DE1695074A1 - Process for the manufacture of antibiotics - Google Patents

Description

. Zumstein - Dr. Έ. AssmoAA

Dr. R. Koenigsberger 1 CM) r η Τ /

Dipl. Phys. R. Holzhauer 1 O »D U7 4

call & nfonwcMic

Munich 2, Bräuhaussfcöfc * 4 / M LABQRAfORZES LIHXSED ₉ UK. Process ζυχ Production of Antibiotics »Addendum 2U Patent ■ .- ,, - CPatent & ameldiu: g 0 34- 984 IY1 / 12p)

The present invention relates to improvements in Derivatives of 7-aminocepnalosporanic acid (7-Α0Λ). The hior Epozifiach disclosed connections are under Beaugrifthae named on the Gephamring system (see J.A.C.S. 1962, itf, 3400)

2 ϋ% HI a / 1 1 δ 7

Y,

the Hamptpatent ».. ·» (i & tent &iameldting; S 34 934 T? l / I2j) s: lnd describes new derivatives of 7-ACA, among others the general formula

(together with their salts) where R denotes a water atom and Ir eix.e denotes acyl grappe . important part of the door, it improves stability against degradation in vivo (as e.g.

Ee vrorde now found "that determines Aside" among the general formula X above fall, the important property besiteen, against grassy organisms at ozmler Yarabgabe particularly active on being »like by animal rerulance becomes obvious »as well as after the oral preparation

209133/1167

be more stable in vivo than the corresponding 3-acetoxymethyl compounds .ngen.

The present invention provides a method for the preparation of a compound of the general formula

A.
- R - CO.NH.

II

COOH
(where R is a pnenylthio-, halogenophenyl-, aminophenyl-, halogenophenoxy-, lower-alkylphenoxy-, lower-AJiylptienyl-, lower-alifanoylozyplienyl-, di-lower-alkosyphonyl-, phenoxy-, lower-alkoxycaxbonamidophonyl-lower-alkylthio- , Diphenylamino-, cycloalkylthio-, lower-Alkoiyphenyl-lower- ^ allcjlthio-, lower ~ Alkylpheiiyl-lower-alkylthio-, Kitrophenyl-lower-aliylthio-, Amlnophonjl-lower-aliylthio-, ITapathji- or Haphtnylthio group or a cycloalkyl group with 5, 6 or 7 carbon atoms and H is an alkene or alkenylene group; or R is a phenyl, lower-allylthio or thieny group and
R is an alkene or alkenylene group with at least 2 carbons «

209833/1 ¹

material atoms means) and their salts, which are thereby identified » is that a compound of the general formula

III CH ₂ QAc

or a water-soluble salt thereof, wherein Z is hydrogen or means an acyl group with the formula:

R ² - R - 00 - U

(where R is a phenylthio, halogenophenyl »tritilaminophenyl,

Di-halogenophenoxy, lower alkylphenoxy, lower alkylphenyl, lower alianoyloxyphenyl, phenoxy, lower alkoxycarbonamidopheiiyl lower alkylthio. Di-Piienylamiiio-, cycloalkylthio, low <> ^ Alko3Qrphenyl-'niedrig "al] {yl · thio, low-Al ^ lphenylHaiedrig <- alicylthio-- _t Nitrophenylniedrig-alkylthio, or Haphthyl- Haphthylthiogruppe or OycloaUkylgruppe m .tt denotes 5, 6 or 7 carbon atoms and R denotes an alkene or alkenylene group; or R is a 3? henyl ~, ZLLedrigMlkyltnio ~ or thienyl group and R is an alkene or alkesylene group with at least 2 Eohlen-

BAD ORIGINAL 209133/1167

st off at oden means) is set with a metallaside or ammonium field in a strongly polar medium that the resulting compound, in which Z is hydrogen, in an and 'for the usual manner with. acylating an aoyl-forming agent which contains the group IT, and that the trityl group is then removed from the xrltylaminophenyl group, or that, if desired, the lower-alkoxycarbonyl group I is removed from the lower-alkcucycaronamidophenyl-low-all ^ lthlo group, to give the desired compound of the formula II au, in which R and R have the meanings given above, and that, if desired, this compound of the formula II is converted into a sale.

The group R is preferably a straight chain; " Group and preferably also contains 2, 3 or 4 carbon atoms «. The term "lower" in the alkyl and the like groups Alkozygruppen means having 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms. The expression “cycloalkyl ¹ * in the cycloalkyl and cycloalkylthio groups means groups with 5 to 6 or 7, preferably 6, carbon atoms.

The substituted phenyl group can contain more than one of the radicals listed, awo.i or more halogen, etc.

209133/1167

The term "halogen" preferably means chlorine or Preferably means bromine and the term "alkoxy" Methosy.

If R contains a reactive amino group it will be apparent that such a group must be protected. Examples of protective groups are the trityl group and lower-alkoxy carbonyl group and the tert-butoxycarbonyl group. The Sohutssgruppe can be removed in the usual way by acid hydrolysis, for example using aqueous acetic acid or aqueous trifluoroacetic acid. R ¹ groups that require protection "are the aminophenyl" and amittophenyl-lower alkylthio groups.

The preferred method according to the present invention comprises reacting a compound of the formula

R ¹ - R - CO - HH

(in which R and R have the meanings given above) or a water-soluble salt thereof with a metallaside in a strongly polar medium.

20 913 3/1167 bad original

As metal azides, the alkali metal acid are, in particular liatrlumazide preferred.

Where salts of the compounds of formula III are used » are suitable salts, for example, sodium, potassium or Ammonium salt. Water is generally the most suitable reaction medium, but a water-miscible organic I can be used solvent wife K ^ F-Dlmetnyl-formamid or Aoeton added although this tends to reduce the yield.

The reaction temperature is appropriate end at least 15 ⁰ C and in general to below the boiling point of the reaction mixture, but under hall »the ZersetsungspumJct the reagents. With aqueous media you can. Temperatures are -Uses up in about 100 ⁰ C.

Me left time while the reaction progresses should be, τοη depends on the temperature used, but can be determined by yore smoke.

Me reaction partners are advantageously used in a ratio τοη approx. 1 KoI equivalent of the compound γ to 1 to 10 mol equivalents of AsId. The pH of the solution is advantageously within the limits 3 to 8, preferably 6 to 7,

209833/1 167 _BAD

. »■ 8

Vifem siotwendig * should® the pH dor Xt9mmg on dsn

Value by adding "Ines Buffers wi © Ammonium"&"etat _f odes? at Yersra & du & g of an Al & alinetallsaXses of Verhiiuti & ag of the general pore ©! Y can be adjusted by adding ■ for example * acetic acid.

| l The Reefctleneprodnkt feaa ron the RoaktioasiPiachimg, the

l) 9iepj.9lswei £ f © modified connection of the formula T void, other sufcst & nzen ontlmlta ». 'ktmn _t according to the usual Terfahrea eiasclO-iaßlicife. Crystallization, electrophoresis * Ghromto «graphi © ρ Bete'jpdlmig with a Xonenauetauschnarii or by a G © g0S, ßtrom ~ Tteiliings-9'experienced like that of Liueh and Benson beechviebeae (l3sal _e 0feem. 1948, 20, 121) separated from /Medal*

E: In a suitable way of doing this, there is “tLbersohüoelges Aeid with the connection of the formula T in Waeee? umausetaen until an optimal intensity of the XI bond is obtained. The gewOnsoht © tert ^ indung II can dasnsit a organieohen Löaungeoittel, beisplelßv; else Sss.1^3äureäthylest@r _r 035.-t37ah.ierl; are »the extract: washed li & wi with water _t dried and distilled until dry. The resulting raw material can ciazra dmrch a uegenstrozmrertoilung Bwisohen Eesig-

unü. a PtiosphatpxUT.for be cleaned

209833/1187

BATH ORIGINAL

and can eventually go through failures »for example a Seelga & nreäthyleetexVPetroleusilöinäng be cleaned.

The compounds of the above formula V can by reaction of 7-AOA with a suitable aoylating agent * Suitable aoylating agents are.la

generally as used for the acylation of amino ^ amides, for example peptides, are suitable and include special aoyl halides, especially chloride or bromide, and mixed anhydrides, for example, st & aart from the corresponding acid and a halo-amelsensurealkyleeter. The acylation is carried out in an aqueous medina carried out, for example in a water-miscible ketone such as acetone or in aqueous tetrahydrofuran "voreuge" - catfish also in the presence of an acid-binding agent, for example sodium bicarbonate. The pH becomes during the reaction, | which are approached at temperatures between 0 and 25 ° C can, vormgeweiae kept at 5 to 7. The acylation can also in an organic liquid medium, for example Ssslgeäureäthyleeter, are carried out, for example by simple back cover.

BAD OBtQlNAt

by doing

äer losasl IX kumaen also, were produced »7-AÖA with the agio, depreciated wi3? i _e by one

the rait

GE

TI

za. form, followed by the AöjlieKimg of the resulting connection. Mess üKsotEtmgen köKn © a in general, among the Toröioliand h ^ m} -e? Itfmmmi Bediagos ^ sxi bag the auoloophile and Aeylieamngarea & uiGiisn dui'cSig, whence they can be found in the bijTTOraugts'i ΐΐΗ1 | .1: ϋ to be listed

Next to it l>: ömis'ü

represent

after. Verfaihrea

Torbinciungest d @ r J? OLt> mel TI auti a ver

aow. .—- oh.

0 ... ■ Λ ■ —0

TIX

the for the

20 9833/1 137

BATH ORIGINAL

from cephalosporin C in 7-ACA. The connection of the Formula TIX can be made from cephalosporin 0 by reacting with the l.zid are produced by methods similar to the above for the implementation of compounds of the formula V with aegis are analogous to those described.

In order to understand the invention, the following examples are given by way of illustration only. Ultraviolet absorption refers to solutions in water or in aqueous phosphate buffer at pH 6.0.

Paper chromatography was performed on Whatman Ko. 1 paper that was buffered to pH 6 when using an n-butanol solvent system or to pH 5 when using an ethyl acetate solvent system. The base ethyl acetate solvent system (XtOAc) was ethyl acetate saturated with 0.1 mol of sodium acetate. The n-butanol solvent system (BBV) was n-butanol (4), water (5), and ethanol (1) (the numbers mean parts by volume). Chromatography was run down in all killen. Temperatures in the examples are given in C ^0.

209833/1167

The fractions on the paper chromatography were recorded as dark corner noticed when the papers with Ultra violet light were irradiated.

example 1

5 AgidomQthyl? ^ _ C 5 '-BhenvlproBionami carboxylic acid

7 ~ (3 ⁱ phenylpropionamido) ceph-3-em-4-carboxylic acid (9.5 g), sodium bicarbonate (2.0 g), sodium azide (3 * 0 g) and water (200 ml) were mixed together for approx Heated at 50 ⁰ O hours. The solution was cooled, sodium bicarbonate solution (8%, 20 ml) was added and washed thoroughly with ethyl acetate (3 ac 100 ml); the resulting clear solution was acidified to pH * with hydrochloric acid under a layer of ethyl acetate. Pas product was purified by extraction i ethyl acetate (3 s; 150 ml) was isolated dor washed with water (2 χ 100 ml), dried and distilled to dryness to 7 to give * 1 g of crude material.

This raw material was prepared by dispensing with ethyl acetate and pH 5 phosphate buffers in the manner of Bush and Denson, Anal. Chem. jgO, 121, (1948), purified.

209833/1167 ^BAD original

Finally, the precipitation from ethyl acetate / Petroleum 3-Asidomethyl ~ 7 * - (3 '-phenylpropionamido) oeph-3-

ea-4 - carbonic acid

Additional compounds were prepared as follows according to the general procedure of Example 1 and purified using the Bush and Denson procedure. The (a) -sections of the examples concern the division of the starting materials and use in the (b) sections of the examples. Further changes appear in the examples such as those in examples 5 » 7» 19 »18 and 29. They Obtained yields and analytical and other data are given in Table I. Generally the products were white and glassy or crystalline in appearance.

Example 2

5-Asidoi »tb ^ l-7- (4 ^t -phenylbutyramido) ceph-3- * m-4-carbonic acid"

Example 3 3-Amidomethyl-7 "(5'-phenylpentanamido) oeph-3-a-4-carbonic acid

Example 4

3 ~ ABldomethyl-7- (3 * -phenylprop-2-en-amido) oeph-3-em-4-

209133/1167

Example 5

(a) ^ Acetoxy methyl-T ^ fottt-ff'-en-ffJ ^ carboxylic acid

Styryleasigsilure (4.0 g) was dissolved in Beneol (20 ml) and thionyl chloride (10 ml) and the solution was refluxed for one hour with exclusion of moisture. The acid chloride so obtained was isolated by removing the bexusol and excess shionyl chloride by distillation and dissolved in dry acetone (25 ml). A solution of τοη 7-AöA (6.8 g), sodium bicarbonate (8.5 g) and acetone (60 ml) in water (85 xal) was ^{cooled to 0} ° O and stirred for five minutes during the addition of this chloride solution one hour at ⁰ ° C., the reaction mixture was allowed to come to tree temperature for a further hour.

The removal of acetone under reduced pressure from the The reaction mixture left a cloudy solution behind Diethyl ether (2 χ 4-0 ml) was washed to clear aa Solution BU left, which was adjusted to pH 1 under a Schioht τοη acetic acid & ureathyl ester. The product was extracted into Eaeigeäuro & thylester (3 χ 200 ml),

Washed until thoroughly with water, dried to 25 ml

BATH ORIGINAL

209033/1167

under reduced .; Pressure distilled »Crystals τοπ 3-Aeet o: * ymethyl-7- (but-3'-en-amido) oeph - ^ - em - ^ - carboxylic acid were collected with cold ethyl acetate and petroleum washed and air dried.

(b) 5 ~ AaidoDietnyl-7- (but-3 * -en-amido) oeph-3-em-4-

carboxylic acid, "

Example 6

em - ^ - car bonti aure

5-Phenylpeu1 -3 ~ on- 3äure (7.0 g) was converted to its Säureohlorid Uterftlhrt with 7-AOA (1O O ₉ g) as in Example 5 (a) condensing Lex-t.

3-Acetoxymethyl-7- (5 * -phenylpent-3 · -en-amido) ceph-3-em-4-carboxylic acid was obtained as an amorphous solid.

b) 3-Aasidomethyl-7- (5 * -phenylpent-3 * -en-amido) c © ph-3- * m-4 ~ carboxylic acid

209833/1167

(α) ? -Acetoxyrnethyl-7- (3 '■ »p-ohlorophenylproplona nldo) οeph-3- em-4-ca rbgnaaure

/ 0- (p-Ohloro ^ enyl) propionic acid (7.45 g) was in it Acid chloride transferred with boiling thionyl chloride and

* the product was dissolved in acetone (25 ml). 3-Acetoxymethyl-7-emlnoceph-3-em-4-carbonate (10 g), sodium bicarbonate (12.5 g), water (125 ml) and acetone (100 ml) were extracted and the solution was boiled to ⁰ O chilled; The acid chloride solution was added to this stirred solution for five minutes and the stirring was continued for one hour at 0 °, then for a further hour at 20 °.

The acetone was reduced by distillation

* Pressure removed , the wet residue was washed with läige & ureäthyleeter (2 χ 50 ml) and washed with hydrogen chloride

acid under a layer of ethyl acetate.

The product was extracted into ethyl acetate (3 × 100 ml), and the ethyl acetate solution was washed with water (2 × 100 ml) washed, dried and under reduced

209133/1187

BATH ORIGINAL

3 * cuck bio 3 evaporated to 30 ml when the crystallization started. Petroleum (boiling point 60-80 ° 0, 200 ml) was carefully ssugfttgt and the crystals were painted, washed with and air-dried

l ~ 7 "(5 '-p-chloroplienylpropionaiaido) cöph-3- to.

3-Aaidomethyl-7-C3'-em-4-carboxylic acid.

Example 8

This compound was prepared using the method described in Example 7 (a), but using 5- (m-chlorophynyl) proplonic acid as the orange material.

(b) 3-ABidomGtliyl-7 '- (3' -m-chlorophenylpropionamido) oeph-3-

BATH

209833/1167

Example 9

(a) ^ Aecitoigymethyl ^? · »^ 3f ^

This YerbiMung was prepared according to the procedure described in Example 7a method, but using / 3 ~ (o ~ Ghlo- * roptheayl) propionsäur © as a starting material.

(b) 3 "Assidoaethyl-7- (3 ⁱ « -o «chlorophenylpropioaamido) cöph» 5-

Example 10

This Terbiadiüig was prepared according to that described in Example 7 (a) , but under Terwendxmg τοιι ^ '-

(b) 3 ~ Asldo2iethyl * -7 · "C 4 * -p-chlorophenylbutyraaido ) ö © ph-3 ~

209833 / 11Θ7 ^ ^{0 0 RIGINAL}

~ 19

11

This yerbi ^ aoimg was heard according to the ancestor described in Example 7 (a) _? but using ^ - (p-bromine-

) as exit material. Ä

3 ~ ABlooraetliyl- "7 ~ C 4 * -p-bromophenylbutyramido) ceph" -3-em-4 ~ cart ems & iire *

Example 12

3-Asiflomci ühjl-'I « (3 *? 4 * -diaietliosyphenylacetaaiido) c sph-3-

209833/1167

carboxylic acid

Example 16

f ml «» Wim n mi Ii iMfi tamest * x *

Example 17

^ Xrtill

(10 g) was

using the method described in Example 7 () _v treated, inter alia, the desired compound ku result of using ^ ■ -MctlV'-i'ohenyloiSßißsäurecblorid (6.2 g).

209833/1167

bad original

3 example 18

5 "Azidomethyl ~ 7 ~ aminooeph-3-em ~ 4-carl3cmB acid (5 _t 0 g) was dissolved in aqueous acetone, which contained sodium bicarbonate, and ^ ait / S-cyclohexyltfeiopropionyl chloride (4.2 g) under> 7e de "treated in general in Example 7 (a) be8Ch] the same procedure to give the desired compound"

Example 21

oarboneSure. ,

BM) 209 & 33/1167

.22

3-Asidometlj3rl-7 ~ (4 'e jclohexylbutyramido) Geph-3 ~ em ~ 4-carboxylic acid,

Example 23

-7 * -Cphe2i7ltliloaoetamido) ceph ~ 3-eia ~ 4-aa: rboxylic acid

Example 24

carbonsäuxe

WHIlIIl IBMWI> ■ l

(2.92 g)

in wäßri £ i; em Office on _p as "liatriumblcarbosiat containing dissolved and mJ / 5 S-MSTL ^ ItMopentanoylcliloria (2.38 g) (see below) (tach the general in Example 7 (a) besohriebenen * ¥ © rfalxrsir, ) treated ,, do the crude product as light brown,

to give solid matter (yield 3 * 27 g »74.5 λ>), with Sat5? iTiffl-2-li; hjlh © sanoat in Aoeton in the ifatriumsala would be transferred. The Erlutalllsatlon from Hethano ^ ither gave the llatrlura «3a.liä of the desired connection as colorless! Rebukes, λ max 260 - 261 ^ (e] ^ _m 242, £ 9860) (pH δ buffer) ,? Raax 3290 (UH), 2120 (Assid), 1757 (/ S-laotam) "1650 and 1535 (COHH), and 1615 (ΟΟ ^ οηΤ ¹ (HuJoI), /% 7 ^ ^1f5 + 113 ° (o 0.996,

209133/1167

Water) ,, R _,? 0.59, Hp 2.61 (Essigeäureäthylester, butanol, pll 5-Puf eraystea t) G ₁ 4 H ₁₈ S

compute! in $ 0 41.3 H 4.45 H 17.2 S 15.7 found δ 41.1 H 4.5 Έ 16.75 S 15 # 25

p is the ratio of the R ^ value to that of 7 * j (3 ~ phenylacetamldc-oepnaXosporic acid) *

2 »methylthiopantanic acid (boiling point 102.5 to 107 ° / 0 _f 9 na aJ * 1p47O2) was obtained by treating 2-bromopentic acid with HatrlummetSijliaercaptid in rüokuenden cylol. D && Acid chloride was obtained from the acid with thionyl chloride in 3eaaol as a pale yellow oil _s bp 53-80 ° / 1.1 mm, i £ 1.4831p which, on the basis of kerximgn & t.lacher resonance spectroscopy, contained approximately 75 # 2-> methylthiopentanoyl chloride .

carbonsävr «

p-AmlnopJien; 7l38sigBäiw? e vuxil? converted into pH-tritylamiiiophenyl acetic acid in a total yield of 67.5% by conversion to In

209133/1167 bad original

! Mpheny3JBethylehlorid la presence of and hydrolysis of the ethyl ester with aqueous HTatriuiahydrosgrd in propylene glycol

pK-rltylsialnopl3. © 2yl acetic acid (50.0 g, 0.127 mol) was dissolved in dry chloroform (500 ml) containing iriethylaiaine (17.65 ml, 12.75 g >> 0.127 mol) and the solution was boiled at 0 Stirred during the addition of Äthylohlorameieensäuree (12.2 ml <, i;>; 9 gj o ₉ 127 mol); the mixture was stirred at 0 ° for 50 minutes as a solution of

(21.7 g>

0.085 col) in concentrated chloroform (500 ml) and triethylamine C17 »65 ml, 12 ₍ , 75 g, C ₅ 127 mol) was added to the extent that the temperature was kept below 3 ° at 0 ° during a? Stirred for hour and warm to room temperature for two hours gela & neji tfoxmoh äs. «Chloroform under reduced pressure

l:? e ^ t was left to a white pest substance su; ii _v d © r crude ^ -ABidomethyl ^ -Cp-'iT-tritylaiBilnophenylac st ami Io) ö «ph-2- © Ei * 4-oarionic acid

The Irityri.-Terbindwng was (ml 200) in a mixture of Bseigeaure (.200 nil), water and acetone (100 mL) \ wil MI Ei.umtemperatur for 3 Stundon quilted,

2 0 9 8 3 3/1167 ^BAD

'.ODeI look is gradually dissolved solid and a soldier of solid was formed · The collected precipitation I / us de XAIT technical acetone (300 WI ₉ 2 & water) /', seen, honeycomb! an insoluble residue A (10.5 g) niLüückollab, and the Aeetonlusung was evaporated under reduced 3raek r.ur Srockne to give a second pest B 4-7.7 s) KU · The solid B was with diethyl ether {400 ml) : Washed triphenyloarbolnol to leave an insoluble residue which was combined with the residue A and crystallized from dimethyllormamide (10 ml), acetone (200 ml), hexene (300 ml)

in twelve portions & i made «

, 3 IR-Spelrfcr ^ um (Nu j oil) tends to bond at 2100 (Aaid) and 1775 cm "* ¹ (/ ^ - lactam).

Example 26

: s BAD ORIGINAL

209833/1 167

OX © JL 27

ι «. ri :. λ: rv.vrnrv λ -sup

was in presence-of ffatriumMoarbonat In laundri @ 3? acetone vie in Example 7 (a)

treated ₉ to yield the desired compound cn.

(b) 3 ~ A £ idOffltihyl ~ 'M f -2 _f

Jgiejgiel ^ a

5 Ag idQHiet: hffl "^^ carbonggura

The general procedure outlined in Example 18 was followed using iron 3-aeidomethyl- 7-aminocepfc-3-em-4-carboneIure (2 ^ 0 g) and / O-phenosypropIoaylchlorld (1.36 g) to obtain the desired compound su result

ORIGINAL

209133/1167

Example 29

The general peat ladle given in Example 19 was followed using 3 ~ As £ dome1 ^ l ~ 7 ~ 8iiilnoceph ~ em-4-carbonic acid (2.0 g) and S- (p-4iethylbenayl) -mercaptoaoetyl chloride ( 1.85 g) _{9 to} give the desired compound «u.

The «was given according to the general in Example 18 Method made using τοη 3 ~ ABidomethyl-7 ~ amlnoceph-3-eitt - ^ - carboneauro (2.0 g) and S- (p-ifitrobensyl) -mercaptoacetylohlorld (2.1 g).

Example 31

~ 7 ~ (S-pHttethoxybengylaeroaptoamido) ceph ~> »

ea 4 orbonalture

The β was given according to the general in Example 13 Method using 3-AEidomethyl-7-amiB.oceph ~ 3—

BAD ORIGINAL 209133/1167

(2.0 g) and S ~ (p ~ metho: ^ fcensyl) «m <3rcapto-acetyl chloride manufactured"

. ^ but osycarbonamidob eng ylmercapto-

acetamido) 8ejgli-3 ~ © m «» 4-car "bo3isS.ure

Tr 1 ι * li Ii —Tv '-TH iir iii ι ir - -ininninii iinifiiinin »■ -

° X 244 nutnax B ¹

(Jp 12!> - · 125 °, X 244 nutnax B ¹ r * 660) was made

1 cm from Mi ^; -: lS "- (p - aiiiij ₁ i () bi3nz-3rl) .iQGrcaptoacetate-hydroQlilori (i

via the Igocyaa & t, unisetining with tert-butyl alcohol and

© de »Metliyleetere with an Ä (equivalent Ia knowledgeable dioxaa. S- (p «tert.-Bwtoxycarfeonami.dot! E: a2jl) -m © roaptoeßsigsSliire (6.23 δ) «nd Kriathylamia (2.11 g) msrdon ia trookenom chloroform (100 ml)

viid the XtSauüg became hot 0 ° during the addition τοη

* Xf? Ovaa. «RjluhlO5? Id (2 ₉ 53 g) for a period of time τοη

Stirred for 5 minutes; the miseftimg was stirred and cooled for a further few hours, after which a solution of 3-ABidometh ^ l ~ 7'-aminoceph «3 ~ enH4- ^ arhonic acid (5» 8 g) and sriäthylamia (2 ₉ 53 g) in Chloroform (100 ml), which had previously been cooled to 0 °, was added in one portion. Stirring was carried out for one hour at 0 ° and one hour at room temperature before the chloroform was reduced under reduced pressure

209033/1167 Original bathroom

Brackish aMastilliert ;, the aorttoMAelbeade Pestfstoftf was dissolved in v & Srigeni Watriumbiarbonat (4 $ ig, 200 ml) and the clear LüBong was with Biätnylätliea? (3 s 100 ial) gawasohsn «Dar wäßrig» rope was extracted with Cblorwasserstoffsfiure angosäxLert »with acetic acid Saylester (3ϊ 100 ail), Sas 7er3.1odLg- & © S.ctx ^ Uct with i '/ aooor gewiaohen, götrocfeist iiiad under reduced sus? Sroc3? N »cl © öt.llli. © ri. The Hüclrstaiid \ iurdo under ¥ orw © M \ mg of an infected. ⁿ DiamoM-piitte ^ i-- ^li Exfcraktion ßerela.Lgt, where Esßi ^ ij ^ .r5äthyleßte: ^ (2C {) ml) and
CpH5 »200 ml) -plias © n τβη / ends vmrcl © ^ around the au

Example:

(3 _t O g) was ia Srifluor-

(5 "0 ml, 7" 65 S, 10-faolier Überschufi) dissolved in _t

LÖecag 'vw.cu.q hei barely any temperature? iirSüirend 13 M.tE, u; «a. Etehen gslaeß ^ n, wonacjb. the tiberaohüssige Kwagen.π bcii 2O ⁰ / 0.1 mm a'odeß.Llliert was. The residue, which contained about »sifluoroacetic acid, was dissolved in Batriumbi *

BATH ORIGINAL

209833/1167

(24 al, H ^ noraial) dissolved »filtered, with

(2-normal) pH 4 acidified? The pH was adjusted to 3 exneut tmd the Pil entered. The solids wiur & e collected _r srdi / sölir little water ge wo, see, sxx & emt: üfi. Ha.triraaljiGar-boaatlösimg (20 ml, 1/4 dissolved iiM with acidic §.U3 ) iogoEitellt on ρΠ 3 © and the gewfänsc & ta Verbin dung g; eyaiiMelt, geimsclien wsnig with water and Tibar Galciuinolilevtia wälireüi SSW @ i Say dried.

209133/1117

Satellite I

Bel- 40 "6 £ 64 pektsm ¹ LiJatra / *: Ie [UImLu
weight Cb) paper chromato-
graphic R ^ values BEV itOAo
& .M. (A) #. * 24 ₉ 6 260 - _Λ 1 ^
1 CSi iSatioa not found
the ItOAo 0 _F 80 0.20 ·; 42.5 "362 226 40 387 390 0.36 O _y 63 0.20 rl 50 a76 225 25th 401 596 O _s 35 0.90 0.38 ν. ·. 55 ₉ 3 35 «r 5 220 25th 415 416 0.52 0.62 0.25 'j- 70.5 * 253 787 10 385 385 0.38 0.68 77 r 5 aso 63 pounds 10 416 416 0.25 0.73 0.25 «> B 47.5 600 10 399 405 0.45 0 ₉ 78 β a. 82.6 258 215 §0 430 427 0.37 0 * 8 * 0.37 6b 2 £ ₅ 8 260 210 40 413 413 0.55 0 ₉ , 79 7a 62 ₉ 2 * i61 210 40 438.5 436 0 ₃ 20 0 ₉ 81 Ib 45 * 2 £ 62 222 40 421.5 423 0.35 0.69 8ft 64 ₉ 4 260 184 40 O ₉ 16 0.76 ob 262 206 40 421.5 426 0.32 0.70 <Yes 71 * 0 221
261 209 40 438.5 427 0.15 O ₉ 76 9b 16 ₉ 8 ago 180 40 421.5 426 0.23 0.67 10a 71 * 4 H60 310
176 432.5 444 0.38 0 ₉ 79 10b 29 91 Ii 356
196 4C 435.5 452 0.52 0.68 11a 32.7 184 40 497 500 O ₉ 57 0.74 11b 41.7 •? 6! 5 326
177 40 480 482 0.66 0.57 0.04 12th 33.6 26i 219 40 433 434 0.08 0 _? 65 0.16 15th 24 * 1 533
369 284 25th 389 399 0.35 0.80 0.15 14th 37.4 340
205 40 407 407 0.30 0.84 0.28 15th 302
311 25th 464 475 0.44 0.78 0.30 16 7! 54 5 455 457 0.48

209833/1167

BATH ORIGINAL

1695G74

example
No.

yield

69.2 60.7 31.2 82.2 43.1 43.4 24 _S 1 45.5

raw 74.5

36.5

26.5 72.8

40.3

86.7 53.5 73.0 67.3

59.3 70.4

Spectrum in
iiclier solution Conc
tration
// ml Equivalent to-
weight (b) found
the paper chromato-
graphic R ^ values 0.68 EtOAc
AM (a) χμ. 1 om calc
net 400 ItOAn 0.76 259 204 404 385 0.52 0.79 262- 212 30th 387 392 0.70 0.73 262 208 425 426 0.55 0.78 270 425 418 0.46 0.77 264 403 415 0.35 0.86 261 410 410 0.60 IfI 261 212 406 O ₉ 57 255 256 3.0 0.28 260
261 242 30th 262
nflex
242 266
. 364 30th O ₃ Oi! 0.72 264 241 30th 500 0.55 0.74 229
262 288
183 30th 503 480 0.21 0.55 • 230
263 254
263 40 486 404 0 "45 0.65 266 202 40 403 436 0.35 0.58 262 200 40 433 468 0.42 0.55 27) 344 20th 464 444 0.35 0.65 223
262 358
200 20th 449 0.132 0.40 247 483 20th 530 0.43 245-
246 450 534 0.05

(a) A.M. means source material and the rightmost »column the table thus gives the Rp values for the output material of the example using the ethyl acetate

209833/1167

BATH ORIGINAL

3jö Bimgsilittelsyßt ems.

(l>) Geseaaen by potentiometric search

* The product τοπ example 5 (b) was finally chosen Diethyl ether recrystallized.

Rj-Werta refer to ^ on Y-Plienylacetamidocephalosporan- " acid (T-PACA) as a unit.

_BA D ORIGINAL

209833/1167

Claims (6)

Claims Ι «Yerfaliren for the production of connections of the general P my formula h1 - it - σο.ΒΗ COOH (where R is a phenylthio-, halogenophenyl-, aminoplienyl-, halogenopheno-, lower-alkylphenoxy-, lower-alkylphenyl-, lower-alkanoyloiyihenyl-, di-lower-alkanolienyl-, phenoxy-, di-lower-alkosycarboneimidophenyl-lower-alkyl "diphenylamino, Oyoloaliylthio-, low-Alkosyplienyl-lower alkylthio, niedrifs-All ^ lphenyl-lower alkylthio, HitrophenyliiJ.edrig-aliylthio-, aminophenyl-lower alkylthio, naphthyl or Kaphthylthiogruppe or Cyoloalkylgruppe with 5 » or 7 carbon atoms and H denotes an acenene or alkenyl group; or BAD ORfGJNAL 209833/1 167 R is an i? Konyl, lower-alkylthio or thienyl group means and R is an alkene or alkenylene group with at least sswel carbon atoms means) and their salts, characterized in that ei: ae compound of the general formula 2 ¹ HH. TJI ^m 6- k Λ -OH ₂ OAc ^ f CO ₂ H or a water soluble salt thereof, wherein Z is hydrogen or an acyl gimp of the formula: R ² - R - CO - IT (where R '~ a phenylthic-, halogenophenyl-, xritylaminophenyl-, Ea3.ogenoph © nooiy · ", lower-alkylphenoxy-, di-lower-Α1 ^ .ϋ3ς $ Γρ ^{η <} " ^{ι: α} ϊ ^ρ 3.-, lower-Al ^ ylphenyl-, lower-Alkanoyloaqrphenyl-, Hienoxy- »lower Alkoaycarbonamidophonyl-lower alkylthic-j; Diphenylamino-, Cycloalkylthio * -, lower-Alkoaqrphenyl-n.1 etli'ig-alkylthj.0", lower-Alhylphenyl -lowerallfylthio-p nitrophenyl-low-alkj ^p lthio, kaphthyl or hapiith; denotes a group or a cyeloalkyl group with 5, 6 or 7 carbon atoms, and BAD ORIGINAL 209833/1167 R is an alkene or alkenylene group; or ο
R is a phenyl, lower-alkylthio or xhienyl group means and R denotes an alkene or alkenylene group having at least two carbon atoms) is reacted with a metal azide or ammonium azide in a strongly polar medium, so that the resulting compound, in which Z is hydrogen, is reacted in a manner known per se with an acylating agent containing the group Vf , is aoylated, and then the srityl group is removed from the sritylaminophenyl group, or that, if desired, the lower alkoxy carbonyl group is removed from the lower alkoxy carbonamidophenyl lower alkylthio group in order to give the equivalent compound of Pormol IX bu, ₁ specified wherein R and R have the meanings above ^ and that usually the compound of the formula ZX in a sale is convicted. 2. The method according to claim 1, characterized in that the metal azide is an allcalimetallaside, preferably sodium azide is. 3. The method according to claim 1 or 2, characterized in that that the water-soluble "salt of the compound of formula II a i- or asraonium salt is » 209633/1167 -37- ■ 169507 A 4. The method according to any one of claims 1 to 3, characterized marked »that the strongly polar medium is water * 5 »Process according to one of claims 1 to 4, characterized in that the reaction with the azide is carried out at a temperature of at least 15 ^° C. 6. The method according to any one of claims 1 to 5 »thereby characterized that the reaction with the Asid at one pH tone 5 to S, preferably 6 to 7 »is carried out. BAD ORIGINAL 209833/1167