AU611164B2 - Novel thiophen compounds and their preparation - Google Patents

Description

LIMLl~ b III~ puL Un Mauc in a tUIIYVII I ,UU IL W&*I.

of the application.

Insert place and date of signature.

Slignature of declarant(a) (no attestation required) Note; initial all alterations.

Declared at Basle, this 28th day of October 1988 SANDOZ Ltd.

du.y atoieofficr DAVIES COLLISON, MELBOURNE and CANBERRA.

AU-AI-18044/F88 0

PCT

WORLD INTELLECTUAL PROPERTY OROANIZATION Internationail Eiurcatu INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) Internationial Patent Classification 4 (11) International PiiI)Iication Number- WO 88/ 10261 C07C 5/60,45/67A 1.cember 1988 (29,12,88) (21) International Application Numiber; PCT/EP88/00525 (T1) Dcsignatel States: AU, I.D, H-U, JP, KR, SU, US.

(22) International Filing Date: 14 June 1988 (14,06,88) Published (31) Priority Application Number: 8714005 Wt nentoasac eot (32) Priority Date: 16 June 1987 (15.06.87) (33) Priority Country: GB I .J P. 1 MlAR 18 (71) Appiloant jbr till designated States except MS: SAN- AUSTRALIAN DOZ AG [CI-/CHI; Lichtstrasse 35, CH-400J2 Basel 19 JAN 18 198 (72) Inventor-, and1 PATENT OFFICE lInventor/Applicant US onlvi F(NPSCHILLING, Peter [CHj'CH],, Ochsengasse 62, ('1--4123 Allseliwil (74) Commiion Representtative,' SANDOZ AG Lichistrasse 3 H-400" B~asel (C H).

Title-. NijvEL THIOPH-EN COMPOUNDS AND THEIR PREPARATION (57) Abstract Processes ror the preparation of N-(2,4-dimchiyhthien.I-y).N-(.niethoxyprop 2.yiy-chloroacetarnide anmd of intermecdiates dicreot', and novel intermediates useful for the preparation or N-(2-imnhyltien-3'yb.N.(I-tmizthoxyprop2.

y1)-ohloroicetamkie.

0N 1 WO 88/10261 PCT/EP88/00525 NOVEL THIOPHEN COMPOUNDS AND THEIR PREPARATIOt! The present invention relates to novel processes for t'he preparation of N-(2,4-dimethylthien-3-yl)-N-(-mlethoxyprop-2-yl)-chlC'roacetamide (hereinafter designated thienyl-chloroacetamide) and If intermediates thereof and to novel intermediates useful for the preparation of the thienyl chl oroacetami de, UK 2 114 566 discloses the thienyl-chloroacetamide, herbicidal properties of said compound and processes for preparing it. The processes in UK 2 114 566 have various disadvantages. EPA 210320 discloses an improved process of preparing the thienyl-chioracetamide employing better available starting materials. Said process has the ecological disadvantage that it involves the use of th 4 onylchloride as oxydatlon agent, The present invention provides novel advantageous processes for the preparation of the thienyl-chloraicetamide and of intermediates therefore, The novel processes allow the preparation of thienyl-chioracetamide in high yields and are ecologically acceptable, The processes involve also novel intermediates.

Accordingly, the invention provides 2,4-dimethyl-,3-dihy.4ro-thiophen- 3-one of formula la, which may also exist in its tautomeric enol-form of formula lb S Ia l b or salts thereof. The compound of formula lb may be converted to its salts in a manner known per se or vice versa.

The compound of formula la or lb ihereinafter designated formula 11 is obt~ined by a) treating a compouni of formula lIt Wnerain R is Hi the aliphatic hydrocarbyl mt~ety of an alkanol, or C 2 4 alkanoyl, withi an organic carbOxylit acid in tfle presence of an amine, or

I:

1' 130-4013 -2b) treating a compound of formula IIb r R 1 Ilib wherein R1 is the aliphatic hydrocarbyl moiety of an alkanol, with NaOH, and converting where desired the thus obtained Na salt of the compound of formula lb into its free keto/enol form.

Process a) is conveniently effected by treating a solution of the compound of formula IIIwith an alkanecarboxylic acid such as glacial acetic acid, propionic acid and the like. The reaction is effected in the fw presence of an amine, e.g. a tertiary amine such as triethylamine or a secondary or primary amine such as l-methoxy-2-propylamine (hereinafter referred to as methoxyisopropylamine). Suitable solvents are solvents which are inert under the reaction conditions, eg. an hydrocarbon such as n-hexane, toluene, xylene, a chlorinated hydrocarbon such as 1,2-dichloroethane, or mixtures thereof. The compound of formula III may also be and is conveniently prepared in situ and reacted further without isolation. More details on this aspect of the invention will be given below. A suitable reaction temperature for process a) lies in the range of 20 0 C 80 0 C, e.g.

O* at 60 0 C 75 0 C. The reaction is preferably effected at pH 5 to 12, more preferably at pH 5 8.

i Process b) is conveniently effected in a solvent which is inert under the reaction conditions, i.e. an alkanol such as methanol. A suitable reaction temperature for process b) lies in the range of 20 0 C to 80 0

C,

i e.g. at 60 0 C. The reaction runs smoothly and there is accordingly no i need to work at higher temperature. The pH is preferably in the range of 5 -12.

Like in process the compound of formula IIlb may be prepared in situ and reacted further without.isolation (see below) The compound of formula III wherein R is hydrogen, may be readily obtained from 4-methyl-4-pentene-2,3-dione of formula IV CH C CO CO CH 3

IV

CH

3 by treatment with H2S in the presence of a base (process c).

Ats Process e) Is essentially a Michael addition and can be effected under Sthe conditions known for such reaction. The reaction is carried out in the J;I U vji .i 130-4013 presence of an anorganic or organic base, e.g. an alkalimetal hydroxide such as NaOH, or a primary, secondary or tertiary amine, such as methoxyiso propylamine, triethylamine and the like. The reaction requires the presence of only catalytical amounts of base.

The reaction of process c) proceeds already at temperature of -40 0

C.

A suitable reaction temperature is for example from 0° to 20°C, e.g. from 0° to The compound of formula IV, H 2 S and the base may be and preferably are employed in equimolar amounts.

Process c) is conveniently effected in a solvent which is inert under the reaction conditions, e.g. in a hydrocarbon such as hexane, toluene, xylene, an alkanol such as methanol, a chlorinated hydrocarbon such as 1,2-dichloroethane or mixtures thereof. The H2S may be introduced in gas form into the reaction mixture.

It is however also possible to add the compound of formula IV to a mixture of H 2 S and a base in a solvent which is inert under the reaction conditior,.

After the reaction is complete, which can be established by known S\ methods, e.g. chromatographically, the compound of formula III may be converted without further isolation to the compound of formula I, employing process The compound of formula Ill may, t'f course, also be i isolated and then reacted in the next step.

Compounds of formula III are obtained by oxydation of the compound of I\ formula V with an aqueous solution of a peroxyde, optionally in the presence of an alkanol or a C 2 4 carboxylic acid (process where process d) is carried out in the absence of an alkanol or a carboxylic acid, the compound of formula III wherein R is H is obtained.

(Compound of formula lila).

-s- WO 88/10261 PCT/EP88/00525 -4- Where process d) is carried out in the presence of an alkanol, a compound of formula III wherein R is the aliphatic hydrocarbyl moiety of an alkanol, is obtained (Compounds of formula Illb). Examples of alkanols suitable for use in process d) are methanol, ethanol, isopropanol, hexanol; they allow the preparation of compounds of formula 1lib, wnerein R is C 1_6alkyl. R 1 is particularly C 1 4 alkyl, most preferably methyl.

Where process d) is carried out in the presence of a C2- 4 carboxylic acid, a compound of formula III is obtained wherein R is C2.

4 alkanoyl (Compounds of formula IIec). Where R is C 2 -4alkanoyl it is preferably acetyl, An example of an aqueous peroxyde suitable for use in process d) is aqueous H 2 0 2 e.g. a 35" H 2 0 2 solution. Reaction d) is exothermic. The reaction temperature lies conveniently between 40C and 801C, e,g. at 606C to Ccopounds of formula ItIb are also obtained by treating the compound of formula Illa with an aliphatic alkanol in the presence of a strong I acid (process e).

In process e) the acid needs only to be present in catalytical amounts, Suitable acids are for example protonating acids such as HCI.

Examples of suitable alkanols (R OH) are methanol, ethanol, isopropanol, hexanol etc. A suitable procedure is for example to employ the alkanol (R OH) as solvent, A suitable reaction temperature is from 200C to 800C, e.g. 400C to 7 The compounds of formula IV and V are known. A suitable process for the preparation of the compound of formula V is disclosed in EPA 210320, 3jA WO 88/10261 PCT/EP88/00525 WO 88/10261 A process for the preparation of the compound of formula IV is disclosed by A. Shabanov et al. in Dokl. Akad. Nauk Azerb. SSR 27(6), 42-46 (1971).

It has been found that the compound of formula IV is, in general, partly obtained in its dimeric form of formula VI 0VI The proportion of dimeric form obtained will depe:nd on the reaction conditions employed for the preparation of the compound of formula VI, it has also been observed that the compound of formula IV dimerizes in undiluted form at room temperature (though said compound can be stored in a hydrocarbon such as hexane or toluene).

It has now been found that the monomeric compound of formula IV may be obtained by pyrolysis of the compound of formula VI (process and this in high yields.

A suitable reaction temperature for process f) is between 400 0 C and 600 0 C at a pressure of 0.01 to 100 Torr, e.g. at 4 to 8 Torr, The compound of formula VI may be distilled under the aforementioned conditions, e.g.

1 in a quartz tube.

i The compound of formula VI is conveniently obtained by elimination i of HBr from the compound of formula VII ItCH 3

CH

3 Br CO CO CH VII in the presence of an acid binding agent (process g).

WO 88/10261 PCT/EP88/00525 -6- Said process g) may be effected under the conditions known for the preparation of olefines from halogenated aliphatic ketones. The reaction is conveniently carried out a solvent which is inert under the reaction condition for example an aliphatic or aromatic hydrocarbon such as hexane or xylene. The reaction temperature is preferably above room temperature, e.g. in the range of 100 0 C to 1301C when employing xylene as a solvent.

Examples of suitable acid binding agents are tertiary alkylamines, such as N(nC 4 Hg 9 3 As indicated earlier, part of the compound of formula 17 will directly dimerize under the reaction conditions to the compound of formula V the latter compound may then be converted to the compound of formula IV by pyrolysis.

The reaction of the compound of formula I with 1-methoxy-2-propylamine allows the production of the N-(l-methoxyprop-'-yl)-2,4-dimethylaminothiophene in high yields (process h).

Such process h) is conveniently effected in an autoclave. 1-Methoxy- 2-propylamine may thereby serve as solvent, The reaction is advantageously carried out in the presence of an acid such as hydrochloric acid. The reaction temperature is preferably above 100 0 C, e.g. between 150 0

C

and 220°C.

Reaction of N- (-methoxyprop-2-yl)-2,4-dimethylaminothiophene with chloroacetylchloride, under the conditions analogous to those of the process of EPA 210320, yield then the desired thienyl-chloroacetamide.

The invention may be illustrated by the following examples in which temperatures are in Centigrades.

-7- Example 1 2,4-Oimethyl-2,3-dihydrothiophen-3-one and 2,4-dimethyl-3hydroxythiophene a. 2,4-Oimethyl-2-hydroxy-tetrahydro-thiophen-3-one Into a solution of 224 mg (0.20 mmol) of 4-methyl-4-pentene-2,3-dione and 202 mg (0.20 mnmol) of triethylamine in 5 ml of n-hexane and 3 ml of 1,2-dichloroethane are introduced within 1 hour and at O-5 internal temperature, 70 mg of H 2S gas. After said hour it is no longer possible to determine the starting material (dione) gaschromatographically. -he clear solution, comprising 2,4-dimethyl-2-hydroxy-tetrahydrothiopnen- 3-one may now, without isolation of the hydroxyketone, be further treated as shown in step b) hereinafter.

Thte hydroxyketone may also be isolated as follows: tne reaction solution is eluated over silica gel employing trlueneietnylacetate 9-1 as eluant, the solvent is evaporated off and the residue distilled in a bulb tube oven. The hydroxyketone suotitle all distills at 0.01 Torr (light yellow oil;, according to NiMR In the form of a :-i trans mixture).

b. Title Compounds (Example 11, To the reaction solution of Example la) are added 0.2 ml acetic acid and the mixture is stirred for 15 hours at 606 (internal temperature), The mifxture is concentrated in vacuo and the residue distributed between S ml hexane and 5 ml IN sodium~ hydroxide, The organic phase Is separated and removed.

The aqueous phaso is covered with 5 Wl hexane and 3 ml saturated am~monium chloride solution are added. The phases are separated and the aqueous phase extracted one more time with 6 ml hexane.

The, combined organic phases are concentirated in vacuo,- The!anr title Compound consists according to NMR determination of a tautomeric mixture Comprising 60 &I keto tompound and 40 n' Ot1 lea a4-Dieth -2,3-dihydrothioohen-3-ofte and Pydrxjne 8a. 2,4-Dimethyl-2-methoxy-tetrahydrothiophel-3-ofle To a solution of 411 g (3.16 mol) of 2,4-dimethyl-tetrahydro-thiophen- 3-one in 3000 nml of methanol are added dropwise, at an internal temperature of 63-55 and over a period of one hour, 256.4 g (2,70 niol) of 35.8 hydrogen peroxide..

The reaction is exothermic; from time to time it is necessary to remove the heating bath, After the addition is completed the reaction mixture is stirred for another 2 hours at the internal temperature of 63-651, the reaction mixture comprises, according to gas chrrnatograpnical determination besides some 2,4-dirnethyl-2-hydroxy-tetranydrothiophene-3-one mainly 2,4-dimrethyl-2-methoxy-tetrahydrothi^,one-3 fzre.

b, 2,4-Oimethyl-la-dlhydrotniophen-3-one and 2,4-dimethyl-3-hydroxythi opene The reaction mixture of Example 2a is cooled to 600 ant~ tnen ^40 M& v an aqueous 3& %I (2,43 moll sodium hydroxide solution are added, After minutes stirring at 601 the reaction mixture hat turned violet. x:t contains according to the gas chromatogram no more 2,4-irietnyi-amethoxy-tetrahydrothi ophen-3-one.

The reaction is then concentrated in varcuo. The residue is diluted with 1500 ml of water and non-pnenollc compounds are remo-wed by extraction with cyclohexane (3 x 300 ml), The aqueOus phase is covered with 300 :11l cyclohexane and, at an internal temperature of 20-250t adjusted at pH t 9.0 by dropwise addition of 20$ ml (1.97 mol) of conc, hydrechloric acid, The phases are separated, and the aqueous ph~se is oxtracted again with cyclohexane (4 x 300 ml). The Combined organic phases are concentrated in vacua and the residue is distilled under kcw absolute pressure, the main fraction distills over at 51-60,0 and 0.,014 Torr, as, a light yellow 011, consisting according to NY of a mixture of the title compound comprising ca. 60 tOf t~'e kett 0A a'd 40 o the enot C_,:poUrd WO 88/10261 p CT/EP88/00525 Example 3t 2,4-Dimethyl-2,3-dihydrothiophene-3-One and 2,4-dimethyl-3hydroxythi ophene a. 2,4-Qimethyl-2-methoxy-tetrahydrothiophen-3-one To a solution of 261 g (2.0 mol) of 2,4-dimethyl-tetranydro~iopnen3 one and 6 g of acetic acid in 600 ml of methanol are added dropwise, at an internal tempe-'ature of 20"254 (external cooling with iceiwater Over a period of 3 hours 207 g (2.1 moll of 34.5 hydrogen peroxide. Tite reaction mixture is then stirred over night at 20-25V. AccordinG to a chromatographical determimation the reaction mixture comprises Deside some 2 ,4-dimetnyl-2-hydroxy-totrahiydrothiohene-3-one.e mainly 2,4-dimethqyi-.-etoxy-tetraydrothophene-3-Qre,.

b ACmty-)-ihd hohn3oi ard Z.4-diymp yroy thioohene Sy adding 5 ml of 30 NiaOH the pH of the evAtion mixture is a-dj1,u4 I from 2.5 to 6.2 "'he methanol is dlstiflled oft a.O (internal temperature a740, duration a hours). During this di~tillation both compound 1,7Aa and compound i?!b (R 1 CH1) are transformed, to the keto/enol mixture ka, and 'b.

I'o the mixture (now two phasesl1 are added SCO ml of toluene arnd*.3 of water. After separation the organic layer J$ washed with ICOl water and the combined aqueous phases are extracted with INO nl iof t~luene. The tohltne is removed by distillation. 269 g of a dark yellow oil (269 gi are ttitned whith 15 dtstillld at iOll Y ield v 2,4 1. Purity -'accoediflg to SgOAph"Ica dotcr-ifatiohl! it 95; y weight WO 88/10261 PCT/EP88/00525 Example 4 :N-(l-methoxyprop-2-yl)-2,4-diniethyl-3-aminothiophene ta 200 ml autoClave are heated, at 190', with stirring 12.8 g (0.10 mol) of the 60 :40 mixture of 2,4-d imethyl 3-di hydrothi ophen -3 -one and 2,4-dimethyi-3-hydroxythiopene, 100 ml of 1-methoxy-2-propylamine and ml conc. hydrochloric acid. The pressure rises thereby to maximum 9 bar.

The reaction mixture is worked up by adding 15 ml of 30 %0 sodium hydroxide solution and removal of the excess of 1-methoxy-2-propylamire in vacuo.

To the evaporation residue are ,dded 100 ml of water and 1C3 mnl szf cyclohexane and the phases separated in a separating furnnel, The aoueoz phase Is extracted again with cyclohexane (3 x 50 nil), ~the combined organic phases are added 50 mil of water. Then 15 -11 c' concb hydrochloric acid are added to adjust the organic Woution at pHi.i The phases are separated and the organi^. pha~e wasnel with water 1 2 x SOmi, The comrbined aqueous phases are covered with 100 ml of cyclohexane a.-i adjusted at pH#13 with 22 ml of 30 sodiu%, hydroxide solution. After separation with a separating funnel the aqueous phases are again extracted with cyclohexane (Z x $0 ml), Tho combined organic phases are completely concentrated to give the title compound having a.9gas chro-atc,graphical purity of 96.3 Example 5 4-MethYl-4-pentene-2,13dione 10.0 9 (0,0$9 mol) of 6-acetyl-2,S-dimethyl-2-(l.2-dioxO-PrOPYI)-Z i- 3,4-dihydropyran is distilled at 6 Tort through a quarts, tube which was preheated at SCOO to give the title compound.

WO 88/10261 PCT/EP88/00525 Example 6 6-Acetyl-2,5-dimethyl-2-(l,2-dioxo-propyl)-2H-3,3-dihydropyran (Compound of formula VI process f) A mixtLure of 60.0 g (0.31 mol) of 4-bromo-4-methyl-pentane-2,3-dione, and 0.1 g hydruquinone in 300 ml of tri-(n-butyl)amine and 1200 ml of xylene is stirred for 10 hours at 1301 internal temperature. The reaction mrixture contains then, according to chrornatographical determination, a mixture of 10 of 4-methyl-4-pentene-2,3-dione and 90 'Q of the title compound.

100 ril of conoc. hydrochloric acid are then added while cooling the reaction mixture with ice. The phases are separated. The organic phase is washed with water (3 x 250 ml) and completely concentrated in vacuo. The residue is distilled to aive tre title cc7.pound 102-106' at 6 -1-rr as a li h y lI' l

Claims (7)

1. Process of preparing 2,4-di methyl -2,3-di hydro-thi ophen -3onle of formula Ia/Ib I S la 1S lH b which comprise a) treating a compound of formula III S0 whri9 sH h lpai yrcry oeyo naknlc w'herein R is H the aliphatic hydroarbyl moiety of at aianolC with aH oranic canvrtyicgwhr acdein the res obat aie Crslto btreatn compound of formula intoitsfeb eoe om theropindi the aomliaIItat lamIwer Ri hydrogebi ~ityon )akni wih corse tandcnting weher4eee-ten thuiotied n sathef 9 2. esthe cmoun of b oasaebi. isfeekt/no om

3.Process of preparing a, cmpdlmofl-fhyrul y- ttdtipn-Cla one1 a)(therin compound of formula 'II1 stated in Claim 1) whereinrgn R. Ishdoe iha lpai lao INi h presence of abae 3. P~~sroeso rprng a oerein of iorul asb stated in Claim 1 b) etheiing compound of formula VI ttdi li ,~hr~ with a peroxyde in the presence of an alkanol R O~1, in which Ris as defined in Claim 1. -13- 130-4013

4. Process of preparing N-(2,4-dimethylthien-3-yl 1-methoxyprop-2-y') chioracetamide comprising the steps of a) preparing N-(l-methoxyprop-2-yl)-2,4-dimethylaminothiophene and b) N-chloroacetylating N-I-methoxyprop-2-yl)-2,4-dimethylaminothio- phene with chioroacetyichioride, characterized in that N-(l-rnethoxyprop-2-yl )-2,4-dimethylaminothio- phene is obtained by reaction of the compound of formula la, Ib or a mixture thereof with 1-methoxy-2-propylamine. The compounds of formulae la and 1b, stated in Claim 1.

6. A compound of formula III stated in Claim I1, wherein R is as stated in Claim 1. The compound of Claim 6, wherein R is H.

08. The compound of Claim 6, wherein R is C 16 alkyl.

9. The compound of Cl-im 6, wherein R is Ca alkanoyl,

92-4 Compounds of formulae Ia and Ib or processes for their preparation substantially as hereinbefore described with reference to the Examples. DAE hs2t a fFbur,19 Sandz A By It aet tony DAIE &O*LIO v I INTERNATIONAL SEARCH REPORT International Application No PCT/ EP 8 8 /00525 1. CLASSIFICATION OF? SUBJECT MATTER (it several classific~tion symbols apply, indigate all)I According to Int ernational Patent Classificationl (IPC) or to both National Cial~lflcation and IPC P 4 C 07 D 3113/32; 333/36; 309/22; C 07 C 45/60; 45/67 11, FIELDS SEARCHED Minimum Documentation Searched Ciassification System I Classitication Symbols 4 C 07 D 333/00; C 07 D 307/00 Documentation Searched other than Minimum Documentation to ti'e Extent that such Documents are Included In tihe Fields Starched Ill. DOCUMENTS CONSIDERED TO BE RELEVANT$ Category Citation of Document, It with indication, where aporoprtate, of the relevantt Passages 12 Relevant to Claim No, A US, A, 2408519 D'AUBIGNY AVISOIN) j1,i2 1 October 1946, see the whole document A US, At 2408518 KARRER) I October 1946, 1,2 see the whole document A US, A, 3980675 VENTURELLO et J 14 September 1976, see the whole document A !SP, A, 0210320 (SANDOZ) 4 February 1987, .4 see claims (cited in the application) A G 2114566 (SANDOZ) 2 Au st 1 3,14 A jGBIsee claims24Ags 83 ,(cited in the application) Special Wieloriee Of Cited dodurtIht5- 14 OV" Watr document published after the innitiiel td~r'0 d4:0 document o dfnnthgeel egneisntotiotity dateI and not in Confict wiln ithe appication bi.t "A dcuet efnngth enrastile# 61 the art which irot cted to undertatnd the OtIriCi0lt Of tucory' uh4fUtyn0 t1'e coiiodolod to be of D~ri~utsr rtvneinvention eerbef d~tumont but Oublahod on of shotr the initernational dCurnst Of particuilar teitance, the etamad lANve1l01k fili no date cannot te Conkidsed novel at Cannot be considvais tO *L documnent which may throw aoubts on ptfrty dliin(s) Of involve ai inveentive step wiie is Cltod to establish tI'C outlicstioni date of another ".YO document of particular tevenee; the Ctlmed~ ;nvetfori COlitiOh or other t~eata toasoA tat ta44,1144) Cahoot to Cgo'dop to ON rtv CAInvonte step1 ty' "O0* document referring to an oral disclosure, use, exhibition or document as Combined with one Or Moe Other such 00tu+ Warti ffl#,4 monts, such tombinstiont boifiig obvious to A D~tOW skilled I" dOtument uilihod biiol"1 the i11tA4stOlrIll Miing date but t the5 ii. Iler then the plionty dale claimed IL' doeutilift Membe 01111 Ih* Wae aent famnily IV. Date of the Actual Completion of the International Searth 9ith September 1988 1al 04lo Meiling of this Internationat 3earCh Report International StatChlnQ Authority EUROPEAN PATENT OFFICE F~tm PCTIISAI2iO fiieCOrld *hoet) teifry 1083) I I International Application No. PCTI/EP 88/005 FtuIkTHER INFORMATION CONTINUED FROM THE SECOND SHEET Vf]OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE I This International search report has not been established in testiect of certain claims under Arijo 17(2) for the follo~ing reasons Claim numbers because they relate to subject matter not required to be searched by this Authority, namely: 2.,Claim numbers because they relate to parts of the international ooilcation that do not comply with the proscribed require- Meoits to such an extent that no meaninofut International search can be carried Out. S~POCrtldsty hiujmWAe because Mv~y are clipendent Cialms aridl are inot drafted In itowdance with the $Koria andc tsrd w~rreof PCT Rule 6.44a), VI.(o) OBSERVATIONS WHICRE UNITY OF INVENTION 13 LACKINGI This International Searching Authority found multiple Inventions In this International applcationt As toliowit ldims 1-9 -c~tlm 10,11 $0 ormn PCP/SA0206 dati 4th Auiqust 1988 As oil f~auired additional search fees were timely Paid by the appicildn, this intefniallona &arth report covets all searcheble claims Of the international Application. I[D As Only corn. Of the f6oUlted additional 660tdh lees were imely paid by the Applicant, this International search report covers only those claims -of the international application for which foss *ere plilc, spcifclil claims: 1. No ret#4ulread a ddlitoni a at nh leats were t 1 m oiY 0 4 d by t hea so icintI, C 0 ae 4us rtly, tI aI htt I ti h ea rth ap6 rt is& r a ttic t ed tO the Invorition Ait t ritetiboned Irk the claims, It Is coveted by claim numnbers- 1- j. 4 At allitifetdhable claimsi lould be starthad without aflort justilyffno in Addiltihill 1ee, the Ifitotntltonl Seatthitg Authidrity did licit iflii payment of thy 600itionat Its, Asms on Protett Q The addltionat search lots *are w~orrnioloid by sticiltanteetet QNo protest accompanied the Paymnent of additional search foes, Itith PCJISAM21O (suPoiemantal sheet (January 0411) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP 8800525 SA 22700 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report The members are as contained in the European Patent Office EDP' ile on 22/Q9/88 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document ['biation Patent familY Publication cited in search report daemember(s) date US-A- 2408519 None US-A- 2408518 None US-A- 3980675 14-09-76 NL-A- 7501651 19-08-75 BE-A- 825575 14-08-75 FR-AB 2261279 12-09-75 DE-A,C 2505902 21-08-75 GB-A- 1496411 30-12-77 CA-A- 1055510 29-05-79 EP-A- 0210320 04-02-87 None GB-A- 2114566 84-08-83 None Z For more details about this annex see Official .Journal of the European Patlent Mifce, No. 1 2182