CN102702080A - Preparation method of 3-trifluoromethyl piperidine derivatives - Google Patents
Preparation method of 3-trifluoromethyl piperidine derivatives Download PDFInfo
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- CN102702080A CN102702080A CN2012102095257A CN201210209525A CN102702080A CN 102702080 A CN102702080 A CN 102702080A CN 2012102095257 A CN2012102095257 A CN 2012102095257A CN 201210209525 A CN201210209525 A CN 201210209525A CN 102702080 A CN102702080 A CN 102702080A
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- 0 C=CC(C[n+]1cccc(C(F)(F)F)c1)=CC=* Chemical compound C=CC(C[n+]1cccc(C(F)(F)F)c1)=CC=* 0.000 description 2
- JTZSFNHHVULOGJ-UHFFFAOYSA-N FC(c1cccnc1)(F)F Chemical compound FC(c1cccnc1)(F)F JTZSFNHHVULOGJ-UHFFFAOYSA-N 0.000 description 1
- OHFZOQIFUMKHBT-UHFFFAOYSA-N OC(CCN(Cc1ccccc1)C1)C1C(F)(F)F Chemical compound OC(CCN(Cc1ccccc1)C1)C1C(F)(F)F OHFZOQIFUMKHBT-UHFFFAOYSA-N 0.000 description 1
- CDIYUKFVPHWMAF-UHFFFAOYSA-N OC(CCNC1)C1C(F)(F)F Chemical compound OC(CCNC1)C1C(F)(F)F CDIYUKFVPHWMAF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a preparation method of 3-trifluoromethyl piperidine derivatives shown as the formula (1), wherein R1 is carbonyl, hydroxyl, amino, acetamido, trifluoroacetyl or benzylamine; R2 is hydrogen, C1-C9 alkyl, aryl, benzyl, CF3CO, R4CO or R5OCO, R4 is C1-C9 alkyl, aryl or benzyl, R5 is C1-C9 alkyl, aryl or benzyl, R3 is hydrogen, C1-C9 alkyl, aryl or benzyl, each group is optionally not substituted or is substituted by substituent groups selected from alkyl, alkylhalide group, hydroxyalkyl, halogen, alkoxy or hydroxyl. The preparation method is characterized in that the method comprises the following steps.
Description
Technical field
The present invention relates to a kind of preparation method of 3-trifluoromethyl piperidine derivative.
Background technology
Because the uniqueness of fluorine atom is introduced into and brings theatrical raising can in the organic molecule organic molecule activity and pharmacology character thereof, especially in the security of exploitation tool, there is remarkable advantages alternative medicine molecule aspect.Thereby having attracted increasing medicine scholar and drugmaker to add the ranks of fluorine-containing medicament research and development, the document of this respect has a lot [1-5].
The piperidines structure is one type of very important midbody in the new drug development, in many medicines, all contains such structure, then is a new direction of new drug development with fluorine atom or fluorine-containing introducing piperidines molecule.Compounds shown in the structural formula (XVII) is not compared this compound and 5-HT with there being the substituted parent of fluorine
1DAnd 5-HT
1DReceptor binding capacity is suitable, but its oral absorption degree improves a lot [6] than parent.
(WO03064421A1 WO2004002490A2) is reported in the verivate behind the introducing trifluoromethyl on the piperidine ring to GSK; Compound can be used for developing antibiotic medicine shown in the structural formula (XVIII, XIX and XX).
The method of introducing trifluoromethyl at the ortho position of carbonyl and amino has following several kinds of modes basically:
1, (J.Chem.Soc, Perkin Trans.I 1977,1365 such as Dani é le Cantacuz é ne; Tetrahedron Lett.1999,40,6347; J.Chem.Soc; .Perkin Trans.I 1991; 2147) report is sloughed an one's share of expenses for a joint undertaking hydrogen iodide subsequently and is generated enamine by the inferior amine salt midbody of enamine and fluorine reagent CF3I addition generation iodine, and hydrolysis obtains the substituted carbonyl compound of ortho position trifluoromethyl (seeing reaction formula 4).
Reaction formula 4
2, patent (WO03064421A1; WO2004002490A2) report obtains the silyl enol ether compound by the piperidone of tertiary butyl carbonyl-protection under alkaline condition, generates the substituted piperidone compound of 3-trifluoromethyl with the CF3I reaction again; This compound reacts with benzylamine again, through reduction, obtains 3-trifluoromethyl-4-amino piperidine compound (seeing reaction formula 5) behind the debenzylation.
Reaction formula 5
3, Yoshimitsu Itoh etc. (Tetrahedron 2006,62,7199; Org.Lett.2005; 7,4883) report at low temperatures that carbonyl compound or silyl enol ether compound are in the presence of lithium reagent; Generate the enol lithium reagent, obtain the substituted carbonyl compound of ortho position trifluoromethyl (seeing reaction formula 6) with the reaction of fluorine reagent CF3I at low temperatures subsequently.
Reaction formula 6
Simultaneously, (Journal of Fluorine Chemistry, 2006,127539 such as Yoshimitsu Itoh; Org.Lett.2005,7,649; Org.Lett.2005,7,4883) also attempt obtaining the substituted carbonyl compound of ortho position trifluoromethyl (seeing reaction formula 7) with the enol tiron and the reaction of fluorine reagent CF3I of carbonyl compound.
Reaction formula 7
4, (Chem.Eur.J.2006,12,2579 such as Patrick Eisenberger and Vitaliy Petrik; Tetrahedron Lett.2007,48,3327) use fluorine reagent A or trifluoromethyl methyl iodide respectively under alkaline condition, with the beta-ketoester reaction, obtain the substituted keto ester compound by utilizing of trifluoromethyl (seeing reaction formula 8).
Reaction formula 8
5, Michael J.Krische etc. (Angew.Chem.Int.Ed., 2011,50,4173) adopt the iridium complex catalyzer from the trifluoromethyl building block through committed step: the oxidation of C-C key makes up; Prepare 1-Boc-trifluoromethyl-4-hydroxy piperidines (seeing reaction formula 9) through polystep reaction.
Reaction formula 9
(WO03064421A1 in the above method; WO2004002490A2) also provided 3 of the 4-piperidone methods of introducing trifluoromethyls, but this method need be used the gaseous reagent CF3I, and need under very low temperature, react, very difficult amplification.Also all there are these several problems in above-mentioned several method, reaction needed low temperature, and use gas fluorine reagent methyl iodide or will use comparison expensive Electron Affinities trifluoromethyl reagent such as Togni reagent (structural formula A, reaction formula 8), iridium catalyst (reaction formula 9) etc.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of 3-trifluoromethyl piperidine derivative is difficult to control to solve the existing operation condition that exists in the method for 3-trifluoromethyl piperidine derivative for preparing, and cost is high; Be not suitable for the technical problem of scale operation etc.; The inventive method, reaction conditions is gentle, is convenient to operation; Cost is low, and is suitable for suitability for industrialized production.
For realizing the object of the invention, technical scheme of the present invention is:
The preparation method of 3-trifluoromethyl piperidine derivative shown in a kind of formula (I),
R wherein
1Be carbonyl, hydroxyl, amino, kharophen, trifluoroacetyl group or benzylamine; R
2Be hydrogen, C1-C9 alkyl, aryl, benzyl, CF
3CO, R
4CO or R
5OCO; R
4Be C
1-C
9Alkyl, aryl or benzyl; R
5Be C
1-C
9Alkyl, aryl or benzyl R
3Be hydrogen, C
1-C
9Alkyl, aryl, benzyl, above-mentioned each group is optional not to be substituted or to be selected from the substituting groups replacement of being made up of alkyl, alkylhalide group, hydroxyalkyl, halogen, alkoxyl group or hydroxyl by one or more; It is characterized in that this method may further comprise the steps:
In a preferred embodiment of the present invention, work as R
1Be amino, R
2Be tertbutyloxycarbonyl, R
3When being hydrogen, this method may further comprise the steps:
(1) compound and bromobenzyl shown in the formula (VII) are at compound shown in 0 ° of C to 80 ° of C reaction production (VIII);
(2) compound shown in the formula (VIII) in the presence of reductive agent in-78 ° of C to 50 ° of C reaction productions (IX) with compound (X);
(3) formula (IX) and (X) shown in mixture, earlier after the reductive agent effect, compound shown in the production (XI) under the oxygenant effect again;
(4) compound shown in the oxidation production (XII) under-78 ° of C to 50 ° of C of compound shown in the formula (XI);
(5) compound and oxammonium hydrochloride shown in the formula (XII) are at compound shown in 0 ° of C to 50 ° of C reaction production (XIII);
(6) compound shown in the formula (XIII) is in the presence of reductive agent and catalyzer, at compound shown in 0 ° of C to 50 ° of C reaction production (XIV);
(7) compound and trifluoroacetic anhydride (TFAA) shown in the formula (XIV) are at compound shown in 0 ° of C to 50 ° of C reaction production (XV);
(8) compound shown in the formula (XV) is a catalyzer with palladium/carbon in organic solvent, compound shown in the hydrogenation production (XVI) under pressure 1 ~ 40atm;
(9) compound and tert-Butyl dicarbonate shown in the formula (XVI) are at compound shown in 0 ° of C to 50 ° of C reaction production (XVII);
(10) compound shown in the formula (XVII) is in the presence of alkaline reagents, at compound shown in 0 ° of C to 100 ° of C reaction production (XVIII);
This method is shown in reaction formula 2;
Reaction formula 2
In a more preferred embodiment, used solvent is selected from ethers, ester class, THF, toluene, methylene dichloride, 1,2-ethylene dichloride or acetone in the step (1).
In a more preferred embodiment, the original reagent of going back used in the step (2) is selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN or red aluminium.
In a more preferred embodiment, used solvent is selected from ethers, ester class, alcohols or halogenated hydrocarbon in the step (3); Said reductive agent is selected from borine; Said oxygenant is selected from ydrogen peroxide 50 or Sodium peroxoborate.
In a more preferred embodiment, oxidation described in the step (4) is Swern oxidation or Dess-Martin oxidation.
In a more preferred embodiment, used solvent is selected from ethers, alcohols, toluene or ester class in the step (6), and said reductive agent is selected from Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN, and said catalyzer is selected from nickelous chloride.
In a more preferred embodiment, used solvent is selected from ethers, ester class, THF, toluene, methylene dichloride or 1,2-ethylene dichloride in the step (8).
In a more preferred embodiment, used solvent is selected from ethers, ester class, alcohols, THF, toluene or acetone in the step (10), and said alkaline reagents is salt of wormwood or yellow soda ash.
In another preferred embodiment of the present invention, work as R
1Be carbonyl, R
2Be tertbutyloxycarbonyl, R
3When being hydrogen, this method may further comprise the steps:
(1) compound and bromobenzyl shown in the formula (VII) are at compound shown in 0 ° of C to 80 ° of C reaction production (VIII);
(2) compound shown in the formula (VIII) in the presence of reductive agent in-78 ° of C to 50 ° of C reaction productions (IX) with compound (X);
(3) formula (IX) and (X) shown in mixture, earlier after the reductive agent effect, compound shown in the production (XI) under the oxygenant effect again;
(4) compound shown in the formula (XI) is a catalyzer with palladium/carbon in organic solvent, hydrogenation production (XIX) compound under pressure 1 ~ 40atm;
(5) compound and tert-Butyl dicarbonate shown in the formula (XIX) are at compound shown in 0 ° of C to 50 ° of C reaction production (XX);
(6) compound shown in the formula (XX) is under-78 ° of C to 50 ° of C, compound shown in the oxidation production (XXI);
This method is shown in reaction formula 3.
Reaction formula 3
In a more preferred embodiment, used solvent is selected from ethers, ester class, THF, toluene, methylene dichloride, 1,2-ethylene dichloride or acetone in the step (1).
In a more preferred embodiment, the original reagent of going back used in the step (2) is selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN or red aluminium.
In a more preferred embodiment, used solvent is selected from ethers, ester class, alcohols or halogenated hydrocarbon in the step (3); Said reductive agent is selected from borine; Said oxygenant is selected from ydrogen peroxide 50 or Sodium peroxoborate.
In a more preferred embodiment, oxidation described in the step (6) is Swern oxidation or Dess-Martin oxidation.In a more preferred embodiment of the present invention, oxidation described in the said step (6) is Swern oxidation or Dess-Martin oxidation.
The present invention contains substituent verivate with 3-5-flumethiazine or its and prepares 3-trifluoromethyl piperidine derivative as starting raw material; Reaction does not generally need low temperature, and is simple to operate, can amplify easily; Suitability for industrialized production, and starting raw material cheap, be easy to get.
Embodiment
The invention provides compound shown in the preparation formula (I), or the process of its salt.At this preparation process of compound of the present invention is described.
Run through in the following description of this process being to be understood that when suitable, will be on various reactants and midbody, the mode that can understand easily with the technician in organic synthesis field increases suitable protection base, removes subsequently.The example of the conventional steps that uses this protection base and suitable protection base has for example been described in " blocking group in the organic synthesis " [7].Also be appreciated that; Control from a kind of group or substituting group converts another kind of group into or substituting group can carry out at any midbody or the end product to the synthesis path of end product through chemistry, wherein the inherent uncompatibility of possible the type of the conversion function of only being carried by the reagent of use in molecule or the conversion of leading in the process of state limits.The technician in organic synthesis field can understand this inherent uncompatibility easily, and carries out suitable conversion and synthesis step through suitable order and overcome their method.Hereinafter has provided the example of conversion, is appreciated that described conversion not only is confined to general group or the substituting group in the illustration conversion.The reference and the explanation of other suitable conversion have been provided in " comprehensive organic conversion: " [8] to functional group's preparatory work guide.The organic chemistry textbook; The reference and the explanation of other suitable reactions have for example been described in " Advanced Organic Chemistry " [9] and " organic synthesis " [10]; The purification process of midbody and end product comprises the for example positive on post or flap or reverse-phase chromatography, recrystallization, distillation and liquid-liquid or leaching, and these methods all are that those skilled in the art understand easily.
Only if it is different explanation is arranged, the same in the definition of substituting group and group and the formula (I).
Except as otherwise noted, term " room temperature " and " envrionment temperature " are illustrated in 16 ° of temperature between C to 25 ° of C.
Below in conjunction with specific embodiment, further illustrate the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Ratio and per-cent are based on weight, unless stated otherwise.
Embodiment 1: preparation N-benzyl-3-5-flumethiazine quaternary ammonium salt
The m-trifluoromethyl pyridine (495g, 3.36mol), benzyl bromine (583.6g, 3.43mol; 1.02eq) be dissolved in the 1L sherwood oil, gained solution slowly is heated to 50 ℃ under mechanical stirring, reacted 32 hours; Separate out solid, filter, solid is used the sherwood oil rinsing; Drain white solid (compound shown in the formula (VIII)) 1000g, yield: 93.8%, solid directly carries out next step reaction.
Embodiment 2: preparation N-benzyl-3-Trifluoromethyl-1,2,5,6-tetrahydropyridine and N-benzyl-3-Trifluoromethyl-1,2,3,6-tetrahydropyridine
N-benzyl-3-5-flumethiazine quaternary ammonium salt (1000g, 3.15mol), Peng Qinghuana (387g, 10.2mol; 3.0eq) be suspended in the 10L sherwood oil, with the gas displacement in the solution 3 times, again solution is refrigerated to-15 ℃～-30 ℃ with dry ice ethanol with nitrogen, add acetic acid (197ml; 1.0mol), under mechanical stirring, slowly drip anhydrous methanol (5.0L), after methyl alcohol dropwises; Reaction mixture is warming up to room temperature naturally, stirred overnight, next day standing demix; Behind methyl alcohol and sherwood oil separatory, methyl alcohol is used petroleum ether extraction (3.0LX3) mutually, merges sherwood oil; With its mixture that is concentrated into compound shown in dried formula (IX) and the formula (X) 400g altogether, not purified next step reaction, the yield: 52.6% of directly carrying out of gained compound.
Compound shown in the formula (IX):
1H NMR (300MHz, CDCl
3), δ (ppm): 7.36 ~ 7.26 (m, 5H), 6.42 ~ 6.39 (m, 1H), 3.66 (s, 2H), 3.11 ~ 3.09 (s, 2H), 2.61 ~ 2.58 (m, 2H), 2.31 ~ 2.26 (m, 2H).
MS-ESI: theoretical value (M): 241; Actual value: 242 (M+H
+).
Compound shown in the formula (X):
1H NMR (300MHz, CDCl
3), δ (ppm): 7.34 ~ 7.26 (m, 5H), 5.99 ~ 5.95 (m, 1H), 5.73 ~ 5.69 (m, 1H), 3.63 (s, 2H), 3.15 ~ 3.09 (m, 2H), 2.97 ~ 2.86 (m, 2H), 2.52 ~ 2.46 (m, 1H), 1.79 (s, 1H).
MS-ESI: theoretical value (M): 241; Actual value: 242 (M+H
+).
Embodiment 3: preparation N-benzyl-3-trifluoromethyl-4-hydroxy piperidines
To the mixture of compound shown in formula (IX) and the formula (X) (165g, 0.68mol) in, under agitation slowly add BH
3(2.0eq) solution after the solution addition, continues stirring at room after 4 hours to-THF, is warming up to 50 ℃ of stirred overnight for 1.4L, 1.0mol/L.Remove oil bath next day, naturally cool to room temperature, slowly drip the 200ml shrend and go out, add Sodium peroxoborate then (200g 1.5eq), is warming up to 50 ℃ of stirred overnight subsequently again in batches.Remove THF with the reaction solution rotary evaporation next day; Debris is with ethyl acetate extraction (500mlX3); Combined ethyl acetate, water and saturated common salt washing successively, rotary evaporation is to doing behind the anhydrous sodium sulfate drying; The gained crude product gets product (compound shown in the formula (VI)) 40.0g, productive rate: 22.5% through column chromatography purification.
Compound shown in the formula (XI):
1H NMR (300MHz, CDCl
3), δ (ppm): 7.33 ~ 7.26 (m, 5H), 4.88 (s, 1H), 4.08 (s, 1H), 3.53 (s, 2H), 2.64 ~ 2.62 (m, 1H), 2.42 ~ 2.34 (m, 2H), 1.63 ~ 1.62 (br, 2H).
MS-ESI: theoretical value (M): 259; Actual value: 260 (M+H
+).
Embodiment 4: preparation N-benzyl-3-trifluoromethyl-4-piperidone
(1.3ml, 0.013mol 1.5eq) are dissolved in the 40ml exsiccant methylene dichloride oxalyl chloride; Solution is refrigerated to below-60 ℃ with dry ice ethanol, to wherein dripping DMSO (2.1ml, 0.03mol; 3.0eq) be dissolved in the solution of 15mL methylene dichloride, after dropwising, continue low temperature and stirred 30 minutes; N-benzyl-3-trifluoromethyl-4-hydroxy piperidines (2.5g, dichloromethane solution 10mL 0.01mol) is being injected into below-60 ℃ in the above-mentioned solution, injects the continued low temperature that finishes and stirs about 60 minutes; (8.5mL, 0.058mol 5.8eq) are being injected into wherein below-60 ℃ the exsiccant triethylamine, after injection finishes; Solution rises to stirred overnight at room temperature naturally, and reaction solution is poured in the 50ml frozen water, stirs down, regulates its pH=7 with Hydrogen chloride; Behind organic phase and water separatory, water merges organic phase with dichloromethane extraction (20mLX3); After washing, behind anhydrous sodium sulfate drying, rotary evaporation is concentrated into dried; 1.48g crude product formula (compound shown in (XII)), productive rate: 60%, crude product is not purified directly to carry out next step reaction.
Compound shown in the formula (XII):
1HNMR (300MHz, CDCl
3), δ (ppm): 7.34 ~ 7.26 (m, 5H), 3.74 ~ 3.62 (m, 2H), 3.33 ~ 3.28 (m, 2H), 3.08 ~ 2.99 (br, 1H), 2.67 ~ 2.45 (m, 4H).
MS-ESI: theoretical value (M): 257; Actual value: 258 (M+H
+).
Embodiment 5: preparation N-benzyl-3-trifluoromethyl-4-piperidines ketoxime
(0.5g 0.2mmol) is dissolved in the 10ml ethanol N-benzyl-3-trifluoromethyl-4-piperidone, adds oxammonium hydrochloride (0.5g; 0.8mmol, 4.0eq), stirring at room 10 minutes; The reaction solution rotary evaporation to doing, is added to the water residue, behind its pH=7-8 of wet chemical accent; With ethyl acetate extraction (10mlX3), combined ethyl acetate, water and saturated brine washing successively; Rotary evaporation is concentrated into driedly behind anhydrous sodium sulfate drying, and gained crude product (compound shown in (XIII)) directly carries out next step reaction.
Embodiment 6: preparation N-benzyl-3-trifluoromethyl-4-amino piperidine
Embodiment 5 gained dissolving crude products behind 20mL methyl alcohol, add catalytic amount nickelous chloride and Peng Qinghuana (0.2g, 5.2mmol), gained solution stirred overnight at room temperature; Next day, direct rotary evaporation was extremely done, and the gained residue is added to the water, and uses ethyl acetate extraction; Merge organic phase, behind anhydrous sodium sulfate drying, rotary evaporation is to doing; The gained crude product is through column chromatography, preceding assorted recovery continued sodium borohydride reduction, 2 times repeatedly; The TLC demonstration still has product to generate, final product (compound shown in the formula (the XIV)) 200mg that gets, two step total recoverys: 40%.
Compound shown in the formula (XIV):
1H NMR (300MHz, CDCl3), δ (ppm): 7.34 ~ 7.26 (m, 5H), 3.53 (s, 2H), 3.33 (s, 1H), 3.18 (br, 2H), 2.56 ~ 2.42 (br, 4H), 1.72 ~ 1.71 (br, 1H), 1.58 ~ 1.54 (br, 1H).
MS-ESI: theoretical value (M): 258; Actual value: 259 (M+H
+).
Embodiment 7: preparation N-benzyl-3-trifluoromethyl-4-trifluoroacetamido piperidines
(0.57g 0.22mmol) is dissolved in the 10mL methylene dichloride N-benzyl-3-trifluoromethyl-4-amino piperidine, adds TFAA (0.56g; 0.4ml; 1.2eq), stirring at room 1 hour, directly rotary evaporation is to doing; Rotary evaporation is to doing again to add 3ml toluene in the residue, and gained crude product (compound shown in the formula (XV)) is not purified directly to carry out next step reaction.
Compound shown in the formula (XV):
1HNMR (300MHz, CDCl
3), δ (ppm): 6.6 (br, 1H), 4.35 ~ 2.64 (br, 6H), 2.06 ~ 1.68 (br, 2H), 1.67 (s, 9H).
MS-ESI: theoretical value (M): 364; Actual value: 363 (M-H
+).
Embodiment 8: preparation N-Boc-3-trifluoromethyl-4 amino piperidine
Embodiment 7 products therefroms are dissolved in the 30ml methyl alcohol, add 10%Pd/C (20mg), hydrogen exchange 3 times.After it's 24 hours is past stirring at room, in reaction solution, add salt of wormwood (0.6g, 4.4mmol), the tertiary butyl two carbonic ether (0.6g; 2.8mmol), stir under the room temperature after 3 hours, add again salt of wormwood (1.8g, 13.1mmol); Reflux is spent the night, next day stopped reaction, gained reaction solution rotary evaporation is to doing; Residue joins in the ETHYLE ACETATE, and solution is washed after filtering, behind anhydrous sodium sulfate drying; Rotary evaporation is concentrated into dried, and the thick product of gained gets 121mg product formula (compound shown in (XVIII)) through column purification, four step total recoverys: 20%.
Compound shown in the formula (XVIII):
1HNMR (300MHz, CDCl
3), δ (ppm): 3.79 ~ 3.26 (b r, 4H), 2.3 (br, 1H), 1.71 ~ 1.62 (br, 3H), 1.46 (s, 9H).
MS-ESI: theoretical value (M): 268; Actual value: 213 (M-55)
+, 245 (M-55+MeOH)
+
Embodiment 9: preparation N-Boc-3-trifluoromethyl-4 hydroxy piperidine and N-Boc-3-trifluoromethyl-4 carbonyl piperidines
(82.0g 0.316mol) is dissolved in the 1.5L ETHYLE ACETATE, adds Boc2O (100g, 0.474mol with compound shown in the formula (XI) of embodiment 3 preparation gained; 1.5eq), the hydrogenation of 10%Pd-C (8.0g) room temperature, TLC follows the tracks of; Stir 72 hours afterreactions and finish, reaction solution filters Pd/C through filtration, and the gained solution rotating is evaporated to dried; In residue, add normal hexane and make it crystallization, get white solid (compound shown in the formula (XX)) 70.0g, productive rate: 84%:
Compound shown in the formula (XX):
1H NMR (300MHz, CDCl
3), δ (ppm): 4.44 (s, 1H), 3.93 ~ 3.89 (br, 2H), 3.30 ~ 3.15 (br, 2H), 2.32 ~ 2.29 (br, 1H), 1.94 (s, 1H), 1.85 ~ 1.81 (dd, 1H), 1.70 ~ 1.64 (m, 1H), 1.48 (s, 9H).
MS-ESI: theoretical value (M): 269; Actual value: 270 (M+H
+), 292 (M+Na
+).
Embodiment 10: preparation N-Boc-3-trifluoromethyl-4-carbonyl piperidines
(0.3ml, 3.3mol 1.5eq) are dissolved in the exsiccant methylene dichloride (20ml), and the gas in the solution is with N2 displacement three times with the oxalyl chloride that heavily steams; Be refrigerated to about-65 ℃ with dry ice ethanol again, to wherein drip exsiccant DMSO (0.6g, dichloromethane solution 3.0eq) is after dropwising; Continue low temperature and stirred 10 minutes, again with raw material (compound shown in the XX) (0.6g, dichloromethane solution 2.2mmol) joins wherein, adds the continued low temperature that finishes and stirs 10 minutes; Drip below-50 ℃ dry triethylamine (2ml, 13.2mol, 6.0eq), after dropwising; Naturally rise to stirred overnight at room temperature, in solution, add 10ml water next day, standing demix, water is with dichloromethane extraction (10mlX2) behind the separatory; Merge organic phase, use dilute hydrochloric acid solution successively, water and saturated sodium-chloride water solution are washed, behind anhydrous sodium sulfate drying; Rotary evaporation gets white solid (compound shown in (XXI)) 0.5g, productive rate: 84% to doing.
Compound shown in the formula (XXI):
1H NMR (300MHz, CDCl3), δ (ppm): 4.28 ~ 3.93 (br 4H), 3.48 ~ 3.43 (br, 1H), 3.12 ~ 3.05 (br, 1H), 2.54 ~ 2.49 (br, 1H), 1.48 (s, 9H).
MS-ESI: theoretical value (M): 267; Actual value: 268 (M+H
+), 290 (M+Na
+).
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; The present invention is not restricted to the described embodiments; That describes in the foregoing description and the specification sheets just explains principle of the present invention; The present invention also has various changes and modifications under the prerequisite that does not break away from spirit and scope of the invention, and these variations and improvement all fall in the scope of requirement protection of the present invention.The scope that the present invention requires to protect is defined by appending claims and equivalent thereof.
Reference:
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Claims (14)
1. the preparation method of 3-trifluoromethyl piperidine derivative shown in the formula (I),
R wherein
1Be carbonyl, hydroxyl, amino, kharophen, trifluoroacetyl group or benzylamine; R
2Be hydrogen, C
1-C
9Alkyl, aryl, benzyl, CF
3CO, R
4CO or R
5OCO; R
4Be C
1-C
9Alkyl, aryl or benzyl; R
5Be C
1-C
9Alkyl, aryl or benzyl; R
3Be hydrogen, C
1-C
9Alkyl, aryl or benzyl, above-mentioned each group is optional not to be substituted or to be selected from the substituting groups replacement of being made up of alkyl, alkylhalide group, hydroxyalkyl, halogen, alkoxyl group or hydroxyl by one or more; It is characterized in that this method may further comprise the steps:
2. the preparation method of 1 described 3-trifluoromethyl piperidine derivative as requested is characterized in that, works as R
1Be amino, R
2Be tertbutyloxycarbonyl, R
3When being hydrogen, this method may further comprise the steps:
(1) compound and bromobenzyl shown in the formula (VII) are at compound shown in 0 ° of C to 80 ° of C reaction production (VIII);
(2) compound shown in the formula (VIII) in the presence of reductive agent in-78 ° of C to 50 ° of C reaction productions (IX) with compound (X);
(3) formula (IX) and (X) shown in mixture, earlier after the reductive agent effect, compound shown in the production (XI) under the oxygenant effect again;
(4) compound shown in the oxidation production (XII) under-78 ° of C to 50 ° of C of compound shown in the formula (XI);
(5) compound and oxammonium hydrochloride shown in the formula (XII) are at compound shown in 0 ° of C to 50 ° of C reaction production (XIII);
(6) compound shown in the formula (XIII) is in the presence of reductive agent and catalyzer, at compound shown in 0 ° of C to 50 ° of C reaction production (XIV);
(7) compound and trifluoroacetic anhydride (TFAA) shown in the formula (XIV) are at compound shown in 0 ° of C to 50 ° of C reaction production (XV);
(8) compound shown in the formula (XV) is a catalyzer with palladium/carbon in organic solvent, compound shown in the hydrogenation production (XVI) under pressure 1 ~ 40atm;
(9) compound and tert-Butyl dicarbonate shown in the formula (XVI) are at compound shown in 0 ° of C to 50 ° of C reaction production (XVII);
(10) compound shown in the formula (XVII) is in the presence of alkaline reagents, at compound shown in 0 ° of C to 100 ° of C reaction production (XVIII);
This method is shown in reaction formula 2;
Reaction formula 2.
3. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 2 is characterized in that, used solvent is selected from ethers, ester class, THF, toluene, methylene dichloride, 1,2-ethylene dichloride or acetone in the step (1).
4. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 2 is characterized in that, the original reagent of going back used in the step (2) is selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN or red aluminium.
5. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 2 is characterized in that, used solvent is selected from ethers, ester class, alcohols or halogenated hydrocarbon in the step (3); Said reductive agent is selected from borine; Said oxygenant is selected from ydrogen peroxide 50 or Sodium peroxoborate.
6. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 2 is characterized in that, oxidation described in the step (4) is Swern oxidation or Dess-Martin oxidation.
7. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 2; It is characterized in that; Used solvent is selected from ethers, alcohols, toluene or ester class in the step (6), and said reductive agent is selected from Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN, and said catalyzer is selected from nickelous chloride.
8. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 2 is characterized in that, used solvent is selected from ethers, ester class, THF, toluene, methylene dichloride or 1,2-ethylene dichloride in the step (8).
9. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 2 is characterized in that, used solvent is selected from ethers, ester class, alcohols, THF, toluene or acetone in the step (10), and said alkaline reagents is salt of wormwood or yellow soda ash.
10. the preparation method of 1 described 3-trifluoromethyl piperidine derivative as requested is characterized in that, works as R
1Be carbonyl, R
2Be tertbutyloxycarbonyl, R
3When being hydrogen, this method may further comprise the steps:
(1) compound and bromobenzyl shown in the formula (VII) are at compound shown in 0 ° of C to 80 ° of C reaction production (VIII);
(2) compound shown in the formula (VIII) in the presence of reductive agent in-78 ° of C to 50 ° of C reaction productions (IX) with compound (X);
(3) formula (IX) and (X) shown in mixture, earlier after the reductive agent effect, compound shown in the production (XI) under the oxygenant effect again;
(4) compound shown in the formula (XI) is a catalyzer with palladium/carbon in organic solvent, hydrogenation production (XIX) compound under pressure 1 ~ 40atm;
(5) compound and tert-Butyl dicarbonate shown in the formula (XIX) are at compound shown in 0 ° of C to 50 ° of C reaction production (XX);
(6) compound shown in the formula (XX) is under-78 ° of C to 50 ° of C, compound shown in the oxidation production (XXI);
This method is shown in reaction formula 3;
Reaction formula 3.
11. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 10 is characterized in that, used solvent is selected from ethers, ester class, THF, toluene, methylene dichloride, 1,2-ethylene dichloride or acetone in the step (1).
12. the preparation method of 3-trifluoromethyl piperidine derivative according to claim 10 is characterized in that, the original reagent of going back used in the step (2) is selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN or red aluminium.
13. preparation method according to claim 10 is characterized in that, used solvent is selected from ethers, ester class, alcohols or halogenated hydrocarbon in the step (3); Said reductive agent is selected from borine; Said oxygenant is selected from ydrogen peroxide 50 or Sodium peroxoborate.
14. preparation method according to claim 10 is characterized in that, oxidation described in the step (6) is Swern oxidation or Dess-Martin oxidation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2181996A1 (en) * | 2002-01-29 | 2010-05-05 | Glaxo Group Limited | Aminopiperidine derivatives |
| CN102344407A (en) * | 2010-08-03 | 2012-02-08 | 艾琪康医药科技（上海）有限公司 | 3-droperidol derivative and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2181996A1 (en) * | 2002-01-29 | 2010-05-05 | Glaxo Group Limited | Aminopiperidine derivatives |
| CN102344407A (en) * | 2010-08-03 | 2012-02-08 | 艾琪康医药科技（上海）有限公司 | 3-droperidol derivative and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| FLAVIANE FRANCISCO HILÁRIO等: "Synthesis of cis-3-methyl-4-aminopiperidine derivatives", 《SYNTHETIC COMMUNICATIONS》 * |
| HARRIE J.M.GIJSEN等: "Development of two diastereoselective routes towards trans-4-aminomethyl- piperidin-3-ol building blocks", 《TETRAHEDRON》 * |
| JIE JACK LI: "《有机人名反应及机理》", 31 October 2008, 华东理工大学出版社 * |
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