Wuhan University .Iou,'nal oJ Natural Sciences Vol. 2 No. 3 1 9 9 7 ,3 2 8 ~3 3 2

Studies on Syntheses of Biscrown Ether Compounds V. Syntheses o{ multi-ester type biscrown ether

and schiff-base type color biscrown ether compounds

Niu Changrong,Shi hao,Wu Chengtai ,Yang Tingxian Depar tment of Chemis t ry ,Wuhan Univers i ty , Wuhan 430072,China

Abstract Multi-ester type biscrown ether compound(I) was prepared by the reaction of 6-bromoacetacetlc

ester dibenzo-16-crown-5(7) with phenyl-methyl ether-2,6-diformic acid potassium salt in anhydrous DMF at

refluxed temperature, and color biscrown ether compound ( ! ) was prepared by the reaction of 4'-aminoben- zo-15-crown-5 (12) with 2 , 2 f(O-formoyl naphthyl)ethyl ether (9) in anhydrous ethanol at 40 C under N2.

New compounds( I , i ) were characterized by IR,JH NMR,MS and elemental analysis.

Ke y words multi-ester type biscrown ether, ,S chill-base type color biscrown ether, 6-bromo-acetacetic es- ter-dlbenzo-16-crown-5,4'-amino-benzo- 15-Crown-5 ,synthesis.

0 Introduction

Since Pedersen first reported the synthesis and complexing properties of the crown ether com- pounds, there has been increasing interest in the crown ethers as complexing agents for various cations and anions. These complexing agents have found application in many areas . Staid rl] reported sandwich-type complexes of crown ether com- pounds with metal cations. They connected two crown units together to provide biscrown ether which had attractive cation-binding properties. Since then,an extensive number of biscrown ether have been synthesized. Biscrown ether compounds tend to form stronger complexes with metal ions than the corresponding monocrown ethers by the cooperative action of two adjacent crown units. The applications of biscrown ether in ion-selective electrodes have been briefly reviewed by several authors and the syntheses of biscrown ether have been briefly described in the reviews Ez~. Crown

ether compounds containing centre function groups, as they have special electronic and space

effect,have better and more selective complexes of anions than the classical crown ether compounds. Previously we reported E3-63 the studies on the syn- thesis of biscrown ether. In recent work, we have prepared bisbenzocrown ether containing phenyl- methyl ether multi-ester bridge ( I ), the bridge chain may be able to comform a false crown ether, thus to form a false tribenzocrown ether, so as to improve the combine ability and selectivity. As chromogenic crown ethers have the speciality of se- lectively changing their color when combined with metal ions,they were used in the complexomotric titration and spectrophotometric determination of alkali and alkaline earth metal ions, the chro- mogenic crown ethers was used in the metal ions' selective extraction too. For the purpose of enlarg- ing chromogenic crown ethers type, and finding their new using field,the schiff-base type bisben- zocrown ether ( I ) was designed and synthesized.

* Supported by the National Natural Science Foundation o[ China Received August, 21.1996. Niu Changrong : born in December, 12,1938, Pro/essor

No. 3 Niu Changronget al:Studies on Syntheses of Bis-.- 3Z9

1 E x p e r i m e n t a l

1.1 The synthetic route of crown ether compounds

OH CH 3 [ ~ CH3CIAIcI3 = ~ O H (CH3)2SO'

CH3 1

COOH COOK KMn04 ~ K2C03

= OCH3 DMF = OCH3 COOH COOK

3 4

CH 3 <~OCH3

CH3 2

~o~ /o CH 2 ~-~CHCH2C I

0 II BrCH2CBr C~o~~176

O~CH2B r

O

(4)

~o~ ~[o o~

6 o~O% o o/ O4o

~ OH CHC 13 NaOH

CliO CHO CHO

8 9

330 Wuhan Unh,ersity .Iournal of Natural Sciences Vol. 2

o HOAc ~ ~O O " ]

o

10 11

85%NH2NH2 H20 -

12

(9) + (12)

1.2 Physical measurements Intrared ( IR) spectra were obtained on a

perkin-Elmer IR-450 spectrometer. Nuclear mag- netic resonance (1H NMR)spectra were obtained on a Varian-XL 90 MHz spectrometer (CDCI3, TMS). Elemental analyses were obtained on a perkin-Elemer 204B. Molecular weights were ob- tained by mass spectrometry on a ZAB-HF-3F.

1.3 Materials 2, 6-dimethyl-phenol ( 1 ) , 2, 6-dimethyl-

phenyl-methyl ether (2), phenyl-methyl ether-2,6- diformic acid (3) and phenyl-methyl ether-2,6-di- formic acid potassium salt (4) were prepared as general methods, m.p. of compounds (1""3) are the same as references.

6-hydroxy-dibenzo-16-crown-5 (6) was pre- pared as reportedrT],m, p. 122~"123~ [7] m.

p. 122"--123 C), yield 72%. 6-bromo-acetacetic ester-dibenzo-16-crown-5

(7) was synthesized as reported [s]. m.p. 133"--

135~ [s3 m. p. 133"-~135~ 85%.

2-hydroxy-naphthyl-aldehyde ( 8 ) was pre- pared as reportedr93(ref. [9-1 m. p. 80---81 C ).

2, 2Lbis (o-formaldehyde-naphthyl) diethyl ether (9) was prepared. A mixture of (8)(3. 44 g 20 mmol), anhydrous potassium carbonate (1.38 g, 10 retool) and anhydrous DMF (20 mL) were added to a reactor. The reaction mixture was

=" Oo

II

stirred at 80~ under N2. The solution of 3-oxo-1,

5-dichloropentane (1.43 g,10 mmol) in DMF (20 mL) was dropped to the mixture over a 5""6 h pe- riod. Then the reaction mixture was stirred contin- uously for 16 h at 80C, cooled to room tempera- ture. A small amount of hydrochloric acid and ice- water was added slowly to the solution of reaction, the solid was precipitated, which was filtered to obtain the filter liquor and the filter cake. The fil-

ter liquor was evaporated under reduced pressure to dryness. The residue was cooled to room tem- perature to obtain the solid. The solid and the fil- ter cake were combined to chloroform, and chro- matographed on a alumina (activity) column, was eluted with chloroform. The eluant was concentrat- ed under reduced pressure to 15 mL which was cooled to room temperature and give crystals of the product. The crystals were collected by filtre, and were dried, weight 1.05 g, m. p. 164"--166C, yield 25.4%. IR (Vm~x/cm-~,KBr): 2 900(CH2); 1 675 (C = O ) ; 1 600, 1 445 ( A r ) ; 1 255

(ArOCH2); 1 130 (CH2OCH2 ). Anal. Calcd for C26 H2z O,s: C, 75.12; H, 5. 16. Found: C, 75.35; H,

5.35. 1.4 Syntheses of biscrown ether compounds

Phenyl methyl ether-2' , 6'-diformyloxy-ace- toxy-6-bishenzo-16-crown-5 ( I ) was prepared by two methods. First method: A solution of phenyl

No. 3 Niu Changronget al,:Studies on Syntheses of Bis'" 331

methyl ether-2, 6-diformic acid potassium salt (4) (0. 33 g, 1.2 mmol) in anhydrous DMF (60 mL) was stirred at refluxing temperature under Nz for 1 h. A solution of 6-bromo-acetacetic ester-dibenzo- 16-crown-5(7)(1 g,2.4 mmol) in anhydrous DMF (20 mL) was added at such a rate that the temper- ature of the reaction mixture was kept at refluxing state. After the addition was completed, the mix- ture was stirred continuously for 16 h at reflux temperature, cooled to room temperature, and fil- tered. The filtrate was evaporated under reduced pressure to dryness. The residue was cooled and become the viscous materials which was washed tri-times (3 • 10 mL) ,then acetone was added to dissolve the viscous materials, and dried over an- hydrous magnesium sulfate. The solvent was evap- orated in vacuo with a rotary evaporator to dryness to obtain the viscous meterials, for crude product, which was purified by the hot extraction on neutral alumina using chloroform to give the white viscous materials, weight 0.51g,yield 45~ IR (vm.x/cm -~ wax iol):2 900,2 890 (CHz)~I 750 (C=O)~I 735 (C = O)~ 1 600, 1 465 (Ar)~ 1 250, 1 239 (ArOCHz,ArOCH3) ~1 160,1 123(CH2OCH2)~755

( ~ [ ) 8 0 5 ( ~ ).IH NMR(~CDCI3).7.9

H

(2H,S, ~ ) ; 7 .3 (1H,S , - ~ H );

H

6.85(16H,S @ - - H ),5. 3"-5. 7 (2H,m,2 •

I I CH) 3. 7--4. 9(24H,m,12• •

O II

OCH2CO ) ;1.3(3H,s,CH3). MS(m/z)968(M. + , 10% ) ; 623(15) ,565(7). Aral calcd for C51HszO,9 : C,63.02;H,5.43. Found :C,63.22;H,5.41.

2, 2'-di (o-naphtboxy) diethyl ether bridged bis-4Mmino-benzo-15-crown- 5-biscrown ether compound( I )

A solution of open crown ether compound(9) (0. 414 g,1 mmol) in 20 mL of anhydrous ethanol was added, the temperature rose to 40U in the oil bath and was stirred under Nz. A solution of 4'- amino-benzo-15-crown-5(12) (0. 566 g,2 mmol) in 60 mL of anhydrous ethanol was added at such a rate that the temperature of the reaction mixture

was kept at 40"(2. After the addition was complet- ed and was stirred continuously for 40 h. The sol- vent was concentrated under reduced pressure to c. a. 40 mL, cooled to the separation solid and was filtered to give the crystals of the rude product. The product was purified by column chromatogra- phy on neutral alumina using ethanol as eluants to give the yellow solid 0.4 g, m. p. 118~-120 C. yield 42. 4%,IR (Umax/Cm -t KBr). 2 925,2 870(CHz); 1624 (C = N ) ; 1 589, 1 452 (Ar)~ 1 266 (ArOCHz); 1 228 (CHzOCHz).tH NMR (~, CDC13): 3.6 "~ 4.4 (42H, m, 6 • ArOCHz, 7 •

CHzOCHz, 2 • CH = N); 6. 6 ~ 8. 0 (18H, m,

H ~ ~ )'MS(m/z%):945(M+ H

q 1,16);677(6);508(5);436(3). Anal. Calcd for C~4 H~0NzO13 : C, 68. 75 ; H, 6. 30 ; N, 2. 78. Found : C,68.63;H,6.40;N r

2 Results and discussion

The hiscrown ether compound ( I ) containing phenyl methyl ether multi-ester bridge was pre- pared, which was synthesized by its precursors (7) transformed into the corresponding crown ether compound. The reaction was required to complete under anhydrous condition, the yield was reduced when the reaction system have minimal water, we used synthesizing method that compound ( I ) was prepared by two steps reaction. The phenyl methyl ether-2, 6-diformic acid potassium salt was pre- pared and which was dried in vacuo, then the reac- tion of esterfication was completed to obtain the product yield 45%. We tried also that multi-ester type crown ether ( I ) was completed by one step reaction. The following procedure: A solution of pbenylmethyl ether-2, 6-diformic acid and anhy- drous potassium carbonate and anhydrous N, N- dimethylforman~id were added into a reactor, stirred at reflux temperature for 1"--1.5 h. After a solution of 6-bromoacetacetic ester-dibenzo-16- crown-5 in DMF was dropped slowly to the reac- tion mixture to complete the reaction of esterfica- tion, which was transacted to obtain crown ether compound( I ),the yield is lower than the yield of two steps method.

332 Wuhan University .lournal of Natural Sciences Vol. 2

References

1 Bourgoin M,Wong K H,Smid J. Interaction of macrobi- cychc polyethers with Ions and Ion pairs of picrate salt. .I Am Chem soc, 1975,97(12) :3462

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Hua~'ue, 1986,2,151-153 (in Chinese) S Niu Changrong. Wu Chengtai,Mou Wenyu,et al. Stud-

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7 Niu Changrong,Son Jiangao,Xia Xionghing,et al. Stud- ies on synthesis of macrocyclic polyetherss 1 . Synthesis of macrocyclic polyethers with monohydroxyl group at- tached to the crown ether ring. Journal o f wuhan uni-

versity (Natural science edition), 1983 (3): 83-88 (in Chinese )

8 Niu Changrong Wu Chengtai,Tian Weijun. Studies on synthesis of macrocyclie polyethers: I . Synthesis of 2, 3, 9, 10-dibenzo-16-crown-S containing single groups. Journal of Wuhan university, (.Special lssue on Chem-

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Abstract EIn: Wuhan Daxue Xuebao (Ziran Kexue Ban), 1997,43(4) : 468~ 470]

STUDIES ON THE MELT COPOLYMERIZATION OF PHOSPHORUS-CONTAINING DIACID AND

BIS(p-CARBOXYPHENOXY) PROPAND FOR DDS

Fu Jie,Zhuo Renxi,Fan Changlie (Department of Chemistry,Wuhan University,Wuhan 430072 ,China)

Phosphorus containing copolyanhydrides DECP-CPP and DCPP-CPP were synthesized by melt copoly-

merization of bis (p -ca rboxy phenyloxy e t hy l ) , ethyl phosphate ( D C P E ) , bis (p -ca rboxypheny loxy e t h y l ) ,

phenyi phosphate ( D C P P ) and bis ( p - c a r b o x y p h e n o x y ) p r o p a n e acid ( C P P ) . The copolyanhydrides were characterized by ~H N M R , IR spect rometry . In Vitro degradation of copolyanhydrides in phosphate buffer

solution at 37 C were determined. Drug release profile of Rifampicinum ( R F P ) were also studied.

Key words copolyanhydride , po lyphospha te , drug controlled release, RFP