl-1,2,3,6-tetrahydrochysene-4-[4-(trifluoromethoxy) phenoxy group] pyridine;
    3) step 2) product with acid and hydrogen source react in the presence of a catalyst, generation 4-[4-(trifluoromethoxy) phenoxy group] piperidinium salt;
    4) 4-[4-(trifluoromethoxy) phenoxy group] piperidinium salt and alkali reaction, generates 4-[4-(trifluoromethoxy) phenoxy group] piperidines.
  2. 2. method according to claim 1, is characterized in that, step 1), temperature of reaction is 40 ~ 150 DEG C.
  3. 3. method according to claim 1, is characterized in that, step 1), described benzylic halides or substituted benzyl halogenide comprise Benzyl Chloride, cylite, p nitrobenzylchloride, combination to any one or a few in methoxybenzyl chloride.
  4. 4. method according to claim 1, it is characterized in that, step 2), described reductive agent is selected from any one or a few the combination in metal boride, metal alcohol adduct, metal catalyst, and consumption is 0 ~ 5 times of equivalent of N-benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt.
  5. 5. method according to claim 1, is characterized in that, step 2), temperature of reaction is 0 ~ 40 DEG C.
  6. 6. method according to claim 1, is characterized in that, step 3), described acid comprises the non-aqueous solution of trifluoroacetic acid, methylsulfonic acid, tosic acid, Phenylsulfonic acid, phenylformic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrogenchloride.
  7. 7. method according to claim 6, it is characterized in that, the non-aqueous solution of described hydrogenchloride comprises a kind of or several arbitrarily combination in the dichloromethane solution of the ethyl acetate solution of hydrogenchloride, the methanol solution of hydrogenchloride, the ethanolic soln of hydrogenchloride, the aqueous isopropanol of hydrogenchloride, the diethyl ether solution of hydrogenchloride, hydrogenchloride.
  8. 8. method according to claim 1, is characterized in that, step 3), described hydrogen source comprises hydrogen, ammonium formiate; Described catalyzer comprises any one or a few the combination in Raney's nickel, thunder Buddhist nun cobalt, palladium-carbon catalyst, platinum dioxide, ruthenium complexe.
  9. 9. method according to claim 1, is characterized in that, step 3), temperature of reaction is 10 ~ 40 DEG C.
  10. 10. method according to claim 1, is characterized in that, step 4), described alkali comprises mineral alkali or subsalt, and their aqueous solution.
CN201410432628.9A 2014-08-29 2014-08-29 Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine Pending CN105461617A (en)

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Cited By (3)

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CN112724070A (en) * 2021-01-08 2021-04-30 南京方生和医药科技有限公司 Preparation method of alpha, alpha-diphenyl-4-piperidinemethanol
CN113717152A (en) * 2021-09-08 2021-11-30 上海皓鸿生物医药科技有限公司 Preparation method of specific MRK small molecule inhibitor
CN114469946A (en) * 2022-02-24 2022-05-13 首都医科大学附属北京胸科医院 Use of delamasil as a CXCL10 inhibitor

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Publication number Priority date Publication date Assignee Title
CN112724070A (en) * 2021-01-08 2021-04-30 南京方生和医药科技有限公司 Preparation method of alpha, alpha-diphenyl-4-piperidinemethanol
CN113717152A (en) * 2021-09-08 2021-11-30 上海皓鸿生物医药科技有限公司 Preparation method of specific MRK small molecule inhibitor
CN113717152B (en) * 2021-09-08 2022-06-17 上海皓鸿生物医药科技有限公司 Preparation method of specific MRK small molecule inhibitor
CN114469946A (en) * 2022-02-24 2022-05-13 首都医科大学附属北京胸科医院 Use of delamasil as a CXCL10 inhibitor
CN114469946B (en) * 2022-02-24 2023-10-24 首都医科大学附属北京胸科医院 Use of delamanib as CXCL10 inhibitor

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