JP2008528625A - Synthesis of arylpyrrolidones - Google Patents

Abstract

  The present invention provides a method for synthesizing arylpyrrolidones with high yield and high enantiomeric excess.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This invention claims priority to US Provisional Application No. 60 / 648,039, filed January 28, 2005, which is incorporated by reference in its entirety and for all purposes. Included in this specification.

The present invention relates generally to methods for the asymmetric synthesis of aryl pyrrolidones, eg, aryl pyrrolidones useful as intermediates in the manufacture of HIV inhibitors.

結果として、アリールピロリドン類の製造のための新規合成経路の発見が望まれている。これらのピロリドン類は少なくとも１個のキラル中心を有するため、高収率でおよび高いエナンチオマー過剰率(“ｅｅ”)で上記化合物を製造する不斉合成スキームが好ましい。 BACKGROUND OF THE INVENTION The following types of arylpyrrolidones are currently being tested in clinical settings as antiviral agents, such as HIV inhibitors. Clinical trials and new drug application (NDA) submissions require a practical, large-scale synthesis of the active agent.

As a result, the discovery of new synthetic routes for the production of arylpyrrolidones is desired. Since these pyrrolidones have at least one chiral center, asymmetric synthesis schemes that produce the above compounds in high yield and high enantiomeric excess ("ee") are preferred.

  Asymmetric synthesis of arylpiperidinones has been reported, Senda et al., J. Org. Chem., 66: 6852-6856 (2001) (“Senda”). To date, however, asymmetric synthesis of arylpyrrolidones has not been reported. Asymmetric synthesis leading to a high ee of the desired enantiomer would represent a significant advance in the art.

SUMMARY OF THE INVENTION In a first aspect, the present invention provides a method for asymmetric synthesis. The product of this synthesis can be an amide containing heterocycle or a pharmaceutically acceptable salt thereof. The method comprises under conditions sufficient to form an organometallic rhodium (I) complex, a chiral ligand, an α, β unsaturated amide-containing heterocycle, and a boronic ester, including an amide-containing heterocycle and an enantiomer thereof. And asymmetric synthesis of an amide-containing heterocycle or a pharmaceutically acceptable salt thereof. This mixture has an ee of about 60% or greater. In a second aspect, the present invention presents a mixture comprising an amide containing heterocycle and its enantiomers.

〔式中、
Ｒ^１は置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールである。Ｒ^２、Ｒ^３、およびＲ^４は各々独立してＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^５ａ、ＮＯ_２、ＣＮ、ハロゲン、Ｃ(Ｏ)Ｒ^５ｂ、ＮＲ^５ａＲ^５ｂ、Ｃ(Ｏ)ＮＲ^５ａＲ^５ｂおよびＣ(Ｏ)ＯＲ^５ｂから選択される。Ｒ^５ａはＨまたは置換もしくは非置換アルキルである。Ｒ^５ｂはＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、および置換または非置換ヘテロアリールから選択されるメンバーである。〕
の構造を有する。ボロン酸エステルの例は、式II：

〔式中、
Ｒ^６は置換もしくは非置換アリールまたは置換もしくは非置換ヘテロアリールである。Ｒ^７およびＲ^８は、各々独立してＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１０、ＮＯ_２、ＣＮ、およびハロゲンから選択される。Ｒ^７およびＲ^８は、それらが結合している酸素原子と一体となって、また所望により置換または非置換５〜８員環を形成できる。Ｒ^１０はＨまたは置換もしくは非置換アルキルである。〕
を有する。 In an exemplary embodiment, the α, β unsaturated amide-containing heterocycle has the formula I:

[Where,
R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R ² , R ³ , and R ⁴ are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted _{^{heteroaryl, oR 5a, NO 2, CN}} , ^{halogen, C (O) R 5b,} NR 5a R 5b, is selected from C (O) ^NR 5a ^{R 5b} and C (O) ^{oR 5b.} R ^5a is H or substituted or unsubstituted alkyl. R ^5b is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl Be a member. ]
It has the following structure. Examples of boronic esters are of formula II:

[Where,
R ⁶ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R ⁷ and R ⁸ are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Selected from substituted heteroaryl, OR ¹⁰ , NO ₂ , CN, and halogen. R ⁷ and R ⁸ can be united with the oxygen atom to which they are bonded and can optionally form a substituted or unsubstituted 5- to 8-membered ring. R ¹⁰ is H or substituted or unsubstituted alkyl. ]
Have

  The present invention represents several advances in the art. One advance is the asymmetric synthesis of aryl 5-membered lactams. Previously known in this field was only the asymmetric synthesis of aryl 6-membered lactams, as reported by Senda. Aryl 6-membered lactams are not always the same as aryl 5-membered lactams. For example, in Senda, yields of up to 75% have been recorded when an N-benzyl 6-membered lactam substrate reacts with an aryl moiety. Surprisingly, for aryl 5-membered lactams, the N-benzyl 5-membered lactam substrate provides only 35% yield. When the benzyl group was replaced with a phenyl group, the reaction yield increased significantly from 35% to about 80%.

は、結合として用いられているときまたは結合に垂直に表示されているときのいずれであっても、表示された部分が分子の残りの部分、固体支持体などに結合する点を示す。 Detailed Description of the Invention and Embodiments Definition symbol

Indicates the point at which the displayed moiety binds to the rest of the molecule, solid support, etc., whether used as a bond or displayed perpendicular to the bond.

  Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

  Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

The compounds of the invention can be prepared as single isomers (eg enantiomers, cis-trans, positions, diastereomers) or as a mixture of isomers. In a preferred embodiment, the compound is prepared as a substantially single isomer. Methods for the production of substantially isomerically pure compounds are known in the art. For example, using enantiomerically enriched mixtures and pure enantiomeric compounds in combination with enantiomerically pure synthetic intermediates in combination with reactions that leave the chiral center unchanged or undergo its complete transformation, Can be manufactured. Alternatively, intermediates along the final product or synthetic route can be separated into single stereoisomers. Techniques for reversing a specific stereocenter or leaving it unchanged, and techniques for resolving a mixture of stereoisomers are known in the art, and it is the person of ordinary skill in the art to select the appropriate method for a particular situation. Within the scope of the technology. In general, Furniss et al. (Eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5 ^TH ED., Longman Scientific and Technical Ltd., Essex, 1991, pp. 809-816; and Heller, Acc. Chem. Res. See 23: 128 (1990).

The compounds of the present invention may also contain unnatural proportions of atomic isotopes of one or more of the atoms that constitute such compounds. For example, the compounds may for example tritium ⁽³ H), can be radiolabelled with radioactive isotopes, such as iodine--125 ⁽¹²⁵ I) or carbon -14 ⁽¹⁴ C). All isotope variations of the compounds of the invention, whether radioactive or not, are intended to be included within the scope of the invention.

When substituents are specified by their normal chemical formulas written in left-to-right direction, they represent substituents, chemically equivalent substituents obtained by writing structural formulas in right-to-left direction. Equally included, for example, —CH ₂ O— also means —OCH ₂ —.

The term “alkyl” as such or as part of another substituent, unless otherwise specified, has the indicated number of carbon atoms (ie, C ₁ -C ₁₀ means 1 to 10 carbons), and is completely It means a straight or branched chain, or cyclic hydrocarbon radical, which may be saturated, mono- or polyunsaturated and can be divalent and polyvalent radicals, or combinations thereof. Examples of saturated hydrocarbon radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, such as n-pentyl, n Including, but not limited to, groups such as -hexyl, n-heptyl, homologues and isomers of n-octyl. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups are vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3- Including but not limited to propynyl, 3-butynyl, and higher homologs and isomers. The term “alkyl”, unless otherwise specified, also includes derivatives of alkyl as defined in more detail below, such as “heteroalkyl”. Alkyl groups that are limited to hydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, such as, but not limited to, —CH ₂ CH ₂ CH ₂ CH ₂ — Heteroalkylene "includes groups defined below. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, and such groups having 10 or fewer carbon atoms are preferred in the present invention. A “lower alkyl” or “lower alkylene” is a short chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

  The terms “alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy) are used in their usual sense, and the alkyl is bonded to the rest of the molecule through an oxygen, amino or sulfur atom, respectively. Means group.

The term “heteroalkyl”, by itself or in combination with other terms, unless specified, from the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si and S. Where nitrogen and sulfur atoms may be optionally oxidized, nitrogen heteroatoms may optionally be quaternized, stable linear or branched, or cyclic hydrocarbon radicals, or their Means a combination. These heteroatom (s) O, N and S and Si may be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. _{Examples, -CH 2 -CH 2 -O-CH} 3, -CH 2 -CH 2 -NH-CH 3, -CH 2 -CH 2 -N (CH 3) -CH 3, -CH 2 -S-CH _2- CH ₃ , —CH ₂ —CH ₂ , —S (O) —CH ₃ , —CH ₂ —CH ₂ —S (O) ₂ —CH ₃ , —CH═CH—O—CH ₃ , —Si ( _{CH 3) 3, -CH 2 -CH} = N-OCH 3, and _{-CH = CH-N (CH 3} ) including -CH _3, without limitation. For example, up to two heteroatoms may be consecutive, such as —CH ₂ —NH—OCH ₃ and —CH ₂ —O—Si (CH ₃ ) ₃ . Similarly, the term “heteroalkylene”, by itself or as part of another substituent, includes —CH ₂ —CH ₂ —S—CH ₂ —CH ₂ — and —CH ₂ —S—CH ₂ —CH ₂ —. It means a divalent radical derived from heteroalkyl exemplified by, but not limited to, NH—CH ₂ —. For heteroalkylene groups, heteroatoms can occupy either or both of the chain ends (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene bridging groups, the orientation of the bridging group is not indicated by the orientation in which the formula of the bridging group is described. For example, the formula —C (O) ₂ R′— means both —C (O) ₂ R′— and —R′C (O) ₂ —.

  The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, refer to cyclic forms of “alkyl” and “heteroalkyl”, respectively, unless otherwise specified. In addition, for heterocycloalkyl, the heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl are 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran- Including, but not limited to, 3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like.

The term “halo” or “halogen”, by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom unless otherwise specified. In addition, terms such as “haloalkyl” are intended to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C ₁ -C ₄ ) alkyl” is intended to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. To do.

  The term “aryl”, unless stated otherwise, means a monocyclic or polyunsaturated, aromatic, substituted, polycyclic (preferably 1 to 3 rings) fused or covalently bonded together. To do. The term “heteroaryl” is selected from N, O, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atom (s) are optionally quaternized. Preferably, it means an aryl group (or ring) containing 1 to 4 heteroatoms. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, benzyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- Imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- Furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- Isoquinolyl, 5-isoquinolyl, 2-quinoxalini , Including 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The substituents for the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

  Briefly, the term “aryl” when used in combination with other terms (eg, aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” refers to an alkyl group in which the aryl group is substituted with a carbon atom (eg, a methylene group), eg, an oxygen atom (eg, phenoxymethyl, 2-pyridyloxymethyl, 3- (1- It is intended to include those attached to alkyl groups (eg, benzyl, phenethyl, pyridylmethyl, etc.), including naphthyloxy) propyl and the like.

  Each of the above terms (eg, “alkyl”, “heteroalkyl”, “aryl” and “heteroaryl”) is meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for alkyl and heteroalkyl radicals (including those often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generally “alkyl” Referred to as “group substituents”, which may be one or more of a variety of groups selected from, but not limited to: 0 to (2m ′ + 1), where m ′ is in such radicals -OR ', = O, = NR', = N-OR ', -NR'R ", -SR', -halogen, -SiR'R" R "', -OC (O) R ', - C (O) R ', - CO 2 R', - CONR'R", - OC (O) NR'R ", - NR" C (O) R ' , -NR'-C (O) NR "R"', - NR "C (O) R ', - NR-C ( NR'R "R'") = NR "", - NR-C (NR'R ") = NR '", - S (O) R', - S (O) 2 R ′, —S (O) ₂ NR′R ″, —NRSO ₂ R ′, —CN and —NO ₂ . R ′, R ″, R ″ ′ and R ″ ″ each is preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, eg aryl substituted with 1-3 halogens, substituted Or an unsubstituted alkyl, alkoxy or thioalkoxy group, or an arylalkyl group. When a compound of the present invention contains one or more R groups, for example, each of the R groups is independently a plurality of these groups, each as an R ′, R ″, R ′ ″ and R ″ ″ group. As selected. When R ′ and R ″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R ″ is 1-pyrrolidinyl and 4 -Intended to include, but not be limited to, morpholinyl. From the above description of substituents, one of skill in the art will recognize that the term “alkyl” refers to haloalkyl (eg, —CF ₃ and —CH ₂ CF ₃ ) and acyl (eg, —C (O) CH ₃ , —C (O It is understood to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as () CF ₃ , —C (O) CH ₂ OCH _3, etc.).

Similar to the substituents described for alkyl radicals, substituents for aryl and heteroaryl groups are commonly referred to as “aryl group substituents”. This substituent is, for example: halogen, —OR ′, ═O, ═NR ′, ═N—OR ′, —NR′R ″, —SR ′, —halogen, —SiR′R ″ R ″ ′, —OC (O) R ′, —C (O) R ′, —CO ₂ R ′, —CONR′R ″, —OC (O) NR′R ″, —NR ″ C (O) R ′, —NR′— C (O) NR "R"', - NR "C (O) 2 R', - NR-C (NR'R" R '") = NR"", - NR-C (NR'R") = NR ′ ″, —S (O) R ′, —S (O) ₂ R ′, —S (O) ₂ NR′R ″, —NRSO ₂ R ′, —CN and —NO ₂ , —R ′, — N ₃ , —CH (Ph) ₂ , fluoro (C ₁ -C ₄ ) alkoxy, and fluoro (C ₁ -C ₄ ) alkyl, selected from a number ranging from 0 to the total number of free aromatic ring systems. Where R ′, R ″, R ″ ′ and R ″ ″ are preferably independently hydrogen, substituted or unsubstituted alkyl , Substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the present invention contains one or more R groups, for example, each of the R groups is independently a plurality of these groups, each as an R ′, R ″, R ′ ″ and R ″ ″ group. As selected.

Two substituents on adjacent atoms on the aryl or heteroaryl ring may optionally have the formula —TC (O) — (CRR ′) _q —U—, wherein T and U are independently —NR -, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3). Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be of the formula —A— (CH ₂ ) _r —B—, wherein A and B are independently —CRR′—, —O—. , -NR -, - S -, - S (O) -, - S (O) 2 -, - S (O) 2 NR'- or a single bond, and r is an integer of 1 to 4) Can be substituted with One of the single bonds of the new ring thus formed can be replaced by a double bond if desired. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring are of the formula — (CRR ′) _s —X— (CR ″ R ′ ″) _d — (wherein s and d are independently 0 from an integer 3, and X is -O -, - NR '-, - S -, - S (O) -, - S (O) 2 -, or -S (O) ₂ NR'- ) Substituents. The substituents R, R ′, R ″ and R ′ ″ are preferably independently selected from hydrogen or substituted or unsubstituted (C ₁ -C ₆ ) alkyl.

  The term “heteroatom” as used herein is intended to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

  As used herein, “protecting group” refers to a moiety that is stable under certain reaction conditions, but is cleaved from the substrate under different reaction conditions. The protecting group can also be selected such that it participates in the direct participation of the aromatic ring moiety of the compounds of the invention. See, for example, Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York, 1991 for examples of useful protecting groups.

である。“ｅｅ”についてのさらなる情報は、例えば、Wade, L.G., ORGANIC CHEMISTRY, 5th Ed., Prentice Hall, New Jersey, 2003, pp. 167-207を参照のこと。 As used herein, “enantiomeric excess”, or “ee” is a representation for the excess of one enantiomer over the other in the enantiomeric mixture. “Ee” is usually written as a percentage. Algebraically,

It is. For further information on “ee” see, for example, Wade, LG, ORGANIC CHEMISTRY, 5th Ed., Prentice Hall, New Jersey, 2003, pp. 167-207.

  As used herein, “disorder associated with HIV infection” or “disease associated with HIV infection” refers to a disease state characterized by HIV infection. Disorders associated with such HIV infections include AIDS; Kaposi's sarcoma; opportunistic infections such as those caused by Pneumocystis carini and Mycobacterium tuberculosis; oral candidiasis, hairy vitiligo, and aphthous Oral lesions including ulcers; systemic lymphadenopathy; shingles; thrombocytopenia; aseptic meningitis; toxoplasmosis, cryptococcosis, CMV infection, primary CNS lymphoma, and HIV-related dementia Diseases include, but are not limited to, peripheral neuropathy, seizures, and myopathy.

  As used herein, “HIV reverse transcriptase inhibitors” is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include but are not limited to AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors are delavirdine (Pharmacia and Upjohn U90152S), efavirenz (DuPont), nevirapine (Boehringer Ingelheim), Ro 18,893 (Roche), trovirdin (Lilly), MKC-442 (Triangle), HBY 097. (Hoechst), ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.), and MEN 10979 (Menarini Farmaceutici) It is not limited to.

  As used herein, “HIV protease inhibitor” is intended to refer to a compound that inhibits HIV protease. Examples are saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex / Glaxo Wellcome), nelfinavir (Agouron, AG-1343), parinavir (Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical), CGP-61755 (Ciba -Geigy), PD 173606 (Parke Davis), PD 177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and Upjohn), and ABT-378 It is not limited to. Further examples include cyclic protease inhibitors as described in WO93 / 07128, WO94 / 19329, WO94 / 22840, and PCT application number US96 / 03426.

  “Therapeutically effective amount” means herein a dose that produces an effect on what it is administered to. The exact dosage will depend on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999)).

  As used herein, "reactive functional group" includes olefin, acetylene, alcohol, phenol, ether, oxide, halide, aldehyde, ketone, carboxylic acid, ester, amide, cyanate, isocyanate, thiocyanate, isothiocyanate, amine, hydrazine, Hydrazone, hydrazide, diazo, diazonium, nitro, nitrile, mercaptant, sulfide, disulfide, sulfoxide, sulfone, sulfonic acid, sulfinic acid, acetal, ketal, anhydride, sulfate, sulfenic acid isonitrile, amidine, imide, imidate, nitrone, Hydroxylamine, oxime, hydroxamic acid thiohydroxamic acid, allene, orthoester, sulfite, enamine, inamine, urea, pseudourea, semical Disilazide, carbodiimides, carbamates, imines, azides, azo compounds, azoxy compounds, and including nitroso compounds, but are not limited to. Reactive functional groups also include groups used in the production of bioconjugates, such as N-hydroxysuccinimide ester, maleimide and the like. Methods for the preparation of each of these functional groups are known in the art, and their application or modification for specific purposes is within the ability of those skilled in the art (e.g., Sandler and Karo, eds ORGANIC FUNCTIONAL GROUP PREPARATIONS, Academic Press, San Diego, 1989).

  A “non-covalent protein binding group” is a moiety that interacts with an intact or denatured polypeptide in a binding manner. The interaction can be either reversible or irreversible in the biological environment. Incorporation of a “non-covalent protein binding group” into the chelating agent or complex of the present invention provides the agent or complex with the ability to interact with the polypeptide in a non-covalent manner. Examples of non-covalent interactions include hydrophobic-hydrophobic and electrostatic interactions. Examples of “non-covalent protein binding groups” include anionic groups such as phosphates, thiophosphates, phosphonates, carboxylates, boronates, sulfates, sulfones, thiosulfates, and thiosulfonates.

  As used herein, “bridging group” means a covalent chemical bond containing at least one heteroatom. Examples of bridging groups include —C (O) NH—, —C (O) O—, —NH—, —S—, —O— and the like.

  The term “targeting group”: (1) can actively place a target region, eg, an object (eg, contrast agent) to which it is bound; or (2) is preferentially within a target tissue, eg, a tumor It is intended to mean the part that is actively absorbed or inserted into the. The targeting group can be a small molecule intended to include both non-peptides and peptides. The targeting group may still be a macromolecule including but not limited to saccharides, lectins, receptors, receptor ligands, proteins such as BSA, antibodies, poly (ethers), dendrimers, poly (amino acids), etc. .

  The term “cleavable group” means a moiety that can release a chelate from a conjugate by cleavage of the bond connecting the chelate (or chelate linker arm construct) to the rest of the conjugate. Such cleavage is essentially either chemically or enzymatically mediated. Examples of enzymatically cleavable groups include natural amino acids or peptide sequences ending with natural amino acids.

  In addition to enzymatic cleavage sites, it is within the scope of the invention to include one or more sites that are cleaved by the action of factors other than enzymes. Examples of non-enzymatic cleavage factors include, but are not limited to, acids, bases, light (eg, nitrobenzyl derivatives, phenacyl groups, benzoin esters), and heat. Many cleavable groups are known in the art. For example, Jung et al., Biochem. Biophys. Acta, 761: 152-162 (1983); Joshi et al., J. Biol. Chem., 265: 14518-14525 (1990); Zarling et al., J. Immunol., 124: 913-920 (1980); Bouizar et al., Eur. J. Biochem., 155: 141-147 (1986); Park et al., J. Biol. Chem., 261: 205-210 (1986); Browning et al., J. Immunol., 143: 1859-1867 (1989). An even wider range of cleavable, bifunctional (homo- and hetero-bifunctional) spacer arms are commercially available from suppliers such as Pierce.

II. In a first aspect of the method , the present invention provides a synthetic method. The product of this synthesis can be an amide containing heterocycle or a pharmaceutically acceptable salt thereof. The method includes: a) conditions sufficient to form a product comprising an organometallic rhodium (I) complex, a chiral ligand, an α, β unsaturated amide-containing heterocycle, and a boronic ester containing an amide-containing heterocycle To produce the amide-containing heterocycle or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^１は置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択される。Ｒ^２、Ｒ^３、およびＲ^４は各々独立してＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^５ａ、ＮＯ_２、ＣＮ、ハロゲン、Ｃ(Ｏ)Ｒ^５ｂ、ＮＲ^５ａＲ^５ｂ、Ｃ(Ｏ)ＮＲ^５ａＲ^５ｂおよびＣ(Ｏ)ＯＲ^５ｂから選択される。Ｒ^５ａはＨまたは置換もしくは非置換アルキルである。Ｒ^５ｂはＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、および置換または非置換ヘテロアリールから選択されるメンバーである。〕
の構造を有する。ボロン酸エステルの例は、式II：

〔式中、
Ｒ^６は置換もしくは非置換アリールまたは置換もしくは非置換ヘテロアリールである。Ｒ^７およびＲ^８は各々独立してＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１０、ＮＯ_２、ＣＮ、およびハロゲンから選択される。Ｒ^７およびＲ^８は、それらが結合している酸素原子と一体となって、また所望により置換または非置換５〜８員環を形成できる。Ｒ^１０はＨまたは置換もしくは非置換アルキルである。〕
の式を有し得る。本アミド含有ヘテロ環は、式III：

の式を有し得る。例示的態様において、本合成は不斉である。例示的態様において、本生成物はエナンチオマー的に純粋であり、式IIIに従う式を有する。他の例示的態様において、本合成は式IIIのアミド含有ヘテロ環のエナンチオマーを製造する。他の例示的態様において、本生成物は、さらに式IIIａ：

を有するアミド含有ヘテロ環を含む。 In an exemplary embodiment, the α, β unsaturated amide-containing heterocycle is of the formula I:

[Where,
R ¹ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R ² , R ³ , and R ⁴ are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted _{^{heteroaryl, oR 5a, NO 2, CN}} , ^{halogen, C (O) R 5b,} NR 5a R 5b, is selected from C (O) ^NR 5a ^{R 5b} and C (O) ^{oR 5b.} R ^5a is H or substituted or unsubstituted alkyl. R ^5b is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl Be a member. ]
It has the following structure. Examples of boronic esters are of formula II:

[Where,
R ⁶ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R ⁷ and R ⁸ are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Selected from heteroaryl, OR ¹⁰ , NO ₂ , CN, and halogen. R ⁷ and R ⁸ can be united with the oxygen atom to which they are bonded and can optionally form a substituted or unsubstituted 5- to 8-membered ring. R ¹⁰ is H or substituted or unsubstituted alkyl. ]
Can have the formula: The amide-containing heterocycle has formula III:

Can have the formula: In an exemplary embodiment, the synthesis is asymmetric. In an exemplary embodiment, the product is enantiomerically pure and has a formula according to Formula III. In other exemplary embodiments, this synthesis produces an enantiomer of an amide-containing heterocycle of formula III. In other exemplary embodiments, the product is further of formula IIIa:

An amide-containing heterocycle having

  In an exemplary embodiment, the product has an ee of about 10% or greater. In other exemplary embodiments, the product has an ee of about 30% or greater. In other exemplary embodiments, the product has an ee of about 50% or greater. In other exemplary embodiments, the product has an ee of about 60% or greater. In other exemplary embodiments, the product has an ee of about 70% or greater. In other exemplary embodiments, the product has an ee of about 80% or greater. In other exemplary embodiments, the product has an ee of about 90% or greater. In other exemplary embodiments, the product has an ee of about 95% or greater. In other exemplary embodiments, the product has an ee of about 97% or greater. In other exemplary embodiments, the product has an ee of about 98% or greater. In other exemplary embodiments, the product has an ee of about 99.0% or greater. In other exemplary embodiments, the product has an ee of about 99.2% or greater. In other exemplary embodiments, the product has an ee of about 99.4% or greater. In other exemplary embodiments, the product has an ee of about 99.6% or greater. In other exemplary embodiments, the product has an ee of about 99.8% or greater.

  In an exemplary embodiment, the method has a yield of about 20% or greater. In an exemplary embodiment, the method has a yield of about 30% or greater. In an exemplary embodiment, the method has a yield of about 40% or greater. In an exemplary embodiment, the method has a yield of about 50% or greater. In an exemplary embodiment, the method has a yield of about 60% or greater. In an exemplary embodiment, the method has a yield of about 70% or greater. In an exemplary embodiment, the method has a yield of about 80% or greater. In an exemplary embodiment, the method has a yield of about 90% or greater. In an exemplary embodiment, the method has a yield of about 95% or greater.

  In an exemplary embodiment, the method is performed at a temperature between 40 and 150 ° C. In another exemplary embodiment, the method is performed at a temperature between 50 and 130 ° C. In an exemplary embodiment, the method is performed at a temperature between 60 and 110 ° C. In an exemplary embodiment, the method is performed for a length of time between 2 and 8 hours. In another exemplary embodiment, the method is performed for a length of time between 3 hours and 7 hours. In other exemplary embodiments, the organometallic rhodium (I) complex comprises a chiral ligand selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. In other exemplary embodiments, the chiral ligand comprises an aryl substituted phosphine. In other exemplary embodiments, the chiral ligand is (R) -BINAP or (S) -BINAP.

In other exemplary embodiments, R ⁶ is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted A member selected from isoquinolinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted quinazolinyl and substituted or unsubstituted quinoxalinyl.

In an exemplary embodiment, R ¹ is a member selected from substituted or unsubstituted phenyl and substituted or unsubstituted benzyl. In an exemplary embodiment, R ¹ is substituted or unsubstituted phenyl. In exemplary embodiments, the product may have an ee of about 80% or greater.

  In an exemplary embodiment, the method further comprises the steps of: purifying the mixture of step a) and thus producing a product having a greater ee than after step a). In an exemplary embodiment, the purification comprises subjecting the mixture to a recovery method that includes column chromatography and recrystallization.

の化合物および式IVａ：

の化合物を含む、混合物
〔上記式中、
Ｒ^１１は置換または非置換アルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択される。Ｒ^１２、Ｒ^１３、およびＲ^１４は各々独立してＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１５、ＮＯ_２、ＣＮ、ハロゲン、Ｃ(Ｏ)Ｒ^１５、ＮＲ^１５Ｒ^１６、Ｃ(Ｏ)ＮＲ^１５Ｒ^１６およびＣ(Ｏ)ＯＲ^１５から選択される。Ｒ^１５はＨおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^１６はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。Ｒ^１７は置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。〕。例示的態様において、本混合物は約６０％またはそれより大きいｅｅを有する。 In a second aspect, the present invention provides a mixture of amide-containing heterocycles and enantiomers thereof. This mixture is of formula IV:

And a compound of formula IVa:

A mixture comprising a compound of the above formula:
R ¹¹ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R ¹² , R ¹³ , and R ¹⁴ are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, Selected from substituted or unsubstituted heteroaryl, OR ¹⁵ , NO ₂ , CN, halogen, C (O) R ¹⁵ , NR ¹⁵ R ¹⁶ , C (O) NR ¹⁵ R ¹⁶ and C (O) OR ¹⁵ . R ¹⁵ is a member selected from H and substituted or unsubstituted alkyl. R ¹⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. R ¹⁷ is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. ]. In exemplary embodiments, the mixture has an ee of about 60% or greater.

〔式中、
Ｒ^１１は置換または非置換アルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。Ｒ^１２、Ｒ^１３、およびＲ^１４はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１５、ＮＯ_２、ＣＮ、ハロゲン、Ｃ(Ｏ)Ｒ^１５、ＮＲ^１５Ｒ^１６、Ｃ(Ｏ)ＮＲ^１５Ｒ^１６およびＣ(Ｏ)ＯＲ^１５から独立して選択されるメンバーである。Ｒ^１５はＨおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^１６はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。〕
の式を有する。本ボロン酸エステルは、式II：

〔式中、
Ｒ^６は置換または非置換アリールおよび置換または非置換ヘテロアリールから選択される。Ｒ^７およびＲ^８は各々独立してＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１０、ＮＯ_２、ＣＮ、およびハロゲンから選択される。Ｒ^７およびＲ^８は、それらが結合している酸素原子と一体となって、また所望により置換または非置換５〜８員環を形成できる。Ｒ^１０はＨおよび置換または非置換アルキルから選択される。他の例示的態様において、Ｒ^１１は置換または非置換フェニルおよび置換または非置換ベンジルから選択されるメンバーである。〕
の式を有し得る。他の例示的態様において、Ｒ^１１は置換または非置換フェニルである。 In an exemplary embodiment, the mixture can be made according to a method. The method includes contacting an organometallic rhodium (I) complex, a chiral ligand, an α, β unsaturated N-substituted heterocycle of Formula V under conditions sufficient to form a mixture. The α, β unsaturated N-substituted heterocycle is of the formula V:

[Where,
R ¹¹ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R ¹² , R ¹³ , and R ¹⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member independently selected from heteroaryl, OR ¹⁵ , NO ₂ , CN, halogen, C (O) R ¹⁵ , NR ¹⁵ R ¹⁶ , C (O) NR ¹⁵ R ¹⁶ and C (O) OR ¹⁵ . R ¹⁵ is a member selected from H and substituted or unsubstituted alkyl. R ¹⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. ]
It has the formula. The boronic ester has the formula II:

[Where,
R ⁶ is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. R ⁷ and R ⁸ are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Selected from heteroaryl, OR ¹⁰ , NO ₂ , CN, and halogen. R ⁷ and R ⁸ can be united with the oxygen atom to which they are bonded and can optionally form a substituted or unsubstituted 5- to 8-membered ring. R ¹⁰ is selected from H and substituted or unsubstituted alkyl. In another exemplary embodiment, R ¹¹ is a member selected from substituted or unsubstituted phenyl and substituted or unsubstituted benzyl. ]
Can have the formula: In other exemplary embodiments, R ¹¹ is substituted or unsubstituted phenyl.

〔式中、
Ｒ^１２、Ｒ^１３、およびＲ^１４はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１５、ＮＯ_２、ＣＮ、ハロゲン、Ｃ(Ｏ)Ｒ^１５、ＮＲ^１５Ｒ^１６、Ｃ(Ｏ)ＮＲ^１５Ｒ^１６およびＣ(Ｏ)ＯＲ^１５から独立して選択されるメンバーである。Ｒ^１５はＨおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^１６はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。Ｒ^３０、Ｒ^３２、Ｒ^３３、およびＲ^３４はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１９、ＮＯ_２、ＣＮ、ハロゲン、Ｃ(Ｏ)Ｒ^１９、ＮＲ^１９Ｒ^２０、Ｃ(Ｏ)ＮＲ^１９Ｒ^２０およびＣ(Ｏ)ＯＲ^１９から独立して選択されるメンバーである。Ｒ^３３とＲ^３４またはＲ^３３とＲ^３２またはＲ^３２とＺ^１は、それらが結合している原子と一体となって、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択される少なくとも５員の環を形成する。Ｒ^１９はＨ、置換または非置換アリールおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^２０はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。Ｚ^１は式VII：

(式中、Ｒ^４０、Ｒ^４１、およびＲ^４２はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^４４、ＮＯ_２、ＣＮ、およびハロゲンから独立して選択されるメンバーである。Ｒ^４４はＨおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^４３はハロゲンである。Ｚ^２は置換または非置換アリール、置換または非置換ヘテロアリールから選択されるメンバーである。)
の部分である。〕
の構造を有し得る。 In a third aspect, the present invention provides a method for producing a compound and its enantiomers. The compound has the formula VI:

[Where,
R ¹² , R ¹³ , and R ¹⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member independently selected from heteroaryl, OR ¹⁵ , NO ₂ , CN, halogen, C (O) R ¹⁵ , NR ¹⁵ R ¹⁶ , C (O) NR ¹⁵ R ¹⁶ and C (O) OR ¹⁵ . R ¹⁵ is a member selected from H and substituted or unsubstituted alkyl. R ¹⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. R ³⁰ , R ³² , R ³³ , and R ³⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted Or independently selected from unsubstituted heteroaryl, OR ¹⁹ , NO ₂ , CN, halogen, C (O) R ¹⁹ , NR ¹⁹ R ²⁰ , C (O) NR ¹⁹ R ²⁰ and C (O) OR ¹⁹ Be a member. R ³³ and R ³⁴ or R ³³ and R ³² or R ³² and Z ¹ together with the atoms to which they are attached, are substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted It forms at least a 5-membered ring selected from substituted aryl and substituted or unsubstituted heteroaryl. R ¹⁹ is a member selected from H, substituted or unsubstituted aryl and substituted or unsubstituted alkyl. R ²⁰ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. Z ¹ is represented by formula VII:

Wherein R ⁴⁰ , R ⁴¹ , and R ⁴² are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, A member independently selected from substituted or unsubstituted heteroaryl, OR ⁴⁴ , NO ₂ , CN, and halogen R ⁴⁴ is a member selected from H and substituted or unsubstituted alkyl R ⁴³ is halogen Z ² is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
It is a part of. ]
The structure may be

〔式中、Ｘ^＊は保護基である。Ｒ^１２、Ｒ^１３、およびＲ^１４はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^２５、ＮＯ_２、ＣＮ、およびハロゲンから独立して選択されるメンバーである。〕
で表される。本ボロン酸エステルは式IX：

〔式中、
Ｒ^３０、Ｒ^３２、Ｒ^３３、およびＲ^３４はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１９、ＮＯ_２、ＣＮ、およびハロゲンから独立して選択されるメンバーである。Ｙ^＊はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^１９、ＮＯ_２、ＣＮ、およびハロゲンから選択されるメンバーである。Ｒ^１７およびＲ^１８はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリールから独立して選択されるメンバーであり、そしてＲ^１７およびＲ^１８は、それらが結合している酸素原子と一体となって、所望により置換または非置換４〜８員環を形成する。Ｒ^１９はＨ、置換または非置換アリールおよび置換または非置換アルキルから選択されるメンバーである。〕
の式を有し得る。本アミド含有ヘテロ環は、式Ｘ：

を有する。 The method includes: a) sufficient organometallic rhodium (I) complex, chiral ligand, α, β unsaturated amide-containing heterocycle, and boronic ester to form a mixture comprising an amide-containing heterocycle of formula IX and its enantiomers Contacting under mild conditions, wherein the mixture has an ee of about 60% or greater. The α, β unsaturated N-substituted heterocycle is of the formula VIII:

[Wherein, X ^* is a protecting group. R ¹² , R ¹³ , and R ¹⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member independently selected from heteroaryl, OR ²⁵ , NO ₂ , CN, and halogen. ]
It is represented by The boronic ester has the formula IX:

[Where,
R ³⁰ , R ³² , R ³³ , and R ³⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted Or a member independently selected from unsubstituted heteroaryl, OR ¹⁹ , NO ₂ , CN, and halogen. Y ^* is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR ¹⁹ , NO ₂ , a member selected from CN and halogen. R ¹⁷ and R ¹⁸ are independent of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl And R ¹⁷ and R ¹⁸ together with the oxygen atom to which they are attached form an optionally substituted or unsubstituted 4-8 membered ring. R ¹⁹ is a member selected from H, substituted or unsubstituted aryl and substituted or unsubstituted alkyl. ]
Can have the formula: The amide-containing heterocycle has the formula X:

Have

の化合物およびそのエナンチオマーを製造する工程を含む。 The method further comprises: b) subjecting the product of step a) to a deprotection reaction to remove X ^* , wherein the formula XI:

And a process for producing the enantiomer thereof.

の化合物およびそのエナンチオマーを製造する工程を含む。 The method further includes: c) subjecting the product of step b) to a deprotection reaction to remove Y ^* , and formula XII:

And a process for producing the enantiomer thereof.

の化合物およびそのエナンチオマーを製造する工程を含む。Ｚ^１は式XIV：

〔式中、Ｒ^４０、Ｒ^４１、Ｒ^４２、Ｒ^４３、およびＲ^４４はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^４６、ＮＯ_２、ＣＮ、ハロゲン、Ｃ(Ｏ)Ｒ^４６、ＮＲ^４６Ｒ^４７、Ｃ(Ｏ)ＮＲ^４６Ｒ^４７およびＣ(Ｏ)ＯＲ^４６から独立して選択されるメンバーである。Ｒ^４６はＨおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^４７はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。〕
の部分である。 The method further includes: d) subjecting the product of step c) to an arylation reaction to produce a compound of formula XIII:

And a process for producing the enantiomer thereof. Z ¹ is the formula XIV:

Wherein R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , and R ⁴⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR ⁴⁶ , NO ₂ , CN, halogen, C (O) R ⁴⁶ , NR ⁴⁶ R ⁴⁷ , C (O) NR ⁴⁶ R ⁴⁷ and C (O) OR ⁴⁶ Members who are selected independently from R ⁴⁶ is a member selected from H and substituted or unsubstituted alkyl. R ⁴⁷ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. ]
It is a part of.

の化合物およびそのエナンチオマーを製造する工程を含む。Ｚ^２は置換または非置換アリール、置換または非置換ヘテロアリールから選択されるメンバーであり、それにより、式VIを有する化合物を製造する。 The method further includes: e) arylating the lactam nitrogen of the product of step d) to obtain a compound of formula VI:

And a process for producing the enantiomer thereof. Z ² is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, thereby producing a compound having the formula VI.

〔式中、
Ｒ^５０、Ｒ^５１、Ｒ^５２、Ｒ^５３およびＲ^５４はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^５５、ＳＯ_２ＮＲ^５５Ｒ^５６、ＣＯＮＲ^５５Ｒ^５６、ＮＲ^５５Ｒ^５６、ＮＯ_２、ＣＮ、およびハロゲンから独立して選択されるメンバーであり；そしてＲ^５０、Ｒ^５１、Ｒ^５２、Ｒ^５３およびＲ^５４の任意の２個は、それらが結合している原子と一体となって、所望により置換または非置換５〜８員環を形成する。Ｒ^５５はＨおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^５６はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。〕
の部分である。他の例示的態様において、Ｒ^３２はハロゲンである。他の例示的態様において、Ｒ^３０、Ｒ^３３、およびＲ^３４はＨである。他の例示的態様において、Ｒ^４０、Ｒ^４１、およびＲ^４２はＨである。他の例示的態様において、Ｒ^５１およびＲ^５２は、それらが結合している原子と一体となって、所望により置換または非置換６員環を形成してよい。 In an exemplary embodiment, Z ² is of the formula XV:

[Where,
R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ and R ⁵⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl , Substituted or unsubstituted heteroaryl, OR ⁵⁵ , SO ₂ NR ⁵⁵ R ⁵⁶ , CONR ⁵⁵ R ⁵⁶ , NR ⁵⁵ R ⁵⁶ , NO ₂ , CN, and halogen; and R ⁵⁰ , Any two of R ⁵¹ , R ⁵² , R ⁵³ and R ⁵⁴ together with the atoms to which they are attached form an optionally substituted or unsubstituted 5-8 membered ring. R ⁵⁵ is a member selected from H and substituted or unsubstituted alkyl. R ⁵⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. ]
It is a part of. In another exemplary embodiment, R ³² is halogen. In another exemplary embodiment, R ³⁰ , R ³³ , and R ³⁴ are H. In another exemplary embodiment, R ⁴⁰ , R ⁴¹ , and R ⁴² are H. In other exemplary embodiments, R ⁵¹ and R ⁵² may be joined together with the atoms to which they are attached to form an optionally substituted or unsubstituted 6-membered ring.

〔式中、
Ｒ^６０およびＲ^６１はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、ＯＲ^６２、ＮＯ_２、ＣＮ、ＮＲ^６２Ｒ^６３、Ｓ(Ｏ)_２ＮＲ^６２Ｒ^６３、ＮＲ^６２Ｓ(Ｏ)_２Ｒ^６３、Ｃ(Ｏ)ＮＲ^６２Ｒ^６３、Ｓ(Ｏ)_２Ｒ^６２およびハロゲンから独立して選択されるメンバーである。Ｒ^６２はＨおよび置換または非置換アルキルから選択されるメンバーである。Ｒ^６３はＨ、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリールおよび置換または非置換ヘテロアリールから選択されるメンバーである。〕
から選択されるメンバーである。 In other exemplary embodiments, Z ² is a moiety of formula XVI and a moiety of formula XVII:

[Where,
R ⁶⁰ and R ⁶¹ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR _{^{62, NO 2, CN, NR}} 62 R 63, S (O) 2 NR 62 R 63, NR 62 S (O) 2 R 63, C (O) NR 62 R 63, S (O) 2 R 62 and halogen Members who are selected independently from R ⁶² is a member selected from H and substituted or unsubstituted alkyl. R ⁶³ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. ]
A member selected from

の部分である。
他の例示的態様において、Ｚ^２は式XIX：

の部分である。 In an exemplary embodiment, Z ² is of formula XVIII:

It is a part of.
In another exemplary embodiment, Z ² is of the formula XIX:

It is a part of.

III. Reaction Conditions for the Process The following is provided to illustrate certain diverse methods available for the association of the compounds and mixtures of the present invention, which are useful reactions or reactions for the preparation of the compounds of the present invention. There is no intention to define the range of the order.

試薬および条件：ａ)ＣＨ_３ＣＮ、０.４Ｎ ＨＣｌ、ｒｔ、１時間；ｂ)Ｒｈ(ｃａｔ)、(Ｒ)−ＢＩＮＡＰ、Ｋ_２ＣＯ_３、ジオキサン／Ｈ_２Ｏ、８０℃、６時間；ｃ)ＣＡＮ、ＣＨ_３ＣＮ／Ｈ_２Ｏ ＯＣ ４時間。 The compound used in the present invention is synthesized according to Scheme 1.
Scheme 1

Reagents and conditions: a) CH ₃ CN, 0.4N HCl, rt, 1 hour; b) Rh (cat), (R) -BINAP, K ₂ CO ₃ , dioxane / H ₂ O, 80 ° C., 6 hours; _{c) CAN, CH 3 CN /} H 2 O OC 4 hours.

  In the first step of Scheme 1, compounds 1 and 2 can be reacted under the conditions of step a to form compound 3. Compound 4 can be synthesized by mixing the aryl moiety and borate ester with a palladium catalyst. Compounds 3 and 4 can be reacted under the conditions of step b to form compound 5. Finally, the pyrrolidone nitrogen can be deprotected under the conditions of step c to form compound 6.

Another reaction involved in the method of the present invention is a deprotection reaction. In an exemplary embodiment, the protecting group is removed as shown in Scheme 2.
Scheme 2

  In Scheme 2, compound 6 is reacted with a palladium catalyst to remove the benzyl protecting group and produce compound 7.

Another reaction involved in the method of the present invention is an arylation reaction. In an exemplary embodiment, an aryl moiety can be added as shown in Scheme 3.
Scheme 3

  In Scheme 3, compound 7 is reacted with an aryl moiety and a base to produce compound 8.

Another reaction involved in the method of the present invention is the attachment of the aryl moiety to the lactam nitrogen. In an exemplary embodiment, an aryl moiety is added as shown in Scheme 4.
Scheme 4

  In Scheme 4, compound 8 is reacted with aryl moiety 9 under the reaction conditions described above to produce compound 10.

  The compounds of the present invention are generally synthesized by an appropriate combination of known synthetic methods. Techniques useful for the synthesis of the compounds of the present invention will be readily apparent and available to those skilled in the relevant art.

  Although the invention has been described with reference to specific embodiments, other embodiments and variations of the invention can be devised by other persons skilled in the art without departing from the true spirit and scope of the invention. Is obvious.

General In the following examples, temperatures are given in degrees Celsius (° C.) unless otherwise specified; operations were conducted at room or ambient temperature, “rt”, or “RT” (typically in the range of about 18-25 ° C.). Solvent evaporation was performed under reduced pressure (typically 4.5-30 mm Hg) using a rotary evaporator at bath temperatures up to 60 ° C .; the course of the reaction was typically by thin layer chromatography (TLC) The reaction time is provided for illustrative purposes only; melting points are uncorrected; product showed sufficient ¹ H-NMR and / or microanalytical data; yield is for illustrative purposes only And the following common abbreviations are also used: mp (melting point), L (liter), mL (milliliter), mmol (mmol), g (gram), mg (milligram), min (minute), and h (time).

Unless otherwise noted, all solvents (HPLC grades) and reagents were purchased from suppliers and tapped without further purification. Reactions were carried out under argon unless otherwise specified. Analytical TLC was performed on Whatman Inc. 60 silica gel plates (0.25 mm thick). Compounds were visualized under UV lamp (254 nM) or by color development with KMnO ₄ / KOH, ninhydrin or Hanesian solutions. Flash chromatography was performed using silica gel from Selectro Scientific (particle size 32-63). ¹ H NMR, ¹⁹ F NMR and ¹³ C NMR spectra were performed on a Varian 300 machine at 300 MHz, 282 MHz and 75.7 MHz, respectively. Melting points were recorded on an Electrothermal IA9100 instrument and were uncorrected.

Example 1
Preparation of 6 1.1 Synthesis of 3 p-anisidine 2 (18.48 g, 0.15 mol, 1 eq) and 2,5-dimethoxy-2,5-dihydrofuran, 1 (39.04 g, 0.3 mol, 2 Equivalent) in acetonitrile (750 mL) was added 0.4N aqueous HCl (600 mL) solution. The reaction mixture was stirred at rt for 1 h, quenched with NaHCO ₃ (40.32 g, 0.48 mol, 2 eq against HCl), concentrated under reduced pressure at 27 ° C. and partitioned between EtOAc and H ₂ O. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by column chromatography using hexane: EtOAc (1: 1) to give 1- (4-methoxy-phenyl) -1,5-dihydro-pyrrol-2-one, 3 (10.85 g, 38 %).

1.2 Results The analysis data of structure 3 is shown below.

1.2.a 1- (4-Methoxy-phenyl) -1,5-dihydro-pyrrol-2-one
¹ H NMR (CDCl ₃ ): δ 7.57 (2 H, d, J = 9.2 Hz), 7.14 (1 H, dt, J = 0.8, 6.0 Hz), .6.92 (2 H, d, J = 9.2 Hz), 6.26 (1 H, dt, J = 0.8, 6.0), 4.40 (2 H, t, J = 1.6), 3.80 (3 H, s) ppm.

1. Synthesis of 34 2-Benzyloxy-4-bromo-1-chloro-benzene (120 g, 0.4 mol), diborate (107.5 g, 0.42 mol), KOAc (117.8 g, 3 eq), Pd A mixture of (dppf) ₂ Cl ₂ (1% mole) and 500 mL DMF was degassed with stirring and refilled with nitrogen. The mixture was heated at 80 ° C. for 3 hours. DMF was removed in vacuo and a residue formed. The residue was mixed with ethyl acetate and then filtered. After filtration, the solid was washed with ethyl acetate (3 × 20 mL) and recrystallized with ethyl acetate to give 97 g of pure product. The mother liquor was also concentrated. The residue was purified by column chromatography (10% ethyl acetate / hexane) to give the crude product, which was recrystallized from ethyl acetate. The product was 2- (4-chloro-3-benzyloxy-phenyl) -4,4,5,5, -tetramethyl [1,3,2] dioxaborolane, 4.

1.4 Results The analysis data of structure 4 is shown below.

1.4.a ( 4-Chloro-3-benzyloxy-phenyl) -4,4,5,5, -tetramethyl [1,3,2] dioxaborolane
¹ H NMR (CDCl ₃ ): δ 7.35 (2 H, d, J = 7.6 Hz), 7.28 (1 H, brs), 7.17-7.26 (5 H, m), 7.11 (1 H, s), 5.02 ( 2 H, s), 1.20 (12 H, s) ppm.

1.5 Synthesis of 5 3 (9 g, 47.57 mmol, 1 eq), 4 (32.8 g, 95.14 mmol, 2 eq), chloro (1,5-cyclooctadiene) rhodium (I) dimer ( 352mg, 0.7136mmol, 0.015 eq), (R) -BINAP (1.04g , 1.665mmol, 0.035 eq) and _{K 2 CO 3 (3.3g, 23.8mmol} , 0.5 equiv) A dioxane: water (10: 1) solution of was purged with nitrogen and heated at 80 ° C. in an oil bath for 26 hours. The reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined EtOAc extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography (5: 4 hexane: EtOAc) to give a solid product. Recrystallization from EtOAc and hexane gave the product (R) -4- (3-benzyloxy-4-chloro-phenyl) -1- (4-methoxy-phenyl) -pyrrolidin-2-one, 5. .

1.6 Results The analytical data for structure 5 are shown below.

1.6.a ( R) -4- (3-Benzyloxy-4-chloro-phenyl) -1- (4-methoxy-phenyl) -pyrrolidin-2-one
¹ H NMR (CDCl ₃ ): δ 7.48 (2 H, d, J = 9.2 Hz), 7.44 (2 H, m), 7.32-7.39 (4 H, m), 6.92 (2 H, d, J = 9.2 Hz), 6.86 (1 H, d, J = 1.6 Hz), 6.83 (1 H, dd, J = 0.8, 8.0 Hz), 5.16 (2 H, s), 4.12 (1 H, dd, J = 8.0, 9.6 Hz), 3.81 (3 H, s), 3.75 (1 H, dd, J = 6.8, 9.6 Hz), 3.63 (1 H, dddd, J = 8 Hz), 2.98 (1 H, dd, J = 8.8, 16. 8 Hz), 2.68 (1 H, dd, J = 16.8, 8.4 Hz) ppm.

1.7 Synthesis of 6 5 (16.5 g, 40 mmol, 1 eq) in CH ₃ CN (1400 mL) was added to a solution of cerium ammonium nitrate (CAN) (65.8 g, 0.12 mol, 3 eq) in 50% aqueous CH _3. The CN solution was added dropwise at 0 ° C. The reaction mixture is stirred at 0 ° C. for 1 h and Na ₂ S ₂ O ₃ (45.4 g, 0.36 mol, 9 eq) is added. The reaction mixture was stirred at 0 ° C. for an additional hour and filtered through Celite to remove the precipitate. The filtrate was concentrated under reduced pressure and the residue was partitioned between 5% MeOH in EtOAc and H ₂ O. The aqueous phase was extracted with 5% MeOH in EtOAc and the combined extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated. Purification through column chromatography (40: 1 CH ₂ Cl ₂ : MeOH) gave the product, (R) -4- (3-benzyloxy-4-chloro-phenyl) -pyrrolidin-2-one, 6 Obtained.

1.8 Results The analytical data for structure 6 are shown below.

1.8.a ( R) -4- (3-Benzyloxy-4-chloro-phenyl) -pyrrolidin-2-one
¹ H NMR (CDCl ₃ ): δ 7.41 (d, 2H, J = 7.6 Hz), 7.35 (t, 2H, J = 6.8 Hz), 7.29 (d, 2H, J = 8.0 Hz), 6.78 (d, 1H , J = 2.0 Hz), 6.75 (dd, 1H, J = 2.0, 8.0 Hz), 5.58 (brs, 1H), 5.11 (s, 2H), 3.70 (t, 1H, J = 8.4 Hz), 3.62-3.56 (m, 1H), 2.27 (dd, 1H, J = 6.8, 9.2 Hz), 2.66 (dd, 1H, J = 8.8, 16.8 Hz), 2.36 (dd, 1H, J = 9.2, 17.2 Hz); LCMS m / z 302.20 [M + H] ⁺ .

Example 2
Determination of the effect of R ¹ substituents Tests were conducted with pyrrolidones having various substituents on the endocyclic nitrogen. The general reaction scheme is shown in Scheme 5. Various R ¹ substituents are also mentioned. The results of these tests are as follows:
Scheme 5

  Surprisingly, the% recovery of these reactions increased from 35% to about 80% when the benzyl group was replaced with a phenyl group at the Z position. This is in contrast to the asymmetric synthesis reaction described in Senda, where yields of up to 75% were recorded with piperidinones having a benzyl group in the position corresponding to the Z position.

Example 3
Determination of the effect of boronate ester Y substituents Tests were conducted with boronate esters having various Y substituents. The general reaction scheme is shown in Scheme 6. Various boronic ester substituents are also mentioned. The results of these experiments are as follows:
Scheme 6

Example 4
Determination of the influence of the base in the reaction conditions Tests were carried out with different base types used. The general reaction scheme is shown in Scheme 7. Various bases are also mentioned. The results of these experiments are as follows:
Scheme 7

  All patents, patent applications and other publications cited herein are incorporated by reference in their entirety.

Claims (25)

A process for the preparation of an amide-containing heterocycle or a pharmaceutically acceptable salt thereof:
a) Organometallic rhodium (I) complex, chiral ligand, Formula I:

[Where,
R ¹ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R ² , R ³ , and R ⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, OR ^5a , NO ₂ , CN, halogen, C (O) R ^5b , NR ^5a R ^5b , C (O) NR ^5a R ^5b and C (O) OR ^5b are members independently selected ,
Wherein R ^5a is a member selected from H and substituted or unsubstituted alkyl;
R ^5b is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl Be a member. ]
Of α, β unsaturated amide-containing heterocycles and Formula II:

[Where,
R ⁶ is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R ⁷ and R ⁸ are independent of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Wherein R ⁷ and R ⁸ together with the oxygen atom to which they are attached optionally form a substituted or unsubstituted 5-8 membered ring,
here,
R ¹⁰ is a member selected from H and substituted or unsubstituted alkyl. ]
A boronic ester of formula III

Reacting under conditions sufficient to form a product containing an amide-containing heterocycle, thereby producing the amide-containing heterocycle or a pharmaceutically acceptable salt thereof. The product is of formula IIIa:

The method of claim 1, further comprising an amide-containing heterocycle of:   The method of claim 2, wherein the product has an ee of about 60% or greater.   The method of claim 1, wherein the organometallic rhodium (I) complex comprises a chiral ligand selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.   The method of claim 1, wherein the chiral ligand comprises an aryl substituted phosphine. R ⁶ is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzofuranyl The method of claim 1, wherein the member is a member selected from: substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted quinazolinyl and substituted or unsubstituted quinoxalinyl. The method of claim 1, wherein R ¹ is a member selected from substituted or unsubstituted phenyl and substituted or unsubstituted benzyl. The method of claim 1, wherein R ¹ is substituted or unsubstituted phenyl.   The method of claim 2, wherein the product has an ee of about 80% or greater. 4. The method of claim 3, further comprising the step of b) purifying the mixture of step a) and thus producing a product having a greater ee than after step a).   The method of claim 10, wherein the purification comprises subjecting the mixture to a recovery process including column chromatography and recrystallization. Formula IV:

And a compound of formula IVa:

A mixture comprising a compound of the above formula:
R ¹¹ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R ¹² , R ¹³ , and R ¹⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member independently selected from heteroaryl, OR ¹⁵ , NO ₂ , CN, halogen, C (O) R ¹⁵ , NR ¹⁵ R ¹⁶ , C (O) NR ¹⁵ R ¹⁶ and C (O) OR ¹⁵ ,
here,
R ¹⁵ is a member selected from H and substituted or unsubstituted alkyl;
R ¹⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl And
here,
R ¹⁷ is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. ].   13. The mixture of claim 12, wherein the mixture has an ee of about 60% or greater. a) Organometallic rhodium (I) complex, chiral ligand, formula V:

[Where,
R ¹¹ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R ¹² , R ¹³ , and R ¹⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member independently selected from heteroaryl, OR ¹⁵ , NO ₂ , CN, halogen, C (O) R ¹⁵ , NR ¹⁵ R ¹⁶ , C (O) NR ¹⁵ R ¹⁶ and C (O) OR ¹⁵ ,
here,
R ¹⁵ is a member selected from H and substituted or unsubstituted alkyl;
R ¹⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. ]
An α, β unsaturated N-substituted heterocycle of formula II:

[Where,
R ⁶ is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R ⁷ and R ⁸ are independent of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Wherein R ⁷ and R ⁸ together with the oxygen atom to which they are attached optionally form a 5- to 8-membered ring. ]
13. The mixture of claim 12 prepared by a process comprising reacting with a boronic ester of under conditions sufficient to form the mixture. R ¹¹ is a member selected from substituted or unsubstituted phenyl and substituted or unsubstituted benzyl, claim 12 mixture according. R ¹¹ is a substituted or unsubstituted phenyl, claim 12 mixture according. Formula VI:

[Where,
R ¹² , R ¹³ , and R ¹⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member independently selected from heteroaryl, OR ¹⁵ , NO ₂ , CN, halogen, C (O) R ¹⁵ , NR ¹⁵ R ¹⁶ , C (O) NR ¹⁵ R ¹⁶ and C (O) OR ¹⁵ ,
here,
R ¹⁵ is a member selected from H and substituted or unsubstituted alkyl;
R ¹⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl Is;
R ³⁰ , R ³² , R ³³ , and R ³⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted Or independently selected from unsubstituted heteroaryl, OR ¹⁹ , NO ₂ , CN, halogen, C (O) R ¹⁹ , NR ¹⁹ R ²⁰ , C (O) NR ¹⁹ R ²⁰ and C (O) OR ¹⁹ A member,
here,
R ³³ and R ³⁴ or R ³³ and R ³² or R ³² and Z ¹ together with the atoms to which they are attached, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Forming at least a 5-membered ring selected from aryl and substituted or unsubstituted heteroaryl;
R ¹⁹ is a member selected from H, substituted or unsubstituted aryl and substituted or unsubstituted alkyl;
R ²⁰ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl Is;
Z ¹ is represented by formula VII:

(Where
R ⁴⁰ , R ⁴¹ , and R ⁴² are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member independently selected from heteroaryl, OR ⁴⁴ , NO ₂ , CN, and halogen;
here,
R ⁴⁴ is a member selected from H and substituted or unsubstituted alkyl; and R ⁴³ is halogen. )
Part of;
Z ² is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. ]
A process for the preparation of the compound and its enantiomers:
a) Organometallic rhodium (I) complex, chiral ligand, Formula VIII:

[Where,
X ^* is a protecting group;
R ¹² , R ¹³ , and R ¹⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted It is a member independently selected from heteroaryl, OR ²⁵ , NO ₂ , CN. ]
An α, β unsaturated N-substituted heterocycle of formula IX:

[Where,
R ³⁰ , R ³² , R ³³ , and R ³⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted Or a member independently selected from unsubstituted heteroaryl, OR ¹⁹ , NO ₂ , CN, and halogen;
Y ^* is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR ¹⁹ , NO ₂ is a member selected from CN and halogen;
R ¹⁷ and R ¹⁸ are independent of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl And R ¹⁷ and R ¹⁸ together with the oxygen atom to which they are attached form an optionally substituted or unsubstituted 4-8 membered ring,
Wherein R ¹⁹ is a member selected from H, substituted or unsubstituted aryl and substituted or unsubstituted alkyl. ]
A boronic ester of formula X:

Reacting under conditions sufficient to form a mixture comprising a amide-containing heterocycle and an enantiomer thereof, wherein the mixture has an ee of about 60% or greater;
b) subjecting the product of step a) to a deprotection reaction to remove X ^* , to obtain the formula XI:

And the enantiomers thereof;
c) subjecting the product of step b) to a deprotection reaction to remove Y ^* to give the formula XII:

And the enantiomers thereof;
d) subjecting the product of step c) to an arylation reaction to form Formula XIII:

[Where,
Z ¹ is the formula XIV

(Where
R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , and R ⁴⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Independently from aryl, substituted or unsubstituted heteroaryl, OR ⁴⁶ , NO ₂ , CN, halogen, C (O) R ⁴⁶ , NR ⁴⁶ R ⁴⁷ , C (O) NR ⁴⁶ R ⁴⁷ and C (O) OR ⁴⁶ Is a selected member,
here,
R ⁴⁶ is a member selected from H and substituted or unsubstituted alkyl;
R ⁴⁷ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. )
It is a part of. ]
And the enantiomers thereof;
e) Arylating the lactam nitrogen of the product of step d) to give a compound of formula VI:

[Where,
Z ² is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. ]
And the enantiomers thereof,
Thereby producing a compound having the formula VI. Z ² has the formula XV:

[Where,
R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ and R ⁵⁴ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl , Substituted or unsubstituted heteroaryl, OR ⁵⁵ , SO ₂ NR ⁵⁵ R ⁵⁶ , CONR ⁵⁵ R ⁵⁶ , NR ⁵⁵ R ⁵⁶ , NO ₂ , CN, and halogen; and R ⁵⁰ , Any two of R ⁵¹ , R ⁵² , R ⁵³ and R ⁵⁴ are united with the atom to which they are bonded and united with the atom to which they are bonded, optionally substituted or unsubstituted 5 Form an 8-membered ring,
here,
R ⁵⁵ is a member selected from H and substituted or unsubstituted alkyl;
R ⁵⁶ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. ]
The method of claim 17, wherein The method of claim 17, wherein R ³² is halogen. The method of claim 18, wherein R ³⁰ , R ³³ , and R ³⁴ are H. The method of claim 17, wherein R ⁴⁰ , R ⁴¹ , and R ⁴² are H. R ⁵¹ and R ⁵² are, they together with the atoms to which are attached, form a substituted or unsubstituted 6-membered ring, The method of claim 18, wherein. Z ² is a moiety of formula XVI and a moiety of formula XVII:

[Where,
R ⁶⁰ and R ⁶¹ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR _{^{62, NO 2, CN, NR}} 62 R 63, S (O) 2 NR 62 R 63, NR 62 S (O) 2 R 63, C (O) NR 62 R 63, S (O) 2 R 62 and halogen A member selected independently from
here,
R ⁶² is a member selected from H and substituted or unsubstituted alkyl;
R ⁶³ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl It is. ]
The method of claim 17, wherein the method is a member selected from: Z ² is of formula XVIII:

24. The method of claim 23, wherein Z ² is the formula XIX:

The method of claim 17, wherein