MIZUTANI, Toshio

NAKAGAWA, Masataka

NISHIZAWA, Yoshihiko

Kyoto University Research Information Repository

Title Synthesis of Acyl Phosphorates and their Biological ActivitiesAuthor(s)NISHIZAWA, Yoshihiko; NAKAGAWA, Masataka;MIZUTANI, ToshioCitation防虫科学 (1961), 26(1): 4-7Issue Date1961-02-28URL http://hdl.handle.net/2433/158229RightType Departmental Bulletin PaperTextversionpublisherKyoto Universityoxydihydro-IX vom Schrnp. 151-152~ (aus Toluol)zerlegt werden kann,Persaure-Oxydation von IX fuhrt zu einem Sulfonvom Schmp. 181', welches das andere trans-Isomere von VIII ist.kurze Zeit mit Zn-Staub in· Eisessig vorsichtigcrwarmt, Beim Einruhren in Wasser fallt einGemisch von VII und XII(= der VII entsprechendeThioather) aus. Mit CH2Clz lasst sich im Fallevon Va-das VIIa-lsomere extrahieren, das nachdcm Umkristallisieren bei 205' schmilzt, Vb liefertVIIb vom Schmp. :195' (aus Alkohol).IX CllH h02S (246,3) S Ber. 13,0CllH 160aS (264,3) S Ber, 12, 1Gef.13,2. Gef.12, 3CllHllO.S (278, 3) aus VIla: S Ber. 11, 5 Gef. 11,2aus VIIb: S Ber, 11,5 Gef, 11,5synthetisiert: S Ber, 11,5 . Gef.11, 4Reduk tion von Via und Vlb: 3stdg. Kochenvon VI a bzw, b mit aktiviertem Zn-Staub inEisessig fUhrt in beiden Fallen zu einem Thio-athergemisch, das in IX vom Schmp. 60' (inorgan. Losungsmitteln leicht losltch) und Hydr-Das in beiden Fallen als zweites .Reduktionspro-dukt mitentstandene XII schrnilzt .bei 125' (ausMethanol).Oxydation von VIla und VIIb: Mehrstdg,Erhitzen von VIla und b mit Peressigsaure fuhrtin beiden Fallen zum Sulfon VIII vom Schmp.186' (aus Toluol), das auch aus der trans-IVaentsprechenden S02·Verbindu';1g und Cyclopenta-dien synthetisiert werden kann.VIlaVIIbXIICllHl~OaS (262,3) S Ber. 12, 2CllIlllOaS (262,3) S Ber. 12,2CllHllOZS (246, 3)' S Ber, 13,0Gef.12,3Gef.12,O'Gef.13,2Der Deutschen Forschungsgemcinschaft unddem Verband der Chemischen Industria sei furdie Forderung dieser im Marz 1960 experimen-tell abgeschlossenen Untersuchungen bestensgedankt, Vorliegende Arbeit ist im Juni undJuli zahlreichen Stellen alsManuskript zugang-lich gemacht worden.Literatur(1) Riemschneider, R., Gallert, II. und Andres, P.,Mh, Chern, (im Druck) und Dtsch, Bundes Pat.1081886 vom2. 5.1958.(2) Riemschneider, R. und Wucherpfennig, W.,Natunoiss., 48, 130 (1961).(3) Bottcher, B. und Riemschneider, R., Patent-anmcldungen, Vgl. auch (4).(4) Truce, E.W., Goldhamer, D. L., Kruse, R.II.,]. A mer. chetn, Soc. 81, 4930· (1959) undfriihere Arbeiten.(5) Farbtoerke HOECHST, U. S. Pat. 2799685.Synthesis of Acyl Phosphorates and their Biological Activities. Yoshihiko NISIIIZAWA, MasatakaNAKAGAWA 'and Toshio MIZUTANI (Sumitomo Chern. Co. Ltd., Osaka) Received Nov. 12, 1960.Botyu-Kagaku, 26, 4, 1961; (in English)2., Acyl Phosphorate nCl)'€i'Jjji;-c -c-Cl)$'\'1 gyiRtf~, i41JlIi!&ur, *~~7.( ((f,:&:1~~J~I:rH:'\;).~. 0 tt :kW.z!'£!lliTfrIilfJ'll'lID 35.', 11. 12 51:l!I1.1j~ ~ :.--~!lJ.1iUO)lVf:re.iJlJ:Ir.:lO~'''(', ~:t'~I.t:llHllO) Acyl Phosphorate m~iS~v, "CO)i1.ltt,~!.I.C}J~1t~.!W~Mvt.:. U~I;,O){I:;Sl!JI.t--:'tl:Ir. Dipterex J; I) ~~iJJll~,~rttjJ~~vt.:tJ;, IlulrlIlllibl!Jlr.j1 v "('~1'1i~ lr.lUtltJ;sm ~ -z, CtJ;l~j I;, t» c ts-> t.:.G. Schrader'? reported already that 0, O-diethyl-O-acetyl phosphorate* (I) is the biological activephosphorate. After that, no one had reported 'indetail about the degree of biological activities ofthe phosphorate (I) and the analogues comparingwith the commercial insecticides.The present' authors prepared some acyl phos-. phorates to understand clearly the biological ac-tivities of the acyl phosphorates towards warmblood animals and insects, and it is consideredthat these data would be of value upon the studies* ' Phosphorus .compounds in this paper werenamed according to the Drake Committee'sReport (Chem. Eng. News, 30, 4515 (1952))m at :n ~l- ro 26 ;YJ- Iof the organophosphorus insecticides.1) Preparation of acyl phosohorates.Acyl phosphorates were prepared by the followingthree methods~)a) (RO)aP-O+R'COCIob) (RO):'Pc1 +R'COOlIoc) (RO)j)-O-C"CHCOOC~lh6C~H~ ')+R'COOH -The yield of the products by the method (a)was the highest and almost all phosphorates wereprepared by this method. All of the productswere liquid and purified by distillation under reduc-ed pressure. The proof of structure of these com-pounds was given by the microanalytical data, theinfrared absorption spectra and the alkaline hydro-lysis, namely, the IR-spectra of the productsshowed the streching vibration bands of' carbonylgroup at 1755cm-1, P=O group at 1300cm-I,o 0II IIP-O-C~H~ group at 1150crrr' and -C-O-P- group3000 2000 1500 1200 1000 900 BOO 7003 4 5 6 7 8 9 10 11 12 13 14Fig. 1 Infrared Absorption Spectrum of O. 0-Diethyl-Ovchloroacetyl phosphorate (II).at970 cm-l~) (see Fig. 1). The alkaline ·hydrolysisof benzoyl phosphorate (VI) gave benzoic acid.2) The biological activities of acyl phosphoratesTopical test was conducted by using Ephestiarail/ella as follows; each compound was dissolvedinto acetone to prepare a series of acetone solutionscontaining from 0.067 to 2 f'6 of the compounds(g/cc). Each 111000 cc of these solutions wasapplied to the body of the insect by means. ofmicrometer syringe and, after keeping it for 3 daysat 25' C, the kill percent was calculated. Theinsect utilized in this test had almost the same bodyweights and each solution was applied to a groupof these twenty bodies in order to calculate themean fatal per cent.For comparing the activity of synthetic sampleswith that of the commercial insecticides, Dlpterex'"(0, 0-dimethyl-(l-hydroxy-2, 2, 2-trichloro-ethyl)phosphonate) wes tested at the same time.The toxicity of acyl phosphorate towards warm-blood animals was tested by oral administrationto mice; each test emulsion was prepared bydilution of 5076 emulsifiable concentrate composedof 50 parts active ingredient and 50 parts polyeth-ylene glycol nonylphenyl ester by weight.Each emulsion thus prepared was given into thestomach of mice by metalic tube. The volumeof instilment was 0.5 ml per 109 of body weight ofmice and each consentration of the solution wasapplied to a group of five bodies of mice. .After keeping it for seventy two hours, thesymptoms of poisoning was observed. Rough LD50(mg/kg) value was calculated according to theLitchfield and Wilcoxon's method, .and then byYield (f'o) b p 'c(a-method) "C .~mHg. nn (t )No. RTable I Yields, physical constants, and microanalytical data of acyl phosphorates,o 0II It(C~lhO)Y-O-C-RP"h-o-s-p'ho-r-u-s-Chlorine Carbon Hydrogen(%) (%) (%) (%)Calcd. Found Calcd, Found Calcd. Found Calcd.FoundCHa- 48II CICHz- 51III CIzCH-. 43IV ChC- 38V CHz=CH(CHDa- 40VI C6H~ 61119114-115125-126132-13i139-140119-1201.00.91.21.01.00.91. 4230(24)1. 4191(29)1. 4508(27)1. 4182(25)1. 4358(29)1. 4854(29. 5)15.81 15.65.- - 36.7336.8113.4513.21 15.40 15.5331.2431.3911.7011.7826.7926.9027.1727.3510.3510.5535.5635.3924.0324.259. 69 9. 81 - 56. 25' 56. 1112.0212.36 - - 51.1651.356.635.214.153.339.065.816.575.50 .4.413.308. 935.635;Table II The biological activities of acyl phosphorates.o 0II II(C2H~0)2P-0-C-R2.02.04.36.26.315.0Oral Toxicity towardsMice LD~o mg/kgEphestia cautera (topical method)kill 5'620rlw9rm~rL~EErI1_-.zr{~El'm 0. 68r'--/w.:.:...::.o:..:rm=- _100 100 55. 6 30. 070 30 10 20100 80 10 1090 50 0 070 40 20 1090 50 0 090 80 10 080 20 10 080 . 40 0 090 50 0 090 50 0 090 80 0 0RClla-DipterexCICH.-DipterexCl·,CH-Dipterexci.c-DipterexCH2=(CHDs-DipterexC6H~­DipterexVIIIVIII.VINo.changing the concentration of the solution nearthe value, the true LD~o value was determined byrepeating the above experimental processes.The results of the biological activities of acylphosphorates are shown in Table II.It may be summarized from Table II that theactivities towards insect of acyl phosphorates area little higher than that of Dipterex and the toxi-cities towards mice are very higher than that ofDipterex.Experimental1) Preparation of acyl phosphorates.The following examples illustrate the preparationof acyl phosphorates. Other compounds preparedare shown in Table I and their biological activitiesare shown in Table II.Caution: All of the phosphorates are powerfulcholinesterase inhibitors and thereforehighly toxic.2) Preparation of 0,0 -diethyl-O-trichloroacetylphosphorate (IV) by the method (a).A mixture of 27. 3g (0. 15M) of triethyl pho-sphorate, 16.4g (0. 1M) of trichloroacetyl chlorideand 2 drops of triethylamine was heated at 110-130°C for 4 hours. And then, the product wasdistilled under a reduced pressure, b. p. 132-134°C/lmmllg, yielded 12. 9g' (485'6 from trichloroacetylchloride), nD2~ 1.4182.Anal. Found. P, 10.55; C, 24.25; H, 3,30;ci, 35, 3~. Caled. for C6H100~ClaP, P, 10.35 ;C, 24.03;H, 3. 33; ci, 35. 563) Preparation of 0, Oediethyl-Oetrichloroacetylphosphorate (IV) by the method (b).A solution of 32. 6g (0. 2M) of trichloroaceticacid in 100 ml of acetone was neutralized by 16.8gof sodium hydrogen carbonate in small quantityof water. Water was distilled off by azeotropewith acetone, 50 ml of acetone was added furtherand then 34. 5g of O! O-diethyl phosphorochloridatewere added. A mixture was refluxed for 5 hours.The precipitate was filtered off, the filtrate wasconcentrated and then residual' oil was distilledunder a reduced pressure, b. p. 132-133·C/l mmllg.Yield 13.6g (235'6), nD2~ 1. 4183,Anal. Found, C, 23. 91; II, 3. 51; CI, 35. 38Calcd, for COHlOO~ClaP, C, 24.03; II, 3,33;ci, 35.56The infrared absorption spectrum of this productwas coincided with that of the method (a).4) Hydrolysis of 0. O~diethyl-O-benzoylphospho-rate (VI).To 50 ml of 0, 05N aqueous solution of sodiumhydroxide, were added 2.6g of (VI) and heated for3 hrs. A solution w~s acidified. by hydrochloricacid and then concentrated. White crystals wereprecipitated and filtered off (0. 8g). The crystalswere recrystalized from water and melted at 121°C.A mixture of the crystals with the authentic ben-zoic acid melted at 121-122° C.Anal. . Found, C, 68. 66 ; H, .5. 05 .Calcd. for C1Hp~! C, 68, 85 ; H! 4, 9~6Summary ReferencesSeveral acyl phosphorates were prepared andtheir biological activities were tested. These acylphospho rates showed II little higher activity to-wards insect than Dipterex lind the toxicities ofthese acyl phosphorates towards mice were alsohigher than that of Dipterex.AcknowledgementThe authors wish to thank the Sumitomo Chern.Co., Ltd. for permission to publish this work.They are indebted to coworkers in the pesticidal,the biological and the analytical sections in thislaboratory.1) Schrader, G. BIOS Final Report, No. 714(194,7)2) Nishizawa, Y. and M. Nakagawa, Jap. Pat.Anounced No. 6374 (1960)3) Nishizawa, Y. and T. Mizutani, jap, Pat.Anounced No. 6375 (1960)4) Nishizawa, Y. and M. Nakagawa, Jap. Pat.Applied No. 31528 (1957)Nishizawa, Y., Agr. Biol, Chern. 25, 229(1961).Cramer, F. et· al., Bcr.; 91, 70·4, (1958)5) Bellamy, L. J. The Infra-red Spectra 0/ Com·plcx Moleculcs (1958)6) Lorenz, W. U. S. P. 2, 701, 22An Attempt to Reduce and Increase Insecticide-Resistance in D. melanottaster by SelectionPressure. Genetical and Biochemical Studies on Negatively Correlated Cross- Resistance in Droso-phila- mclanogaster I. ZenichiOOlTA (Department of Genetics, Faculty of Medicine, OsakaUniversity, Osaka, Japan). Received Nov. 22, 1960. Botyu-Kagaku, 26, 7, 1961. (in English)3. Selection pressure I:~"? -C~mJ~lH!U1i:tt~~~~"ltitl1JD~"lt~iitJj. ·t·1 p ~ EI r)~ EI r) /,(.:r.I:::.:t3 tt Q negatively correlated cross- resistance O)}fl {i;1.: {t.~N(~f1Jf1'C I.~m;r.;- (:kIUNJ~l~"N$ in(L;'J~.f{~D 35. 11. 22 ~JlI!4'-1 pi"" ? ~" ? rCx.O)Zf} Dt{~~U:l:65±PHili:Ir.<b Z,fi;Et'E0) DDT IlUiJ:¥I,i1'H!;::y.O)1'n'Eli, DnC,parathion N J: [f phenylurea (PU) I<::jf L -CxX:f1U/J:t'E (cross-resistance) fj:Jj;t Z, '/J:, phenyl-thiourea (PTU) Ir.j:fv -C liiI! Ir.)'il'jit tsJrlIUict'E (iI!fi]OO3CXl1UiJ:t'E negatively correlated cross-resistance) ~ b t: i; "9. :t t:.Zf} m~(gU:l: 50 ±PHili:Ir.ibZ,Tullf!1l'::';J 7- :--:l1lJ/LtEO)i1'lm:Y'O)1'n'Eli,I:.~1 i; 0) ~!M'iIJ Ir. jf v -C ~3Z:l1lJ/J:t'.E ;g b t: i; "9I:. c ;g-~1.' rz {'U{'f v tz, v t:.'/J{? -C. P'TUvselectionpressure 11: J:? -C u DDT, DIIC, parathion I<::xf v -CKlUJict'E1.'.::. ;J 7- :--1r.X-f v -C:!lUIJ:t'E0)*yc ;gb t: i; i-, PU-selection pressure 1;1; Ut i; O)~~n'Jlr.;tf v-Clltt/Lt'!:O)*~ ~ b t: i; T I:. c H<'i~ t, tz:~~, DDT lltt/Ct'E c ;}l'lltt/J:t'EO)*M:1'J' i; ts Z, lfi!.it population tz PTU-selection pressure ;g ~@I'J'-t!Z,C.clr.J:?-C DDT lltt/ct1,nm:y.;glJ]PI!.lv, ~H:lht:'*YCI;t DDT, DHC, parathtorr ul:llttM1L' fvIE~.::. ;J 7- :--:f1ft;,Ct'!:1.' tY) '? tt: :t t: PU-selection pressure J: ~ LE ~ ?Jh t:*M: Ir.li,DDT, BIIC, parathion :f1fl1Lt1 c IUiCM.::. ;J 'j- :-- J11J/J:t'E;g mI P!jlr. b t: G'~ I:. c ;g ~i£IJIJ v tt .The cross-resistance pattern of Drosophila melanogastcr to DDT, nnc, and parathion is nega-tively correlated with its resistance to phenylthioureafP'TU), but is positively correlated withphcnylurcafPUj-resistance. As a result of the genetical analyses in previous papers, thefollowing working hypothesis was introduced by the author: "The dominant P'I'U-susceptibilityand dominant PU-resistance may be a pleiotropic expression of the dominant gene for resistanceto DDT, nIle and parathion at locus 65± on the 2nd chromosome; and the dominantfactor for PTU- and PU-resistancc on the 3rd chromosome is a pleiotropic expression of thedominant gene for resistance to nicotine sulfate at locus 50±.The present investigation has aimed to test the hypothesis by means of applying selectionpressure with PTU and PU to synthetic populations consisting of several strains resistant toDDT,BHC and parathion, and strains susceptible to those insecticides.7

Acyl Phosphorate類の合成とその毒性

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Acyl Phosphorate類の合成とその毒性

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