KR20170080190A - Method for preparing eight-membered heterocycles using catalytic cycloaddition of 1,5-dipole and eight-membered heterocycles prepared thereby - Google Patents

Abstract

The present invention relates to 1,5-dipole (1,5-dipole); And an enol diazoacetate in the presence of a metal catalyst. The present invention also provides a method for producing an 8-membered heterocyclic compound.
According to the production method of the present invention, an 8-membered heterocyclic compound can be produced in a high yield by inducing a [5 + 3] cyclization addition reaction to 1,5-dipole and enodiaacetic acid compound in the presence of a rhodium catalyst.

Description

A method for preparing an 8-membered heterocyclic compound using a [5 + 3] cyclization addition reaction of 1,5-dipole and an 8-membered heterocyclic compound prepared by the method -dipole and eight-membered heterocycles prepared thereby.

The present invention relates to a method for preparing an 8-membered ring compound through a [5 + 3] cyclization addition reaction of a 1,5-dipole based on a metal catalyst, and a method for preparing an 8- .

 Dipolar cycloaddition is an effective method for the synthesis of heterocyclic compounds in a single process in which no by-products are produced.

In the past, studies have been conducted focusing on the [3 + 2] cycloaddition reaction in which 1,3-dipoles are reacted with 2π-dipolarophiles themselves, Methods for the formation of heterocyclic compounds other than 5-membered rings of different sizes by introducing additional variants such as 2-dipole, 1,4-dipole or 1,5-dipole have been studied but limited.

[4 + 2] cyclization using, for example, 2-alkyl-2,3-butadienoate and 1,4-dipole synthon A method for producing six-membered heterocycles through an addition reaction has been disclosed, and atypical 1,2-dipole 2-acrylcyclopropane-1,1-dicarboxylic acid (2 -arylcyclopropane-1,1-dicarboxylate) has been disclosed for a dimerization reaction to produce tetralin via a similar cyclization addition reaction.

Such examples clearly demonstrate a compatible match such as the complexation of the product as well as the cyclization structure in the relationship between the dipole and the proton bipole itself and, as it is known to be controllable, eventually a new 1, n- Dipole development is urgently required.

Eight-membered heterocycles, on the other hand, are compounds that form a structural core in a number of biologically important natural products and medicines, and are among the most notable compounds. Although the high-order cyclization addition reaction is an efficient synthesis method for producing an 8-membered heterocyclic compound using a single process, the enthalpy and entropy factors that interfere with the higher-order cyclization addition reaction are very limited. For this reason, most 8-membered heterocyclic compounds are synthesized by cross-coupling reaction, Heck reaction, or ring-closing metathesis.

In the past, only a few pioneering studies on the [5 + 3] cycloaddition reaction for the synthesis of such 8-membered heterocyclic compounds have been reported. For example, as shown in Figure 1 (a), the 3-oxidopyrylium zwitterionic intermediate synthesized in situ from acetoxypyranone is doubly linked by dimerization 8-membered heterocyclic compounds (Hendrickson et al., 1980).

In addition, as shown in Fig. 1 (b), a [5 + 3] cyclization addition reaction between molybdenum p complexes and allylic acetals was induced using Lewis acid catalyst, - (oxa-) or aza- [3.3.1] bicyclic complexes have been reported (Liebeskind et al.).

A method of synthesizing an 8-membered ring compound by intramolecular cyclization using the in situ synthesized 1,5-ampholytic intermediate such as the above example has been disclosed, but its range is very limited.

Accordingly, a study is needed on a method for producing an 8-membered heterocyclic compound in a high yield through a [5 + 3] cyclization addition reaction using a novel 1, n-dipole.

 (a) X. Xu, M. P. Doyle, Acc. Chem. Res. 2014, 47, 1396; (b) K. V. Gothelf, K. A. J ㆈ rgensen, Chem. Rev. 1998,98, 863; (c) 1,3-Dipolar Cycloaddition Chemistry, Vol. 1 & 2 (Ed .: A. Padwa), Wiley, New York, 1984, p. 1521.  Selected references for 1,2- and 1,4-dipole precursors: (a) R. Huisgen in Topics in Heterocyclic Chemistry (Ed .: R. Castle), Wiley, New York, 1969, chap. 8; (b) A. Padwa, S. R. Harring, M. A. Semones, J. Org. Chem. 1998, 63, 44; (c) I. Ungureanu, P. Klotz, A. Schoenfelder, A. Mann, Chem. Commun. 2001,958; (d) V. Nair, A. R. Sreekanth, N. Abhilash, M. M. Bhadbhade, R. C. Gonnade, Org. Lett. 2002, 4, 3575; (e) B. Alcaide, P. Almendros, I. Fernøndez, C. Løzaro-Milla, Chem. Commun. 2015, 51, 3395; (f) Y. Li, X. Su, W. Zhou, W. Li, J. Zhang, Chem. Eur. J. 2015, 21, 4224.  (a) X.-F. Zhu, J. Lan, O. Kwon, J. Am. Chem. Soc. 2003, 125, 4716; (b) R. A. Novikov, A. V. Tarasova, V. A. Korolev, V. P. Timofeev, Y. V. Tomilov, Angew. Chem. Int. Ed. 2014, 53, 3187; Angew. Chem. 2014, 126, 3251.  Recent review: K. C. Majumdar, RSC Adv. 2011, 1, 1152.  Selected references: (a) P. A. Wender, A. G. Correa, Y. Sato, R. Sun, J. Am. Chem. Soc. 2000, 122, 7815; (b) M. Potowski, J. O. Bauer, C. Strohmann, A. P. Antonchick, H. Waldmann, Angew. Chem. Int. Ed. 2012, 51, 9512; Angew. Chem. 2012, 124, 9650; (c) Z.-L. He, H.-L. Teng, C.-J. Wang, Angew. Chem. Int. Ed. 2013, 52, 2934; Angew. Chem. 2013, 125, 3006; (d) Z.-L. He, C.-J. Wang, Chem. Commun. 2015, 51, 534.  (a) J. B. Hendrickson, J. S. Farina, J. Org. Chem. 1980, 45, 3361; (b) R. G. Arrayøs, L. S. Liebeskind, J. Am. Chem. Soc. 2003, 125, 9026.  (a) E. O. M. Orlemans, B. H. M. Lammerink, F. C. J. M. V. Veggel, W. Verboom, S. Harkema, D. N. Reinhoudt, J. Org. Chem. 1988, 53, 2278; (b) F. A. G. El-Essawy, S. M. Yassin, I. A. El-Sakka, A. F. Khattab, I.S. Madsen, A. Senning, J. Org. Chem. 1998, 63, 9840; (c) D. Garayalde, C. Nevado, ACS Catal. 2012, 2, 1462.

Disclosure of Invention Technical Problem [7] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a novel 5-dipole (1,5-dipole) The present invention is directed to a method for producing an 8-membered heterocyclic compound.

In order to accomplish the above object, the present invention provides a 1,5-dipole represented by the following general formula (1); And a step of reacting enol diazoacetate represented by the following formula (2) in the presence of a metal catalyst:

[Chemical Formula 1]

(2)

(3)

(In the above Formulas 1 to 3,

R ¹ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, Or a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;

R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted arylalkyl group, A substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;

R ³ is a substituted or unsubstituted phenyl group;

R ⁴ is a silyl ester group;

And R < ⁵ > is an alkyl group having 1 to 8 carbon atoms.

Each of R ¹ and R ² is independently a substituted or unsubstituted phenyl group, an alkyl group having 1 to 5 carbon atoms, or a naphthyl group;

R ³ is tolyl, Ph, (4-OMe) C ₆ H ₄ or 4-CF ₃ (C ₆ H ₄ );

R ⁴ is a triisopropylsilyl group or a tert-butyldimethylsilyl group;

R ⁵ is characterized in that it is an alkyl group having 1 to 5 carbon atoms.

The metal catalyst may be at least one selected from the group consisting of bis [rhodium α, α, α ', α'-tetramethyl-1,3-benzene dipropionic acid] 3-benzenedipropionic acid)], [ Rh 2 (esp) 2]), rhodium pivalate dimer (rhodium (II) pivalate dimer, [Rh 2 (OPiv) 4]), tetrakis [(S) - (+) - (1-adamantyl) - (N-phthalimido) acetato] dirhodium (II) (Tetrakis [(S) - (II) (Tetrakis [(S) -N-phthaloylvalidate] dirhodium (II) (Rh ₂ (S-PTAD) ₄ )], tetrakis [ _{, [Rh 2 (S-PTV} ) 4]) and di-rhodium (II) tris (N- phthaloyl - (S) - tert-ryusi carbonate) (dirhodium (II) tris ( N-phthaloyl- (S) - tert-leucinate, Rh ₂ (S-PTTL) ₄ ].

Further, the production method is characterized in that the reaction is carried out at 0 to 60 ° C.

Further, the production method is characterized in that dichloromethane, dichloroethane or toluene is used as a solvent.

Further, the production method is characterized in that an additional adsorbent is added and reacted.

The present invention also provides an 8-membered heterocyclic compound represented by formula (3): < EMI ID =

(3)

(In the above Formulas 1 to 3,

R ¹ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, Or a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;

R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted arylalkyl group, A substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;

R ³ is a substituted or unsubstituted phenyl group;

R ⁴ is a silyl ester group;

And R < ⁵ > is an alkyl group having 1 to 8 carbon atoms.

The 8-membered heterocyclic compound is characterized by being any one of the following compounds:

1) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl-3-tosyl-4,6a-dihydro-3H-pyrido [ d] [l, 4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1,10-diphenyl-3-tosyl-4,6a-dihydro -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

2) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

3) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- methoxyphenyl) Pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

4) Synthesis of (1Z, 5Z) -methyl-10- (4- (tert -butyl) phenyl) -5 - ((tert- butyldimethylsilyl) oxy) -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 3-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

5) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

6) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- chlorophenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -10- (4-chlorophenyl) -1 -phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

7) Synthesis of (1Z, 5Z) -methyl-10- (4-acetylphenyl) -5 - ((tert- butyldimethylsilyl) oxy) (1Z, 5Z) -methyl-10- (4-acetylphenyl) -5 - ((tert-butyldimethylsilyl) oxy) -1 -phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

8) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

9) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (3- methoxyphenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -10- (3-methoxyphenyl) - 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

10) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (naphthalen- Pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

11) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -9-methyl-1,10-diphenyl-3-tosyl-4,6a-dihydro- 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- -tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

12) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -8-methyl-1,10-diphenyl-3-tosyl-4,6a-dihydro- 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- -tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

13) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- phenyl- 1- (p- tolyl) -3-tosyl-4,6a-dihydro-3H- [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

14) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4-methoxyphenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -1- (4-methoxyphenyl) - 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

15) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) Methyl-5 - ((tert-butyldimethylsilyl) oxy) -10-phenyl-lH- 3,4-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

16) Synthesis of (1Z, 5Z) -methyl- l- (4-bromophenyl) -5- (tert- butyldimethylsilyl) oxy- Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 1- (4-bromophenyl) -5- (tert- butyldimethylsilyl) 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

17) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4- fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

18) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

19) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (3-fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

20) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl-3- (phenylsulfonyl) 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1,10- diphenyl- 3- (phenylsulfonyl) -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

21) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -3 - ((4-methoxyphenyl) sulfonyl) -1,10- -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- -methoxyphenyl) sulfonyl) -1,10-diphenyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

22) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10- 6-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) , 10-diphenyl-3 - ((4- (trifluoromethyl) phenyl) sulfonyl) -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}.

According to the process for producing an 8-membered heterocyclic compound according to the present invention, a [5 + 3] cyclization addition reaction to 1,5-dipole and enodiaacetic acid compounds is induced in the presence of a rhodium catalyst, Compounds can be prepared.

FIG. 1 is a view showing a reaction formula showing a process for preparing an 8-membered ring compound according to a conventional [5 + 3] cyclization addition reaction.
FIG. 2 is a view showing a reaction formula showing a process for preparing an 8-membered heterocyclic compound according to the process for producing an 8-membered heterocyclic compound according to the present invention.
3 is a diagram showing an anticipatory mechanism of a reaction for producing an 8-membered heterocyclic compound by reacting a pyridinium ampholytic ion 1,5-dipole and enodiaacetic acid under a rhodium catalyst, according to an example of the present invention.
4 is a diagram showing the X-ray crystal analysis results and chemical formulas of the cyclic compound prepared by the method according to Example 1-4.
5 is a diagram showing the formula of the cyclic compound prepared by the method according to Examples 2-1 to 2-12.
6 is a diagram showing the formula of the cyclic compound prepared by the method according to Examples 2-13 to 2-22.
7 is a diagram showing reaction schemes and yields showing a process for producing an 8-membered heterocyclic compound according to the methods of Examples 3-1 to 3-6.

In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

Embodiments in accordance with the concepts of the present invention can make various changes and have various forms, so that specific embodiments are illustrated in the drawings and described in detail in this specification or application. It should be understood, however, that the embodiments according to the concepts of the present invention are not intended to be limited to any particular mode of disclosure, but rather all variations, equivalents, and alternatives falling within the spirit and scope of the present invention.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, the terms "comprises ", or" having ", or the like, specify that there is a stated feature, number, step, operation, , Steps, operations, components, parts, or combinations thereof, as a matter of principle.

And, unless specified otherwise, the following terms and phrases used herein have the following meanings.

"Alkyl" is a hydrocarbon having a normal, secondary, tertiary or cyclic carbon atom. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C ₁ -C ₂₀ alkyl), 1 to 10 carbon atoms (i.e., C ₁ -C ₁₀ alkyl), or 1 to 6 carbon atoms C ₁ -C ₆ alkyl). Examples of suitable alkyl groups include methyl (Me, -CH _3), ethyl _{(Et, -CH 2 CH 3)} , 1- propyl (n -Pr, n - _{propyl, -CH 2 CH 2 CH 3)} , 2- propyl ( i -Pr, i - _{propyl, -CH (CH 3) 2)} , 1- butyl (n -Bu, n - _{butyl, -CH 2 CH 2 CH 2 CH} 3), 2- methyl-1-propyl (i - Bu, i - _{butyl, -CH 2 CH (CH 3)} 2), 2- butyl (s -Bu, s - _{butyl, -CH (CH 3) CH 2} CH 3), 2- methyl-2-propyl (t -Bu, t - _{butyl, -C (CH 3) 3)} , 1- pentyl (n - _{pentyl, -CH 2 CH 2 CH 2 CH} 2 CH 3), 2- pentyl _{(-CH (CH 3) CH 2} CH ₂ CH _3), 3- pentyl _{(-CH (CH 2 CH 3)} 2), 2- methyl-2-butyl _{(-C (CH 3) 2 CH} 2 CH 3), 3- methyl-2-butyl (- _{CH (CH 3) CH (CH} 3) 2), 3- methyl-1-butyl _{(-CH 2 CH 2 CH (CH} 3) 2), 2- methyl-1-butyl (-CH ₂ CH (CH ₃₎ CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ) _{CH (CH 2 CH 3) (} CH 2 CH 2 CH 3)), 2- methyl-2-pentyl _{(-C (CH 3) 2 CH} 2 CH 2 CH 3), 3- methyl-2-pentyl (-CH _{(CH 3) CH (CH 3} ) CH 2 CH 3), 4- methyl-2-pentyl _{(-CH (CH 3) CH 2} CH (CH 3) 2), 3- methyl-3-pentyl (-C ( CH ₃₎ (CH ₂ CH _{3) 2),} 2-methyl-3-pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2,3- dimethyl-2-butyl _{(-C (CH 3) 2 CH} (CH 3 ) _2), 3,3-dimethyl-2-butyl _{(-CH (CH 3) C (} CH 3) 3, and octyl (- (CH ₂₎ include ₇ CH _3), but are not limited to.

"Alkoxy" means a group having the formula -O-alkyl wherein the alkyl group as defined above is attached to the parent compound through an oxygen atom. The alkyl portion of the alkoxy group may contain from 1 to 20 carbon atoms (i.e., C ₁ -C ₂₀ alkoxy), from 1 to 12 carbon atoms (i.e., C ₁ -C ₁₂ alkoxy), or from one to six carbon atoms C ₁ -C ₆ alkoxy). Examples of suitable alkoxy groups are methoxy (-O-CH ₃ or -OMe), ethoxy (-OCH ₂ CH ₃ or -OEt), t-butoxy (-OC (CH ₃ ) ₃ or -O-tBu) , And the like.

The "haloalkyl" is an alkyl group in which at least one of the hydrogen atoms of the alkyl group defined above is substituted with a halogen atom. The alkyl portion of the haloalkyl group is optionally substituted with from 1 to 20 carbon atoms (i.e., C ₁ -C ₂₀ haloalkyl), from 1 to 12 carbon atoms (i.e., C ₁ -C ₁₂ haloalkyl), or from 1 to 6 carbon atoms I.e., C ₁ -C ₆ alkyl). Examples of suitable haloalkyl groups include such as _{-CF 3, -CHF 2, -CFH 2} , -CH 2 CF 3 , but are not limited to.

"Aryl" means an aromatic hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, the aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

"Alkenyl" is one or more unsaturated regions, carbon-carbon, hydrocarbons having normal, secondary, tertiary or cyclic carbon atoms with sp ² double bonds. For example, an alkenyl group may have 2 to 20 carbon atoms (i.e., C ₂ -C ₂₀ alkenyl), 2 to 12 carbon atoms (i.e., C ₂ -C ₁₂ alkenyl), or 2 to 6 carbon atoms (I.e., C ₂ -C ₆ alkenyl). Examples of suitable alkenyl groups include ethylene or vinyl (-CH = CH _2), allyl _{(-CH 2 CH = CH 2)} , cyclopentenyl (-C ₅ H _7), and 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH = CH ₂ ).

"Alkynyl" is one or more unsaturated moieties, that is, hydrocarbons having normal, secondary, tertiary or cyclic carbon atoms with carbon-carbon, sp triple bonds. For example, an alkynyl group may have 2 to 20 carbon atoms (i.e., C ₂ -C ₂₀ alkynyl), 2 to 12 carbon atoms (i.e., C ₂ -C ₁₂ alkynyl), or 2 to 6 carbon atoms (I.e., C ₂ -C ₆ alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C? H), propargyl (-CH _{2 C?} H), and the like.

"Arylalkyl" refers to a non-cyclic alkyl radical in which one hydrogen atom bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced by an aryl radical. Typical arylalkyl groups include but are not limited to benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2- It does not. The arylalkyl group may have from 6 to 20 carbon atoms, for example, the alkyl moiety may contain from 1 to 6 carbon atoms and the aryl moiety may comprise from 6 to 14 carbon atoms.

"Heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom such as O, N or S. For example, the carbon atoms of the alkyl group a hetero atom that is attached to the parent molecule (for example, O, N or S) if substituted, the resulting alkoxy group-heterocyclic group, respectively (e.g., -OCH _3, and so on) , An amine (for example, -NHCH ₃ , -N (CH ₃ ) _2, etc.), or a thioalkyl group (for example, -SCH ₃ ). When the non-terminal carbon atom of the alkyl group that is not attached to the parent molecule is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl group may be substituted with an alkyl ether (e. CH ₂ -O-CH _3, etc. _2), alkyl amines _{(e.g., -CH 2 NHCH 3, -CH 2} N (CH 3) 2 and the like), or a thioalkyl ether (e.g., -CH ₂ -S is -CH _3). When the terminal carbon atom of the alkyl group is replaced by a hetero atom (e.g., O, N or S), the resulting heteroalkyl group may be substituted with a hydroxyalkyl group (e.g., -CH ₂ CH ₂ -OH), an aminoalkyl group For example, -CH ₂ NH ₂ ), or an alkylthiol group (for example, -CH ₂ CH ₂ -SH). Heteroalkyl groups may have, for example, from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. C ₁ -C ₆ heteroalkyl means a heteroalkyl group having from 1 to 6 carbon atoms.

The term "heterocycle" or "heterocyclyl" includes saturated, partially unsaturated, and aromatic rings (ie, heteroaromatic rings). The substituted heterocycle includes, for example, a heterocyclic ring substituted with any substituent, including a carbonyl group, and examples of the heterocycle include pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl ), Thiazolyl, tetrahydrothiophenyl, sulfur tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indole Pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrofuranyl, 6H-1,2, 5-thiadiazinyl, 2H, 6H-1, 6H-1,2,4-tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, Thienyl, thianthrenyl, pyranyl, isobenzofuranyl, quinolyl, Indazolyl, isoindolyl, 3H-indolyl, 1H-indazolyl, isoxazolyl, isothiazolyl, pyridazinyl, indolizinyl, isoindolyl, , Pyrazinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, Heterocyclyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, Thiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, Tetrahydrofuranyl, and the like.

"Heteroaryl" refers to an aromatic heterocyclyl having one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, Includes all those listed in the definition of "heterocyclyl ", including, but not limited to, benzyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl and the like.

"Heteroarylalkyl" refers to an alkyl group, as defined herein, wherein a hydrogen atom is replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroaryl alkyl include -CH ₂ - pyridinyl, -CH ₂ - pyrrolyl, -CH ₂ - oxazolyl, -CH ₂ - indolyl, -CH ₂ - isoindolyl, -CH ₂ - Purifying carbonyl, -CH ₂ - furanyl, -CH ₂ - thienyl, -CH ₂ - benzo furanyl, -CH ₂ - benzo thiophenyl, -CH ₂ - carbazolyl, -CH ₂ - imidazolyl, -CH ₂ -thiazolyl, -CH _{2-isoxazolyl,} -CH _2-pyrazolyl, -CH ₂ - isothiazolyl, -CH _2-quinolyl, -CH ₂ - isoquinolyl, -CH ₂ - pyrido lay, - CH ₂ - pyrimidyl, -CH ₂ - pyrazyl, -CH (CH ₃₎ - pyridinyl, -CH (CH ₃₎ - pyrrolyl, -CH (CH ₃₎ - oxazolyl, -CH (CH ₃₎ - indolyl, -CH (CH ₃₎ - isoindolyl, -CH (CH ₃₎ - Fourier carbonyl, -CH (CH ₃₎ - furanyl, -CH (CH ₃₎ - thienyl, -CH (CH ₃₎ benzo furanyl, -CH (CH ₃₎ - benzo thiophenyl, -CH (CH ₃₎ - carbazolyl, -CH (CH ₃₎ - imidazolyl, -CH (CH ₃₎ - thiazolyl, -CH ( CH ₃₎ - isoxazolyl, -CH (CH ₃₎ - pyrazolyl, -CH (CH ₃₎ - isothiazolyl, -CH (CH ₃₎ - quinolyl, -CH (CH ₃₎ - isoquinolyl, -CH (CH ₃₎ - pyrido multiple material, -CH (CH ₃₎ - pyrimidine Pyridyl, -CH (CH ₃₎ -, and the like pyrazyl.

The term "substituted ", for example, with respect to alkyl, etc., means, for example," substituted alkyl "and the like refer to alkyl in which at least one hydrogen atom is each independently substituted with a non-hydrogen substituent, Typical substituents include ^{-X, -R, -O -, =} O, -OR, -SR, -S -, -NR 2, -N + R 3, = NR, -CX 3, -CN, -OCN, - SCN, -N = C = O, -NCS, -NO, -NO 2, = N 2, -N 3, -NHC (= O) R, -C (= O) R, -C (= O) NRR ^{_{-S (= O) 2 O -}} , -S (= O) 2 OH, -S (= O) 2 R, -OS (= O) 2 OR, -S (= O) 2 NR, -S (= O) R, -OP (= O) (OR) ₂ , -N (= O) (OR) 2, -N (= O) (O -) 2, -N (= O) (OH) 2, -N (O) (OR) (O -), -C ( = O) R, -C (= O) X, -C (S) R, -C (O) OR, -C (O) O -, -C (O) O -, -C (O) SR, Wherein each X is independently halogen, F, Cl, Br, or I, and R is selected from the group consisting of - (CH2) Are independently H, alkyl, aryl, arylalkyl, heterocycle, or protecting group or prodrug moiety.

Hereinafter, the present invention will be described in detail.

A method for preparing an 8-membered heterocyclic compound represented by the following formula (3) according to the present invention is a 1,5-dipole represented by the following formula (1); And an enol diazoacetate represented by the following formula (2) in the presence of a metal catalyst, and may further include other processes as required.

[Chemical Formula 1]

(2)

(3)

More specifically, the 8-membered heterocyclic compound according to the present invention can be produced by the reaction scheme shown in FIG. At this time, the yield of the 8-membered heterocyclic compound is not influenced by the stability or stereostructure of the 1,5-dipole.

In the above 1,5-dipole, R ¹ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, Or a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group .

R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group.

R ³ is preferably a substituted or unsubstituted phenyl group, R ⁴ is preferably a silyl ester group, and R ⁵ is preferably an alkyl group having 1 to 8 carbon atoms.

More preferably, R ¹ and R ² are each independently a substituted or unsubstituted phenyl group, an alkyl group having 1 to 5 carbon atoms, or a naphthyl group, and R ³ is selected from tolyl, Ph, (4-OMe) C ₆ H ₄ or 4-CF ₃ (C ₆ H ₄ ). More preferably, R ⁴ may be a triisopropylsilyl group or a tert-butyldimethylsilyl group, and R ⁵ may be an alkyl group having 1 to 5 carbon atoms.

In particular, the 1,5-dipole is a pyridinium zwitterions or an N-sulfonyl-substituted pyridinium zwitterions compound including R ¹ , R ² and R ³ Lt; / RTI >

In addition, in the process for producing an 8-membered ring compound according to the present invention, the form of the enol diacetic acid containing R ⁴ and R ⁵ is not particularly limited, and an 8-membered ring compound can be produced with excellent yield.

The metal catalyst to be added to the reaction may be at least one selected from the group consisting of bis [rhodium α, α, α ', α'-tetramethyl-1,3-benzene diphopropionic acid] tetramethyl-1,3-benzenedipropionic acid)] , [Rh 2 (esp) 2]), rhodium pivalate dimer (rhodium (II) pivalate dimer, [Rh 2 (OPiv) 4]), tetrakis [(S) - (S) - (+) - (1-adamantyl) - (N-phthalimido) acetato (Tetrakis (S) -N-phthaloylvalidate] (II) (Rh ₂ (S-PTAD) ₄ )], tetrakis [(S) -N- phthaloylvalidate] dirhodium (II), [Rh ₂ (S-PTV) ₄ ] or dirhodium (II) tris (N-phthaloyl- (S) -tert-leucinate) and [Rh ₂ (S-PTTL) ₄ ]).

 Meanwhile, the reaction is preferably carried out in the presence of an inert solvent. The inert solvent is not particularly limited as long as it does not significantly inhibit the progress of the reaction. Examples thereof include water; Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; and cyclic or cyclic ethers such as diethyl ether, dioxane, tetrahydrofuran, and 1,2-dimethoxyethane N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylacetamide, N, N-dimethylacetamide, and the like, Amides such as 1,3-dimethyl-2-imidazolidinone and N-methyl-2-pyrrolidone, nitriles such as acetonitrile, dimethylsulfoxide and the like can be used singly or in combination, Dichloromethane, dichloroethane or toluene can be used.

The reaction is preferably carried out at 0 to 60 ° C for 4 to 12 hours to induce the polycondensation [5 + 3] cyclization addition reaction. When the reaction temperature is outside the above range, the 8-membered heterocycle The yield of the compound may drop sharply.

The 8-membered heterocyclic compound derivative represented by the above formula (3) obtained through the above reaction may be isolated from the reaction system according to a conventional method after completion of the reaction, and may be subjected to recrystallization, column chromatography, distillation To carry out further purification.

In the preparation of the above-mentioned 8-membered heterocyclic compound, the reaction mixture may further include an adsorbent to increase the yield of the reaction product. As the adsorbent described above, 4 Å M.S. is a typical example.

As shown in FIG. 3, a method for producing an 8-membered heterocyclic compound according to the present invention as described in detail above will be described. Using dichloromethane as a solvent, 1,5-dipolar amphoteric ion (1a) The [5 + 3] cyclization addition reaction is induced by the rhodium catalyst ([Rh ₂ (OPiv) ₄ ]) in the reaction solution in which the diazoacetic acid (2a) is dissolved to produce the 8-membered heterocyclic compound (3a) .

In the formation of the above-mentioned 8-membered heterocyclic compound (3a), the first step is to prepare rhodium (II) having electrophilic reaction sites between metal-carbene and vinylogous positions II) catalyst and the nitrogen gas from the enol diazoacetic acid is lost. The nucleophilic attack of 1,5-dipolar amphoteric ion (1a) was induced by the intramolecular cyclization reaction in the vinylogous positions of the rhodium (II) catalyst, and the 8-membered heterocycle Compound (3a) is produced, whereby an 8-membered heterocyclic compound is obtained by reacting (1Z, 5Z) -methyl-5 - ((tert- butyldimethylsilyl) oxy) -1,10- , 6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) 1, 10-diphenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate}.

Therefore, in the method for producing an 8-membered heterocyclic compound according to the present invention as described above in detail, 1,5-dipole and enol diazoacetic acid are reacted in the presence of a rhodium catalyst to produce 8- As a method for producing a heterocyclic compound, it is possible to produce an 8-membered heterocyclic compound derivative that is user-friendly and has a structure desired by the user.

The present invention also provides an 8-membered heterocyclic compound derivative represented by the formula (3), wherein the compound is any one of the following compounds:

(3)

In the above 1,5-dipole, R ¹ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, Or a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group .

R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group.

R ³ is preferably a substituted or unsubstituted phenyl group, R ⁴ is preferably a silyl ester group, and R ⁵ is preferably an alkyl group having 1 to 8 carbon atoms.

The 8-membered heterocyclic compound may be any one of the following compounds:

1) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl-3-tosyl-4,6a-dihydro-3H-pyrido [ d] [l, 4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1,10-diphenyl-3-tosyl-4,6a-dihydro -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

2) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

3) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- methoxyphenyl) Pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

4) Synthesis of (1Z, 5Z) -methyl-10- (4- (tert -butyl) phenyl) -5 - ((tert- butyldimethylsilyl) oxy) -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 3-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

5) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

6) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- chlorophenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -10- (4-chlorophenyl) -1 -phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

7) Synthesis of (1Z, 5Z) -methyl-10- (4-acetylphenyl) -5 - ((tert- butyldimethylsilyl) oxy) (1Z, 5Z) -methyl-10- (4-acetylphenyl) -5 - ((tert-butyldimethylsilyl) oxy) -1 -phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

8) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

9) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (3- methoxyphenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -10- (3-methoxyphenyl) - 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

10) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (naphthalen- Pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

11) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -9-methyl-1,10-diphenyl-3-tosyl-4,6a-dihydro- 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- -tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

12) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -8-methyl-1,10-diphenyl-3-tosyl-4,6a-dihydro- 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- -tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

13) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- phenyl- 1- (p- tolyl) -3-tosyl-4,6a-dihydro-3H- [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

14) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4-methoxyphenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -1- (4-methoxyphenyl) - 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

15) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) Methyl-5 - ((tert-butyldimethylsilyl) oxy) -10-phenyl-lH- 3,4-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

16) Synthesis of (1Z, 5Z) -methyl- l- (4-bromophenyl) -5- (tert- butyldimethylsilyl) oxy- Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 1- (4-bromophenyl) -5- (tert- butyldimethylsilyl) 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

17) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4- fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

18) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

19) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (3-fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

20) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl-3- (phenylsulfonyl) 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1,10- diphenyl- 3- (phenylsulfonyl) -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

21) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -3 - ((4-methoxyphenyl) sulfonyl) -1,10- -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- -methoxyphenyl) sulfonyl) -1,10-diphenyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-

22) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10- 6-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) , 10-diphenyl-3 - ((4- (trifluoromethyl) phenyl) sulfonyl) -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}.

Hereinafter, the present invention will be described in more detail with reference to examples. The examples and experimental examples presented are only a concrete example of the present invention and are not intended to limit the scope of the present invention.

Examples 1-1 to 1-11: Preparation of 8-membered ring compound according to reaction conditions

(0.2 mol), rhodium (II) catalyst (2.0 mol%), solvent (1.0 mL) and temperature conditions (0 ° C., 25 ° C. And 60 [deg.] C) to produce an 8-membered ring compound derivative, and enodiazoacetic acid (3.0 equivalents) having a stable structure was mixed with various solvents, and enodiazoacetic acid tert-butyldimethyl-thylsilyl (TBS) protecting group was reacted with substituted enol diazoacetic acid or triisopropylsilyl (TIPS) protecting group-substituted enol diazoacetic acid. In addition, the reaction mixture of Examples 1-9 was further added with an adsorbent (4 ANGSTROM) to increase the yield.

More specifically, a long test tube (15 X 150 mm) was used for the reflux effect and an amphoteric ion and rhodium catalyst were mixed in a solvent in a test tube equipped with a stirrer bar in the form of a triangle under a nitrogen atmosphere A reaction mixture was prepared. A solution of enol diazoacetic acid mixed in a solvent (0.5 mL) was added to the reaction mixture via a syringe pump for 3 minutes. The reaction mixture was stirred at room temperature for 4 to 7 hours to prepare a cyclic compound. The stirred reaction mixture was filtered through a celite pad and then washed three times with 10 mL of a solvent. The organic solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by chromatography on silica gel to obtain the ring compound according to Examples 1-1 to 1-11. The internal standard (CH ₂ Br ₂ ) was added to the ring compound to determine the NMR yield of the product through chemical integration. The yields for each of these are shown in Table 1 above.

In addition, a single crystal x-ray analysis was performed on the cyclic compound prepared by the method according to Example 1-4, and the analysis result is shown in FIG.

As shown in Fig. 4, the ring compound prepared through the crystal x-ray analysis clearly confirmed that the 8-membered heterocyclic compound was prepared.

Examples 2-1 to 2-22: Preparation of 8-membered ring compound for 1,5-dipole zwitterion type

(5 + 3) at various temperatures and with various kinds of 1,5-dipolar zwitterions (0.1 mmol), [Rh ₂ (OPiv) ₄ ] catalyst (2.0 mol%), dichloromethane (CH ₂ Cl ₂ , ] Cyclization addition reaction was induced to prepare an 8-membered ring compound derivative, and various solvents were reacted with TBS protecting group-substituted enol diazoacetic acid (3.0 equivalents). At this time, in order to increase the reaction yield in the preparation of the 8-membered ring compound, the reaction mixture of Example 2-1 to 2-3, Example 2-5, Example 2-10 and Example 2-19 was added with 40 mg (4 ANGSTROM) was further added to the reaction system and the reaction was carried out at the same temperature as in Example 1-1 to obtain an 8-membered heterocyclic compound according to Examples 2-1 to 2-22, Characteristic analysis data are as follows. In addition, the NMR yield of the product was determined through integration using the internal standard material (CH ₂ Br ₂ ), and the 8-membered ring compound thus prepared was shown in FIGS. 5 and 6.

≪ Example 2-1 >

1) 1) Synthesis of (1Z, 5Z) -methyl-5- ((tert- butyldimethylsilyl) oxy) -1,10-diphenyl- 2-d] [1, 4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1,10-diphenyl-3-tosyl-4,6a dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate} (3a):

< Example  2-2>

(P-tolyl) -3-tosyl-4,6-dihydro-3H-pyrido [l, 2-dihydroxy- , 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- 3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate (3b):

&Lt; Example 2-3 >

(4-methoxyphenyl) -1-phenyl-3-tosyl-4,6-dihydro-3H-pyrido &lt; / RTI &gt; [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate (3c)

<Example 2-4>

(Tert-butyldimethylsilyl) oxy) -1-phenyl-3-tosyl-4,6-dihydro-3H 5-methyl-10- (4- (tert-butyl) phenyl) -5- (tert-butoxycarbonylamino) 3-pyrido [1,2-d] [1,4] diazocine-6-carboxylate (3d):

<Example 2-5>

(4-fluorophenyl) -1-phenyl-3-tosyl-4,6-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate}

<Example 2-6>

6) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- chlorophenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -10- (4-chlorophenyl) -1 dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate} (3f):

<Example 2-7>

(1Z, 5Z) -methyl-10- (4-acetylphenyl) -5- (tert- butyldimethylsilyl) oxy- 1 -phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [ 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl-10- (4- acetylphenyl) -5- (tert- butyldimethylsilyl) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate (3g)

<Example 2-8>

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1-phenyl-10- (m-tolyl) -3-tosyl-4,6a-dihydro-3H-pyrido [ , 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

<Example 2-9>

(3-methoxyphenyl) -1-phenyl-3-tosyl-4,6,6-dihydro-3H-pyrido &lt; / RTI &gt; [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate}

<Example 2-10>

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (naphthalen- [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate}

&Lt; Example 2-11 >

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -9-methyl-1,10-diphenyl- 2-d] [1, 4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate (3k)

&Lt; Example 2-12 >

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -8-methyl-1,10-diphenyl-3-tosyl-4,6a- dihydro-3H-pyrido [ 2-d] [1, 4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy-8- -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

&Lt; Examples 2-13 >

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10-phenyl- 1- (p- tolyl) -3-tosyl- , 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

&Lt; Examples 2-14 >

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4- methoxyphenyl) -10- phenyl-3-tosyl-4,6a-dihydro-3H- [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1- (4-methoxyphenyl) phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate}

&Lt; Example 2-15 &

(1 Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10-phenyl-3-tosyl-1- (4- (trifluoromethyl) phenyl) 3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate} (3o):

&Lt; Example 2-16 >

(1 Z, 5Z) -methyl-l- (4-bromophenyl) -5- (tert- butyldimethylsilyl) oxy-10-phenyl-3-tosyl-4,6a-dihydro-3H- [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 1- (4-bromophenyl) -5- (tert- butyldimethylsilyl) phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-

&Lt; Example 2-17 &

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4- fluorophenyl) -10- phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1- (4-fluorophenyl) phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate (3q)

&Lt; Examples 2-18 >

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10-phenyl- 1- (m-tolyl) -3-tosyl- , 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

&Lt; Example 2-19 &

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (3- fluorophenyl) -10- phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 1- (3-fluorophenyl) phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-6-carboxylate}

<Example 2-20>

(1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl-3- (phenylsulfonyl) -4,6a- dihydro-3H- 2-d] [1, 4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- , 6a-dihydro-3H pyrido [1,2-d] [1,4] diazocine-6-carboxylate (3t)

&Lt; Example 2-21 &

(1 Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -3 - ((4-methoxyphenyl) sulfonyl) -1,10- 5-methyl-5 - ((tert-butyldimethylsilyl) oxy) -3 - ((4-methoxyphenyl) ) sulfonyl) -1,10-diphenyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}

&Lt; Example 2-22 &

(1, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl- Dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) 3-pyrido [1,2-d] [1,4] diazocine-6-carboxylate} (3v):

Examples 3-1 to 3-6: Preparation of 8-membered ring compound by stereoselective reaction of rhodium catalyst and rhodium catalyst chiral ligand

Asymmetric cyclization addition reaction was induced in 1,5-dipolar zwitterions (0.1 mmol), rhodium catalysts of various forms or rhodium catalyzed chiral ligand (2.0 mol%), toluene (1.0 mL) (3.0 equivalents) of TBS-protected enol diazoacetic acid (0.5 eq.) In toluene (0.5 mL) was stirred at 0 ° C for 5 hours to prepare a cyclic compound. The organic solvent was removed in the same manner as in Example 1-1 Followed by washing and filtration to prepare 8-membered ring compounds according to Examples 3-1 to 3-6. NMR yields of the products were determined through integration using an internal standard material (CH ₂ Br ₂ ), and the NMR spectra of the products of the reaction schemes And enantiomeric excess (ee) are shown in Figure 7 and Table 2 below.

Claims (8)

A 1,5-dipole represented by the following formula (1); And a step of reacting enol diazoacetate represented by the following formula (2) in the presence of a metal catalyst: [Formula 3] &lt; EMI ID =
[Chemical Formula 1]

(2)

(3)

(In the above Formulas 1 to 3,
R ¹ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, Or a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;
R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted arylalkyl group, A substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;
R ³ is a substituted or unsubstituted phenyl group;
R ⁴ is a silyl ester group;
And R &lt; ⁵ &gt; is an alkyl group having 1 to 8 carbon atoms. The method according to claim 1,
R ¹ and R ² are each independently a substituted or unsubstituted phenyl group, an alkyl group having 1 to 5 carbon atoms, or a naphthyl group;
R ³ is tolyl, Ph, (4-OMe) C ₆ H ₄ or 4-CF ₃ (C ₆ H ₄ );
R ⁴ is a triisopropylsilyl group or a tert-butyldimethylsilyl group;
R ⁵ is a production process, characterized in that an alkyl group having 1 to 5 carbon atoms. The method according to claim 1,
The metal catalyst may be at least one selected from the group consisting of bis [rhodium α, α, α ', α'-tetramethyl-1,3-benzene dipropionic acid] _{benzenedipropionic acid)], [Rh 2} (esp) 2]), rhodium pivalate dimer (rhodium (II) pivalate dimer, [Rh 2 (OPiv) 4]), tetrakis [(S) - (+) - (1 - (N-phthalimido) acetato] dirhodium (II) (Tetrakis [(S) - (+) - (1-adamantyl) (II) (Tetrakis [(S) -N-phthaloylvalidate] dirhodium (II) (Rh ₂ (S-PTAD) ₄ )], tetrakis [(S) -N- phthaloylvalidate] _{Rh 2 (S-PTV) 4} ]) and di-rhodium (II) tris (N- phthaloyl - (S) - tert-ryusi carbonate) (dirhodium (II) tris ( N-phthaloyl- (S) -tert- leucinate and Rh ₂ (S-PTTL) ₄ ). The method according to claim 1,
At a temperature of 0 to 60 占 폚. The method according to claim 1,
Dichloroethane, or dichloromethane, dichloroethane or toluene as a solvent. The method according to claim 1,
Wherein an adsorbent is further added and reacted. The 8-membered heterocyclic compound represented by the formula (3)
(3)

(In the above Formulas 1 to 3,
R ¹ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, Or a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;
R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted arylalkyl group, A substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;
R ³ is a substituted or unsubstituted phenyl group;
R ⁴ is a silyl ester group;
And R &lt; ⁵ &gt; is an alkyl group having 1 to 8 carbon atoms. 8. The method of claim 7,
The 8-membered heterocyclic compound is characterized in that the 8-membered heterocyclic compound is any one of the following compounds:
1) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl-3-tosyl-4,6a-dihydro-3H-pyrido [ d] [l, 4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1,10-diphenyl-3-tosyl-4,6a-dihydro -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}
2) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
3) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- methoxyphenyl) Pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-
4) Synthesis of (1Z, 5Z) -methyl-10- (4- (tert -butyl) phenyl) -5 - ((tert- butyldimethylsilyl) oxy) -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 3-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}
5) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-
6) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (4- chlorophenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -10- (4-chlorophenyl) -1 -phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
7) Synthesis of (1Z, 5Z) -methyl-10- (4-acetylphenyl) -5 - ((tert- butyldimethylsilyl) oxy) (1Z, 5Z) -methyl-10- (4-acetylphenyl) -5 - ((tert-butyldimethylsilyl) oxy) -1 -phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
8) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
9) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (3- methoxyphenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -10- (3-methoxyphenyl) - 1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-
10) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- (naphthalen- Pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -1-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-
11) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -9-methyl-1,10-diphenyl-3-tosyl-4,6a-dihydro- 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- -tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}
12) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -8-methyl-1,10-diphenyl-3-tosyl-4,6a-dihydro- 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- -tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}
13) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -10- phenyl- 1- (p- tolyl) -3-tosyl-4,6a-dihydro-3H- [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
14) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4-methoxyphenyl) (1Z, 5Z) -methyl-5 - ((tert-butyldimethylsilyl) oxy) -1- (4-methoxyphenyl) - 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
15) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) Methyl-5 - ((tert-butyldimethylsilyl) oxy) -10-phenyl-lH- 3,4-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}
16) Synthesis of (1Z, 5Z) -methyl- l- (4-bromophenyl) -5- (tert- butyldimethylsilyl) oxy- Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 1- (4-bromophenyl) -5- (tert- butyldimethylsilyl) 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
17) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (4- fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
18) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy- ) -3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
19) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1- (3-fluorophenyl) Pyrido [l, 2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- 10-phenyl-3-tosyl-4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-
20) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10-diphenyl-3- (phenylsulfonyl) 1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) oxy) -1,10- diphenyl- 3- (phenylsulfonyl) -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}
21) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -3 - ((4-methoxyphenyl) sulfonyl) -1,10- -3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- tert- butyldimethylsilyloxy- -methoxyphenyl) sulfonyl) -1,10-diphenyl-4,6a-dihydro-3H-pyrido [1,2- d] [1,4] diazocine-
22) Synthesis of (1Z, 5Z) -methyl-5- ((tert-butyldimethylsilyl) oxy) -1,10- 6-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate {(1Z, 5Z) -methyl- 5- (tert- butyldimethylsilyl) , 10-diphenyl-3 - ((4- (trifluoromethyl) phenyl) sulfonyl) -4,6a-dihydro-3H-pyrido [1,2-d] [1,4] diazocine-6-carboxylate}.

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