聶友松，鐘　敏，李　航，賀賢然（江漢大學(xué)　交叉學(xué)科研究院，湖北　武漢　430056）

N-（二苯基亞甲基）甘氨酸叔丁基酯的合成

聶友松，鐘敏，李航，賀賢然*
（江漢大學(xué)交叉學(xué)科研究院，湖北武漢430056）

摘要：N-（二苯基亞甲基）甘氨酸叔丁基酯可由鄰苯二甲酸酐和甘氨酸分4個(gè)步驟制得，且產(chǎn)率可觀。此方法的最后一步是二苯甲酮與甘氨酸叔丁酯的縮合反應(yīng)，以氯化鐵六水合物為催化劑，該合成方法方便可行。

關(guān)鍵詞：二苯甲酮；氯化鐵（III）六水合物；合成

0　Introduction

Benzophenone Schiff base derivatives of glycine tert-butyl ester was an interesting basic matter for the synthe?sis of higher amino acids by phase transfer catalyst［1- 5］. In 1987，Martin J. O′Donnell［6］reported the synthesis method of Schiff base derivatives of amino acids，which is a commonly used method for the preparation of imine that was the condensation of an aldehyde or ketone with a primary amine. If the carbonyl component was a ketone，it was required the forcing conditions（high reaction temperature，nonstoichiometric amounts of reagents，added protic or Lewis acids，and/or long reaction time）or combined catalysts-drying reagents such as TiCl4，molecular sieves or catalyst prepared from molecular sieves，silica gel and alumina. But preparation of Schiff base derivatives of higher amino acids was not desirable. Until now，synthesis of the Schiff base derivatives mainly had two routes. One route was the condensation of benzophenone and amino acid esters with the removal of water by BF3-Et2O［7］，the other preparation method was based on transmission of the reactive benzophenone imine and ester salt［6］.

1　Experiment

1.1Materials and methods

The melting points were determined on a XT-4 apparatus（uncorrected）. The IR spectra were recorded from KBr pellets at a range of 400－4 000 cm-1on a Perkin Elmer（Spectrum One）spectrometer.1HNMR and13CNMR spectra were obtained at a Varian Unity Inova-600MHz spectrometer. Chemical shifts are reported in δrelative to TMS. M/Z spectra were recorded at a Agilent 1100 LC-MSD/Trap SL.

1.2General procedure

1.2.1 Synthesis of N-phthaloyl glycine 15. 0 g（0. 2 mol）glycine，32. 6 g（0. 22 mol）phthalic anhydride and 100 mL glacial acetic acid were put into a three-mouth flask respectively with a magneton stirrer. The mixture was heated to 150-160℃（oil-bath temperature）for 5 h and distilled under vacuum condition，then the acetic acid was removed. The solid was resolved by hot methanol and filtrated immediately. The filtrate was poured into water. The solid products were precipitated，and then dry the precipitate under the vacuum condition. 36. 5 g white crys?tal of N-phthaloyl glycine was obtained and the yield was 89 ％. Melting point：191-192℃. IR（KBr）：3 435，3 224，1 773，1 723，1 620，1 467，1 417，1 384；1HNMR（300 Hz，CDCl3）：δ=4. 503（s，2H），7. 743-7. 914 （m，4H，Ph）；13CNMR（300 Hz，CDCl3）：δ=38. 666（C-2），123. 946，132. 105，134. 55（Ar），167. 518（C-3），172. 283（C-1）；M/Z：227. 8（M +Na）.

1.2.2 Synthesis of N-phthaloyl glycine tert-butyl ester 10. 25 g（0. 05 mol）N-phthaloyl glycine，3. 5 g（0. 05 mol）tert-butyl alcohol，7. 9 g（0. 1 mol）pyridine，75 mL dichloromethane were put into a three-mouth flask respective?ly with a mechanical stirrer and a drying tube. The flask was put into a ice-salt bath，and 2. 0 mL phosphorus oxychlo?ride was added dropwise slowly into the reaction mixture. After 30 min of reaction，the ice-salt bath was removed，and the reaction continued for 1 h under room temperature. Then the pH of the reaction mixture was adjusted with 0. 5mol/L hydrochloric acid to 5-6. The organic layer was washed by 2 ％ NaHCO3and saturated brine respectively，and the resolvent was removed by vacuum distillation. 11. 0 g white crystal of N-phthaloyl glycine tert-butyl ester was obtained by recrystallization and the yield was 85％. Melting point：93-94℃. IR（KBr）：2 983，2 931，1 778，1 745，1 715，1 611，1 468，1 417，1 389；1HNMR（300 Hz，CDCl3）：δ=1. 470（s，9H），4. 344（s，2H），7. 723-7. 897（m，4H）；13CNMR（300 Hz，CDCl3）：δ=28. 576（C-1），40. 286（C-4），83. 403（C-2），124. 114 -134. 711（Ar），166. 859（C-5），168. 210（C-3）；M/Z：283. 8（M+Na）.

1.2.3 Synthesis of glycine tert-butyl ester 5. 22 g（0. 02 mol）N-phthaloyl glycine tert-butyl ester，80 mL tertbutyl alcohol were added into a three-mouth flask respectively with a mechanical stirrer and a condensing tube. Then the device was put into an oil-bath for refluxing，and hydrazine hydrate 85％1. 2 mL（0. 02 mol）was added dropwise slowly into the reaction mixture，which refluxed for another 15 min after all the hydrazine hydrate was added into the flask. The reaction mixture was cooled then. After diluted by water，the pH of the mixture was ad?justed with Na2CO3to 7-8. Removing the resolvent by vacuum distillation，the mixture was filtrated and the filtrate was extracted by ether. The extraction was washed by saturated brine and dried by anhydrous MgSO4. After remov?ing the resolvent by vacuum distillation，1. 99 g colorless liquid of glycine tert-butyl ester was obtained by vacu?um drying and the yield was 76 ％. IR（KBr）：339，2 975，2 918，733，1 646；1HNMR（300 Hz，CDCl3）：δ=1. 467 （s，9H），3. 316（s，2H）；13CNMR（300 Hz，CDCl3）：δ=28. 294（C-1），44. 783（C-4），81. 324（C-2），173. 672 （C-3）；M/Z：131. 9（M+Na）.

1.2.4 Synthesis of N-（diphenylmethylene）glycine tert-butyl ester 0. 91 g（0. 005 mol）benzophenone，0. 72 g （0. 005 5 mol）glycine tert-butyl ester，30 mL toluene and 0. 1 g catalyst was put into a three-mouth flask respec?tively with a magneton stirrer and a condensing tube. Refluxing 3 h，the reaction mixture was cooled and washed with water and 0. 5 mol/L NaHCO3. The resolvent toluene was removed by vacuum distillation. The residue was ex?tracted by ethyl acetate. The extraction was washed by 0. 5 mol/L hydrochloric acid，0. 5 mol/L NaHCO3and satu?rated brine and dried by anhydrous Na2SO4. By removing the resolvent and recrystallization，0. 83 g colorless crys?tal of N-（diphenylmethylene）glycine tert-butyl ester was obtained and the yield was 92％. Melting point：109-110℃；IR（KBr）：3 446，3 030，2 976，1 735，1 623，1 577，1 448，1 404，1 384；1HNMR（300 Hz，CDCl3）：δ= 1. 464（s，9H），4. 122（s，2H），7. 719-7. 666（m，10H）；13CNMR（300 Hz，CDCl3）：δ=28. 319（C-1），56. 509 （C-4），81. 210（C-2），127. 935-139. 586（ArH），166. 859（C-5），168. 210（C-3）；M/Z：295. 9（M+Na）.

2　Results and Discussion

We now report a convenient and inexpensive preparation of the benzophenone Schiff base derivatives of gly?cine tert-butyl ester. The procedure was base on dehydration of benzophenone and amino acid esters with the inex?pensive Iron（III）chloride hexahydrate as the catalyst. Firstly，glycine was taken as the starting raw material and its amino group was protected by phthalic anhydride using glacial acetic acid as the catalyst［8］. The N-phthaloyl glycine was then esterified with tert-butyl alcohol to give N-phthaloyl glycine tert-butyl ester by using phosphorus oxychloride as the dehydrating agent［9-10］. The glycine tert-butyl ester was obtained by hydrazinolysis of N-phthalo?yl glycine tert-butyl ester with hydrazine hydrate［9］. The final condensation was conducted by mixing benzophe?none and glycine tert-butyl ester at a molar ratio of 1∶1. 1 in toluene refluxing 5 h in the presence of catalyst，and the reaction mixture was purified by extraction and recrystallization methods to obtain the colorless crystal of N-（diphenylmethylene）glycine tert-butyl ester.

3　Conclusion

The N-（diphenylmethylene）glycine tert-butyl ester was obtained by synthesizing benzophenone and amino acid esters with Iron（III）chloride hexahydrate as catalyst. The results show the catalyst Iron（III）chloride hexahy?drate is very efficient，which can improve the reaction yield in a large extent.

References

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（責(zé)任編輯：陳曠）

Received：2014-11-20

Biography：NIE Yousong（1990—），male，graduate candidate，majors in medicinal chemistry.

*Corresponding Author：HE Xianran（1983—），male，associate professor，doctor，majors in organic chemistry and medicinal chemistry. E-mail：hexianran@163. com

Synthesis of N-（diphenylmethylene）Glycine Tert-Butyl Ester

NIE Yousong，ZHONG Min，LI Hang，HE Xianran*
（Institute for Interdisciplinary Research，Jianghan University，Wuhan 430056，Hubei，China）

Abstract：The N-（diphenylmethylene）glycine tert-butyl ester has been accomplished in 4 steps from phthalic anhydride and glycine with good yield. The last step in this approach is a condensation reaction of benzophenone with glycine tert-butyl ester using the Iron（III）chloride hexahydrate as a catalyst，which is a convenient synthetic method.

Keywords：benzophenone；Iron（III）chloride hexahydrate；synthesis

DOI：10.16389/j.cnki.cn42-1737/n.2015.01.004

中圖分類號(hào)：TQ031.2

文獻(xiàn)標(biāo)志碼：A

文章編號(hào)：1673-0143（2015）01-0024-03