CN114656417A - Synthesis method and application of chiral oxazoline - Google Patents

Abstract

[1,4- (4S/R) -di (R) -2-oxazoline group]Benzene [ R: CH (CH)₃)₂,CH₂Ph]The synthesis method comprises the step of synthesizing a target macromolecular palladium complex Pd [ R: CH (CH)₃)₂,CH₂Ph]Firstly reacting with silver trifluoromethanesulfonate or silver nitrate, then reacting with alkali such as amino alcohol, bipyridine or triethylamine, and decomposing the complex to obtain chiral oxazoline ligand compounds I and II, wherein the structural formulas are as follows:

R:I:L‑CH(CH₃)₂II:D‑CH₂use of Ph of the chiral oxazoline compound II in the preparation of an anti-cancer agent, which shows inhibitory activity in the human breast cancer cell MCF-7 assay as an anti-cancer agent.

Description

Synthesis method and application of chiral oxazoline

One, the technical field

The invention relates to a method for synthesizing a chiral compound, in particular to a method for synthesizing a compound containing chiral oxazoline groups.

Second, background Art

Chiral oxazoline and metal complexes have been drawing attention because they exhibit good asymmetric catalytic activity and high enantioselectivity in a number of reactions such as Didls-Alder (Diels-Alder) diene cycloaddition reaction, Michael condensation reaction, Friedel-Crafts condensation reaction, Aldol reaction, Henry reaction, nitrile silicification and the like [1-4 ].

(1)(a)Glos，M.；Reiser，O.Org.Lett.2000，2(14)，2045.(b)Braga，A.L.Vargas，F.； Sehnem，J.A.；Braga，R.C.J.Org.Chem.2005，70(22)，9021.(c)Breit，B.；Schmidt，Y.； Chem.Rev.2008，108(8)，2928.(d)McManus，H.A.；Guiry，P.J.J.Org.Chem.2002，67(24)， 8566.

(2)Wang，W.B.；Fang，J.M.J.Org.Chem.1998，63，1356.

(3)(a)Fu，G.C.Acc.Chem.Res.2006，39(11)，853.(b)Hargaden，G.C.；Patrick J.Guiry， P.J.Chem.Rev.2009，109(6)，2505.(c)McManu，H.A.；Guiry，P.J.Chem.Rev.2004，104(9)， 4151.

(4)(a)Takamichi，Y.；Masatoshi，O.；Takahiro，K.；Dai，M.；Kiyoshi，S.；Motowo， Y.Tetrahedron：Asymmetry 2003，14，3275.(b)Cristina G.-Y.，

P.J.；Frank R.； Günter，H.Organometallics 2004，23，5459.(c)Delphine，F.；Montserrat，G.，Francisco， J.，Guillermo，M.；Mercè，R.，Miguel，A.M.，；José，M.Organometallics 2004，23(13)， 3197.(d)Koch，G.；Guy，C.；Loiseleur，O.；Pfaltz，A.；Pretot，R.；Schaffner，S.； Schnider，P.；Von Matt，P.Recueil des Travaux Chimiques des Pays-Bas 1995，114(4/5)， 206.(e)Sprinz，J.；Helmchen，G.Tetra.Lett.1993，34(11)，1769.(f)Franco，D.；Gomez， M.；Jimenez，F.；Muller，G.；Rocamora，M.；Maestro，M.A.；Mahia，J.Organometallics 2004，23(13)，3197。

The applicant has long worked on the development of asymmetric compounds and successively applied for patent applications, zl200610096004.x, CN101016311A, CN101099936A, 200810020198.4, CN101279954A, 200810022278.3 and 200910116614.5.

Third, summary of the invention

The invention aims to provide a synthesis method for the field of asymmetric synthesis, in particular for preparing chiral pharmaceutical compounds, and solves the technical problem of one-step synthesis of ligand oxazoline by selecting a metal complex.

The chiral oxazoline compound is prepared from palladium complex [ R: CH (CH)₃)₂]With silver triflate or silver nitrate and then with a base such as aminoalcohol, bipyridine or triethylamine to give the following chemical names: [1,4- (4S) -diisopropyl-2-oxazolinyl group]Benzene, its chemical formula is as follows:

the chiral oxazoline compound II is prepared from palladium complex [ R: CH₂Ph]With silver triflate or silver nitrate and then with a base such as aminoalcohol, bipyridine or triethylamine to give the following chemical names: [1,4- (4R) -dibenzyl-2-oxazoline group]Benzene, its chemical formula is as follows:

the chiral compound is synthesized by using target macromolecular palladium complex Pd [ R: CH (CH)₃)₂]And Pd [ R: CH₂Ph]Firstly reacting with silver trifluoromethanesulfonate or silver nitrate, then reacting with alkali such as amino alcohol, bipyridine or triethylamine, and decomposing the complex to obtain the chiral oxazoline ligand compound. The flow is shown as follows:

the R group: the L-valinol is selected from D-phenylalaninol.

The compound has already filed a chinese patent in 2010: a chiral oxazoline and a synthetic method thereof. Application No.: 2010105600901. At present, the compound II is found to show a certain inhibiting effect in anti-tumor human breast cancer cells (MCF-7), and the index IC50 value reaches 8.24 +/-0.11.

Description of the drawings

1. FIG. 1 is a nuclear magnetic structural hydrogen spectrum of a target compound I.

2. FIG. 2 is a nuclear magnetic structure carbon spectrum diagram of the target compound I.

3. FIG. 3 is a nuclear magnetic structural hydrogen spectrum of the objective compound II.

2. FIG. 4 is a nuclear magnetic structure carbon spectrum of the target compound II.

Fifth, detailed description of the invention

Preparation of (I) chiral Compound 1

1. Process for the preparation of chiral compound 1

0.2240g of L-palladium complex (the synthesis method is shown in Chinese patent: chiral bis-oxazoline palladium complex crystal and synthesis method; application number: 2015102587058) and 0.7g of silver trifluoromethanesulfonate are dissolved in dichloromethane solution under anhydrous and anaerobic conditions, and 0.8251g of L-valinol and 1.0mL of triethylamine are added, or 0.1000g of bipyridine is added. The reaction solution immediately became clear. After 48 hours of reflux, the reaction was stopped. Hot filtering, and naturally volatilizing to obtain 0.1240g of crystals; yield: 85 percent; m.p.48-50 ℃; [ alpha ] to]²⁵ _D＝-111.9°(c＝0.429,CHCl₃)；¹H NMR(600MHz,298K,CDCl₃)δppm 7.97(s, 4H,ArH),4.40(t,J＝8.1Hz,2H,CH×2),4.10-4.15(m,4H，CH₂×2),1.85-1.88(m, 2H,CH×2),1.03(d,J＝6.0Hz,6H,CH₃×2),0.94(d,J＝6.0Hz,6H,CH₃×2)；¹³C NMR(150MHz,298K,CDCl₃)δppm 162.8,130.3,128.1,72.8,70.2,32.8,18.9,18.1 (×2)；HRMS(EI)m/z(％)calcd.for C₁₈H₂₄N₂O₂ 300.1838；found 300.1833.ν_max(cm^-1) 3273,2976,2960,2932,2889,2869,1643,1512,1469,1408,1382,1366,1350,1320, 1296,1276,1214,1180,1108,1077,1047,1014,971,955,900,891,838,726,698, 675,659,540。

2. Preparation method of chiral compound II

0.0325g of D-palladium complex (see the synthesis method in the specification) under anhydrous and oxygen-free conditionsThe national patent discloses a chiral oxazoline palladium complex crystal and application thereof; application No.: 202210290030.5) and 0.2g of silver trifluoromethanesulfonate in 30mL of dichloromethane, and adding 0.8251g of D-phenylglycinol and 2.0mL of triethylamine, the reaction solution becomes clear immediately. After 48 hours of reflux, the reaction was stopped. Hot filtering, and naturally volatilizing to obtain 0.0135g of crystal and yield; 88 percent; [ alpha ] of]²⁵ _D＝+39.1°(c 0.098,CHCl₃)；¹H NMR(500MHz,298K,CDCl₃)δppm 7.98(s,4H),7.22-7.32(m,10H,ArH),4.59-4.61 (m,2H,CH×2),4.37(t,J＝8.9Hz,2H,CH×2),4.16(t,J＝7.9Hz,2H,CH×2),3.23, 3.26(dd,J＝5.1,5.1Hz,2H,CH×2),2.71,2.75(dd,J＝9.0,9.0Hz,2H,CH₂× 2)；¹³C{1H}NMR(125MHz,298K,CDCl₃)163.4,137.8,130.2,129.2,128.6,128.2,126.6, 72.0,68.0,41.8；HRMS(EI)m/z(％)calcd for C₂₆H₂₄N₂O₂ 396.1838；found 396.1833.ν_max(cm^-1)3420,3081,3054,3031,2988,2956,2893,2231,1647,1608,1497,1454,1406, 1359,1343,1317,1293,1276,1262,1201,1174,1073,1046,1017,967,953,860,840, 755,697,669,548,527。

Application of (II) chiral compound II in resisting tumor breast cancer

The compound (I) designed and synthesized according to the target shows stronger inhibitory activity (ED50 < 10.0 mu g/mL) in the test of breast cancer cells (MCF-7). Reference [ j.natl.cancer inst.1990, 82 (13): 1107-1112]The test was carried out by the method described in (1). Briefly, human cancer cells (DU145, PC-3, A549, KB, KB-VIN, etc.) used were placed in a single medium (RPMI-1640 containing 10% (v/v) calf serum), and morphological characteristics and growth conditions of the cells in the culture were examined with a microscope. The cells were placed at 2.5cm²The culture dish was incubated at 37 ℃ in a humidified atmosphere containing 5% CO 2. The cell lines grow adherently. The process of sample preparation and dilution and inoculation into the cell fluid should be aseptic. The test samples were typically dissolved in DMSO and stored at-70 ℃. In a 96 well culture plate, each well was placed at different concentrations of test sample and approximately 5000-. IC50 values for inhibition of cancer cell growth by SRB (sulfoformaldehyde B)And (4) determining the method. The results of some of the anti-cancer activity tests of the compounds of the present invention are shown in table 1.

TABLE 1 anticancer Activity data (IC50 values) of (I)

The IC50 is the effective concentration to inhibit growth of half of the cancer cells, indicating anti-cancer activity. The unit is μ M; NA: has no inhibitory activity. The human cancer cells used in this experiment were purchased from ATCC in the United states.

Claims (3)

1. [1,4- (4S) -diisopropyl-2-oxazoline group shown in the following chemical formula (I)]The synthesis method of the benzene comprises synthesis, separation and purification, wherein the synthesis is to synthesize a target macromolecular palladium complex Pd [ R: CH (CH)₃)₂]Firstly reacting with silver trifluoromethanesulfonate or silver nitrate, then reacting with alkali such as amino alcohol, bipyridine or triethylamine, and decomposing the complex to obtain a chiral oxazoline ligand compound I, wherein the structural formula of the chiral oxazoline ligand compound I is as follows:

2. [1,4- (4R) -dibenzyl-2-oxazoline group shown in the following chemical formula (II)]The synthesis method of benzene comprises synthesis, separation and purification, wherein the synthesis is to synthesize the target macromolecular palladium complex Pd [ R: CH₂Ph]With silver triflate or silver nitrate and then with a base such as aminoalcohol, bipyridine or triethylamine to give the following chemical names: [1,4- (4R) -dibenzyl-2-oxazoline group]Benzene, its chemical formula is as follows:

3. use of a chiral oxazoline compound II in the preparation of an anti-cancer agent, which is useful as an anti-cancer agent showing inhibitory activity in a human breast cancer cell MCF-7 assay.

Images