CN102093260B - Stereospecific Synthesis of Piperidine Derivatives - Google Patents

Abstract

The present invention relates to the stereospecific synthesis of piperidine derivatives. More particularly, the present invention relates to dialdehyde or dinitrile compounds useful for the stereospecific synthesis of piperidine, pyrrolidine and azepane derivatives.

Description

Stereospecific Synthesis of Piperidine Derivatives

Background technique

Piperidine is a six-membered ring containing five carbon atoms and one nitrogen atom. Its derivatives are widely used as structural units in the synthesis of piperidine-containing organic compounds for pharmaceutical and other purposes.

The stereochemical configuration of piperidine ring atoms is critical to the pharmaceutical activity of piperidine-containing organic compounds. Therefore, efficient and stereospecific synthesis of piperidine derivatives is very important.

Contents of the invention

One aspect of the present invention relates to dialdehyde or dinitrile compounds which are useful in the preparation of stereochemically pure piperidine derivatives. The compounds of the present invention have the following general formula I:

Formula I

Wherein, R ¹ is an amino protecting group; R ² is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ - C _{Heterocycloalkyl} , aryl or heteroaryl; X is C(O)H or CN; n is 0, 1 or 2. The compound is characterized in that R ¹ is C(O)Ot-Bu, C(O)OCH ₂ Ph, C(O)CH ₃ , C(O)CF ₃ , CH ₂ Ph or C(O)O-Ph or R ² is C ₁ -C ₆ alkyl (eg, methyl).

的立体化学。以下是本发明的两个示例性化合物：For the general formula above, some of the compounds have

stereochemistry. The following are two exemplary compounds of the invention:

wherein Boc represents tert-butoxycarbonyl.

Another aspect of the present invention relates to a synthetic method comprising contacting a dialdehyde or dinitrile compound of general formula I with a compound of general formula II:

H ₂ NR ³

Formula II

Wherein, R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₇ heterocycloalkyl, aryl or heteroaryl,

To prepare the piperidine compound of general formula III:

Formula III,

Wherein, R ¹ , R ² , R ³ and n are as defined above. In one embodiment, ^R1 is C(O)Ot-Bu, C(O) _OCH2Ph , C(O)CH3, C( _O ) _CF3 , _CH2Ph , or C(O)O-Ph R ² is H or C ₁ -C ₆ alkyl (eg, CH3); R ³ is H or CH2Ph; n is 0, 1 or 2.

The method also includes removing R ³ from the compound of general formula III, where n is 1, and coupling the resulting compound with a quinolinone compound to form a compound of the following general formula:

Wherein, R ¹ is H, C(O)Ot-Bu, C(O)OCH ₂ Ph, C(O)CH ₃ , C(O)CF ₃ , CH ₂ Ph or C(O)O-Ph; R ² is H or C ₁ -C ₆ alkyl; R ³ is H or CH ₂ Ph; R ⁵ is H or carboxyl protecting group; R ⁴ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₇ heterocycloalkyl, aryl or heteroaryl. The resulting compound has the following stereochemistry:

优选

preferred

The dialdehyde compound that is used to prepare general formula (III) compound can obtain by the reduction reaction of the diester compound of following general formula:

Alternatively, it can be obtained by reducing a diester compound to a diol compound and then oxidizing the diol compound.

时，因此获得的通式III的化合物是二醛化合物可以通过

的还原获得。In the above method, when the dialdehyde compound of general formula I is

When, the compound of general formula III thus obtained is Dialdehyde compounds can pass through

The recovery obtained.

时，因此获得的通式III的化合物是

二醛化合物可以通过

的还原获得。In addition, in the above method, when the dialdehyde compound of general formula I is

When, the compound of general formula III thus obtained is

Dialdehyde compounds can pass through

The recovery obtained.

The dinitrile compound used in the above method can be prepared by treating the diamide compound of the general formula with a dehydrating agent:

Wherein, R ¹ is an amino protecting group; R ² is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ - C ₇ heterocycloalkyl, aryl or heteroaryl. The diamide compound can be prepared by direct amidation of the diester compound shown above with ammonia, or by hydrolysis of the diester to a diacid followed by amidation of the diacid.

In the above method, when the dinitrile compound of general formula I is

二腈化合物可以通过使

脱水制备，而该化合物又可以通过对

(如，)进行酰胺化而制备。 When, the compound of general formula III is

Dinitrile compounds can be obtained by making

Dehydration preparation, and the compound can be obtained by

(like, ) is prepared by amidation.

二腈化合物可以通过对

进行脱水合成，而该化合物又可以通过对(如，

)进行酰胺化而制备。该方法还可以包括在碱，例如六甲基二硅基胺基(disilazide)锂(LiHDMS)存在下用R²L处理以下化合物：In addition, in the above method, when the dinitrile compound of general formula I is When, the compound of general formula III thus obtained is

Dinitrile compounds can be

dehydration synthesis, and the compound can be obtained by (like,

) is prepared by amidation. The method may also include treating the following compound with ^R2L in the presence of a base, such as lithium hexamethyldisilazide (LiHDMS):

R ² in R ² L is an alkyl group, such as methyl, and L is I, Br, MeSO ₄ ; the compound of general formula I is synthesized stereoselectively. Additionally, the method may comprise reacting a compound of formula III (wherein R ³ is H) with an acid (eg, oxalic acid or a chiral acid) to form a salt and stereospecifically purifying the salt.

The term "alkyl" means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. The term "alkoxy" means O-alkyl. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, and butoxy. The term "alkylene" means an alkyl diradical. Examples of "alkylene" include, but are not limited to, methylene and ethylene.

The term "alkenyl" denotes a straight or branched chain hydrocarbon having one or more C=C double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" herein denotes a _C2-10 straight or branched chain hydrocarbon containing one or more C≡C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

The term "aryl" denotes a 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system, wherein each ring may have 1-4 substituents. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The term "cycloalkyl" denotes saturated and partially unsaturated hydrocarbon groups having 3 to 12 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term "heteroaryl" denotes an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having one or more heteroatoms (eg, O, N or S). Examples of heteroaryl groups include: pyridyl, furyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl and thiazolyl. The term "heteroaralkyl" means an alkyl group substituted with a heteroaryl group.

The term "heterocycloalkyl" denotes a non-aromatic 3-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having one or more heteroatoms (eg, O, N or S). Examples of heterocycloalkyl include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. A heterocycloalkyl group can be a carbohydrate ring, such as glucosyl.

The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups described herein include both substituted and unsubstituted moieties. Examples of substituents include, but are not limited to: halogen, hydroxy, amino, cyano, nitro, mercapto, alkoxycarbonyl, amide, carboxyl, alkanesulfonyl, alkylcarbonyl, ureido, carbamoyl, carboxyl, Thiourea group, thiocyano group, sulfonamide group, alkyl group, alkenyl group, alkynyl group, alkoxyl group, aryl group, heteroaryl group, cyclyl group (cyclyl) and heterocyclyl group (heterocyclyl group), wherein the alkyl group, Alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cyclic and heterocyclyl groups may be further substituted.

The term "amino-protecting group" means a functional group which, when attached to an amino group, prevents interference with the amino group. Such protecting groups can be removed by conventional methods. Examples of amino protecting groups include, but are not limited to, alkyl, acyl, and silyl. Commonly used amino protecting groups are C(O)Ot-Bu, C(O) _OCH2Ph , C(O) _CH3 , C(O) _CF3 , _CH2Ph and C(O)O-Ph. Amino protecting groups have been described by TW Greene and PGM Wuts in Protective Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons (1991).

The term "dehydrating agent" means a chemical agent capable of removing water from another chemical substance when in contact with that substance. Examples of dehydrating agents include, but are not limited to, benzenesulfonyl chloride, cyanuric chloride, ethyl dichlorophosphate, phosphorus oxychloride, or phosphorus pentoxide.

Other features, objects and advantages of the invention can be understood from the description and claims.

Detailed ways

The dialdehyde compound of the present invention can be prepared by a known method. For example, as shown in Scheme 1 below, dialdehyde compounds can be prepared from commercially available L-glutamic acid. More specifically, the amino and carboxyl groups of diacid 1 can be protected to obtain compound 2, which is then alkylated with alkylating agents such as MeI, _MeBr and _Me2SO4 to form compound 3. It should be noted that the stereoselectivity of the alkylation of compound 2 at the C-4 position can be controlled by the stereochemistry at the C-2 position. Thus, the 4S isomer of compound 3 was mainly formed. See Hanessian et al., Tetrahedron Lett., 1998, 39, 5887; and Gerwick et al., Tetrahedron Lett., 2003, 44, 285. After this stereospecific alkylation, compound 3 was reduced to obtain the desired dialdehyde compound 4, maintaining the stereochemistry at the C-2 and C-4 positions.

plan 1

The dialdehyde compounds described herein can be reacted with primary amines or ammonia under reductive amination conditions requiring a reducing agent to form piperidine compounds. Reducing agents used in reductive aminations are well known in the art. Examples thereof include NaBH ₄ , NaCNBH ₃ and NaBH(OAc) ₃ . As shown in Scheme 2 below, dialdehyde compound 4 reacts with benzylamine and _NaBH to form N-benzylpiperidine compound ₅ , which reacts with ammonia and NaBH to form cyclic N-containing compound 6 with free ring N.

Scenario 2

Dialdehyde compounds may be unstable and may be used in further reactions without isolation or purification. Scheme 3 below shows a one-pot procedure for the conversion of protected L-glutamic acid 2b to piperidine compound 6b, which reacts with oxalic acid to give piperidine oxalate compound 7b. In this method, there is no need to isolate the intermediate dialdehyde compound 4b from the reaction.

Option 3

Shown below are some other piperidine compounds and enantiomers that can be prepared from dialdehyde compounds.

The piperidine compound can be used as a structural unit for the synthesis of other organic compounds.

The dialdehyde compounds described above can also be prepared from diesters by a reduction-oxidation sequence. For example, as shown in Scheme 4 below, reduction of diester compound 3 in the presence of _LiAlH4 forms diol compound 22, which is subjected to Swern oxidation to obtain dialdehyde compound 4.

Option 4

Similar to dialdehyde compounds, dinitrile compounds can be obtained by dehydrating the corresponding diamides, and dinitrile compounds are used to prepare cyclic N-containing compounds. For example, as shown in Scheme 5 below, amination of a diester compound yields diamide compound 23, which is treated with a dehydrating agent to yield dinitrile compound 24. The dinitrile compound 24 is then treated with ammonia or benzylamine under catalytic hydrogenation conditions in a one-pot manner to obtain compound 6.

Option 5

Compound 6 can be resolved by reacting compound 6 with an acid such as oxalic acid to obtain its salt form, followed by recrystallization or triturating with a suitable solvent. In some instances chiral acids may be used. The diastereomeric excess (de) of purified compound 6 can exceed 99.9%.

Scheme 6 below shows an alternative one-pot method for the synthesis of diamide 23, which can be used to prepare piperidine compounds as shown in Scheme 5. Hydrolysis of diester compound 3 gave diacid compound 26, which was aminated under mild conditions to give diamide 23. See Pozdnev, V.F. Tetrahedron Letters, 1995, 36, 7115. This method minimizes the possibility of racemization since the method requires mild conditions.

Option 6

The diacid 26b can also be prepared by following Scheme 7 by alkylating γ-methyl-N-Boc-L-glutamate in the presence of lithium diisopropylamide followed by the intermediate ( 26b', 26b") hydrolysis. The diastereomeric excess (de) of the alkyl product 26b was high as determined by HPLC analysis of the diamide 23 obtained from the alkyl product 26b.

Option 7

Diamide 23 can be converted to dinitrile 24 using cyanuric chloride as a dehydrating agent at low temperature (Scheme 8). This dehydration method is described by Aureggi, V. et al. in Org. Synth. 2008, 85, 72.

Option 8

Alternatively, dinitrile 24 was synthesized from diacid 26 in one pot as shown in Scheme 9 below.

Option 9

Scheme 10 below shows a method for the synthesis of piperidine 6b from commercially available L-glutamic acid.

Scheme 10

Scheme 11 below shows an alternative synthesis of piperidine 6b.

Scheme 11

The above method can also be used to synthesize pyrrolidine and azepane under mild conditions. Scheme 12 shown below is a general procedure for the synthesis of 5-7 membered cyclic N-containing compounds.

Scheme 12

(化合物29c)可用于合成CHK1抑制剂和DPP-4抑制剂。参见PCT公开WO2005066163和WO2002068420。Cyclic N-containing compounds are useful building blocks for the synthesis of other compounds. (3S)-3-(tert-butoxycarbonylamino)-pyrrolidine (compound 29a) can be used in the synthesis of Rho-kinase inhibitors. See PCT publications WO 2008105442 and WO 2008105058. (3S)-3-(tert-butoxycarbonylamino)-piperidine (compound 29b) can be used in the synthesis of Tie-2-kinase inhibitors. See J. Med. Chem., 50, 2007, 627-640). The (3R)-3-(tert-butoxycarbonylamino)-piperidine enantiomer of compound 29b has been widely used in the preparation of dipeptidyl peptidase IV (DPP-4) inhibitors, such as Alogliptin. See PCT Publication WO 2007112368. 3-tert-butoxycarbonylaminohexahydro-2-aza

(Compound 29c) can be used to synthesize CHK1 inhibitors and DPP-4 inhibitors. See PCT publications WO2005066163 and WO2002068420.

Scheme 13 below shows the coupling of piperidine compound 6b with quinolinone 30 to form intermediate 31, which after deprotection and acidification affords compound 34, a candidate antibacterial drug (see U.S. Patent 6,329,391 ).

Scheme 13

Schemes 1-13 shown above are for illustration only. Modifications can be made to make and use the compounds of the invention. Chemical transformations useful in the practice of the present invention can be found, for example, in R. Larock, "Comprehensive Organic Transformations," VCH Press (1989); T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis." Groups in Organic Synthesis), 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, "Fieser and Fieser's Reagents for Organic Synthesis", John Wiley Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and later editions.

The following examples are for illustration only and do not in any way limit the rest of the disclosure. Without further elaboration, it is believed that one skilled in the art can, using the description herein, fully utilize the present invention. All publications cited herein are hereby incorporated by reference in their entirety.

Embodiment 1 : the preparation of (S)-2-tert-butoxycarbonylamino-glutaric acid dimethyl ester (compound 2b)

L-Glutamic acid (200 g) and MeOH (800 mL) were added to a 3-liter four-necked flask, then cooled to -10°C. SO ₂ Cl ₂ (324 g) was added dropwise at <10° C., and the mixture was stirred at room temperature for 18 hours. The reaction was monitored by LC/MS. Ethyl acetate (800 mL), Na ₂ CO ₃ (200 g), H ₂ O (200 g) and di-tert-butyl dicarbonate (280 g) were added sequentially. After stirring at room temperature for 18 hours, the resulting mixture was washed with water (400 mL×2), and then diluted with toluene (400 mL). The organic layer was separated and evaporated in vacuo to obtain compound 2b (314 g, crude yield 84%).

Example 2 : Synthesis of (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-glutaric acid dimethyl ester (compound 3b)

A solution of 1M LiHMDS in THF (1500 mL) was added to a 5 L four-necked flask at -78°C under nitrogen. To this solution was added dropwise a solution containing crude compound 2b (a solution of 210 g in 1000 ml dry THF) at <-60°C, followed by stirring at -78°C for 1.5 hours. To the resulting solution was added MeI (175 g in 100 mL dry THF) at <-60°C. The reaction was stirred at -78°C for 4 hours, then quenched with MeOH (35 g) at -60°C and 2N HCl (1500 mL) at -10°C. Toluene (1000 mL) was added to the resulting solution and stirred for 0.5 hours. The organic layer was separated and treated with _Na2S2O3 solution (175 g in 1000 mL of water) with stirring for 30 minutes, during which time the color of _the mixture changed from dark _brown to light yellow. The organic layer was evaporated in vacuo to obtain compound 3b (212 g, crude yield 96%). ¹ H 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).

Example 3 : One-pot synthesis of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methyl-N-benzyl-piperidine (compound 5b)

A solution of crude compound 3b (50.0 g) in toluene (750 mL) was cooled to -78°C while stirring under nitrogen. At <-60°C, cold DIBALH (500 mL, 1M solution in toluene, -78°C) was added dropwise to this solution to obtain (2S,4S)-2-tert-butoxycarbonylamino-4-methyl-pentane Dialdehyde (ie, compound 4b). After stirring at -78°C for 30 min, a mixture of benzylamine (22.5 g in 25 mL toluene) and MeOH (12.5 mL) was added. The cooling bath was removed and the temperature of the solution was allowed to rise to -10°C. Then _NaBH4 (6.5 g) and acetic acid (10.0 g) were added. The reaction mixture was stirred at room temperature for 18 hours and treated with 2N HCl (3000 mL) at -10°C. The aqueous layer was extracted with dichloromethane (500 mL x 3). The combined organic layers were concentrated to give a brown oil which was purified by a short column of silica gel with ethyl acetate, 1/4 (v/v) methanol/ethyl acetate and 4/16/80 (v/v /v) Ammonia/methanol/ethyl acetate was eluted to obtain compound 5b (15.6 g, 30%). ¹ HNMR (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).

Alternatively, compound 5b can be prepared by the following method.

A solution of crude 3b (38.0 g) in toluene (650 mL) was cooled to -78°C while stirring under nitrogen. To this solution was added cold DIBALH (700 mL, 1M in toluene, 78°C) dropwise at <60°C. After stirring at -78°C for 30 minutes, a solution of benzylamine (15.0 g in 45 mL MeOH) was added. The cooling bath was then removed and the temperature of the solution was allowed to rise to -10°C. Then _NaCNBH3 (15.0 g) and ethyl acetate (300 mL) were added. The reaction mixture was stirred at room temperature for 18 hours and treated with 2N HCl (700 mL) at -10°C. The aqueous layer was extracted with dichloromethane (200 mL x 2). The combined organic layers were concentrated to give a brown oil which was purified by a short column of silica gel with ethyl acetate, methanol/ethyl acetate 1:4 (v/v) and ammonia (28-30%)/methanol /Ethyl acetate 4/16/80 (v/v/v) was eluted to obtain compound 5b (10.0 g, 25.0%).

Compound 5b was converted to compound 5b.HCl in the following manner:

A suspension of compound 5b in toluene was triturated with HCl in diethyl ether (1M) at 0-5°C to the equivalence point. The resulting solution crystallized on standing conditions. The crystals were collected by filtration, washed with tert-BuOMe, and dried to obtain compound 5b·HCl (9.8 g, 100%) as a white powder. Melting point: 173°C (toluene).

Example 4: Synthesis of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine hydrochloride (compound 6b·HCl)

Compound 5b.HCl (3.3 g) was dissolved in methanol (100 mL). To this solution was added 10% Pd-C catalyst (0.74 g). The solution was stirred for 24 hours in a Parr hydrogenation flask under 75 psi hydrogen pressure. After filtering off the catalyst, the volatiles were removed under reduced pressure to give a yellow oil which was triturated with ether. The resulting solution precipitated upon stirring. The precipitate was collected by filtration, washed with tert-BuOMe, and dried to obtain compound 6b·HCl (2.5 g, 96.6% purity) as a white powder. Melting point: 168°C (ether).

Example 5 : One-pot synthesis of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine (compound 6b)

A solution of crude compound 2b (16.0 g) in toluene (240 mL) was cooled to -78°C while stirring under nitrogen. Cold DIBALH (160 mL, 1M in toluene) was added dropwise to the solution at a rate such that the temperature of the solution was kept at <-60°C. After stirring at -78°C for 1 hour, aqueous ammonia solution (50 mL, 30%) and acetic acid (1.7 g) were added. The cooling bath was replaced by an ice bath and the reaction mixture was stirred at 0-5°C for 1.5 hours. NaBH ₄ (1.1 g) was added and the reaction was monitored by LC/MS. After 1 h, additional NaBH ₄ (0.5 g) was added. The ice bath was removed and the reaction was stirred at room temperature for 18 h. Diatomaceous earth (Celite) (45 g) was added with stirring The mixture was heated to 50° C. to remove ammonia and filtered through Celite-Alumina gel with suction in a sintered glass funnel. The filtrate was extracted with 10% KHSO _aqueous solution (80 ml×2). Celite- The alumina gel was rinsed three times with 185 mL of 1/10 (v/v) methanol/ethyl acetate for more than 10 minutes, then suction filtered. The combined filtrate was extracted with 10% aqueous _KHSO4 (100 mL × 2) All _KHSO4 extracts were combined, washed with toluene (50 mL x 2), neutralized with ammonia and extracted with ethyl acetate (200 mL x 3). The combined organic layers were evaporated in vacuo to obtain crude compound 6b (7.3 g , 61%). The analytical sample was purified by silica gel column chromatography, eluted with 1/10/0.05 (v/v/v) methanol/ethyl acetate/ammonia and then recrystallized with hexane to obtain light yellow granular crystals Compound 6b. Melting point: _63-64 ° ^C (hexane); ), 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).

Compound 6b was prepared on a 50 g and 100 g scale in a manner similar to that described above.

Resolution of compound 6b can be achieved by converting it into a salt form followed by recrystallization or trituration with a suitable solvent system. Table 1 below shows that resolution with various acids and recrystallization/trituration with various solvents gave high diastereomeric excess (de) values.

Table 1: Purification of compound 6b in salt form

entry Resolution acid (0.5 molar equivalent) Solvent system method de value (%), thick 6b Yield (free base) de value (%), pure 6b 1 d-Tartrate Acetone/water 18/1(v/v) recrystallization 95 69 99.8 2 Di-o-toluoyl-d-tartaric acid 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 hot grinding 97.5 71 99.0 5 Oxalic acid Acetone/water 20/1(v/v) hot grinding 97.5 73 ＞99.9

Example 6: Synthesis of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine oxalate (compound 6b.0.5H ₂ C ₂ O ₄ )

A saturated solution of crude compound 6b (7.3 g) and oxalic acid (1.5 g) in methanol was suspended in tert-BuOMe (100 mL) at 40 °C. The mixture was cooled to room temperature and stirred for 48 hours. During stirring a precipitate formed. The precipitate was collected by filtration, washed with tert-BuOMe, and dried to obtain compound 6b·0.5H ₂ C ₂ O ₄ (7.3 g, 83% recovery, >97.0% purity) as a white powder.

Melting point: 203°C (tert-BuOMe). The crude oxalate was recrystallized from 1/4 (v/v) methanol/tert-BuOMe to obtain pure compound 6b·0.5H ₂ C ₂ O ₄ with a recovery of 82%.

Compound 6b·0.5H ₂ C ₂ O ₄ was treated with base to obtain compound 6 as a white powder, melting point: 63-64°C (hexane). Its NMR data is the same as that of the previously prepared compound 6b.

Embodiment 7 :

One-pot synthesis of (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine oxalate (compound 6b·0.5H ₂ C ₂ O ₄ )

LiHMDS solution (520 mL of 1M in THF) was added to a 1 L four-necked flask at -78°C under nitrogen. To this solution was added dropwise a solution of crude compound 2b (60.0 g in 300 mL dry THF) at <-60°C. The reaction mixture was stirred at -78°C for 1.5 hours. MeI (a solution of 44.4 g in 20 mL dry THF) was added. After stirring at -70°C for 2 hours, diisopropylamine (30.0 g) was added to quench unreacted MeI. The mixture was stirred at -70°C for 2.5 hours.

To this solution was added cold DIBALH (600 mL, 1M in toluene) dropwise at a rate such that the temperature of the solution was maintained at <-60°C (about 1 hour). After stirring at -70°C for 0.5 hours, aqueous ammonia solution (360 mL, 30%) was added to the mixture over a period of 5 minutes. The reaction temperature was raised to -40°C, ammonia gas (ca. 70-80 g) was introduced, followed by _NaBH4 (12.0 g). After stirring at -10°C for 10 hours, the reaction temperature was further raised to room temperature over 6 hours while monitoring by LC/MS. The released ammonia is captured by ice water. Aqueous 20% NaOH (400 mL) was added with stirring. The mixture was filtered through an alumina gel using suction in a sintered glass funnel. The organic layer of the filtrate was washed with water (300 mL x 2) and evaporated in vacuo to obtain crude compound 6b (16.4 g). The alumina gel was washed thoroughly with methanol and filtered by suction. The filtrate was evaporated in vacuo. The residue was filtered through celite, washing with ethyl acetate. The filtrate was concentrated in vacuo to obtain crude compound 6b (5.0 g). The combined crude products were purified by flash chromatography eluting with ethyl acetate to 1/10/0.1 (v/v/v) methanol-ethyl acetate-triethylamine to obtain pure compound 6b (10.8 g, 23% Based on crude compound 2b).

To determine the optical purity of compound 6b, the optical antipodes (ie (3R,5R)) were synthesized in the same manner as described in Examples 1-7, except that D-glutamic acid was used instead of L-glutamic acid. Compound 6b and its optical enantiomers were obtained by derivatization with (S)-(+)-1-(1-naphthyl)ethyl isocyanate, and the resulting chiral urea was analyzed by HPLC. The results showed that the optical purity of compound 6b was greater than 98%.

Embodiment 8 : the synthesis of piperidine compound 8-21

Compounds 8-10 were individually synthesized in the same manner as described in Examples 1-3, except that an amino-protecting agent other than di-tert-butyl dicarbonate was used.

Compound 8, ¹ H NMR (CDCl ₃ , 300MHz): δ0.81 (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/e 339.2 (M ⁺ +1), compound 8·HCl, white powder, melting point: 215°C (tert-BuOMe).

Compounds 11-13 were synthesized in the same manner as described in Examples 1 and 5, except that an amino protecting agent other than di-tert-butyl dicarbonate was used.

Compound 11, ¹ H NMR (CDCl ₃ , 300MHz): δ0.83 (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/e 249.2 (M ⁺ +1).

Compound 11·0.5H ₂ C ₂ O ₄ was obtained as white powder. Melting point: 155°C (tert-BuOMe).

Compounds 14-21 were synthesized in the same manner as described in Examples 1 and 5, except that no alkylation was carried out, or the alkylation was carried out with a different alkylating agent.

Compound 14: Melting point: 120-122°C (hexane); ¹ H NMR (CDCl ₃ , 300MHz): δ4.80-4.87 (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: ¹ H NMR (CDCl ₃ , 300MHz): δ0.78(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: ¹ H NMR (CDCl ₃ , 300MHz): δ1.40(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: ¹ H NMR (CDCl ₃ , 300MHz): δ1.40(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: ¹ H NMR (CDCl ₃ , 300MHz): δ1.40(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: ¹ H NMR (CDCl ₃ , 300MHz): δ1.40(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: ¹ H NMR (CDCl ₃ , 300MHz): δ1.40(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: ¹ H NMR (CDCl ₃ , 300MHz): δ1.40(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).

Example 9: Synthesis of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methyl-N-benzyl-piperidine (compound 5b) by sequential reaction of oxidation-reduction amination

A solution of compound 3b (10.2 g) in THF (50 mL) was added to an ice-cold suspension of _LiAlH4 (3.8 g) in THF (150 mL) with stirring. After stirring at room temperature for 1 hour, the reaction was cooled to 0°C again and treated with 35 mL of 10% KOH. The resulting mixture was filtered through celite and evaporated. The residual oil was purified by flash column chromatography using ethyl acetate as eluent to afford diol 22b (6.9 g, 84%). ¹ H 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 ⁺⁺ twenty three).

To cold dichloromethane (149 mL, -70°C) was added oxalyl chloride (9.1 g) with stirring. After 5 minutes, dry DMSO (11.2 g) was added dropwise at -65°C to -70°C. To this solution was then added (2S,4S)-2-tert-butoxycarbonylamino-4-methyl-pentane-1,5-diol 22b (6.9 g) in dichloromethane (35.5 mL) solution. After stirring at -65°C to -70°C for 15 minutes, pre-cooled triethylamine (26.5 g, -70°C) was added, and stirring was continued for 15 minutes. The mixture was then treated with a solution of potassium persulfate (Oxone) (6.0 g) in water (113 mL) while stirring. The separated organic layer was transferred to a flask, cooled to -50°C, and treated sequentially with anhydrous _MgSO4 (3.1 g) and pre-cooled benzylamine (3.5 g, -50°C) in THF (20 mL). After 15 minutes, sodium triacetoxyborohydride (18.8 g) was added and stirred overnight at -15°C to 0°C. The resulting mixture was washed with brine, and the separated organic layer was evaporated. The residue was purified by a short silica gel column eluting with 1/20 to 1/10 (v/v) ethyl acetate-hexane to obtain compound 5b (4.8 g, 53.3%).

Embodiment 10 : the synthesis of (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-glutaric acid diamide (compound 23b)

Method A: A suspension of compound 3b (33.0 g, 114.0 mmol) in aqueous ammonia (28-32%, 300 mL) was stirred at room temperature. The mixture gradually changed from a suspension of granular yellow powder to a suspension of white solid within 3-4 hours. After stirring at room temperature for 12 hours, the solid was filtered and lyophilized under vacuum. The dried solid was recrystallized from 10-12 parts of hot water to obtain compound 23b (17.9 g, 61%) as white needles. Melting point: 204-206°C (H ₂ O); ¹ H NMR ( ⁴ d-MeOH, 300MHz): δ1.16(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/e 282.1 (M ⁺ +23).

Method B: To a solution of compound 3b (11.6 g, 40.1 mmol) in THF (60 mL) was added 1 N aqueous NaOH (90 mL) dropwise at -10°C to -5°C with stirring. Stirring was continued at 0-5°C for 1 hour with LC/MS monitoring. At the end of the reaction (about 1 hour), the reaction was treated with 3N HCl (35-40 mL) until the color changed to Congo red. The aqueous solution was extracted with ethyl acetate (160 mL×2). The combined extracts were evaporated under reduced pressure to obtain (2S,4S)-2-tert-butoxycarbonylamino-4-methyl-glutaric acid (compound 26b) (12.5 g, about 100% crude yield, vacuum dry), as a viscous oil. ¹ H 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, piperidine (3.9 g, 49.3 mmol), Boc ₂ O (23.5 g, 107.7 mmol) and ammonium bicarbonate (8.1 g, 102.5 Millimoles). The reactant gradually changed from transparent to a white powder suspension. After stirring at room temperature for 12 hours, the precipitate was filtered off and dried in vacuo to obtain compound 23b (10.3 g, 99%). HPLC analysis showed that the purity of compound 23b was 95.2%, and the diastereomeric excess value (de value) of compound 23b was 99.4%.

Embodiment 11: Synthesis of (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-glutaric acid (compound 26b) by γ-methyl (2R)-N-Boc-L-glutamate ) and the conversion of 26b to the diamide (compound 23b)

Method A: Cool a solution of diisopropylamine (5.3 g, 52.4 mmol) in 40 ml of THF to -70°C, add n-butyllithium (21 ml, 2.5M hexane solution). The yellow clear solution was stirred at -70°C for 0.5 hours and at 0°C for 15 minutes. At -60°C to -70°C, lithium salt of γ-methyl(2R)-N-Boc-L-glutamate (5.5 g, 20.6 ml mole, prepared by titrating 5.4 g of the free acid to a pH of 8.0), the cloudy mixture thus obtained was diluted with 5-10 mL of THF under vigorous stirring. MeI (4.6 g, 32.4 mmol) in THF (10 mL) was injected at -60°C to -70°C over 15 minutes. After stirring for 1 hour, MeI (1.0 g) was added by injection. The reaction was stirred at -70°C to -30°C for 1 hour and held at -30°C until LC/MS showed a major signal for the lactam 26b". At temperatures below -10°C, the resulting mixture was acidified with 6N HCl to pH 1-2, diluted with toluene (50 mL) with stirring. The organic phase was washed successively with _Na2S2O3 solution (1.5 g, 20 mL in water) and _water (50 mL ₎ . Lactam 26b" was obtained after evaporation (4.4 g, 88%). MS: m/e 266.0 (M ⁺ +23). Dicyclohexylamine (DCHA) salt (26b″·DCHA): MP 162-164°C (t-BuOMe). To an ice-cooled solution of 26b″ (4.4 g) in THF (25 mL) was added hydroxide monohydrate An ice-cooled aqueous solution of lithium (18 mL). After stirring at 0°C for 3 hours, the resulting mixture was acidified with 6N HCl to pH 1-2 at a temperature below -10°C and diluted with ethyl acetate (30 mL) with stirring. The organic phase was washed with water (30 mL) and evaporated to give 26b (4.1 g, 76% based on γ-methyl-N-Boc-L-glutamate). Diamide 23b (2.6 g, based on γ-methyl-N-Boc-L-glutamate) was prepared from 26b (4.1 g, 15.7 mmol) in a manner similar to Method B described in Example 10 was 49%). HPLC analysis showed that the de value of compound 23b was 95%.

Method B (one pot from γ-methyl(2R)-N-Boc-L-glutamate): A solution of diisopropylamine (9.2 g, 90.9 mmol) in 80 mL THF was cooled to - At 70°C, n-BuLi (36.4 mL, 2.5M in hexane) was added via cannula below -60°C. The yellow transparent solution was stirred at -70°C for 0.5 hours and at 0°C for 15 minutes. Lithium salt of γ-methyl(2R)-N-Boc-L-glutamate (11.0 g, 41.2 mg) dried in THF (60 mL) was added over 40 minutes at -60°C to -70°C. mole, prepared by titrating 5.4 g of the free acid to a pH of 8.0), the cloudy mixture thus obtained was diluted with 5-10 mL of THF under vigorous stirring. MeI (10.2 g, 71.9 mmol) in THF (15 mL) was injected at -60°C to -70°C over 15 minutes. After stirring at -70°C for 3.5 hours. Then aqueous sodium hydroxide solution (1N, 42 ml) was added at -30°C, followed by stirring at 0°C for 3 hours. The resulting mixture was acidified with 6N HCl to pH 1-2 at below -10°C and diluted with ethyl acetate (100 mL) with stirring. The organic phase was washed with water (50 mL) and evaporated to give diacid 26b (10.7 g, 99%). Diamide 23b (5.2 g, 49% based on γ-methyl-N-Boc-L-glutamate) was prepared from 26b (10.7 g) in a manner similar to Method B described in Example 10 . HPLC analysis showed that the de value of compound 23b was 94%.

Example 12 : Synthesis of (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-glutaronitrile (compound 24b)

Method A: To an ice-cooled solution of compound 23b (12.3 g, 47.4 mmol) in dichloromethane (70 mL) containing pyridine (23.5 g, 297.1 mmol) was added benzenesulfonyl chloride (31.1 g, 176.1 mmol) dropwise . After the addition, the ice bath was removed and the reaction was stirred at room temperature for 30 hours. The mixture was then diluted with dichloromethane (70 mL), washed with water (70 mL×2), the separated organic layer was evaporated, and the residue was filtered through 5 silica gel cartridges, washed with 2/3 (v/v) ethyl acetate-hexane alkane elution. The collected solution was evaporated. The residual solid was recrystallized from hot 1/1 (v/v) t-BuOMe-hexane (118 mL) to obtain compound 24b (9.7 g, 92%) as white crystals. Alternatively, the crude residue was purified directly by recrystallization from 4-5 parts of hot 1/1 (v/v) t-BuOMe-hexane in 86% isolated yield. GC analysis showed that the purity of compound 24b was 93%, and the diastereomeric excess value (de value) of compound 24b was greater than 99%. Melting point: 108-110°C (1/1t-BuOMe-hexane); ¹ H NMR (CDCl ₃ , 300MHz): δ1.40 (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: To an ice-cooled solution of compound 23b (181.0 g, 698.8 mmol) in DMF (905 mL) was added cyanuric chloride (128.8 g, 698.4 mmol) in one portion at 0-10°C. After stirring at 0-10°C for 1.5 hours, the ice bath was removed and stirring was continued at ambient temperature for 2.5 hours. The mixture was then poured into ice water (2.5 L) with stirring over 5 minutes; then stirred for 10 minutes to precipitate a white solid in the form of needles. The slurry was filtered, the solid was washed with water (500 mL), and dried to obtain crude compound 24b (160.0 g, >99%). The crude compound was dissolved in 800 mL (ca. 5 parts) of hot ethyl acetate (50-60 °C) and filtered through celite to remove insoluble solids. The filtrate was evaporated in vacuo to obtain compound 24b (125.0 g, 80%). GC analysis showed that the purity of 24b was 93%, and the diastereomeric excess value (de value) of 24b was greater than 99%.

Method C (one-pot synthesis from compound 26b): To a solution of compound 26b (21 g) in DMF (147 mL) were added sequentially Boc ₂ O (45.0 g, 206.2 mmol), ammonium bicarbonate (15.7 g , 198.6 mmol) and pyridine (7.6 g, 96.1 mmol). The reaction solution gradually changed from transparent to a suspension of white powder. After stirring at room temperature for 4 hours, the resulting mixture was removed by rotary evaporation below 45 °C to remove volatiles. The resulting solution was cooled in an ice bath and then treated with cyanuric chloride (14.8 g, 80.3 mmol) in one portion at 0-10 °C. After stirring at ice bath temperature for 2.0 hours, additional cyanuric chloride (7.4 g) and DMF (40 mL) were added and stirring was continued at ambient temperature for 1.5 hours. The mixture was poured into ice water (560 mL) with stirring over 5 minutes and stirred for 10 minutes to precipitate a white solid as needles. The slurry was filtered and the solid was washed successively with water (500 mL) to obtain crude compound 24b (23.0 g, >99%) after drying. Crude 24b was dissolved in 115 mL (ca. 5 parts) of hot ethyl acetate (50-60 °C) and filtered through a short plug of silica gel to remove insoluble solids. The filtrate was evaporated under vacuum to afford compound 24b (11.5 g, 64% based on compound 26b). GC analysis showed that the purity of compound 24b was 93%, and the de value was greater than 99%.

Example 13 : Compound 6b was synthesized by reductive amination of (S)-2-tert-butoxycarbonylamino-glutaronitrile (compound 24b) by catalytic hydrogenation.

Method A: To a solution of compound 24b (3.6 g, 16.1 mmol) in MeOH (120 mL) containing Raney nickel (ca. 3 g, wet weight) was added aqueous ammonia (24 mL, 28-32%). The mixture was then hydrogenated on a Parr Shaker at 80 psi, monitored by LC/MS. At the end of the reaction, the mixture was filtered through celite and evaporated. The residual oil was filtered through a silica gel column (5-10 parts), eluting with 0.1% triethylamine in ethyl acetate, then evaporated to give compound 6b (2.4 g, 69%).

Compound 6b was isolated as a salt. The hydrogenated solution was filtered through clay (activated, 100 mesh), evaporated and the residue dissolved in 10 parts hot i-PrOH. The solution formed under heating was treated with 0.5-0.6 millimolar equivalent of oxalic acid until transparent, and then allowed to stand overnight at room temperature. Compound 6b·0.5H ₂ C ₂ O ₄ (2.3 g, 55%) was isolated as a white powder by filtration and trituration with t-BuOMe and THF sequentially. GC analysis showed the compound to have a de value of 94%.

Compound 6b can be prepared in a similar manner as above, using 1/20-1/5 (v/v) ammonia-methanol and/or ammonium salt additives, or using 10% Pd-C as a catalyst.

Method B: Compound 24b (8.4 g, 37.6 mmol) and benzylamine (6.0 g, 56.1 mmol, 1.5 molar equiv) were dissolved in 10% Pd-C (4.2 g) in MeOH (240 mL) under 80 psi pressure The solution in was hydrogenated on a Parr shaker and monitored by LC/MS. At the end of the reaction, the mixture was filtered through a clay plug (activated, 100 mesh) and evaporated to obtain compound 6b (8.0 g, 99%). Compound 6b can also be prepared in about the same yield using less than 1.5 molar equivalents of benzylamine (ie, 1.0-1.5 molar equivalents). The ¹ H-NMR of compound 6b was found to be identical to that of the authentic sample, with a clear doublet at 0.8 ppm confirming the desired stereochemistry and the absence of stereoisomer by-products. Crude 6b was crystallized from 4-5 parts of n-heptane at -5°C to obtain compound 6b as colorless granular crystals. GC analysis showed the compound to have a de value of 94%.

The optical purity of compound 6b was greater than 98%, as determined by the chiral urea method described in Example 7.

Method C: Compound 24b (5.0 g, 22.4 mmol) and benzylamine (2.5 g, 23.3 mmol, 1.04 molar equivalents) were prepared in a solution containing 10% Pd-C (1.5 g, containing 50 wt. , Aldrich Degussa type) and activated carbon (0.5 g) in 7N methanolic ammonia (50 mL, 15.6 molar equivalents) were hydrogenated on a Parr shaker. The hydrogenation reaction was monitored using LC/MS. At the end of the reaction, the mixture was filtered through celite and compound 6b was obtained after evaporation (5.1 g, >99% crude yield). GC analysis showed the compound to have a diastereomeric impurity content of 0.85%. To remove diastereomeric impurities, compound 6b was purified as follows:

To a suspension of oxalic acid (1.06 g, ca. (53 mL) solution. The mixture was heated at reflux with vigorous stirring for 9 hours. The recooled mixture was filtered and washed with cold acetone to obtain the oxalate salt of compound 6b. To a suspension of this oxalate _salt (4.8 g) in water (20.7 mL) was added sequentially 10% _Na2CO3 (27.0 g, 6.0 parts) and ethyl acetate (45 mL) with stirring. After stirring for 15 minutes, the product was filtered through a sintered glass funnel to remove suspended sodium oxalate. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (45 mL). The combined organic extracts (about 90 mL) were washed with water (18 mL) and evaporated to give pure compound 6b (3.6 g, 75%) as a white powder. Melting point: 63-64°C (hexane). GC analysis showed the purity of compound 6b to be greater than 99%, with no diastereomeric impurities present in the compound.

If a smaller amount (ie 5, 10 or 20 mL) of 7N methanolic ammonia was added, compound 6b was obtained in comparable yield and purity. The total amount of solvent was kept at 50 ml for each batch. Using the method described in Example 7, the optical purity of compound 6b was greater than 99%.

Example 14 : Resolution of compound 6b.

To remove stereoisomers, crude compound 6b was carried out by recrystallization with 0.5 molar equivalents of D-(-)-tartaric acid in hot acetone-water (18/1 (v/v) to 36/1 (v/v)) purification. Purified compound 6b (73% recovery) was greater than 99.5% pure to the desired isomer as determined by GC analysis. Other chiral acids such as (+)-dibenzoyl-D-tartaric acid and (+)-di-1,4-toluoyl-D-tartaric acid can also be used to increase the purity of the isomers while having acceptable recovery rate.

As determined by the chiral urea method described in Example 7, the chiral purity of compound 6b is greater than 99.5%.

Example 154 : Synthesis of (2S)-2-tert-butoxycarbonylamino-glutaric acid diamide (Compound 27b)

Under stirring, pyridine (15.1 g, 190.9 mmol), Boc ₂ O (91.2 g, 417.9 mol) and ammonium bicarbonate (31.4 g, 397.2 mmol). After 12 hours at room temperature, the reaction mixture was evaporated. The residue was triturated with tert-BuOMe (500 mL), and the precipitate was collected by filtration and dried in vacuo to obtain compound 27b (37.3 g, 97%). Melting point: 130-132°C (MeOH); ¹ H NMR ( ⁴ d-MeOH, 300MHz): δ1.45 (s, 9H), 1.85-1.90 (m, 1H), 2.04-2.07 (m, 1H), 2.31 (t, J = 7.7 Hz, 2H), 4.02-4.05 (m, 1H); MS: m/e 268.1 (M ⁺⁺ 23).

Embodiment 16 : the synthesis of (2S)-2-tert-butoxycarbonyl amino-glutaronitrile (compound 28b)

To an ice-cooled solution of 27b (37.0 g, 150.9 mmol) in DMF (185 mL) was added cyanuric chloride (27.7 g, 150.2 mmol) in one portion at 0-10 °C. After stirring at the same temperature for 1.5 hours, the ice bath was removed and stirring was continued at ambient temperature for 1.5 hours. The mixture was then poured into ice water (555 mL) with stirring over 5 minutes; stirring for a further 10 minutes gave a slurry. The slurry was filtered and the solid was washed with water (200 mL) and dried. The filtrate was extracted with ethyl acetate (200 mL). The solid was dissolved in the extract and filtered through a short plug of silica gel. The filtrate was evaporated and the residual solid was dissolved in 110 mL of hot tert-BuOMe (60°C) and diluted with hexane (200 mL). After 3 hours at room temperature, the mixture was filtered and washed with 50 mL of hexane to afford 28b (26.0 g, 82%) as white crystals. Melting point: 94-96°C (hexane); ¹ H NMR (CDCl ₃ , 300MHz): δ1.45 (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).

The title compound 28b (25.5 g, 81%) was also prepared from 27b (37.0 g, 0.15 mol) in a similar manner as described in Example 12 (Method A).

Example 17 : Synthesis of (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-glutaronitrile (compound 24b) and conversion to compound 6b

A solution of 1 M LiHMDS in THF (110 mL) was added to a 500 mL flask at -78°C under nitrogen. To this solution was added dropwise a solution containing compound 28b (10.5 g, 50.0 mmol in 80 mL of anhydrous THF) below -65°C, followed by stirring at -78°C for 3 hours. To the resulting solution was added MeI (4.7 mL) below -65°C. The reaction was stirred at -65°C to -78°C and monitored by LC/MS. After 3 hours, the reaction was quenched with MeOH (2.4 mL) at -60°C and 2N HCl (167 mL) at -10°C. Toluene (70 mL) was added, and the mixture was stirred for 0.5 hours. The organic layer was separated _{and treated with Na2S2O3 solution} (11 g in 96 mL of water) for 30 minutes with _stirring . The organic layer was evaporated in vacuo to obtain crude product, which was purified by recrystallization from 1/5 (v/v) tert-BuOMe-hexane to obtain compound 24b (9.3 g, 83%). GC analysis indicated a 2:1 ratio of compound 24b to its diastereomer. Compound 6b (3.3 g, 31% based on 28b) was obtained with a de value of 96% after catalytic hydrogenation of compound 24b and purification by trituration of oxalate salt (Table 1).

Example 18 : Synthesis of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine (compound 6b)

The title compound 6b (9.5 g, 73%) was prepared from 24b (13.6 g, 60.9 mmol) in a similar manner as described in Example 13 (Method C). GC analysis showed that the de value of compound 6b was 94%.

Embodiment 19 : the synthesis of (2S)-2-tert-butoxycarbonyl amino-succinic acid diamide (compound 29b)

To a solution of N-Boc-L-aspartic acid (29.5 g, 126.5 mmol) in THF (348 mL) were added pyridine (11.7 g, 147.9 mmol), _Boc2O (70.5 g, 323.0 mmol) and ammonium bicarbonate (24.3 g, 307.4 mmol). The reaction mixture was stirred at room temperature for 12 hours, then evaporated. The residue was diluted with ethyl acetate (250 mL) and washed with water (50 mL) with stirring. The organic layer was evaporated to obtain compound 29b (20.1 g, 69%).

Melting point: 190-192°C (MeOH); ¹ H NMR ( ⁴ d-MeOH, 300MHz): δ1.44 (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 : the synthesis of (2S)-2-tert-butoxycarbonyl amino-succinonitrile (compound 28a)

Compound 28a (9.0 g, 54%) can be synthesized from compound 27a (19.8 g, 85.6 mmol), pyridine (45.0 g, 6.65 equiv) and benzenesulfonyl chloride in a manner similar to that described in Example 12 (Method A). (59.6 g, 3.9 eq) was prepared.

Melting point: 134-136°C (hexane); ¹ H NMR (CDCl ₃ , 300MHz): δ1.46 (s, 9H), 2.95 (dd, J=6.6, 3.4Hz, 2H), 4.80-4.96 (m, 1H), 5.32 (d, J = 8.7 Hz, 1H),; MS: m/e 218.0 (M ⁺⁺ 23).

Example 21: Synthesis of (3S)-3-(tert-butoxycarbonylamino)-pyrrolidine (compound 29a)

Compound 29a (7.0 g, 71%) can be prepared from compound 28a (10.3 g, 52.8 mmol) in a similar manner as described in Example 13 (Method C).

Compound 29a·0.5H ₂ C ₂ O ₄ , melting point: 170°C (dec.) (tert-BuOMe); ¹ H NMR ( ⁴ d-MeOH, 300MHz): δ1.44(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).

Example 22 : Synthesis of (3S)-3-(tert-butoxycarbonylamino)-piperidine (compound 29b)

Compound 29b (7.0 g, 72%) can be prepared from compound 28b (10.1 g, 48.3 mmol) in a similar manner as described in Example 13 (Method C). The method described in Example 7 was used to measure, and the optical purity of compound 29b was greater than 99%.

Example 23 : Synthesis of 2-tert-butoxycarbonylamino-adipamide (compound 27c)

Compound 27c (2.4 g, 76%) can be prepared in a similar manner to that described in Example 10 (Method B) from 2-tert-butoxycarbonylamino-glutaric acid (3.2 g, 12.3 mmol).

Melting point: 135-137°C (MeOH); ¹ H NMR ( ⁴ d-MeOH, 300MHz): δ1.43 (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 : Preparation of 2-tert-butoxycarbonylamino-adiponitrile (compound 28c)

Compound 28c (1.5 g, 73%) can be prepared from compound 27c (2.4 g, 9.3 mmol) in a similar manner as described in Example 12 (Method B).

Melting point: 61-63°C (hexane); ¹ H NMR (CDCl ₃ , 300MHz): δ1.44 (s, 9H), 1.80-1.87 (m, 2H), 1.90-2.00 (m, 2H), 2.43 ( t, J = 6.6 Hz, 2H), 4.50-4.60 (m, 1H), 5.00-5.20 (m, 1H); MS: m/e 246.0 (M ⁺ +23).

(化合物29c) Example 25 : 3-tert-butoxycarbonylaminohexahydro-2-aza

(Compound 29c)

Compound 29c (3.4 g, 71%) was prepared as a yellow oil from compound 28c (5.0 g, 22.4 mmol) in a manner similar to that described in Example 13 (Method C).

¹ H 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: Melting point: 207°C (dec.) (tert-BuOMe).

other implementations

All the features disclosed in the specification can be combined in any combination. Various features disclosed in the specification may be replaced by features serving the same, equivalent or similar purpose. Thus, unless stated otherwise, various features disclosed are one example only of a series of equivalent or similar features.

Through the above description, those skilled in the art can easily determine the main features of the present invention, and can make various changes and improvements to the present invention under the premise of not departing from the spirit and scope of the present invention, so that it is applicable to various application and conditions. Accordingly, other implementations are within the scope of the following 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.