CN103864673A - Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning - Google Patents

Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning Download PDF

Info

Publication number
CN103864673A
CN103864673A CN201410077353.1A CN201410077353A CN103864673A CN 103864673 A CN103864673 A CN 103864673A CN 201410077353 A CN201410077353 A CN 201410077353A CN 103864673 A CN103864673 A CN 103864673A
Authority
CN
China
Prior art keywords
hydroxy piperidine
benzyl
formula
solvent
tertbutyloxycarbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201410077353.1A
Other languages
Chinese (zh)
Other versions
CN103864673B (en
Inventor
林志刚
徐军
刘艳琴
阙利民
江岳恒
蔡彤�
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ABA Chemicals Corp
Original Assignee
ABA Chemicals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ABA Chemicals Corp filed Critical ABA Chemicals Corp
Priority to CN201410077353.1A priority Critical patent/CN103864673B/en
Publication of CN103864673A publication Critical patent/CN103864673A/en
Application granted granted Critical
Publication of CN103864673B publication Critical patent/CN103864673B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention relates to preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and a method for chirality turning. The preparation mainly comprises the following steps: resolving N-benzyl-3-hydroxy piperidine as a raw material to obtain a (S) or (R)-1-benzyl-3-hydroxy piperidine camphorsulfonic acid salt, performing alkali freedom to obtain (S) or (R)-1-benzyl-3-hydroxy piperidine, performing palladium carbon hydrogenation debenzylation/t-butyloxycarboryl protection to obtain (S) or (R)-1-t-butyloxycarboryl-3-hydroxy piperidine, acylating substituting sulfonyl chloride of (R) or (S)-1-substituting-3-hydroxy piperidine as a raw material to obtain (R) or (S)-1-substituting-3-hydroxy piperidine sulfonate, substituting by using substituting carboxylate to obtain (S) or (R)-1-substituting-3-hydroxy piperidine carboxylic ester, and performing alkaline hydrolysis to obtain (S) or (R)-1-substituting-3-hydroxy piperidine. The synthesis route is gentle in reaction condition, and is applicable to industrial large-scale production.

Description

The method of the preparation of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine and chirality upset
Technical field
The present invention relates to the synthetic of a kind of compound, be specifically related to the method for preparation and the chirality upset of a kind of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine.
Background technology
(S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine is a kind of important medicine intermediate.Its synthetic method of reporting in document is now mainly as follows:
Method one (asymmetric synthesis):
Figure BDA0000472750690000011
Main literature: Tetrahedron, 63,331-336; 2007.
Method two (enzyme asymmetric reduction):
Figure BDA0000472750690000012
Main literature: Organic Letters, 11 (6), 1245-1248; 2009.
Method three (chemical resolution method):
Figure BDA0000472750690000013
Main literature: WO2004064730; WO2004072086.
In chemical resolution method, because the water-soluble purifying that is difficult for of 3-hydroxy piperidine obtains, more difficult industrialized problem.In split process, easily there is chiral impurity simultaneously.
Summary of the invention
The object of this invention is to provide a kind of preparation method of new chirality 1-tertbutyloxycarbonyl-3-hydroxy piperidine.This synthetic route has no bibliographical information, and reaction conditions gentleness is applicable to industrialized production.
Particularly, the invention provides the preparation method of a kind of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine, mainly comprise step:
1) taking N-benzyl-3-hydroxy piperidine of formula I as raw material, under the effect of chirality camphorsulfonic acid CSA, split to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate of formula IIs or (R)-1-benzyl-3-hydroxy piperidine camsilate of formula IIr;
2) (R)-1-benzyl-3-hydroxy piperidine camsilate of (the S)-1-benzyl-3-hydroxy piperidine camsilate of the formula IIs described in step 1) or formula IIr is free through alkali, obtains (S)-1-benzyl-3-hydroxy piperidine of formula III s or (R)-1-benzyl-3-hydroxy piperidine of formula III r;
3) step 2) described (S)-1-benzyl-3-hydroxy piperidine of formula III s or (R)-1-benzyl-3-hydroxy piperidine of formula III r be through the de-benzyl of palladium charcoal catalytic hydrogenation, obtains (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVs or (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVr with tertiary fourth oxygen acid anhydrides carbonyl-protection simultaneously
Wherein, the resolving agent of the resolution reaction in step 1) is chirality d-camphorsulfonic acid D-CSA or l-camphor sulfonic acid L-CSA, the mol ratio of described chirality d-camphorsulfonic acid D-CSA or l-camphor sulfonic acid L-CSA and raw material N-benzyl-3-hydroxy piperidine is 0～0.6:1, preferably: 0.3～0.5:1.
Wherein, the solvent system of the resolution reaction in step 1) is: as the organic alcohols solvent of methyl alcohol, ethanol, Virahol, as the organosilane ester solvent of vinyl acetic monomer, Iso Butyl Acetate; As the organic ketone solvent of 2-butanone, acetone; As THF, isopropyl ether, the organic ether kind solvent of methyl tertiary butyl ether; Or arbitrary combination wherein.
Wherein, step 2) described alkali is sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, wherein the mol ratio of above-mentioned alkali and raw material N-benzyl-3-hydroxy piperidine is 1～10:1, preferably 1～1.5:1.
Wherein, the solvent system of step 3) reaction is: as the organic alcohols solvent of methyl alcohol, ethanol, Virahol; As the organosilane ester solvent of vinyl acetic monomer, Iso Butyl Acetate; As THF, isopropyl ether, the organic ether kind solvent of methyl tertiary butyl ether; Or arbitrary combination wherein.
Wherein, in step 3), the weight ratio of (R)-1-benzyl-3-hydroxy piperidine of (S)-1-benzyl-3-hydroxy piperidine of palladium charcoal and substrate formula III s or formula III r is 0.01～0.5:1; Temperature of reaction is between 0 DEG C～80 DEG C; Described reaction pressure is 1atm～30atm; Wherein the mol ratio of (R)-1-benzyl-3-hydroxy piperidine of (S)-1-benzyl-3-hydroxy piperidine of tertbutyloxycarbonyl acid anhydrides and substrate formula III s or formula III r is 1～2:1.
The present invention also provides the chirality method for turning of above-mentioned chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine, mainly comprises step:
4), taking (R)-1-replacement-3-hydroxy piperidine of formula Vr or (S)-1-replacement-3-hydroxy piperidine (V) of formula Vs as raw material, under the effect that replaces SULPHURYL CHLORIDE, acidylate obtains (R)-1-replacement-3-hydroxy piperidine sulphonate of formula VIr or (S)-1-replacement-3-hydroxy piperidine sulphonate of VIs;
5) (S)-1-replacement-3-hydroxy piperidine sulphonate of (the R)-1-replacement-3-hydroxy piperidine sulphonate of the formula VIr described in step 4) or VIs is substituted carboxylate salt and replaces, structure overturn to obtain (S)-1-replacement-3-hydroxypiperidine carboxylic acid's ester of formula VIIs or (R)-1-replacement-3-hydroxypiperidine carboxylic acid ester of formula VIIr;
6) (R)-1-replacement-3-hydroxypiperidine carboxylic acid ester of (the S)-1-replacement-3-hydroxypiperidine carboxylic acid's ester of the formula VIIs described in step 5) or formula VIIr obtains (S)-1-replacement-3-hydroxy piperidine of formula VIIIs or (R)-1-replacement-3-hydroxy piperidine of formula VIIIr through basic hydrolysis;
Figure BDA0000472750690000041
Wherein, R is benzyl, carbobenzoxy-(Cbz) or tertbutyloxycarbonyl;
R 1, R 2the lower paraffin hydrocarbons of C1～C3, substituted-phenyl;
Wherein, the step 2 that described chirality-1-replacement-3-hydroxy piperidine is claim 1) described (S)-1-benzyl-3-hydroxy piperidine of formula III s or (R)-1-benzyl-3-hydroxy piperidine of formula III r; Or (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVs or (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVr described in claim 1 step 3).
Wherein, the SULPHURYL CHLORIDE described in step 4) is Methanesulfonyl chloride, p-methyl benzene sulfonic chloride, 4-Nitrobenzenesulfonyl chloride or p-bromobenzenesulfonyl chloride; The solvent system of acylation reaction is: the organosilane ester solvent as vinyl acetic monomer, Iso Butyl Acetate: if the organochlorine of methylene dichloride, trichloromethane, ethylene dichloride, chlorobenzene is for kind solvent: as isopropyl ether, and the organic ether kind solvent of methyl tertiary butyl ether, tetrahydrofuran (THF).
Wherein, the carboxylate salt described in step 5) is sodium-acetate or Sodium Benzoate; The solvent system that replaces upset reaction is: as the organic amide kind solvent of DMF, methane amide; As the organosilane ester solvent of vinyl acetic monomer, Iso Butyl Acetate; If the organochlorine of methylene dichloride, trichloromethane, ethylene dichloride, chlorobenzene is for kind solvent; As the organic ether kind solvent of isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF); Organic alcohols solvent as methyl alcohol, ethanol: or comprise a class of above-mentioned solvent or a few class mixed solvent and and the mixed solvent system of water.
Wherein, the alkali of the hydrolysis reaction in step 6) is sodium hydroxide, lithium hydroxide, potassium hydroxide; Sodium carbonate, salt of wormwood or ammoniacal liquor; Wherein the mol ratio of the raw material N-benzyl-3-hydroxy piperidine described in above-mentioned alkali and step 4) is 1～100:1.The solvent of hydrolysis reaction is water; As the organic alcohols solvent of methyl alcohol, ethanol; As the organic ether kind solvent of tetrahydrofuran (THF); Or comprise its mixed solvent system.
Aforesaid method of the present invention has solved in chemical resolution method, because the water-soluble purifying that is difficult for of 3-hydroxy piperidine obtains, and more difficult industrialized problem.Solve the utilization of chiral impurity in split process simultaneously.This synthetic route has no bibliographical information, and reaction is clean, is applicable to industrialized production.
For above and other objects of the present invention, feature and advantage can be become apparent, preferred embodiment cited below particularly, is described in detail below.
Embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is further described, but the present invention is not limited to this embodiment.
Synthesizing of step 1) (S) or (R)-1-benzyl-3-hydroxy piperidine camsilate
Embodiment 1:(S)-1-benzyl-3-hydroxy piperidine camsilate synthetic
(1) synthetic () of (S)-1-benzyl-3-hydroxy piperidine camsilate
In 1000ml there-necked flask, add N-benzyl-3-hydroxy piperidine (95.6g, 0.5mol), Virahol 478ml drip L-CSA(58g, 0.25mol) 116ml aqueous isopropanol, stirring at room temperature 1 hour, separate out solid and occur, 0 DEG C is incubated 2 hours, filters, cold isopropanol 30ml washing, is dried to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate 75g.(ee:95%) (theory: 105.9g).(S)-1-benzyl-3-hydroxy piperidine camsilate of 95%ee value, with the Virahol recrystallization of 3 times of amounts, can obtain (S)-1-benzyl-3-hydroxy piperidine camsilate (99%ee).
(2) synthetic (two) of (S)-1-benzyl-3-hydroxy piperidine camsilate
In 1000ml there-necked flask, add N-benzyl-3-hydroxy piperidine (95.6g, 0.5mol), ethyl acetate 478ml drip L-CSA(58g, 0.25mol) 290ml ethyl acetate solution, stirring at room temperature 1 hour, separate out solid and occur, 0 DEG C is incubated 2 hours, filters, ethyl acetate 30ml washing, is dried to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate 95g.(ee:88%) (theory: 105.9g).
(3) synthetic (three) of (S)-1-benzyl-3-hydroxy piperidine camsilate
In 1000ml there-necked flask, add N-benzyl-3-hydroxy piperidine (95.6g, 0.5mol), 2-butanone 478ml drip L-CSA(58g, 0.25mol) 290ml2-butanone solution, stirring at room temperature 1 hour, separate out solid and occur, 0 DEG C is incubated 2 hours, filters, 2-butanone 30ml washing, is dried to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate 88g.(ee:93%) (theory: 105.9g).
(4) synthetic (four) of (S)-1-benzyl-3-hydroxy piperidine camsilate
In 1000ml there-necked flask, add N-benzyl-3-hydroxy piperidine (95.6g, 0.5mol), 2-butanone 478ml drip L-CSA(69.6g, 0.3mol) 290ml2-butanone solution, stirring at room temperature 1 hour, separate out solid and occur, 0 DEG C is incubated 2 hours, filters, 2-butanone 30ml washing, is dried to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate 108g.(ee:75%) (theory: 105.9g).
(5) synthetic (five) of (S)-1-benzyl-3-hydroxy piperidine camsilate
In 1000ml there-necked flask, add N-benzyl-3-hydroxy piperidine (95.6g, 0.5mol), 2-butanone 478ml drip L-CSA(52.2g, 0.225mol) 290ml2-butanone solution, stirring at room temperature 1 hour, separate out solid and occur, 0 DEG C is incubated 2 hours, filters, 2-butanone 30ml washing, is dried to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate 83g.(ee:95%) (theory: 95.3g).
(6) synthetic (six) of (S)-1-benzyl-3-hydroxy piperidine camsilate
In 1000ml there-necked flask, add N-benzyl-3-hydroxy piperidine (95.6g, 0.5mol), THF478ml, drip L-CSA(58g, 290ml THF solution 0.25mol), stirring at room temperature 1 hour, separates out solid and occurs, 0 DEG C is incubated 2 hours, filter, THF30ml washing, is dried to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate 83g.(ee:92%) (theory: 105.9g).
Embodiment 2:(R)-1-benzyl-3-hydroxy piperidine camsilate synthetic
In 1000ml there-necked flask, add N-benzyl-3-hydroxy piperidine (95.6g, 0.5mol), Virahol 478ml drip D-CSA(58g, 0.25mol) 116ml aqueous isopropanol, stirring at room temperature 1 hour, separate out solid and occur, 0 DEG C is incubated 2 hours, filters, cold isopropanol 30ml washing, is dried to obtain (R)-1-benzyl-3-hydroxy piperidine camsilate 75g.(ee:95%) (theory: 105.9g).(R)-1-benzyl-3-hydroxy piperidine camsilate of 95%ee value, with the Virahol recrystallization of 3 times of amounts, can obtain (R)-1-benzyl-3-hydroxy piperidine camsilate (99%ee).
Step 2) (S) or (R)-1-benzyl-3-hydroxy piperidine synthetic
Embodiment 3:(S)-1-benzyl-3-hydroxy piperidine synthetic
(1) synthetic () of (S)-1-benzyl-3-hydroxy piperidine
In 1000ml there-necked flask, add (S)-1-benzyl-3-hydroxy piperidine camsilate (99%ee of arbitrary preparation in (1) in embodiment 1, (2), (3), 84.7g, 0.2mol), methylene dichloride 423ml, drips 1N aqueous sodium hydroxide solution (210ml), stirring at room temperature 1 hour, divide the phase of anhydrating, organic phase anhydrous sodium sulfate drying, concentrated (S)-1-benzyl-3-hydroxy piperidine 38g that to obtain.(ee:99%; LC-MS:m/e=191.3) (theory: 38.25g).
(2) synthetic (two) of (S)-1-benzyl-3-hydroxy piperidine
In 1000ml there-necked flask, add (S)-1-benzyl-3-hydroxy piperidine camsilate (99%ee of arbitrary preparation in (4) in embodiment 1, (5), (6), 84.7g, 0.2mol), ethyl acetate 423ml, drips 1N wet chemical (150ml), stirring at room temperature 1 hour, divide the phase of anhydrating, organic phase anhydrous sodium sulfate drying, concentrated (S)-1-benzyl-3-hydroxy piperidine 36g that to obtain.(ee:99%; LC-MS:m/e=191.3) (theory: 38.25g).
Embodiment 4:(R)-1-benzyl-3-hydroxy piperidine synthetic
In 1000ml there-necked flask, add (R)-1-benzyl-3-hydroxy piperidine camsilate (99%ee of preparation in embodiment 2,84.7g, 0.2mol), methylene dichloride 423ml, drips 1N aqueous sodium hydroxide solution (210ml), stirring at room temperature 1 hour, divide the phase of anhydrating, organic phase anhydrous sodium sulfate drying, concentrated (R)-1-benzyl-3-hydroxy piperidine 38g that to obtain.(ee:99%; LC-MS:m/e=191.3) (theory: 38.25g).
Step 3): (S) or (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine synthetic
Embodiment 5:(S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine synthetic
(1) synthetic () of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 1000mL autoclave, add (S)-1-benzyl-3-hydroxy piperidine (38.25g, 0.2mol) that in embodiment 3 prepared by (1), methyl alcohol 200ml, add 10% palladium charcoal (3.8g), and tertbutyloxycarbonyl acid anhydrides (43.6g, 0.2mol), atmosphere of hydrogen, control pressure～5atm,～40 DEG C, react HPLC raw material ((S)-1-benzyl-3-hydroxy piperidine) <0.2% 15 hours; Reaction solution is cooled to room temperature, and stopped reaction filters, and reclaims palladium charcoal, and filtrate decompression is concentrated into dry, adds ethyl acetate/normal hexane recrystallization, separates out solid, filters; Solid washs with a small amount of normal hexane; Be dried to obtain product (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～36g.(theory: 40.2g) (HPLC content～99%; Ee:99%; LC-MS:m/e=201.3).
(2) synthetic (two) of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 1000mL autoclave, add (2) preparation (S)-1-benzyl-3-hydroxy piperidines (38.25g, 0.2mol) in embodiment 3, ethyl acetate 200ml, add 10% palladium charcoal (1.9g), and tertbutyloxycarbonyl acid anhydrides (48g, 0.22mol), atmosphere of hydrogen, control pressure～10atm,～50 DEG C, react HPLC raw material ((S)-1-benzyl-3-hydroxy piperidine) <0.2% 15 hours; Reaction solution is cooled to room temperature, and stopped reaction filters, and reclaims palladium charcoal, and filtrate decompression is concentrated into 1/2, adds normal hexane recrystallization, separates out solid, filters; Solid washs with a small amount of normal hexane; Be dried to obtain product (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～37g, (theory: 40.2g) (HPLC content～99%; Ee:99%; LC-MS:m/e=201.3).
(3) synthetic (three) of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 1000mL autoclave, add (2) preparation (S)-1-benzyl-3-hydroxy piperidines (38.25g, 0.2mol) in embodiment 3, THF200ml, add 10% palladium charcoal (0.95g), and tertbutyloxycarbonyl acid anhydrides (54.5g, 0.25mol), atmosphere of hydrogen, control pressure～20atm,～40 DEG C, react HPLC raw material ((S)-1-benzyl-3-hydroxy piperidine) <0.2% 15 hours; Reaction solution is cooled to room temperature, and stopped reaction filters, and reclaims palladium charcoal, and filtrate decompression is concentrated into dry, adds ethyl acetate/normal hexane recrystallization, separates out solid, filters; Solid washs with a small amount of normal hexane; Be dried to obtain product (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～38g, (theory: 40.2g) (HPLC content～99%; Ee:99%; LC-MS:m/e=201.3).
Embodiment 6:(R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine synthetic
In 1000mL autoclave, add (R)-1-benzyl-3-hydroxy piperidine (38.25g, 0.2mol) of preparation in embodiment 4, methyl alcohol 200ml, add 10% palladium charcoal (0.95g), and tertbutyloxycarbonyl acid anhydrides (43.6g, 0.2mol), atmosphere of hydrogen, control pressure～5atm,～60 DEG C, react HPLC raw material ((R)-1-benzyl-3-hydroxy piperidine) <0.2% 15 hours; Reaction solution is cooled to room temperature, and stopped reaction filters, and reclaims palladium charcoal, and filtrate decompression is concentrated into dry, adds ethyl acetate/normal hexane recrystallization, separates out solid, filters; Solid washs with a small amount of normal hexane; Be dried to obtain product (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～36g.(theory: 40.2g) (HPLC content～99%; Ee:99%; LC-MS:m/e=201.3).
Synthesizing of step 4) (R) or (S)-1-replacement-3-hydroxy piperidine sulphonate
Embodiment 7:
(1) synthetic () of (R)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine (30.2g, 0.15mol) of preparation in embodiment 6, methylene dichloride 180ml, triethylamine (18.2g; 0.18mol), control 0～10 DEG C, drip methylsulfonyl chloride (18.9g, 0.165mol), stirring at room temperature 1 hour, the cancellation that adds water, divides the phase of anhydrating, organic phase washing, anhydrous sodium sulfate drying, concentrates to obtain (R)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines 39.8g.(yield:95%; LC-MS:m/e=279.1) (theory: 41.9g).
(2) synthetic (two) of (R)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine (30.2g, 0.15mol) of preparation in embodiment 6, Iso Butyl Acetate 180ml, triethylamine (18.2g; 0.18mol), control 0～10 DEG C, drip methylsulfonyl chloride (18.9g, 0.165mol), stirring at room temperature 1 hour, the cancellation that adds water, divides the phase of anhydrating, organic phase washing, anhydrous sodium sulfate drying, concentrates to obtain (R)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines 39.8g.(yield:95%; LC-MS:m/e=279.1) (theory: 41.9g).
Embodiment 8:(R)-1-benzyl-3-methylsulfonic acid phenylpiperidines synthetic
In 500ml there-necked flask, add (R)-1-benzyl-3-hydroxy piperidine (28.7g, 0.15mol) of preparation in embodiment 4, methylene dichloride 180ml, triethylamine (18.2g; 0.18mol), control 0～10 DEG C, drip methylsulfonyl chloride (18.9g, 0.165mol), stirring at room temperature 1 hour, the cancellation that adds water, divides the phase of anhydrating, organic phase washing, anhydrous sodium sulfate drying, concentrated (R)-1-benzyl-3-methylsulfonic acid phenylpiperidines 37.2g that to obtain.(yield:92%; LC-MS:m/e=269.4) (theory: 40.4g).
Embodiment 9:(R)-1-tertbutyloxycarbonyl-3-p-nitrophenyl sulfonic group piperidines synthetic
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine (30.2g, 0.15mol) of preparation in embodiment 6, methylene dichloride 180ml, triethylamine (18.2g; 0.18mol), control 0～10 DEG C, drip 4-Nitrobenzenesulfonyl chloride (36.6g, dichloromethane solution 0.165mol), stirred overnight at room temperature, cancellation adds water, divide the phase of anhydrating, organic phase washing, anhydrous sodium sulfate drying, concentrates to obtain (R)-1-tertbutyloxycarbonyl-3-p-nitrophenyl sulfonic group piperidines 54.5g.(yield:94%; LC-MS:m/e=386.4) (theory: 58.0g).
Embodiment 10:(R)-1-tertbutyloxycarbonyl-3-p-methyl benzenesulfonic acid phenylpiperidines synthetic
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine (30.2g, 0.15mol) of preparation in embodiment 6, ethylene dichloride 180ml, triethylamine (18.2g; 0.18mol), room temperature drips p-methyl benzene sulfonic chloride (31.4g, dichloroethane solution 0.165mol), 50～60 DEG C of reactions are spent the night, the cancellation that adds water, the phase of point anhydrating, organic phase washing, anhydrous sodium sulfate drying, concentrates to obtain (R)-1-tertbutyloxycarbonyl-3-p-methyl benzenesulfonic acid phenylpiperidines 48.0g.(yield:90%; LC-MS:m/e=355.5) (theory: 53.3g).
Embodiment 11:(S)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines synthetic
In 500ml there-necked flask, add embodiment 5(1) (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine (30.2g, 0.15mol) of arbitrary preparation in (2) (3), methylene dichloride 180ml, triethylamine (18.2g; 0.18mol), control 0～10 DEG C, drip methylsulfonyl chloride (18.9g, 0.165mol), stirring at room temperature 1 hour, the cancellation that adds water, divides the phase of anhydrating, organic phase washing, anhydrous sodium sulfate drying, concentrates to obtain (S)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines 39.8g.(yield:95%; LC-MS:m/e=279.1) (theory: 41.9g).
Step 5) overturn to obtain (S) or (R)-1-replacement-3-hydroxypiperidine carboxylic acid ester
Embodiment 12:(S)-1-tertbutyloxycarbonyl-3-acetoxyl group piperidines synthetic
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines (27.9g, 0.1mol) that in embodiment 7 prepared by (1) or (2), DMF100ml, sodium-acetate (16.4g; 0.2mol), 60 DEG C of reactions are spent the night, the cancellation that adds water, and ethyl acetate is extracted, and organic phase washing, concentrates to obtain (S)-1-tertbutyloxycarbonyl-3-acetoxyl group piperidines crude product.(yield :～100%; LC-MS:m/e=243.3) (theory: 24.3g).
Embodiment 13:
(1) synthetic () of (S)-1-tertbutyloxycarbonyl-3-benzoxy phenylpiperidines
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines (27.9g, 0.1mol) that in embodiment 7 prepared by (1) or (2), DMF100ml, Sodium Benzoate (28.8g; 0.2mol), 80 DEG C of reactions are spent the night, and reaction solution is cooling, the cancellation that adds water, and dichloromethane extraction, organic phase washing, concentrates to obtain (S)-1-tertbutyloxycarbonyl-3-benzoxy phenylpiperidines crude product.(yield :～100%; LC-MS:m/e=305.4) (theory: 30.5g).
(2) synthetic (two) of (S)-1-tertbutyloxycarbonyl-3-benzoxy phenylpiperidines
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-p-nitrophenyl sulfonic group piperidines (38.6g, 0.1mol) of preparation in embodiment 9, DMF100ml, Sodium Benzoate (28.8g; 0.2mol), 80 DEG C of reactions are spent the night, and reaction solution is cooling, the cancellation that adds water, and dichloromethane extraction, organic phase washing, concentrates to obtain (S)-1-tertbutyloxycarbonyl-3-benzoxy phenylpiperidines crude product.(yield :～100%; LC-MS:m/e=305.4) (theory: 30.5g).
(3) synthetic (three) of (S)-1-tertbutyloxycarbonyl-3-benzoxy phenylpiperidines
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-p-methyl benzenesulfonic acid phenylpiperidines (35.5g, 0.1mol) of preparation in embodiment 10, DMF100ml, Sodium Benzoate (28.8g; 0.2mol), 90 DEG C of reactions are spent the night, and reaction solution is cooling, the cancellation that adds water, and dichloromethane extraction, organic phase washing, concentrates to obtain (S)-1-tertbutyloxycarbonyl-3-benzoxy phenylpiperidines crude product.(yield :～100%; LC-MS:m/e=305.4) (theory: 30.5g).
Embodiment 14:(S)-1-benzyl-3-benzoxy phenylpiperidines synthetic
In 500ml there-necked flask, add (R)-1-benzyl-3-methylsulfonic acid phenylpiperidines (26.9g, 0.1mol) of preparation in embodiment 8, DMF100ml, Sodium Benzoate (28.8g; 0.2mol), 90 DEG C of reactions are spent the night, and reaction solution is cooling, the cancellation that adds water, and dichloromethane extraction, organic phase washing, concentrates to obtain (S)-1-benzyl-3-benzoxy phenylpiperidines crude product.(yield :～100%; LC-MS:m/e=295.4) (theory: 29.5g).
Embodiment 15:(R)-1-tertbutyloxycarbonyl-3-acetoxyl group piperidines synthetic
In 500ml there-necked flask, add (S)-1-tertbutyloxycarbonyl-3-methylsulfonic acid phenylpiperidines (26.9g, 0.1mol) of preparation in embodiment 11, DMF100ml, sodium acetate (16.4g; 0.2mol), 90 DEG C of reactions are spent the night, and reaction solution is cooling, the cancellation that adds water, and dichloromethane extraction, organic phase washing, concentrates to obtain (R)-1-tertbutyloxycarbonyl-3-acetoxyl group piperidines crude product.(yield :～100%; LC-MS:m/e=233.3) (theory: 23.3g).
Step 6): basic hydrolysis obtains (S) or (R)-1-replacement-3-hydroxy piperidine
Embodiment 16:(S)-1-benzyl-3-hydroxy piperidine synthetic
In 500ml there-necked flask, add (S)-1-benzyl-3-benzoxy phenylpiperidines crude product (0.1mol) of preparation in embodiment 14, methyl alcohol 50ml; Water 50ml, then add sodium hydroxide 6g(0.15mol), room temperature reaction spends the night, reaction solution thin up, and dichloromethane extraction, organic phase washing, concentrated, obtain product (S)-1-benzyl-3-hydroxy piperidine～18g.(HPLC content～99%; Ee:99%; LC-MS:m/e=191.3) (theory: 19.1g).
Embodiment 17:(S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine synthetic
(1) synthetic (four) of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 500ml there-necked flask, (the S)-1-tertbutyloxycarbonyl-3-acetyl Oxypertine crude product (0.1mol) that adds embodiment 12 to prepare, methyl alcohol 50ml; Water 50ml, then add sodium hydroxide 6g(0.15mol), room temperature reaction spends the night, reaction solution thin up, dichloromethane extraction, organic phase washing, concentrated, ethyl acetate/normal hexane recrystallization, is dried to obtain product (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～16g.(HPLC content～99%; Ee:99%; LC-MS:m/e=201.3) (theory: 20.1g).
(2) synthetic (five) of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 500ml there-necked flask, (the S)-1-tertbutyloxycarbonyl-3-acetyl Oxypertine crude product (0.1mol) that adds embodiment 12 to prepare, methyl alcohol 50ml; Water 50ml, then add sodium hydroxide 6g(0.15mol), room temperature reaction spends the night, reaction solution thin up, dichloromethane extraction, organic phase washing, concentrated, ethyl acetate/normal hexane recrystallization, is dried to obtain product (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～16g.(HPLC content～99%; Ee:99%; LC-MS:m/e=201.3) (theory: 20.1g).
(3) synthetic (six) of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 500ml there-necked flask, (the S)-1-tertbutyloxycarbonyl-3-acetyl Oxypertine crude product (0.1mol) that adds embodiment 12 to prepare, methyl alcohol 50ml; Water 50ml, then add potassium hydroxide 9.1g(～0.15mol), room temperature reaction spends the night, reaction solution thin up, dichloromethane extraction, organic phase washing, concentrated, ethyl acetate/normal hexane recrystallization, is dried to obtain product (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～15g.(HPLC content～99%; Ee:99%; LC-MS:m/e=201.3) (theory: 20.1g).
(4) synthetic (seven) of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 500ml there-necked flask, (the S)-1-tertbutyloxycarbonyl-3-acetyl Oxypertine crude product (0.1mol) that adds embodiment 12 to prepare, THF50ml; Water 50ml, then add sodium hydroxide 6g(0.15mol), room temperature reaction spends the night, reaction solution thin up, dichloromethane extraction, organic phase washing, concentrated, ethyl acetate/normal hexane recrystallization, is dried to obtain product (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～16g.(HPLC content～99%; Ee:99%; LC-MS:m/e=201.3) (theory: 20.1g).
(5) synthetic (eight) of (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine
In 500ml there-necked flask, (the S)-1-tertbutyloxycarbonyl-3-acetyl Oxypertine crude product (0.1mol) that adds embodiment 12 to prepare, ethanol 100ml; Strong aqua 10ml, room temperature reaction spends the night, reaction solution concentrating under reduced pressure, thin up, dichloromethane extraction, organic phase washing, concentrated, ethyl acetate/normal hexane recrystallization, is dried to obtain product (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～16g.(HPLC content～99%; Ee:99%; LC-MS:m/e=201.3) (theory: 20.1g).
Embodiment 18:(R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine synthetic
In 500ml there-necked flask, add (R)-1-tertbutyloxycarbonyl-3-acetoxyl group piperidines crude product (0.1mol) of preparation in embodiment 15, methyl alcohol 50ml; Water 50ml, then add sodium hydroxide 6g(0.15mol), room temperature reaction spends the night, reaction solution thin up, dichloromethane extraction, organic phase washing, concentrated, ethyl acetate/normal hexane recrystallization, is dried to obtain product (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine～16g.(HPLC content～99%; Ee:99%; LC-MS:m/e=201.3) (theory: 20.1g).
Although the present invention discloses as above with preferred embodiment; so it is not in order to limit the present invention; any person of ordinary skill in the field; without departing from the spirit and scope of the invention; when doing a little change and improvement, therefore the present invention's protection domain is when being as the criterion depending on the claim person of defining.

Claims (10)

1. a preparation method for chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine, is characterized in that, comprises step:
1) taking N-benzyl-3-hydroxy piperidine of formula I as raw material, under the effect of chirality camphorsulfonic acid CSA, split to obtain (S)-1-benzyl-3-hydroxy piperidine camsilate of formula IIs or (R)-1-benzyl-3-hydroxy piperidine camsilate of formula IIr;
2) (R)-1-benzyl-3-hydroxy piperidine camsilate of (the S)-1-benzyl-3-hydroxy piperidine camsilate of the formula IIs described in step 1) or formula IIr is free through alkali, obtains (S)-1-benzyl-3-hydroxy piperidine of formula III s or (R)-1-benzyl-3-hydroxy piperidine of formula III r;
3) step 2) described (S)-1-benzyl-3-hydroxy piperidine of formula III s or (R)-1-benzyl-3-hydroxy piperidine of formula III r be through the de-benzyl of palladium charcoal catalytic hydrogenation, obtains (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVs or (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVr with tertiary fourth oxygen acid anhydrides carbonyl-protection simultaneously
Figure FDA0000472750680000011
2. method according to claim 1, it is characterized in that, the resolving agent of the resolution reaction in step 1) is chirality d-camphorsulfonic acid D-CSA or l-camphor sulfonic acid L-CSA, and the mol ratio of described chirality d-camphorsulfonic acid D-CSA or l-camphor sulfonic acid L-CSA and raw material N-benzyl-3-hydroxy piperidine is 0～0.6:1.
3. method according to claim 1, is characterized in that, the solvent system of the resolution reaction in step 1) is: as the organic alcohols solvent of methyl alcohol, ethanol, Virahol, as the organosilane ester solvent of vinyl acetic monomer, Iso Butyl Acetate; As the organic ketone solvent of 2-butanone, acetone; As isopropyl ether, the organic ether kind solvent of methyl tertiary butyl ether; Or arbitrary combination wherein.
4. method according to claim 1, it is characterized in that, step 2) described alkali is sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, wherein the mol ratio of above-mentioned alkali and raw material N-benzyl-3-hydroxy piperidine is 1～10:1.
5. method according to claim 1, is characterized in that, the solvent system of step 3) reaction is: as the organic alcohols solvent of methyl alcohol, ethanol, Virahol; As the organosilane ester solvent of vinyl acetic monomer, Iso Butyl Acetate; As isopropyl ether, the organic ether kind solvent of methyl tertiary butyl ether; Or arbitrary combination wherein.
6. method according to claim 1, is characterized in that, in step 3), the weight ratio of (R)-1-benzyl-3-hydroxy piperidine of (S)-1-benzyl-3-hydroxy piperidine of palladium charcoal and substrate formula III s or formula III r is 0.01～0.5:1; Temperature of reaction is between 0 DEG C～80 DEG C; Described reaction pressure is 1atm～30atm; Wherein the mol ratio of (R)-1-benzyl-3-hydroxy piperidine of (S)-1-benzyl-3-hydroxy piperidine of tertbutyloxycarbonyl acid anhydrides and substrate formula III s or formula III r is 1～2:1.
7. a chirality method for turning for chirality-1-replacement-3-hydroxy piperidine, is characterized in that, comprises step:
4), taking (R)-1-replacement-3-hydroxy piperidine of formula Vr or (S)-1-replacement-3-hydroxy piperidine (V) of formula Vs as raw material, under the effect that replaces SULPHURYL CHLORIDE, acidylate obtains (R)-1-replacement-3-hydroxy piperidine sulphonate of formula VIr or (S)-1-replacement-3-hydroxy piperidine sulphonate of VIs;
5) (S)-1-replacement-3-hydroxy piperidine sulphonate of (the R)-1-replacement-3-hydroxy piperidine sulphonate of the formula VIr described in step 4) or VIs is substituted carboxylate salt and replaces, structure overturn to obtain (S)-1-replacement-3-hydroxypiperidine carboxylic acid's ester of formula VIIs or (R)-1-replacement-3-hydroxypiperidine carboxylic acid ester of formula VIIr;
6) (R)-1-replacement-3-hydroxypiperidine carboxylic acid ester of (the S)-1-replacement-3-hydroxypiperidine carboxylic acid's ester of the formula VIIs described in step 5) or formula VIIr obtains (S)-1-replacement-3-hydroxy piperidine of formula VIIIs or (R)-1-replacement-3-hydroxy piperidine of formula VIIIr through basic hydrolysis;
Figure FDA0000472750680000031
Wherein, R is benzyl, carbobenzoxy-(Cbz) or tertbutyloxycarbonyl;
R 1, R 2the lower paraffin hydrocarbons of C1～C3, substituted-phenyl;
Wherein, the step 2 that described chirality-1-replacement-3-hydroxy piperidine is claim 1) described (S)-1-benzyl-3-hydroxy piperidine of formula III s or (R)-1-benzyl-3-hydroxy piperidine of formula III r; Or (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVs or (R)-1-tertbutyloxycarbonyl-3-hydroxy piperidine of formula IVr described in claim 1 step 3).
8. method according to claim 7, is characterized in that, the SULPHURYL CHLORIDE described in step 4) is Methanesulfonyl chloride, p-methyl benzene sulfonic chloride, 4-Nitrobenzenesulfonyl chloride or p-bromobenzenesulfonyl chloride; The solvent system of acylation reaction is: the organosilane ester solvent as vinyl acetic monomer, Iso Butyl Acetate: if the organochlorine of methylene dichloride, trichloromethane, ethylene dichloride, chlorobenzene is for kind solvent: as isopropyl ether, and the organic ether kind solvent of methyl tertiary butyl ether, tetrahydrofuran (THF).
9. method according to claim 7, is characterized in that, the carboxylate salt described in step 5) is sodium-acetate or Sodium Benzoate; The solvent system that replaces upset reaction is: as the organic amide kind solvent of DMF, methane amide; As the organosilane ester solvent of vinyl acetic monomer, Iso Butyl Acetate; If the organochlorine of methylene dichloride, trichloromethane, ethylene dichloride, chlorobenzene is for kind solvent; As the organic ether kind solvent of isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF); Organic alcohols solvent as methyl alcohol, ethanol: or comprise a class of above-mentioned solvent or a few class mixed solvent and and the mixed solvent system of water.
10. method according to claim 7, is characterized in that, the alkali of the hydrolysis reaction in step 6) is sodium hydroxide, lithium hydroxide, potassium hydroxide; Sodium carbonate, salt of wormwood or ammoniacal liquor; Wherein the mol ratio of the raw material described in above-mentioned alkali and step 4) is 1～100:1; The solvent of hydrolysis reaction is water; As the organic alcohols solvent of methyl alcohol, ethanol; As the organic ether kind solvent of tetrahydrofuran (THF); Or comprise its mixed solvent system.
CN201410077353.1A 2014-03-04 2014-03-04 The method of the preparation of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine and chirality upset Active CN103864673B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410077353.1A CN103864673B (en) 2014-03-04 2014-03-04 The method of the preparation of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine and chirality upset

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410077353.1A CN103864673B (en) 2014-03-04 2014-03-04 The method of the preparation of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine and chirality upset

Publications (2)

Publication Number Publication Date
CN103864673A true CN103864673A (en) 2014-06-18
CN103864673B CN103864673B (en) 2016-03-23

Family

ID=50903747

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410077353.1A Active CN103864673B (en) 2014-03-04 2014-03-04 The method of the preparation of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine and chirality upset

Country Status (1)

Country Link
CN (1) CN103864673B (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104140390A (en) * 2014-07-16 2014-11-12 雅本化学股份有限公司 Racemization recycling method for chirality 1-benzyl-3-hydroxypiperidine
CN104262301A (en) * 2014-10-09 2015-01-07 西安近代化学研究所 Method for synthesizing S-(+)-tetrahydrofuran-3-methanol
CN104557674A (en) * 2015-01-13 2015-04-29 江苏中邦制药有限公司 Preparation method of (S)-N-Boc-3-hydroxypiperidine
WO2015131299A1 (en) * 2014-03-04 2015-09-11 雅本化学股份有限公司 Method of preparation and chiral inversion of chiral-1-t-butoxycarbonyl-3-hydroxy piperidine
CN104693108B (en) * 2013-12-06 2017-05-31 重庆博腾制药科技股份有限公司 A kind of preparation method of bruton's tyrosine kinase (Btk) intermediate
CN107021916A (en) * 2016-02-02 2017-08-08 浙江医药股份有限公司 A kind of preparation method of trans -3- methyl -5- benzylamino piperidines

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1809576A (en) * 2003-02-14 2006-07-26 辉瑞大药厂 Antiparasitic terpene alkaloids
CN100345823C (en) * 2003-01-14 2007-10-31 赛特凯恩蒂克公司 Compounds, compositions and methods
CN103204801A (en) * 2013-04-12 2013-07-17 兰州远辉生物科技有限公司 Synthesis method for N-Boc-3-piperidone
WO2013112323A1 (en) * 2012-01-23 2013-08-01 Eli Lilly And Company Phenyl methanesulfonamide derivatives useful as mgat - 2 inhibitors
WO2014015495A1 (en) * 2012-07-26 2014-01-30 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100345823C (en) * 2003-01-14 2007-10-31 赛特凯恩蒂克公司 Compounds, compositions and methods
CN1809576A (en) * 2003-02-14 2006-07-26 辉瑞大药厂 Antiparasitic terpene alkaloids
WO2013112323A1 (en) * 2012-01-23 2013-08-01 Eli Lilly And Company Phenyl methanesulfonamide derivatives useful as mgat - 2 inhibitors
WO2014015495A1 (en) * 2012-07-26 2014-01-30 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
CN103204801A (en) * 2013-04-12 2013-07-17 兰州远辉生物科技有限公司 Synthesis method for N-Boc-3-piperidone

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KOUICHI TAKAHASHI,等: "A concise and practical catalytic asymmetric synthesis of (-)-CP-99,994 and (-)-L-733,061", 《TETRAHEDRON LETTERS》 *
SONA KOVACKOVA,等: "The synthesis of piperidine nucleoside analogsda comparison of several methods to access the introduction of nucleobases", 《TETRAHEDRON》 *
SONA KOVACKOVA,等: "The synthesis of piperidine nucleoside analogsda comparison of several methods to access the introduction of nucleobases", 《TETRAHEDRON》, vol. 67, no. 7, 16 December 2010 (2010-12-16), pages 1485 - 1500 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104693108B (en) * 2013-12-06 2017-05-31 重庆博腾制药科技股份有限公司 A kind of preparation method of bruton's tyrosine kinase (Btk) intermediate
WO2015131299A1 (en) * 2014-03-04 2015-09-11 雅本化学股份有限公司 Method of preparation and chiral inversion of chiral-1-t-butoxycarbonyl-3-hydroxy piperidine
CN104140390A (en) * 2014-07-16 2014-11-12 雅本化学股份有限公司 Racemization recycling method for chirality 1-benzyl-3-hydroxypiperidine
CN104140390B (en) * 2014-07-16 2016-06-08 雅本化学股份有限公司 The racemization recovery method of a kind of chirality 1-benzyl-3-hydroxy piperidine
CN104262301A (en) * 2014-10-09 2015-01-07 西安近代化学研究所 Method for synthesizing S-(+)-tetrahydrofuran-3-methanol
CN104262301B (en) * 2014-10-09 2016-01-13 西安近代化学研究所 A kind of method of synthesis S-(+)-tetrahydro 3 furanmethanol
CN104557674A (en) * 2015-01-13 2015-04-29 江苏中邦制药有限公司 Preparation method of (S)-N-Boc-3-hydroxypiperidine
CN107021916A (en) * 2016-02-02 2017-08-08 浙江医药股份有限公司 A kind of preparation method of trans -3- methyl -5- benzylamino piperidines
CN107021916B (en) * 2016-02-02 2020-06-12 浙江医药股份有限公司 Preparation method of trans-3-methyl-5-benzylaminopiperidine

Also Published As

Publication number Publication date
CN103864673B (en) 2016-03-23

Similar Documents

Publication Publication Date Title
CN103864673B (en) The method of the preparation of chirality-1-tertbutyloxycarbonyl-3-hydroxy piperidine and chirality upset
CN109956870A (en) A kind of Luo Shasi his synthetic method and its midbody compound
CN101941969B (en) Preparation method of moxifloxacin hydrochloride
CN100460396C (en) Intermediate of telmisartan, its preparation and use
CN107011404A (en) A kind of method using cholic acid as Material synthesis lithocholic acid
CN104447620B (en) 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate
CN110183445A (en) The synthetic method of Moxifloxacin and its derivative
WO2011145867A2 (en) Method for preparing alkyl lactate, and method for preparing lactamide by using same
CN102796090B (en) Method for preparing iloperidone
CN108299466B (en) Improved dolutegravir synthesis method
WO2015131299A1 (en) Method of preparation and chiral inversion of chiral-1-t-butoxycarbonyl-3-hydroxy piperidine
CN103992241B (en) The preparation method of N-substituted-phenyl glycine
CN105294556A (en) Method for preparing montelukast acid
CN105801482B (en) A kind of preparation method of the bromo- 8- difluoro-methoxies -1,4- dihydroquinoline -3- carboxylic acid, ethyl esters of 1- cyclopropyl -4- oxos -7-
CN106946724A (en) The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2
CN108467353A (en) A kind of preparation method of the pure t-butyl sulfonamide of mapping
CN103304472A (en) Method for synthesizing 1-BOC-3-piperidone
CN108623602A (en) A method of prepare and purify and replaces Buddhist nun according to Shandong
CN108558715A (en) A method of preparing the pure t-butyl sulfonamide of mapping
CN114717280A (en) Synthesis method of monopilavir
CN104326927B (en) A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate
CN102633683B (en) Synthesis method of 1-hydroxymethyl cyclopropylacetonitrile
CN102079720B (en) Method for preparing 1-benzylpiperidine-4-carboxaldehyde
CN113004245A (en) Preparation method of desloratadine
CN105237605B (en) A kind of intermediate and its preparation method and application for synthesizing gestodene

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant