CN102093260B - Stereospecific synthesis of piperidine derivative - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to stereospecific synthesis of a piperidine derivative, in particular to a dialdehyde or dintrile compound. The compound can be applied to stereospecific synthesis of piperidine, pyrrolidine and azacycloheptane derivatives.
Description
Background technology
Piperidines is the six-ring containing five carbon atoms and a nitrogen-atoms.Structural unit when its derivative is widely used as synthesizing containing piperidines organic compound of medicine and other purposes.
The three-dimensional chemical configuration of piperidine ring atom is most important to the pharmaceutical activity of the organic compound containing piperidines.Therefore, effectively and to synthesize piperidine derivative extremely important on Stereoselective ground.
Summary of the invention
One aspect of the invention relates to dialdehyde or dinitrile compound, and these compounds can be for the preparation of the pure piperidine derivative of stereochemistry.Compound of the present invention has following general formula I:
General formula I
Wherein, R
1it is amino protecting group; R
2h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl; X is C (O) H or CN; N is 0,1 or 2.The feature of this compound is, R
1c (O) Ot-Bu, C (O) OCH
2ph, C (O) CH
3, C (O) CF
3, CH
2ph or C (O) O-Ph; Or R
2c
1-C
6alkyl (as, methyl).
To general formula above, some of them compound has
stereochemistry.Below two exemplary compounds of the present invention:
Wherein Boc represents tert-butoxycarbonyl.
Another aspect of the present invention relates to synthetic method, and this synthetic method comprises makes the dialdehyde of general formula I or dinitrile compound contact with the compound of general formula I I:
H
2NR
3
General formula I I
Wherein, R
3h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl,
Piperidine compounds with preparation general formula III:
General formula III,
Wherein, R
1, R
2, R
3with n according to above definition.In one embodiment, R
1c (O) Ot-Bu, C (O) OCH
2ph, C (O) CH
3, C (O) CF
3, CH
2ph or C (O) O-Ph; R
2h or C
1-C
6alkyl (as, CH3); R
3h or CH2Ph; N is 0,1 or 2.
Described method also comprises removes R from compound of formula III
3, the n in general formula III is 1, makes compound and the coupling of quinolinone (quinolinone) compound of generation, forms the compound of general formula below:
Wherein, R
1h, C (O) Ot-Bu, C (O) OCH
2ph, C (O) CH
3, C (O) CF
3, CH
2ph or C (O) O-Ph; R
2h or C
1-C
6alkyl; R
3h or CH
2ph; R
5h or carboxyl-protecting group; R
4h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl.The compound producing has following stereochemistry:
The reduction reaction of diester compound that can be by following general formula for the preparation of the dialdehyde compounds of general formula (III) compound obtains:
Or by diester compound is reduced to diol compound, is then oxidized this diol compound and obtains.
In the above methods, the dialdehyde compounds when general formula I is
time, the compound of the general formula III therefore obtaining is
dialdehyde compounds can be passed through
reduction obtain.
In addition, in the above in method, when the dialdehyde compounds of general formula I is
time, the compound of the general formula III therefore obtaining is
dialdehyde compounds can be passed through
reduction obtain.
The dinitrile compound using in aforesaid method can be prepared by process the diamide compound of following general formula with dewatering agent:
Wherein, R
1it is amino protecting group; R
2h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl.Diamide compound can be prepared by the diester compound shown in above and the direct amidation of ammonia, or by diester is hydrolyzed to diacid, then diacid is carried out to amidation and prepare.
In the above methods, the dinitrile compound when general formula I is
time, the compound of general formula III is
dinitrile compound can be by making
dehydration is standby, and this compound can be by right
(as,
) carry out amidation and prepare.
In addition, in the above methods, when the dinitrile compound of general formula I is
time, the compound of the general formula III therefore obtaining is
dinitrile compound can be by right
dewater synthetic, and this compound can be by right
(as,
) carry out amidation and prepare.The method can also be included in alkali, and for example the silica-based amido of hexamethyl two (disilazide) lithium (LiHDMS) is used R under existing
2l processes following compound:
R
2r in L
2be alkyl, as methyl, L is I, Br, MeSO
4; Synthesize the compound of general formula I Stereoselective.In addition, described method can comprise and makes general formula III (R wherein
3h) compound with acid (as, oxalic acid or chiral acid) reaction salify exist side by side body select ground purifying described in salt.
Term " alkyl " represents the straight or branched hydrocarbon containing 1-6 carbon atom.The example of alkyl includes but not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.Term " alkoxyl group " represents O-alkyl.The example of alkoxyl group includes but not limited to: methoxyl group, oxyethyl group and butoxy.Term " alkylidene group " represents alkyl double-basis.The example of " alkylidene group " includes but not limited to: methylene radical and ethylidene.
Term " thiazolinyl " indicates the hydrocarbon of the straight or branched of the two keys of one or more C=C.The example of thiazolinyl includes but not limited to: vinyl, 1-butylene base and crotyl.
Term " alkynyl " represents the C containing one or more C ≡ C triple bonds herein
2-10the hydrocarbon of straight or branched.The example of alkynyl includes but not limited to: ethynyl, 2-propynyl and 2-butyne base.
Term " aryl " represents the aromatic ring system of 6-carbon monocycle, 10-carbon dicyclo, 14-carbon three rings, and wherein each ring can have 1-4 substituting group.The example of aryl includes but not limited to: phenyl, naphthyl and anthryl.Term " cycloalkyl " indicates the undersaturated alkyl of saturated and part of 3-12 carbon atom.The example of cycloalkyl includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl and ring octyl group.
Term " heteroaryl " represents to have the member ring systems of aromatics 5-8 unit monocycle, 8-12 unit's dicyclo or 11-14 unit three rings of one or more heteroatomss (as O, N or S).The example of heteroaryl comprises: pyridyl, furyl, imidazolyl, indyl, indazolyl, benzimidazolyl-, pyrimidyl, thienyl, quinolyl and thiazolyl.Term " heteroaralkyl " represents the alkyl being replaced by heteroaryl.
Term " Heterocyclylalkyl " represents to have the member ring systems of the first monocycle of non-aromatic 3-8,8-12 unit's dicyclo or 11-14 unit three rings of one or more heteroatomss (as O, N or S).The example of Heterocyclylalkyl includes but not limited to: piperazinyl, pyrrolidyl, alkyl dioxin (dioxanyl), morpholinyl and tetrahydrofuran base.Heterocyclylalkyl can be carbohydrate ring, as glucosyl.
Alkyl as herein described, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl comprise replacement and unsubstituted part.Substituent example includes but not limited to: halogen, hydroxyl, amino, cyano group, nitro, sulfydryl, alkoxy carbonyl, amide group, carboxyl, alkane alkylsulfonyl, alkyl-carbonyl, urea groups, carbamyl, carboxyl, thioureido, thiocyanogen, sulfoamido, alkyl, thiazolinyl, alkynyl, alkoxyl group, aryl, heteroaryl, cyclic group (cyclyl) and heterocyclic radical (heterocyclyl), alkyl wherein, thiazolinyl, alkynyl, alkoxyl group, aryl, heteroaryl, cyclic group and heterocyclic radical can further be substituted.
Term " amino protecting group " represents a kind of functional group, can prevent that amino is interfered when being connected with amino.This protecting group can be removed by ordinary method.The example of amino protecting group includes but not limited to: alkyl, acyl group and silyl.Conventional amino protecting group is C (O) Ot-Bu, C (O) OCH
2ph, C (O) CH
3, C (O) CF
3, CH
2ph and C (O) O-Ph.Amino protecting group is the protecting group > > (Protective Groups in Oranic Synthesis) in < < organic synthesis by T.W.Greene and P.G.M.Wuts; the 2nd edition, in JohnWiley and Sons (1991), describe.
Term " dewatering agent " is illustrated in can be from this material except the chemical reagent anhydrating while contacting with another kind of chemical substance.The example of dewatering agent includes but not limited to: benzene sulfonyl chloride, cyanuryl chloride, dichloro etherophosphoric acid, phosphoryl chloride or five phosphorus oxide.
By the content of describing and claims, can understand other features of the present invention, target and advantage.
Embodiment
Dialdehyde compounds of the present invention can adopt known method preparation.For example, shown in following scheme 1, dialdehyde compounds can be prepared by commercial available Pidolidone.More specifically, can protect amino and the carboxyl of diacid 1, obtain compound 2, then with alkylating agent for example MeI, MeBr and Me
2sO
4make compound 2 alkylations, form compound 3.It should be noted that compound 2 can control by the stereochemistry of C-2 position in the alkylating stereoselectivity of C-4 position.Therefore, mainly form the 4S isomer of compound 3.Referring to Hanessian etc., Tetrahedron Lett., 1998,39,5887; With Gerwick etc., TetrahedronLett., 2003,44,285.After this stereospecific alkylation, compound 3 is reduced and obtains required dialdehyde compounds 4, has kept the stereochemistry of C-2 and C-4 position.
Scheme 1
Dialdehyde compounds as herein described can be reacted under the reduction amination condition of reductive agent needing with primary amine or ammonia, forms piperidine compounds.The reductive agent using in reduction amination is well-known in the art.Its example comprises NaBH
4, NaCNBH
3and NaBH (OAc)
3.As shown in following scheme 2, dialdehyde compounds 4 and benzylamine and NaBH
4reaction forms N-benzylpiperidine compound 5, with ammonia and NaBH
4reaction forms the free ring-type of the upper N of ring containing N compound 6.
Scheme 2
Dialdehyde compounds may be unsettled, and can be without isolated or purified for further reaction.Following scheme 3 illustrates an autoclave method that the Pidolidone 2b of protection is converted into piperidine compounds 6b, and piperidine compounds 6b reacts with oxalic acid and obtains piperidine oxalate salt compound 7b.In the method, without separation of intermediates dialdehyde compounds 4b from reaction.
Scheme 3
Below shown in be some other piperidine compounds and the enantiomorph that can be prepared by dialdehyde compounds.
Described piperidine compounds can be as the structural unit of synthetic other organic compound.
Above-described dialdehyde compounds can also be prepared by diester by redox consecutive reaction.For example, as shown in following scheme 4, diester compound 3 is at LiAlH
4exist lower reduction to form diol compound 22, make described diol compound that Swern oxidation occur and obtain dialdehyde compounds 4.
Scheme 4
Similar with dialdehyde compounds, can, by corresponding diamide is dewatered and obtains dinitrile compound, use dinitrile compound to prepare ring-type containing N compound.For example, as shown in following scheme 5, diester compound is carried out to amination reaction, obtain diamide compound 23, with dewatering agent, process this diamide compound, obtain dinitrile compound 24.Then, with an autoclave, under shortening condition, with ammonia or benzylamine, process this dinitrile compound 24, obtain compound 6.
Scheme 5
Can split in the following manner (resolution) compound 6: make compound 6 react and obtain its salt form with acid (as oxalic acid), then use appropriate solvent recrystallization or grinding.Can use chiral acid in some instances.Diastereomeric excess (de) value of the compound 6 after purifying can surpass 99.9%.
Scheme 6 illustrates an autoclave method of alternative synthetic diamide 23 below, and diamide 23 can be used for preparing piperidine compounds, as shown in scheme 5.Diester compound 3 hydrolysis are obtained to diacid compounds 26, under mild conditions, this compound is carried out to amination and obtain diamide 23.Referring to Pozdnev, V.F.TetrahedronLetters, 1995,36,7115.This method reduces to minimum by racemic possibility, because the method requires gentle condition.
Scheme 6
Diacid 26b can also, make the alkylation of γ-methyl-N-Boc-L-glutamate by 7 preparations of following scheme under LDA (lithiumdiisopropylamide) exists, then make intermediate (26b ', 26b ") hydrolysis.Alkyl product 26b diastereomeric excess (de) value of carrying out HPLC analysis mensuration by the diamide 23 to by alkyl product 26b acquisition is very high.
Scheme 7
Use at low temperatures cyanuryl chloride diamide 23 can be converted into dintrile 24 (scheme 8) as dewatering agent.This dewatering is by Aureggi, and V. etc. describe in organic synthesis (Org.Synth.) 2008,85,72.
Scheme 8
Or, as shown in following scheme 9, by diacid 26, with an autoclave, synthesize dintrile 24.
Scheme 9
Below shown in scheme 10 are the methods by the synthetic piperidines 6b of the available Pidolidone of business.
Scheme 10
Scheme 11 illustrates the method for another kind of synthetic piperidines 6b below.
Scheme 11
Aforesaid method is also used in synthesis of pyrrolidine and azepan (azepane) under mild conditions.Below shown in scheme 12 be that synthetic 5-7 unit ring-type is containing the general method of N compound.
Scheme 12
Ring-type is the useful structural unit for the synthesis of other compounds containing N compound.(3S)-3-(tert-butoxycarbonyl is amino)-tetramethyleneimine (compound 29a) can be used for synthetic Rho-kinase inhibitor.Referring to the open WO 2008105442 of PCT and WO 2008105058.(3S)-piperidines (compound 29b) can be for the synthesis of Tie-2-kinase inhibitor for-3-(tert-butoxycarbonyl is amino).Referring to J.Med.Chem., 50,2007,627-640).The enantiomorph of compound 29b (3R)-3-(tert-butoxycarbonyl is amino)-piperidines has been widely used in and has prepared DPP IV (DPP-4) inhibitor, for example Alogliptin.Referring to the open WO 2007112368 of PCT.The amino six hydrogen-2-azepine of 3-tert-butoxycarbonyl
(compound 29c) can be used for synthetic CHK1 inhibitor and DPP-4 inhibitor.Referring to the open WO2005066163 of PCT and WO2002068420.
Scheme 13 illustrates and makes piperidine compounds 6b and quinolinone 30 couplings below, forms intermediate 31, and this intermediate carries out obtaining compound 34 after deprotection and acidifying, and this compound is a kind of candidate's antibacterials (referring to United States Patent (USP) 6,329,391).
Scheme 13
Above shown in scheme 1-13 be only for explanation.Can improve to prepare and use compound of the present invention.Being used for implementing chemical transformation of the present invention can be referring to for example R.Larock, the comprehensive organic chemistry of < < transforms > > (Comprehensive Organic Transformations) ，VCH press (1989); T.W.Greene and P.G.M.Wuts, protecting group > > in < < organic synthesis (Protective Groups in Organic Synthesis), the 3rd edition, John Wiley and Sons (1999); L.Fieser and M.Fieser, < < takes formula and karl fischer's reagent > > (Fieser and Fieser ' s Reagents for Organic Synthesis), John Wileyand Sons (1994) for organic synthesis; L.Paquette compiles, the reagent pandect > > using in < < organic synthesis (Encyclopedia ofReagents for Organic Synthesis), John Wiley and Sons (1995) and version after it.
Example below, only for explanation, forms the restriction of all the other contents to disclosing never in any form.Without further detailed description, believe that those skilled in the art can utilize the present invention completely according to description herein.All publications are all in full with reference to being incorporated into herein listed herein.
embodiment 1: the preparation of (S)-2-tert-butoxycarbonyl amino-Methyl glutarate (compound 2b)
Pidolidone (200 grams) and MeOH (800 milliliters) are added in 3 liter of four neck flask, be then cooled to-10 ℃.In 10 ℃ of <, drip SO
2cl
2(324 grams), stir the mixture under room temperature 18 hours.With LC/MS monitoring reaction.Order adds ethyl acetate (800 milliliters), Na
2cO
3(200 grams), H
2o (200 grams) and tert-Butyl dicarbonate (280 grams).After stirring at room 18 hours, the mixture water of formation (400 milliliters * 2) washing, then uses dilution with toluene (400 milliliters).Separated organic layer, vacuum-evaporation, obtains compound 2b (314 grams, thick productive rate 84%).
embodiment 2: (2S, 4S)-2-tert-butoxycarbonyl amino-4-methyl-Methyl glutarate (compound 3b) synthetic
Under nitrogen ,-78 ℃, by 1M LiHMDS in the solution (1500 milliliters) of THF joins the four neck flasks of 5 liters.In <-60 ℃, in this solution, drip the solution (210 grams of solution 1000 milliliters of dry THF) containing crude compound 2b, then in-78 ℃, stir 1.5 hours.In <-60 ℃, in the solution forming, add MeI (175 grams of solution at 100 milliliters of anhydrous THF).In-78 ℃, stir this and react 4 hours, then at-60 ℃, with MeOH (35 grams) with at-10 ℃, with 2N HCl (1500 milliliters), will react quencher.In the solution forming, add toluene (1000 milliliters) and stir 0.5 hour.Separated organic layer, uses Na under stirring
2s
2o
3solution (175 grams of solution in 1000 ml waters) is processed 30 minutes, and during this period, the color of being somebody's turn to do changes into light yellow from dark-brown.Vacuum-evaporation organic layer, obtains compound 3b (212 grams, thick productive rate 96%).
1H NMR(CDCl
3，300MHz)：δ1.22(d，J＝6.9Hz，3H)，1.43(s，9H)，1.45(m，1H)，1.86(ddd，1H)，2.00(dd，2H)，2.58(dd，1H)，3.67(s，3H)，3.73(s，3H)，4.35(br s，3H)，4.97(d，J＝6.0Hz，1H)；MS：m/e 312.0(M
++23)。
embodiment 3: an autoclave is synthesized (3S, 5S)-3-(tert-butoxycarbonyl is amino)-5-methyl-N-benzyl-piperidines (compound 5b)
Under nitrogen, in the time of stirring, by crude compound 3b (50.0 grams), the solution in toluene (750 milliliters) is cooled to-78 ℃.In <-60 ℃, in this solution, drip cold DIBALH (500 milliliters, 1M toluene solution ,-78 ℃), obtain (2S, 4S)-2-tert-butoxycarbonyl amino-4-methyl-glutaraldehyde (that is, compound 4b).In-78 ℃ of stirrings, after 30 minutes, add the mixture of benzylamine (22.5 grams of solution in 25 milliliters of toluene) and MeOH (12.5 milliliters).Remove cooling bath, make solution temperature be increased to-10 ℃.Then add NaBH
4(6.5 grams) and acetic acid (10.0 grams).Stirring at room reaction mixture 18 hours, processes with 2N HCl (3000 milliliters) in-10 ℃.Dichloromethane extraction for waterbearing stratum (500 milliliters * 3).The organic layer merging is concentrated, obtain brown oil, this oily matter carries out purifying by silica gel short column, with ethyl acetate, 1/4 (v/v) methanol/ethyl acetate and 4/16/80 (v/v/v) ammonia hydroxide/methanol/eluent ethyl acetate, obtain compound 5b (15.6 grams, 30%).
1HNMR(CDCl
3，300MHz)：δ0.83(d，J＝7.0Hz，3H)，1.04(ddd，1H)，1.45(s，9H)，1.55(ddd，1H)，1.79-1.81(m，2H)，2.12(dd，1H)，2.67-2.71(m，2H)，3.43(d，1H)，3.46(d，1H)，3.85(m，1H)，5.33(d，1H)，7.22-7.42(m，5H)；MS：m/e 305.0(M
++1)。
Or, can adopt following methods to prepare compound 5b.
Under nitrogen, in the time of stirring, by crude product 3b (38.0 grams), the solution in toluene (650 milliliters) is cooled to-78 ℃.In 60 ℃ of <, in this solution, drip cold DIBALH (700 milliliters, 1M toluene solution, 78 ℃).In-78 ℃ of stirrings, after 30 minutes, add benzylamine solution (15.0 grams of solution in 45 milliliters of MeOH).Then remove cooling bath, make solution temperature be increased to-10 ℃.Then add NaCNBH
3(15.0 grams) and ethyl acetate (300 milliliters).Stirring at room reaction mixture 18 hours, processes with 2N HCl (700 milliliters) in-10 ℃.Methylene dichloride for waterbearing stratum (200 milliliters * 2) extraction.The organic layer merging is concentrated, obtain brown oil, this oily matter carries out purifying by silica gel short column, with ethyl acetate, methanol/ethyl acetate 1: 4 (v/v) and ammoniacal liquor (28-30%)/methanol/ethyl acetate 4/16/80 (v/v/v) wash-out, obtain compound 5b (10.0 grams, 25.0%).
In such a way compound 5b is converted into compound 5bHCl:
In 0-5 ℃, the suspension by compound 5b in toluene grinds to stoichiometric point with the diethyl ether solution (1M) of HCl.The solution forming produces crystallization under standing condition.Filter and collect crystallization, with uncle-BuOMe washing, after being dried, obtain the compound 5bHCl (9.8 grams, 100%) of white powder.Fusing point: 173 ℃ (toluene).
embodiment 4: (3S, 5S)-3-(tert-butoxycarbonyl amino)-5-methyl piperidine hydrochloride (compound 6bHCl) synthetic
Compound 5bHCl (3.3 grams) is dissolved in methyl alcohol (100 milliliters).In this solution, add 10%Pd-C catalyzer (0.74 gram).Under 75psi hydrogen-pressure, in Pa Er (Parr) hydrogenation flask, stir this solution 24 hours.After filtration catalizer, under decompression, remove volatile matter, obtain yellow oil, this oily matter grinds with ether.The solution forming under agitation produces precipitation.Filter collecting precipitation thing, with uncle-BuOMe washing, the dry rear compound 6bHCl (2.5 grams, 96.6% purity) that obtains white powder.Fusing point: 168 ℃ (ether).
embodiment 5: an autoclave is synthesized (3S, 5S)-3-(tert-butoxycarbonyl is amino)-5-methyl piperidine (compound 6b)
Under nitrogen, in the time of stirring, by crude compound 2b (16.0 grams), the solution in toluene (240 milliliters) is cooled to-78 ℃.With certain speed, to dripping cold DIBALH (160 milliliters, 1M toluene solution) in this solution, make solution temperature remain on <-60 ℃.In-78 ℃ of stirrings, after 1 hour, add ammonia soln (50 milliliters, 30%) and acetic acid (1.7 grams).With ice bath, substitute cooling bath, in 0-5 ℃ of stirred reaction mixture 1.5 hours.Add NaBH
4(1.1 grams, and react with LC/MS monitoring.After 1 hour, then add NaBH
4(0.5 gram).Remove ice bath, stirring at room reaction 18 hours.Under stirring, add diatomite (Celite) (45 grams).Mixture is heated to 50 ℃ with except deammoniation, in the glass funnel of sintering, utilizes suction to filter by diatomite-alumina gel.Filtrate 10%KHSO
4the aqueous solution (80 milliliters * 2) extraction.Diatomite-alumina gel continues for three times more than 10 minutes with 1/10 (v/v) methanol/ethyl acetate drip washing of 185 milliliters, then suction filtration.The filtrate 10%KHSO merging
4the aqueous solution (100 milliliters * 2) extraction.By all KHSO
4extraction liquid merges, with toluene (50 milliliters * 2) washing, with ammonia neutralization, with ethyl acetate (200 milliliters * 3) extraction.The organic layer vacuum-evaporation merging, obtains crude compound 6b (7.3 grams, 61%).Analytic sample carries out purifying by silica gel column chromatography, with 1/10/0.05 (v/v/v) methanol/ethyl acetate/ammoniacal liquor wash-out, then uses hexane recrystallization, obtains the compound 6b of light yellow granule crystal form.Fusing point: 63-64 ℃ (hexane);
1h NMR (CDCl
3, 300MHz): δ 0.80 (d, J=6.6Hz, 3H), 1.14 (ddd, 1H), 1.40 (s, 9H), 1.58 (ddd, 1H), 1.95 (dd, 1H), 2.16 (m, 1H), 2.65 (dd, 1H), 2.82 (dd, 1H), 2.90 (dd, 1H), 3.70 (m, 1H), 5.41 (m, 1H); MS:m/e 215.2 (M
++ 1).
According to being similar to above-mentioned mode, with the scale of 50 grams and 100 grams, prepare compound 6b.
The fractionation of compound 6b can realize in the following manner: be translated into salt form, then use suitable solvent systems recrystallization or grinding.Following table 1 illustrates with various acid and splits with all kinds of SOLVENTS recrystallization/grinding, obtains high diastereomeric excess (de) value.
Table 1: the purifying of the compound 6b of salt form
| Entry | Split acid (0.5 molar equivalent) | Solvent systems | Method | De value (%), thick 6b | Productive rate (free alkali) | De value (%), pure 6b |
| 1 | D-tartrate | Acetone/water 18/1 (v/v) | Recrystallization | 95 | 69 | 99.8 |
| 2 | Two-o-toluyl-d-tartrate | Acetone | Recrystallization | 95 | 78 | 98.8 |
| 3 | Oxalic acid | I-PrOH/ water 10/1 (v/v) | Recrystallization | 95 | 70 | 98.2 |
| 4 | Oxalic acid | Acetone | Heat grinds | 97.5 | 71 | 99.0 |
| 5 | Oxalic acid | Acetone/water 20/1 (v/v) | Heat grinds | 97.5 | 73 | ＞99.9 |
embodiment 6: (3S, 5S)-3-(tert-butoxycarbonyl is amino)-5-methyl piperidine oxalate salt (compound 6b0.5H
2c
2o
4) synthetic
In 40 ℃, by crude compound 6b (7.3 grams) and oxalic acid (1.5 grams), the saturated solution in methyl alcohol is suspended in uncle-BuOMe (100 milliliters).Mixture is cooled to room temperature and stirs 48 hours.During churning form precipitation.Filter collecting precipitation thing, with uncle-BuOMe washing, the dry rear compound 6b0.5H that obtains white powder
2c
2o
4(7.3 grams, the rate of recovery 83%, purity > 97.0%).
Fusing point: 203 ℃ (uncle-BuOMe).Thick oxalate obtains pure compound 6b0.5H with 1/4 (v/v) methyl alcohol/uncle-BuOMe recrystallization
2c
2o
4, the rate of recovery is 82%.
With alkaline purification compound 6b0.5H
2c
2o
4, the compound 6 of acquisition white powder, fusing point: 63-64 ℃ (hexane).Its NMR data are identical with the compound 6b preparing above.
embodiment 7:
One autoclave is synthesized (3S, 5S)-3-(tert-butoxycarbonyl is amino)-5-methyl piperidine oxalate salt (compound 6b0.5H
2c
2o
4)
Under nitrogen, in-78 ℃, LiHMDS solution (the THF solution of 520 milliliters of 1M) is joined in the four neck flasks of 1 liter.In <-60 ℃, to the solution (60.0 grams of solution in 300 milliliters of dry THF) that drips crude compound 2b in this solution.In-78 ℃ of stirred reaction mixtures 1.5 hours.Add MeI (44.4 grams of solution in 20 milliliters of dry THF).In-70 ℃ of stirrings, after 2 hours, add the unreacted MeI of diisopropylamine (30.0 grams) quencher.In-70 ℃, stir the mixture 2.5 hours.
With given pace, in this solution, drip cold DIBALH (600 milliliters, 1M toluene solution), make the temperature of solution keep <-60 ℃ (approximately 1 hour).In-70 ℃ of stirrings, after 0.5 hour, within 5 minute cycle, ammonia soln (360 milliliters, 30%) is added in this mixture.Make temperature of reaction be increased to-40 ℃, introduce ammonia (about 70-80 gram), then add NaBH
4(12.0 grams).In-10 ℃ of stirrings, after 10 hours, when being monitored by LC/MS, in 6 hours, make temperature of reaction further be increased to room temperature.The ammonia discharging is caught by frozen water.Under stirring, add the 20%NaOH aqueous solution (400 milliliters).In sintered glass funnel, adopt suction by alumina gel filtering mixt.The organic layer water of filtrate (300 milliliters * 2) washing, vacuum-evaporation, obtains crude compound 6b (16.4 grams).Alumina gel thoroughly cleans with methyl alcohol, passes through suction filtration.Filtrate vacuum-evaporation.Resistates, by diatomite filtration, washs by ethyl acetate.Filtrate vacuum concentration, obtains crude compound 6b (5.0 grams).The crude product merging carries out purifying by flash chromatography, with ethyl acetate to 1/10/0.1 (v/v/v) methyl alcohol-ethyl acetate-triethylamine wash-out, obtains pure compound 6b (10.8 grams, 23% based on crude compound 2b).
For the optical purity of deterministic compound 6b, according to the mode synthesizing optical enantiomorph (i.e. (3R, 5R)) with identical described in embodiment 1-7, except using D-Glu to substitute Pidolidone.With (S)-(+)-1-(1-naphthyl) ethyl isocyanate is derivative, obtain compound 6b and optical antipode thereof, the chirality urea of generation carries out HPLC analysis.Result shows that the optical purity of compound 6b is greater than 98%.
embodiment 8: piperidine compounds 8-21's is synthetic
According to the independent synthetic compound 8-10 of the mode with identical described in embodiment 1-3, except using the amino protecting agent that is different from tert-Butyl dicarbonate.
Compound 8,
1h NMR (CDCl
3, 300MHz): δ 0.81 (d, J=6.3Hz, 3H), 1.04 (ddd, 1H), 1.58 (ddd, 1H), 1.84-1.88 (m, 2H), 2.16 (dd, 1H), 2.68-2.78 (m, 2H), 3.43-3.48 (m, 2H), 3.90 (m, 1H), 5.05 (s, 2H), 5.75 (br s, 1H), 7.22-7.42 (m, 10H); MS:m/e339.2 (M
++ 1), compound 8HCl, white powder, fusing point: 215 ℃ (uncle-BuOMe).
According to the mode synthetic compound 11-13 with identical described in embodiment 1 and 5, except using the amino protecting agent that is different from tert-Butyl dicarbonate.
Compound 11,
1h NMR (CDCl
3, 300MHz): δ 0.83 (d, J=6.6Hz, 3H), 1.19 (ddd, 1H), 1.70 (m, 1H), 1.82 (ddd, 1H), 2.20 (m, 1H), 2.71 (dd, 1H), 2.88 (dd, 1H), 2.95 (dd, 1H), 3.83 (m, 1H), 5.10 (s, 2H), 5.62 (m, 1H), 7.25-7.40 (m, 5H); MS:m/e249.2 (M
++ 1).
Make the compound 110.5H of white powder
2c
2o
4.Fusing point: 155 ℃ (uncle-BuOMe).
According to the mode synthetic compound 14-21 with identical described in embodiment 1 and 5, except not carrying out alkylation, or carry out alkylation with different alkylating agents.
Compound 14: fusing point: 120-122 ℃ (hexane);
1h NMR (CDCl
3, 300MHz): δ 4.80-4.87 (m, 1H), 3.45-3.55 (m, 1H), 2.98,3.02 (ABq, J=3.0Hz, 1H), 2.73-2.79 (m, 1H), 2.57-2.63 (m, 1H), 2.44-2.50 (m, 1H), 1.75-1.79 (m, 1H), 1.60-1.70 (m, 1H), 1.46-1.55 (m, 1H), 1.44 (s, 9H); MS:m/e 201.2 (M
++ 1).
Compound 15:
1h NMR (CDCl
3, 300MHz): δ 0.78 (t, 3H), 1.29 (m, 2H), 1.35 (s, 9H), 1.40 (ddd, 1H), 1.73-1.76 (m, 2H), 2.08-2.15 (t, 1H), 2.65 (dd, 1H), (2.82 dd, 1H), 2.90 (dd, 1H), 3.70 (m, 1H); MS:m/e 229.2 (M
++ 1).
Compound 16:
1h NMR (CDCl
3, 300MHz): δ 1.40 (s, 9H), 1.62 (dd, 1H), 2.20-2.40 (m, 2H), 2.50 (dd, 2H), 2.82 (dd, 1H), 2.90 (dd, 1H), 3.75 (m, 1H), 7.13-7.32 (m, 5H); MS:m/e 277.2 (M
++ 1).
Compound 17:
1h NMR (CDCl
3, 300MHz): δ 1.40 (s, 9H), 1.58 (ddd, 2H), 2.20-2.40 (m, 3H), 2.50 (m, 2H), 2.65 (dd, 2H), 3.75 (m, 1H), 7.13-7.32 (m, 5H); MS:m/e 291.4 (M
++ 1).
Compound 18:
1h NMR (CDCl
3, 300MHz): δ 1.40 (s, 9H), 1.81 (s, 1H), 1.91-1.95 (m, 1H), 2.03-2.22 (t, 2H), 2.68-2.72 (d, 2H), 2.84-3.01 (dd, 2H), 3.76 (m, 1H), (4.96 dd, 1H), 4.99-5.01 (m, 1H), 5.68-5.77 (m, 1H); MS:m/e 241.2 (M
++ 1).
Compound 19:
1h NMR (CDCl
3, 300MHz): δ 1.40 (s, 9H), 1.65 (s, 3H), 1.81 (m, 2H), 1.96 (m, 2H), 2.03-2.22 (m, 1H), 2.68-2.72 (d, 2H), 2.84-3.01 (m, 2H), (3.76 m, 1H), 4.58 (s, 1H), 4.68 (s, 1H); MS:m/e 255.2 (M
++ 1).
Compound 20:
1h NMR (CDCl
3, 300MHz): δ 1.40 (s, 9H), 1.54 (s, 3H), 1.76 (s, 3H), 2.16 (m, 1H), 2.65 (dd, 1H), 2.82 (dd, 1H), 2.68-2.73 (dd, 2H), 2.84-2.88 (d, 2H), 3.00-3.04 (dd, 2H), 3.74 (m, 1H), 5.02-5.07 (m, 1H); MS:m/e 269.2 (M
++ 1).
Compound 21:
1h NMR (CDCl
3, 300MHz): δ 1.40 (s, 9H), 1.58 (ddd, 1H), 1.95 (dd, 1H), 2.16 (m, 1H), 2.68-2.73 (dd, 2H), 2.84-2.88 (d, 2H), 3.00-3.04 (dd, 2H), 3.78 (s, 1H), 6.08-6.32 (m, 1H), 6.32-6.37 (d, 1H), 7.15-7.33 (m, 5H); MS:m/e 317.2 (M
++ 1).
embodiment 9: by synthetic (3S, the 5S)-3-of consecutive reaction (tert-butoxycarbonyl is amino)-5-methyl-N-benzyl-piperidines (compound 5b) of oxidation-reduction amination
Under stirring, the solution by compound 3b (10.2 grams) in THF (50 milliliters) adds ice-cold LiAlH
4(3.8 grams) are in the suspension of THF (150 milliliters).After stirring at room 1 hour, reaction is cooled to 0 ℃ again, with 35 milliliters of 10%KOH, processes.The mixture forming evaporates after by diatomite filtration.Remaining oily matter carries out purifying by flash column chromatography, by ethyl acetate, as elutriant, obtains glycol 22b (6.9 grams, 84%).
1H NMR(CDCl
3，300MHz)：δ0.94(d，J＝7.0Hz，3H)，1.43(s，9H)，1.56-1.65(m，1H)，1.66-1.83(m，2H)，3.38-3.42(m，1H)，3.43-3.60(m，2H)，3.60-3.70(m，1H)，3.71-3.80(m，1H)，4.86(br s，1H)；MS：256.0(M
++23)。
Under stirring, in cold methylene dichloride (149 milliliters ,-70 ℃), add oxalyl chloride (9.1 grams).After 5 minutes, in-65 ℃ to-70 ℃, drip dry DMSO (11.2 grams).Then in this solution, add (2S, 4S)-2-tert-butoxycarbonyl amino-4-methyl-pentane-1, the solution of 5-glycol 22b (6.9 grams) in methylene dichloride (35.5 milliliters).In-65 ℃ to-70 ℃ stirrings, after 15 minutes, add the triethylamine (26.5 grams ,-70 ℃) of precooling, continue to stir 15 minutes.Then, when stirring with this mixture of water (113 milliliters) solution-treated of potassium hydrogen persulfate (Oxone) (6.0 grams).Separated organic layer is transferred to flask, is cooled to-50 ℃, use in order anhydrous MgSO
4tHF (20 milliliters) solution-treated of the benzylamine of (3.1 grams) and precooling (3.5 grams ,-50 ℃).After 15 minutes, add sodium triacetoxy borohydride (18.8 grams), and spend the night in-15 ℃ to 0 ℃ stirrings.The mixture salt water washing forming, by separated organic layer evaporation.Resistates carries out purifying by silica gel short column, with 1/20 to 1/10 (v/v) ethyl acetate-hexane wash-out, obtains compound 5b (4.8 grams, 53.3%).
embodiment 10: (2S, 4S)-2-tert-butoxycarbonyl amino-4-methyl-pentanedioic acid diamide (compound 23b) synthetic
Method A: the suspension of stirring at room compound 3b (33.0 grams, 114.0 mmoles) in ammoniacal liquor (28-32%, 300 milliliters).In 3-4 hour, mixture is gradually become the suspension of white solid by the suspension of granular yellow powder.After stirring at room 12 hours, filter this solid lyophilize under vacuum.Dry solid, from 10-12 part hot water recrystallization, obtains compound 23b (17.9 grams, 61%), is white needle-like crystals.Fusing point: 204-206 ℃ (H
2o);
1h NMR (
4d-MeOH, 300MHz): δ 1.16 (d, J=6.6Hz, 3H), 1.44 (s, 9H), 1.81-1.90 (m, 2H), 2.46-2.48 (m, 1H), 4.06 (dd, 1H); MS:m/e282.1 (M
++ 23).
Method B: drip the 1N NaOH aqueous solution (90 milliliters) in-10 ℃ to-5 ℃ in THF (60 milliliters) solution of compound 3b (11.6 grams, 40.1 mmoles) under stirring.In 0-5 ℃, continue to stir 1 hour, with LC/MS, detect.When reaction finishes (approximately 1 hour), with 3N HCl (35-40 milliliter) processing reaction liquid until color becomes Congo red.Ethyl acetate for the aqueous solution (160 milliliters * 2) extraction.The extraction liquid vapourisation under reduced pressure merging, obtains (2S, 4S)-2-tert-butoxycarbonyl amino-4-methyl-pentanedioic acid (compound 26b) (12.5 grams, approximately 100% thick productive rate, vacuum-drying), is viscosity oily matter.
1H NMR(CDCl
3，300MHz)：δ1.22(d，J＝7.0Hz，3H)，1.43(s，9H)，2.02-2.07(m，1H)，2.28(ddd，1H)，2.62-2.68(m，1H)，4.50(m，1H)，5.26(d，J＝6.6Hz，1H)；MS：m/e 284.0(M
++23)。
Under stirring, in THF (116 milliliters) solution of compound 26b (12.5 grams), order adds piperidines (3.9 grams, 49.3 mmoles), Boc
2o (23.5 grams, 107.7 mmoles) and bicarbonate of ammonia (8.1 grams, 102.5 mmoles).Reactant is from the transparent white powder suspension that changes into gradually.After stirring at room 12 hours, leach throw out, vacuum-drying obtains compound 23b (10.3 grams, 99%).HPLC analyzes demonstration, and the purity of compound 23b is 95.2%, and the diastereomeric excess value of compound 23b (de value) is 99.4%.
embodiment 11: the transformation efficiency by synthetic (2S, the 4S)-2-tert-butoxycarbonyl amino-4-methyl-pentanedioic acid (compound 26b) of γ-methyl (2R)-N-Boc-L-glutamate and 26b to diamide (compound 23b)
Method A: diisopropylamine (5.3 grams, 52.4 mmoles) is cooled to-70 ℃ at the solution of 40 milliliters of THF, and the temperature by sleeve pipe in <-60 ℃ adds n-Butyl Lithium (21 milliliters, the hexane solution of 2.5M).The solution of yellow transparent stirs 0.5 hour in-70 ℃, and stirs 15 minutes in 0 ℃.In-60 ℃ to-70 ℃, in 40 minutes, be added in (5.5 grams of the lithium salts of γ-methyl (2R)-N-Boc-L-glutamate dry in THF (27 milliliters), 20.6 mmoles, by by 5.4 grams of free acids of titration to pH be 8.0 preparations), under intense agitation, with 5-10 milliliter THF, thus obtained turbid mixture is diluted.At-60 ℃ to-70 ℃, in 15 minutes, be injected at the MeI (4.6 grams, 32.4 mmoles) of THF (10 milliliters).After stirring 1 hour, by injection, adding MeI (1.0 grams).Stir this reaction 1 hour in-70 ℃ to-30 ℃, keep-30 ℃, until LC/MS demonstration lactan 26b " main signal.Lower than-10 ℃ of temperature, with 6N HCl, the mixture making being acidified to pH is 1-2, stirs lower to toluene (50 milliliters) dilution.Organic phase is used Na continuously
2s
2o
3solution (1.5 grams, 20 ml water solution) and water (50 milliliters) washing.After evaporation, obtain lactan 26b " (4.4 grams, 88%).MS：m/e 266.0(M
++23)。Dicyclohexylamine (DCHA) salt (26b " DCHA): MP 162-164 ℃ (t-BuOMe).To 26b, " (4.4 grams) add the ice-cooled aqueous solution (18 milliliters) of a hydronium(ion) oxidation lithium in the ice-cooled solution of THF (25 milliliters).After 0 ℃ is stirred 3 hours, lower than-10 ℃ of temperature, it is 1-2 that the mixture making is acidified to pH with 6N HCl, and under agitation uses ethyl acetate (30 milliliters) to dilute.Organic phase water (30 milliliters) washing, after evaporation, obtain 26b (4.1 grams, take γ-methyl-N-Boc-L-glutamate as benchmark be 76%).According to mode like the method category-B with described in embodiment 10, by 26b (4.1 grams, 15.7 mmoles) prepare diamide 23b (2.6 grams, take γ-methyl-N-Boc-L-glutamate as benchmark be 49%).HPLC analyzes and shows that the de value of compound 23b is 95%.
Method B (by γ-methyl (2R)-N-Boc-L-glutamate one autoclave): by (9.2 grams of diisopropylamines, 90.9 mmoles) solution at 80 milliliters of THF is cooled to-70 ℃, by sleeve pipe, in the temperature lower than-60 ℃, add n-Butyl Lithium (36.4 milliliters, 2.5M hexane solution).This yellow transparent solution, in-70 ℃ of stirrings 0.5 hour, stirs 15 minutes in 0 ℃.In-60 ℃ to-70 ℃, in 40 minutes, be added in (11.0 grams of the lithium salts of γ-methyl (2R)-N-Boc-L-glutamate dry in THF (60 milliliters), 41.2 mmoles, by by 5.4 grams of free acids of titration to pH be 8.0 preparations), under intense agitation, with 5-10 milliliter THF, thus obtained turbid mixture is diluted.At-60 ℃ to-70 ℃, in 15 minutes, be injected at the MeI (10.2 grams, 71.9 mmoles) of THF (15 milliliters).After-70 ℃ are stirred 3.5 hours.Then add aqueous sodium hydroxide solution (1N, 42 milliliters) in-30 ℃, then in 0 ℃, stir 3 hours.In lower than-10 ℃, it is 1-2 that the mixture making is acidified to pH with 6N HCl, stirs lower to ethyl acetate (100 milliliters) dilution.Organic phase water (50 milliliters) washing, obtains diacid 26b (10.7 grams, 99%) after evaporation.According to mode like the method category-B with described in embodiment 10, by 26b (10.7 grams) prepare diamide 23b (5.2 grams, take γ-methyl-N-Boc-L-glutamate as benchmark be 49%).HPLC analyzes and shows that the de value of compound 23b is 94%.
embodiment 12: (2S, 4S)-2-tert-butoxycarbonyl amino-4-methyl-trimethylene cyanide (compound 24b) synthetic
Method A: drip benzene sulfonyl chloride (31.1 grams, 176.1 mmoles) at the solution containing in the methylene dichloride (70 milliliters) of pyridine (23.5 gram of 297.1 mmole) to ice-cooled compound 23b (12.3 gram of 47.4 mmole).After interpolation, remove ice bath, under room temperature, stirring reaction is 30 hours.Then methylene dichloride (70 milliliters) dilution for mixture, water (70 milliliters * 2) washing is by separated organic layer evaporation, and resistates filters by 5 parts of silicagel columns, with 2/3 (v/v) ethyl acetate-hexane wash-out.By the solution evaporation of collecting.Residual solid obtains compound 24b (9.7 grams, 92%) by 1/1 (v/v) t-BuOMe-hexane (118 milliliters) recrystallization of heat, is white crystal.Or thick resistates passes through from 4-5 part heat 1/1 (v/v) t-BuOMe-hexane recrystallization direct purification, isolated yield 86%.GC analyzes and shows that the purity of compound 24b is 93%, and the diastereomeric excess value of compound 24b (de value) is greater than 99%.Fusing point: 108-110 ℃ (1/1t-BuOMe-hexane);
1h NMR (CDCl
3, 300MHz): δ 1.40 (d, J=7.2Hz, 3H), 1.45 (s, 9H), 2.05-2.17 (m, 2H), 2.79-2.82 (m, 1H), 4.70 (br s, 1H), 5.00 (br d, J=8.7Hz, 1H); MS:m/e 246.0 (M
++ 23).
Method B: in 0-10 ℃, the disposable cyanuryl chloride (128.8 grams, 698.4 mmoles) that adds of solution to ice-cooled compound 23b (181.0 grams, 698.8 mmoles) in DMF (905 milliliters).In 0-10 ℃ of stirring, after 1.5 hours, remove ice bath, under envrionment temperature, continue to stir 2.5 hours.Then in 5 minutes, in the time of stirring, mixture is poured into frozen water (2.5 liters); Then stir and within 10 minutes, make white solid with the form precipitation of spicule.Filter this slurries, solid water (500 milliliters) washing, the dry rear crude compound 24b (160.0 grams, > 99%) that obtains.Crude compound is dissolved in 800 milliliters of (approximately 5 parts) hot ethyl acetates (50-60 ℃), by diatomite filtration to remove insoluble solids.Filtrate vacuum-evaporation, obtains compound 24b (125.0 grams, 80%).GC analyzes and shows, the diastereomeric excess value that the purity of 24b is 93%, 24b (de value) is greater than 99%.
Method C (autoclave by compound 26b is synthetic): sequentially add Boc under stirring in DMF (147 milliliters) solution of compound 26b (21 grams)
2o (45.0 grams, 206.2 mmoles), bicarbonate of ammonia (15.7 grams, 198.6 mmoles) and pyridine (7.6 grams, 96.1 mmoles).Reaction solution is by the transparent suspension that gradually becomes white powder.After stirring at room 4 hours, lower than 45 ℃, passing through rotary evaporation gained mixture to remove volatile matter.The solution forming is cooling in ice bath, then at the 0-10 ℃ of disposable cyanuryl chloride (14.8 grams, 80.3 mmoles) of using, processes.At ice bath temperature, stir after 2.0 hours, then add cyanuryl chloride (7.4 grams) and DMF (40 milliliters), continue at ambient temperature to stir 1.5 hours.In 5 minutes, under stirring, this mixture is poured in frozen water (560 milliliters), stir and white solid was precipitated in 10 minutes with spicule.Filter slurries, the continuous water of solid (500 milliliters) washing, the dry rear crude compound 24b (23.0 grams, > 99%) that obtains.Thick 24b is dissolved in 115 milliliters of (approximately 5 parts) hot ethyl acetates (50-60 ℃), by silica gel short column, filters to remove insoluble solids.Under filtrate vacuum, evaporate, obtain compound 24b (11.5 grams, 64% based on compound 26b).GC analyzes and shows that the purity of compound 24b is that 93%, de value is greater than 99%.
embodiment 13: by shortening, make (S)-2-tert-butoxycarbonyl amino-trimethylene cyanide (compound 24b) reduction amination synthetic compound 6b.
Method A: to compound 24b (3.6 grams, 16.1 mmoles) containing add in MeOH (120 milliliters) solution of Raney nickel (approximately 3 grams, weight in wet base) ammoniacal liquor (24 milliliters, 28-32%).Then under 80psi pressure, mixture, at the upper hydrogenation of Parr shaker (Parr Shaker), is monitored by LC/MS.When reaction finishes, mixture, by diatomite filtration, is evaporated.Remaining oily matter is filtered by silicagel column (5-10 part), and with the eluent ethyl acetate containing 0.1% triethylamine, then evaporation, obtains compound 6b (2.4 grams, 69%).
Compound 6b is with the isolated in form of salt.Solution after hydrogenation filters by clay (activation, 100 orders), and evaporation, is dissolved in resistates in 10 parts of hot i-PrOH.The lower solution forming of heating is extremely transparent by the oxalic acid treatment of 0.5-0.6 mmole equivalent, then room temperature standing over night.Order is by filtering and use t-BuOMe and THF to grind, and separation obtains the compound 6b0.5H of white powder
2c
2o
4(2.3 grams, 55%).GC analyzes and shows that the de value of this compound is 94%.
Compound 6b can be used 1/20-1/5 (v/v) ammonia water-methanol and/or ammonium salt additive according to mode similar to the above, or uses 10%Pd-C to be prepared as catalyzer.
Method B: under 80psi pressure, compound 24b (8.4 grams, 37.6 mmoles) and benzylamine (6.0 grams, 56.1 mmoles, 1.5 molar equivalents) at the solution hydrogenation on Parr shaker containing in the MeOH (240 milliliters) of 10%Pd-C (4.2 grams), by LC/MS, monitored.When reaction finishes, mixture filters by clay short column (activation, 100 orders), and evaporation obtains compound 6b (8.0 grams, 99%).Also can use the benzylamine (being 1.0-1.5 molar equivalent) that is less than 1.5 molar equivalents to prepare compound 6b with about identical productive rate.Find compound 6b's
1h-NMR is identical with authentic sample, and what at 0.8ppm, occur clear has bimodally confirmed required stereochemistry, does not have steric isomer by product.Thick 6b in-5 ℃ of crystallizations, obtains the compound 6b of colourless granular crystal with 4-5 part normal heptane.GC analyzes and shows that the de value of this compound is 94%.
Adopt the chirality urea method described in embodiment 7 to measure, the optical purity of compound 6b is greater than 98%.
Method C: under 80psi pressure, make (5.0 grams of compound 24b, 22.4 mmoles) and (2.5 grams of benzylamines, 23.3 mmoles, 1.04 molar equivalents) containing (1.5 grams of 10%Pd-C, containing 50 % by weight water, Aldrich Degussa type) the solution hydrogenation on Parr shaker and in the 7N methanol ammonia (50 milliliters, 15.6 molar equivalents) of gac (0.5 gram).Adopt LC/MS to monitor this hydrogenation reaction.When reaction finishes, mixture, by diatomite filtration, obtains compound 6b (5.1 grams, thick productive rate > 99%) after evaporation.GC analyzes and shows that the diastereomer foreign matter content of this compound is 0.85%.In order to remove diastereomer impurity, compound 6b carries out purifying as follows:
In 40 ℃, under vigorous stirring, in 5 minutes intervals, to oxalic acid (1.06 grams, approximately 0.5 molar equivalent), in the suspension of acetone (53 milliliters) and water (5.1 milliliters), add acetone (53 milliliters) solution of crude compound 6b (5.1 grams).Under backflow and vigorous stirring, heat this mixture 9 hours.Again cooling mixture is filtered and used cold washing with acetone, obtain the oxalate of compound 6b.Under stirring, in the suspension in water (20.7 milliliters) to this oxalate (4.8 grams), order adds 10%Na
2cO
3(27.0 grams, 6.0 parts) and ethyl acetate (45 milliliters).Stir after 15 minutes, the glass funnel by product by sintering filters, to remove the sodium oxalate of suspension.Collected organic layer, ethyl acetate for waterbearing stratum (45 milliliters) extraction.Organic extract liquid (approximately 90 milliliters) waters (18 milliliters) washing merging, evaporation obtains pure compound 6b (3.6 grams, 75%), is white powder.Fusing point: 63-64 ℃ (hexane).GC analyzes and shows that the purity of compound 6b is greater than 99%, does not exist diastereomer impurity in this compound.
If add small amount (5,10 or 20 milliliters) 7N methanol ammonia, with suitable productive rate and purity, obtain compound 6b.To each batch, solvent total amount remains on 50 milliliters.Adopt the method described in embodiment 7 to measure, the optical purity of compound 6b is greater than 99%.
embodiment 14: the fractionation of compound 6b.
In order to remove steric isomer, crude compound 6b is by carrying out purifying with 0.5 molar equivalent D-(-)-tartrate recrystallization in hot acetone-water (18/1 (v/v) is to 36/1 (v/v)).By GC Analysis deterrmination, the required isomer purity of the compound 6b after purifying (rate of recovery 73%) is greater than 99.5%.Also can use other chiral acids, for example (+)-dibenzoyl-D-tartrate and (+)-bis--Isosorbide-5-Nitrae-toluyl-D-tartrate, to improve the purity of isomer, have the acceptable rate of recovery simultaneously.
Adopt the chirality urea method described in embodiment 7 to measure, the chiral purity of compound 6b is greater than 99.5%.
embodiment 154: (2S)-2-tert-butoxycarbonyl amino-pentanedioic acid diamide (compound 27b) synthetic
Under stirring, in the THF (450 milliliters) of N-Boc-L-L-glutamic acid (38.7 grams, 156.5 mmoles) solution, order adds pyridine (15.1 grams, 190.9 mmoles), Boc
2o (91.2 grams, 417.9 mmoles) and bicarbonate of ammonia (31.4 grams, 397.2 mmoles).After lower 12 hours of room temperature, reaction mixture is evaporated.Uncle-BuOMe for resistates (500 milliliters) grinds, and filters collecting precipitation, and vacuum-drying obtains compound 27b (37.3 grams, 97%).Fusing point: 130-132 ℃ (MeOH);
1h NMR (
4d-MeOH, 300MHz): δ 1.45 (s, 9H), 1.85-1.90 (m, 1H), 2.04-2.07 (m, 1H), 2.31 (t, J=7.7Hz, 2H), 4.02-4.05 (m, 1H); MS:m/e 268.1 (M
++ 23).
embodiment 16: (2S)-2-tert-butoxycarbonyl amino-trimethylene cyanide (compound 28b) synthetic
In 0-10 ℃ to ice-cooled 27b (37.0 grams, 150.9 mmoles) disposable cyanuryl chloride (27.7 grams, 150.2 mmoles) that adds in the solution of DMF (185 milliliters).At same temperature, stir after 1.5 hours, remove ice bath and continue at ambient temperature and stir 1.5 hours.Then under agitation mixture was poured in 5 minutes in frozen water (555 milliliters); Stir again and within 10 minutes, obtain slurries.These slurries are filtered, solid water (200 milliliters) washing, dry.Filtrate extracts by ethyl acetate (200 milliliters).Dissolution of solid filters in extraction liquid and by silica gel short column.By filtrate evaporation, residual solid is dissolved in 110 milliliters of hot uncle-BuOMe (60 ℃), then uses hexane (200 milliliters) dilution.After room temperature 3 hours, mixture being filtered and use 50 milliliters of hexane washings, obtaining 28b (26.0 grams, 82%), is white crystals.Fusing point: 94-96 ℃ (hexane);
1h NMR (CDCl
3, 300MHz): δ 1.45 (s, 9H), 2.10-2.20 (m, 2H), 2.40-2.60 (m, 2H), 4.60-4.70 (m, 1H), 5.00-5.20 (m, 1H); MS:m/e 232.1 (M
++ 23).
Title compound 28b (25.5 grams, 81%) can also be according to being prepared by 27b (37.0 grams, 0.15 mole) with (method A) described in embodiment 12 similar mode.
embodiment 17: synthetic (2S, 4S)-2-tert-butoxycarbonyl amino-4-methyl-trimethylene cyanide (compound 24b) is also converted into compound 6b
Under nitrogen, in-78 ℃, the THF of 1M LiHMDS (110 milliliters) solution is joined in the flask of 500 milliliters.Dripping the solution containing compound 28b (10.5 grams, 50.0 mmoles, in 80 milliliters of anhydrous THF) lower than-65 ℃ in this solution, then in-78 ℃, stir 3 hours.Lower than-65 ℃, in the solution forming, adding MeI (4.7 milliliters).In-65 ℃ to-78 ℃ stirring reactions and monitor with LC/MS.After 3 hours, reaction with MeOH (2.4 milliliters), is carried out quencher at-10 ℃ with 2N HCl (167 milliliters) at-60 ℃.Add toluene (70 milliliters), stir the mixture 0.5 hour.Separated organic layer, uses Na under stirring
2s
2o
3solution (11 grams in 96 ml waters) is processed 30 minutes.Vacuum-evaporation organic layer, obtains crude product, and this product, by carrying out purifying with 1/5 (v/v) uncle-BuOMe-hexane recrystallization, obtains compound 24b (9.3 grams, 83%).GC analyzes and shows that the ratio of compound 24b and its diastereomer is 2: 1.Compound 24b shortening and oxalate grind after purifying (table 1), obtain the compound 6b (3.3 grams is 31% based on 28b) that de value 96 is %.
embodiment 18: (3S, 5S)-3-(tert-butoxycarbonyl amino)-5-methyl piperidine (compound 6b) synthetic
Title compound 6b (9.5 grams, 73%) can, according to (method C) with described in embodiment 13 similar mode, be prepared by 24b (13.6 grams, 60.9 mmoles).GC analyzes and shows that the de value of compound 6b is 94%.
embodiment 19: (2S)-2-tert-butoxycarbonyl amino-succinic acid diamide (compound 29b) synthetic
Under stirring, to N-Boc-L-aspartic acid (29.5 grams, 126.5 mmoles), in the solution of THF (348 milliliters), add pyridine (11.7 grams, 147.9 mmoles), Boc
2o (70.5 grams, 323.0 mmoles) and bicarbonate of ammonia (24.3 grams, 307.4 mmoles).Stirring at room reaction mixture 12 hours, then evaporation.Ethyl acetate for resistates (250 milliliters) dilution, stirs lower water (50 milliliters) washing.By organic layer evaporation, obtain compound 29b (20.1 grams, 69%).
Fusing point: 190-192 ℃ (MeOH);
1h NMR (
4d-MeOH, 300MHz): δ 1.44 (s, 9H), 2.64,2.59 (ABq, J=5.4Hz, 2H), 4.37-4.45 (m, 1H); MS:m/e 254.1 (M
++ 23).
embodiment 20: (2S)-2-tert-butoxycarbonyl amino-succinonitrile (compound 28a) synthetic
(9.0 grams of compound 28a, 54%) can be according to (method A) with described in embodiment 12 similar mode, by (45.0 grams of compound 27a (19.8 grams, 85.6 mmoles), pyridines, 6.65 equivalents) and benzene sulfonyl chloride (59.6 grams, 3.9 equivalents) preparation.
Fusing point: 134-136 ℃ (hexane);
1h NMR (CDCl
3, 300MHz): δ 1.46 (s, 9H), 2.95 (dd, J=6.6,3.4Hz, 2H), 4.80-4.96 (m, 1H), 5.32 (d, J=8.7Hz, 1H); MS:m/e218.0 (M
++ 23).
embodiment 21: (3S)-3-(tert-butoxycarbonyl amino)-tetramethyleneimine (compound 29a) synthetic
Compound 29a (7.0 grams, 71%) can, according to (method C) with described in embodiment 13 similar mode, be prepared by compound 28a (10.3 grams, 52.8 mmoles).
Compound 29a0.5H
2c
2o
4, fusing point: 170 ℃ of (dec.) (uncle-BuOMe);
1h NMR (
4d-MeOH, 300MHz): δ 1.44 (s, 9H), 1.90-2.10 (m, 1H), 2.20-2.30 (m, 1H), 3.17-3.37 (m, 2H), 3.38-3.45 (m, 2H), 4.20-4.24 (m, 1H); MS:m/e 187.1 (M
++ 1).
embodiment 22: (3S)-3-(tert-butoxycarbonyl amino)-piperidines (compound 29b) synthetic
Compound 29b (7.0 grams, 72%) can, according to (method C) with described in embodiment 13 similar mode, be prepared by compound 28b (10.1 grams, 48.3 mmoles).Method described in employing embodiment 7 is measured, and the optical purity of compound 29b is greater than 99%.
embodiment 23: 2-tert-butoxycarbonyl amino-hexanodioic acid diamide (compound 27c) synthetic
Compound 27c (2.4 grams, 76%) can, according to (method B) with described in embodiment 10 similar mode, be prepared by 2-tert-butoxycarbonyl amino-pentanedioic acid (3.2 grams, 12.3 mmoles).
Fusing point: 135-137 ℃ (MeOH);
1h NMR (
4d-MeOH, 300MHz): δ 1.43 (s, 9H), 1.60-1.66 (m, 2H), 1.70-1.77 (m, 2H), 2.25 (t, J=5.4Hz, 2H), 3.98-4.02 (m, 1H); MS:m/e 282.0 (M
++ 23).
embodiment 24: the preparation of 2-tert-butoxycarbonyl amino-adiponitrile (compound 28c)
Compound 28c (1.5 grams, 73%) can, according to (method B) with described in embodiment 12 similar mode, be prepared by compound 27c (2.4 grams, 9.3 mmoles).
Fusing point: 61-63 ℃ (hexane);
1h NMR (CDCl
3, 300MHz): δ 1.44 (s, 9H), 1.80-1.87 (m, 2H), 1.90-2.00 (m, 2H), 2.43 (t, J=6.6Hz, 2H), 4.50-4.60 (m, 1H), 5.00-5.20 (m, 1H); MS:m/e 246.0 (M
++ 23).
embodiment 25: the amino six hydrogen-2-azepine of 3-tert-butoxycarbonyl
(compound 29c)
Can, according to (method C) with described in embodiment 13 similar mode, by compound 28c (5.0 grams, 22.4 mmoles), be prepared the compound 29c (3.4 grams, 71%) of yellow oil.
1H NMR(CDCl
3，300MHz)：δ1.41(s，9H)，1.55-1.62(m，4H)，1.65-1.80(m，2H)，2.73，2.78(ABq，J＝4.8Hz，2H)，2.87，2.91(ABq，J＝3.6Hz，2H)，3.60-3.70(m，1H)，5.00-5.10(m，1H)；MS：m/e 215.1(M
++1)。Compound 29c oxalate: fusing point: 207 ℃ of (dec.) (uncle-BuOMe).
Other embodiments
The all features that disclose in specification sheets can be with array mode combination arbitrarily.The various features that disclose in specification sheets can feature identical by playing, of equal value or similar object replace.Therefore, unless otherwise indicated, the various features that disclose are only examples of series of equivalent or similar characteristics.
By above explanation, those skilled in the art can determine principal character of the present invention at an easy rate, can to the present invention, carry out various changes and improvement not deviating under the prerequisite of the spirit and scope of the present invention, so that it is applicable to various application and condition simultaneously.Therefore, other embodiment is also within the scope of appended claims.
Claims (25)
1. the compound of general formula I:
Wherein, R
1be amino protecting group, and described amino protecting group is C (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl; X is CN; N is 1 or 2.
2. compound as claimed in claim 1, is characterized in that, R
2c
1-C
6alkyl.
3. compound as claimed in claim 1, is characterized in that, described compound is
4. compound as claimed in claim 3, is characterized in that, R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h or C
1-C
6alkyl; N is 1 or 2.
5. compound as claimed in claim 1, is characterized in that, described compound is
6. compound as claimed in claim 5, is characterized in that, R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph, R
2c
1-C
6alkyl.
7. compound as claimed in claim 1, is characterized in that, described compound is
8. a synthetic method, the method comprises:
By the compound of general formula I and the compound of general formula I I are contacted, carry out cyclization, form the compound of general formula III:
Wherein, R
1be amino protecting group, and described amino protecting group is C (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl; X is CN; N is 1 or 2;
The compound of general formula I I:
H
2NR
3
General formula I I,
Wherein, R
3h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl, heteroaryl,
The compound of general formula III:
Wherein, R
1, R
2, R
3with n according to above definition.
9. method as claimed in claim 8, is characterized in that, wherein, and R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h or C
1-C
6alkyl; R
3h or CH
2ph; N is 1.
10. method as claimed in claim 9, is characterized in that, the method also comprises the R in the compound of removing general formula III
3, make compound and the quinolinone compounds coupling of formation, form the compound of following general formula:
Wherein, R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h or C
1-C
6alkyl; R
4h or carboxyl-protecting group; R
5h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl.
11. method as claimed in claim 8, is characterized in that, the compound of general formula I is
the compound of general formula III is
12. methods as claimed in claim 11, is characterized in that R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h or C
1-C
6alkyl; R
3h or CH
2ph; N is 1.
13. methods as claimed in claim 12, is characterized in that, the method also comprises the R in the compound of removing general formula III
3, make compound and the quinolinone compounds coupling of formation, form the compound of following general formula:
Wherein, R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h or C
1-C
6alkyl; R
3h or CH
2ph; R
4h or carboxyl-protecting group; R
5h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl.
14. method as claimed in claim 8, is characterized in that, the compound of general formula I is
the compound of general formula III is
15. methods as claimed in claim 14, is characterized in that R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2c
1-C
6alkyl; R
3h or CH
2ph; N is 1.
16. methods as claimed in claim 15, is characterized in that, the method is also removed the R in the compound of general formula III
3, make compound and the quinolinone compounds coupling of formation, form the compound of following general formula:
Wherein, R
1c (O) Ot-Bu, C (O) CH
3, C (O) CF
3or C (O) O-Ph; R
2h or C
1-C
6alkyl; R
3h or CH
2ph; R
4h or carboxyl-protecting group; R
5h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl.
17. methods as claimed in claim 16, is characterized in that R
2cH
3, R
4h, R
5cH
3.
18. methods as claimed in claim 8, is characterized in that, before the method is also included in cyclization, process the compound of general formula V with dewatering agent, obtain dinitrile compound:
Wherein, R
1it is amino protecting group; R
2h, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
8cycloalkyl, C
1-C
7heterocyclylalkyl, aryl or heteroaryl; N is 1 or 2.
19. methods as claimed in claim 18, is characterized in that, dinitrile compound is
The compound of general formula V is
with
The compound of general formula III is
20. methods as claimed in claim 19, is characterized in that, dinitrile compound is
The compound of general formula V is
with
The compound of general formula III is
21. method as claimed in claim 8, is characterized in that, the compound of general formula I is
Wherein, n is 1 or 2, R
1amino protecting group, R
2be alkyl, each X is CN.
22. methods as claimed in claim 21, is characterized in that, the method is also included under alkali existence and uses R
2l processes following compound, synthesizes the compound of general formula I Stereoselective,
Wherein n is 1 or 2, R
1be amino protecting group, each X is CN; R
2r in L
2be alkyl, L is I, Br or MeSO
4.
23. methods as claimed in claim 22, is characterized in that R
2be methyl, alkali is LiHMDS.
24. methods as claimed in claim 21, is characterized in that, the method also comprises the R making wherein
3the compound and the acid-respons that are the general formula III of H form salt, and Stereoselective ground this salt of purifying.
25. methods as claimed in claim 24, is characterized in that, described acid is oxalic acid or chiral acid.
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| CN200910258680.6A CN102093260B (en) | 2009-12-14 | 2009-12-14 | Stereospecific synthesis of piperidine derivative |
| HK11109269.2A HK1155145A1 (en) | 2009-12-14 | 2011-09-01 | Stereoselective synthesis of piperidine derivatives |
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| CN200910258680.6A CN102093260B (en) | 2009-12-14 | 2009-12-14 | Stereospecific synthesis of piperidine derivative |
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| CN102093260A (en) | 2011-06-15 |
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