CS251797B2 - Method of (6r,7r)-(lz)-2-(2-aminothiazole-4-yl)-2-(oxyimino)acetamido)-3-cephaeme-4-carboxyl acid's derivatives preparation - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as an antibacterial agent, by a novel process, by condensing a novel substituted hydroxyiminoacetic acid compound with an amino cephem carboxylic acid compound. CONSTITUTION:The objective compound of formula IV can be prepared by condensing (Z)-2-aminothiazolyl-2-substituted-hydroxyiminoacetic acid compound of formula I (R<1> is H or lower alkyl; n is 2 or 3) or its reactive derivative with (6R, 7R)-7-amino-3-cephem-4-carboxylic acid compound (salt) of formula II [when R<2> is acetoxy, etc., R<4> is (protected) carboxy, and when R<2> is group of formula III (Y is H or hydroxymethyl), R<4> is -COO<->], and when R<4> is protected carboxyl, removing the protecting group. The starting compound of formula I is novel, and can be produced e.g. by reacting the butyric acid derivative of formula V (R<6> is H, etc.; X is halogen) with thiourea.

Description

The cephalosporin compounds of formula I and their pharmaceutically acceptable salts exhibit potent antimicrobial activity against a wide variety of microorganisms, including both gram-positive and gram-negative bacteria. They are useful as antibacterial agents, as feed additives or as chemotherapeutics for warm-blooded animals, including humans, suitable for the treatment of infectious diseases caused by Gram-positive or Gram-negative bacteria. For example, the cephalosporin compounds of formula I and their pharmaceutically acceptable salts have potent activity against bacteria belonging to the genera Staphylococcus, Enterobacteriaceae and Pseudomonae. Specifically, for example, (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) oxyimino] acetamido] -3- ( 1-pyridinomethyl) -3-cephem-4-carboxylate shows a particularly potent activity against these organisms.

According to the present invention, the aforementioned compounds of formula I or their salts can be prepared such that the derivative of (Z) -2-aminothiazoíyl-2- (substituted oxyimino) acetic acid of formula II «^ Ti ^C02H

8- "\ O ^X c-4 | Wherein R ¹ and n are as defined above, or a reactive derivative thereof is condensed with a (6R, 7R) -7-aminocephe-4-carboxylic acid of formula III (II) by a derivative

NHgWj- CHj ^e (III)

R is a protected carboxy group when л

wherein R is carboxy or acetoxy- or (1-methyl-1H-tetrazol-5-yl) thio; or R is -COO when R is a group of formula

and Y is as defined above, or with a salt thereof, when R ⁴ is a protected carboxy group, the protecting group is removed from the resulting product and optionally converted to a pharmaceutically acceptable salt thereof.

Examples of compounds of formula (II) which can be used as starting materials in the process of the present invention are those compounds of formula (II) wherein R ¹ is hydrogen, C 1 -C 4 lower alkyl, such as methyl, ethyl or propyl; and n is an integer of 2 or 3. When a compound of formula III wherein R ⁴ is a protected carboxy group is used, the protecting group is to be one which is readily cleavable by conventional means such as hydrolysis, solvolysis, acid treatment or reduction.

Examples of such protecting groups include lower alkyl groups such as tert-butyl, substituted or unsubstituted phenyl loweralkyl groups such as benzyl, p-methoxybenzyl and p-nitrobenzyl; benzhydryl) tri-lower alkylsilyl groups such as trimethylthiyl groups ipod. When R is carboxy, preferably the compound is. of formula III before the condensation reaction converts the salt. Suitable examples of salts of the compounds of formula (III) are also organic salts, such as salts with inorganic salts, for example sodium or potassium salts of triethylamine or triethylamine.

The compounds of formula (II) are present in the group of formula (I) due to the presence of an isymmetric carbon atom

-C * H < 2 &^gt;

NR ¹ ,

Where the asterisk indicates an asymmetric carbon atom, and where ^r 1 and t is as defined above, they may exist in the form of two optical isomers.

For the purposes of the present invention, both optical isomers of the compounds of formula (I) may be used

II or a ricemic salt thereof.

the compound of formula (III) or a salt thereof

II or a reactive derivative thereof with a compound can be carried out by conventional means. Tik napPíklid

Condensation of the Formula The condensation of a compound of Formula II in free form with a compound of Formula III is carried out in the presence of a dihydrate reagent in a solvent.

Examples of suitable hydrating agents include ricyclstexylcarbodiimide, N-ethyl-N &lt; - &gt; - (trimethylaminopropyl) clbridiimir, phosphorylchhorir, phosphonium chloride, thionyl chloride, thienylphosphine ipod. Also useful as dehydrating agents may be the reagents prepared from dimethylformamide and dimethylsulfonyl, dimethylformimide and dimethylformamide, dimethylformamide and phosgene, or rimethylphosphoramide. Suitable solvents include dioxane, tetrahydrofuran, chloroform, chloroform, rimethylformamide, Ν, Ν-trimethylacctamir, ethyl acetate, pyridine and water. The reaction nottn ^BC l ^{d e p} s ^p rovádí te ^p Lot ^E O ^{d d} of -50 ° + ⁵ ° C, the outlet of ^d -30 to + ²⁰ ° C.

Alternatively, the reactive derivative of a compound of formula II may be condensed with a compound of formula III or a salt thereof, either in the presence or absence of an acid acceptor in a solvent. Examples of suitable reactive derivatives of the compounds of formula (II) include the following acid halides (e.g., chlorides, bromides), mixed anhydrides (e.g., mixed anhydroxide of the compound of formula (II) with alkyl carbonate), reactive esters (e.g. p-nitrophenyl ester, 2,4-dinitrophyl) (E, 2-proposyl ester, 2-proposulfonyl ester), acid azides and acid amides (e.g., imidizslamir, 4-substituted imirlzolamir, triazolimide).

Suitable solvents are dioxane, trathyriofuil, lcitositrile, chloroform, mmeylene chloride, rimethylformamide, N, N-rimethyllCl2, ethyl acetate, pyridine, acetone and water. Examples of suitable acceptors are potassium hydroxide, sodium hydroxide, potassium carbonate),

Examples of acids include alkali metal hydroxides (sodium aplication), alkali metal carbohydrates (for example, alkali metal carbonates (e.g., sodium hydrogen carbonate, potassium hydrogensulfate), triethylamine, triethylamine). ΙιηΐΙΐιψ (iapPíklar ^] ^ "^ Г1 С г ^ ^ 1-У11П1: 1п, N alkylmosioSiiy (iapPíklar N чmlyУmorSfSin). reaction of ^the d d -50 ^a + 50 ° C, výtodou from -30 to + 20 Deň: 32 ° C.

(β-methyl tl: methyl-l-m-1, triethyl, Ы-^-β-β-β), the pyridine i is preferably carried out at a temperature of

Kd ^yz R ⁴ in the compound thus obtained ^E ^ ^b ECN Nina about it ^s formula

I ^^ ^b constitutes cfaánfoou carbonyl oxy group may deprotection carried out conventionally, such as hydrolysis, solvolysis, · kysenn treatment or reduction. When the protecting group is a carboxy group of a t-butyl or a benzyl group, these groups can be removed by treatment with cyanogen.

Examples of suitable acids include formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrogen bromide, and mixtures thereof. The reaction may be carried out in the presence or absence of a solvent. Examples of solvents include water, melanno, ethanol, acetic acid and dioxane. Reaction ^with preference ^{with a} bow ^{and a} di-Toplo at from -30 to + 70% with výtodou from 0 to +30 ° C. Furthermore, ^the fact that ^Z is n ^ei Jato KYSE ^yp sing ^sic yselin ^y tčflorooctové, ^crowd, it is předost pooužtí příoomzoosi in anisole.

When the carboxy protecting group is benzyl, p-methoxybenzyl or p-nitrobenzyl, cleavage of such a protecting group can be accomplished by catalytic hydrogenation of the compound. Examples of suitable catalysts include palladium on barium carbonate, palladium on charcoal and palladium black. Kaaalytická hydrogenation and NACE preferentially ^{EXAMPLE E =} Eq ^and di- ^p s ^p te FOT ^{of 0 t o} Ш ° C výtodou l ^{0 and 40} ° C for atmooférictoto or elevated pressure in a solvent. Suitable reaction solvents include ethanol, ethanol, tetrahydrofuran and water.

The pharmaceutical compounds of the formula I according to the invention can be used in pharmaceutical form or in salt form for pharmaceutical purposes. The pharmaceutically acceptable salts of the compounds of formula (I) include, for example, non-toxic salts with metals such as sodium, potassium, calcium or aluminum salts, salts with zethoxy amines such as trlallylamis (e.g. with organic acids, such as tartaric acid, etc. These salts are readily obtained by treating the compound in an aqueous solvent medium with a steroidal solution of an equimolar amount of an alkali metal reagent or acid.

The starting compounds of formula (II) are novel compounds. They can be prepared by reacting a butyric acid derivative of the formula

XCH 3 COC -COOR ⁶

N \

O

O = C-N-S

I «1 wherein -COOR® tortox pose a ^p-Neto topino ctoán ou ^ ^to R ^b ox ^y with u ^{p to Izu,} X. represents H ^ ogen, and ^{R 1} an machi Stora hereinbefore defined motovinou in přítomnootH aJcceptoru ^alkyl Selin ^{y (for an} example of an organic tertiary amine such as trle1flaπιizt or pyridine) ^p s t ^ Lori from ¹⁰ to 8 ⁰ ° C in an extended ^beta Oust ^e according to (najpítoad treatment ^of Neto direction ^m Ei waters ^Y and a varying altoHo! ^ ^{nc e N} in ^ ^iPad e ^COOR ® ^{Pla d} statuses volition ^ ou ^to Ar ^b ox ^y s ^k t ^p int ^of výsledněto The prodrug is additionally removed by a protecting group.

Throughout the specification and delimitation of the present invention, the term lower alkyl refers to an alkyl group having from 1 to 4 carbon atoms.

Experiment I

C ^ r ^ nt.m) ^ i ^ (^ I ^ b <^ in vitro activity)

The minimum inhibition concentration (MIC, yug / ml) of the test compound was determined by a standard agar plate dilution method (based on the Japanese method for ehemiOheeraPi). Mutller-Hinton agar (MHA; NisssD.

The results are shown in the following Table 1. Tested MIC (j ^ c ^ j / mL) microorganism Compound of the Invention (Note 1) Cefmenoxime (Note: 2) Ceftjzidncr (Note: 3) Stjphyloctccus aureus Terajima 0.78 1.56 12.5 Staphylococcus aureus 252R 25 > 100 > 100 Streptococcus (CN) 478 12.5 > 100 > 100 Baacilus subeti-press ATCC 6633 0,2 ' 1.56 3.13 Klebssella pnrumoniar 5038 <0.05, 0.1 0.1 Enterobacter cloacae TU-680 £ 0.05 0.1 0.2 Serratnj oorcescens 7006 0.05 0.2 0.2 Pseudomonas aeiugacttj 4096 0.39 · 6.25 0.78 Pseudomonas putida ATCC 12633 1.56 100 ALIGN! 12.5 Comment: 1) 6R, 7R) -77 (z) -2- (2- -aminctniajotl4-yl) -2- [((3S) -2-pyrrolidide> c- --Doxoxyiniino] crnaoid <t) -

2)

-3- (1-pyridiciooethyl) -3-cefeo-4-carboxylate

Chemical Name = (6R, 7R) -7 - [(Z) -2- (2-Aminothiazol-4-yl)) - 22-methoxyioino) acetamide <0] -3 - [ ₍ 1-acetyl-1H-tetrazol-5-yl) (thiomethyl) -4-cephem-4-carboxylic acid

Chemical Name = (6R, R7) -7 - {(Z) -2- (2-amino-thiazol-4-yl) -2 - [(2-carboximidazol-1-yl) -4- (2-carboximidazol-4-yl)] -: l) oxyimethyl] -3- (1-pyridinylethyl) -3-cepeo-4-carboxylate.

3) (Protective

II Effects in Bacterial Infections in Mice) Each level was used with 10 male mice of 20-1 g / ml. The mice were administered intraperitoneally. Bacteria are suspended in 6% mucin. The test compounds are administered intra-ovularly 1 hour after infection. The survival rate is determined 7 days after infection. The mean effective dose (ΕΙϋ ^ θ, mg / kg) of the test compound is estimated by analysis.

The results are shown in Table 2 below, together with the MIC (pg / ml) of the test compound, which was estimated by the method as described in Experiment I.

Table 2 *

Tested ED ₅₀ . (mg / kg) microorganism Compound of the Invention (Note 1) Cefmenoxime (Note: 2) CCftazidime (Note: 3) Staphylococcts 0.71 5.32 7.85 aureus Smith (1.56) (1.56) (12.5) Eschiei-iia cdi 0.05 0.16 0.08 KC-14 (0,05) (0,025) (0,05) Seeratia mmrcescens 0.14 0.88 0.54 7006 (0,05) (0.2) (0,2) ' Citrobacter et al 0.06 0.19 0.15 916 (0,1) (0,05) (0.39) Entenbacter 1.37 23.85 26.38 aerogenes (0.39) (1.56 (6,25)

Notes: “Figures in parentheses indicate MIC values, ie minimum inhibitory concentration in µg / ml for each of the test compounds.

(1) to (3): the same notes as under Table 1.

He did. (1) 13.12 g of (6R, 7R) -7-aniline-3- (1-pyridinylmethyl) -3-methyl-4-carboxylate.HI.H ₂ O is suspended in 150 ml of chloroform and 28 ml of the suspension is added. 5 ml of trimethylhorsilane, 17.8 ml of pyridine and 3.1 g of triethylamine at a temperature of -10 to 0 ° C. The mixture is stirred at a temperature from

-5 to 0 ° C for 2 hours.

(2) 6.75 g of (Z) 32- (2-allyl-thiazol-3-yl) -3,3 ((3S) -2-pyrrolidon-3-yl) oxyimino acetic acid is suspended in 200 ml of Ν, Ν-dimethylacetamide. 2.6 g of triethylamine are added to the suspension and the resulting suspension is heated to 65-70 ° C until a clear solution is obtained. The solution was cooled and 50 mL of chloroform was added.

The mixture was cooled to -20 to -25 ° C and added dropwise thereto. 3.84 g of phosphorus oxychloride. The mixture thus obtained is added dropwise at a temperature from -15 to -20 ° C to the solution obtained in (1). The mixture was stirred at the same temperature for 15 minutes and then 200 mL of aqueous 158 sodium chloride solution was added. The mixture was stirred for 20 minutes at 0-5 ° C. '

The aqueous layer was separated, washed with chlorine and then chloroform was evaporated under reduced pressure. The resulting aqueous layer does not pass through a column packed with 700 ml of Diaion HP-20 replaceable resin (a trademark of Mitsubishi)

Ini (tries (LLd., Japan)). The column is washed with about 6 liters of water and then the desired product is eluted with 208 mm ethanol. The eluate was evaporated to about 400 µl under reduced pressure and then filtered. Gains ^{and 9.7 g} of (6R, ^{7R) -7} - ^((Z) -2- ⁽² AAZ -aminith ^{and T L34} У ^{tl -)} -2- ^{[(ЗS) -2-t} Pýtr iěon 3- tl) oxymino-.alpha.-etamido-3- (1-trifluoromethyl) -3-chloro- ^3- carboxylate as a pale yellow powder. *

Yield: 70%

NMR (DpO-δ: 2.2-2.7 (2H, m), 3.1-3.8 (4H, m-, 5.05 (1H, t, J = 7 Hz)), 5.28 (1 H, d,

Hz), 5.36 (1H, d, J = 14Hz), 5.63 (1H, d, Hz—, 6.98 (1H, s)), 8.10 (2H, t, J = 7.5 to) (2H, d, J = 7.5 R)

J = 7Hh, 5.28 (1H,

J = 14 Hz), 5.87 (1H

8.57 (1H, t, J d, J = 5)

U, J = 5

7. Hz), 8.98

^-38, 0 ° (C = 1 /

H ₂ 0)

Examples 2 to

The following compounds were obtained in the same manner as described in Example 1.

Second ^{(6 R,} 7R) - ^- - | (Z) ² 4 - ^{(- i} -шninnth ilzl·l ^- yl) -2 ^- [((3 ^R) 4 2 ^{p 3} · 4 yrrtliclto- ^yl ) tx ^y imtotj acetamidzo-3-U-phthinomethyl-n-eefm ^^ artoXY ^ t

NMR (E 4 O 10: 2.1-2.7 (2H, m), 3.1-3.7 (4H, m), 4.9-5.5 (4H, m), 5.79 (1H) , d, J = 5 (H)),

6.92 (1H, s), 7.8-9.1 (5H, n) [α] D ° + 45.7 ° (C = 1, H ² O)

Third ^{(^,} 7R) -7 - ^ ^{(Z) 4 4 ^{2 (- t} -aImnnt ialz ^l l4 ^4-yl) - ² - ^[(2 - ^p yrrtliclto- ³ - ^yl) -OX ^ oj ^ inojacetam ^-

-3- (4-carbaao ^y t1l- ^p pyridine): oQdtyl-з4-dedem-4-klrbtxplát

Temperature, it melts

^163-166 ° C (dec

NMR (CF 3 CO 2 D): 2.5-3.0 (2H, m), 3.5-4.0 (4H, m), 5.2-5.5 (3H, m), 5.5-5, Δ (1H, m),

5.9 - 6.2 (1H, m, 7.35 (1H, s), 8.4 - 8.7 (2H, m), 9.1 - 9.4 (2H, m).

7R) - 7 - {(Z) - ² - ^(2-i aminnth alztl4-yl) ^-2 - ^^ - ^ p ^ nn RZN-yl) oxy ^^ amino] acetamido)

4. (6R,

-3- (4-iyduztyyitdt14pyrimidinomethyl) -Зcceeem-44carbotylate

^Nus temperature ^{Ta of 162} to I8 ⁴ ° C (extended ^{by about} La) (2H, m, 3.1 to 3.7 (4H, m), 4.8 - 5.0 (2H, m), 5.03 (2H, s), s), 5.24 (1H, d, J = 5Hz), 5.3-5.6 (1H, d, J = 5Hz), 6.81 7.8-8, 2 (2H, m), 8.6-9.0 (2H, m).

NMR (D 2 O) δ: 2.3 - 2.7

5.24 (1 H, (1 H, s,

Fifth ^(6R, 7R) ⁷ 4 - {(Z) --- ⁽² -amino ^and Noth ^IA lzl·l44 ⁴ 1) 4 ² - ^{[(2-p y} 1 · ⁴³ rzliclto ^ - ^yl) oxpiminčj acetamidz ) -3- (34iydrtx mit ^{y y} 1 · ^y pyiUioicmed L41 ^p · L) - cephem ^ - ^ - carboxylase.

Te l ^of the ^p counting from 128 to 135 ° C (decomposition)

NMR (D 2 O δ: 2.1 - 2,8 (2h, m, 3.1 - 3,8 (4H, m), 4.86 (2H, s), 4.9 - 5.1 (2H, m) 5.27 (1H, d, J = 5 Hz) 5.3 - 5,6 (1H, m), 5.83 (1 H, d, J = 5Hz) 6.96 (1 H, s), 7.7 - 8.2 (1h, m, 8.3 - 8,6 (1H, m), 8.6 - 9.1 (2H, m.

• sixth Natrúum (6R, 7R) -7 - {(Z) -2- (2-aminnthiaizl-4-yl) -2- ^{[(2- p} i ^p eri ^with on-3-yl) oxyimino] acetamidoo- 3- (l-mee ^ -lH-tetrazz Sy ^ ¹⁾ tnometyl ⁴³⁴ cephem4carboxylic ^ - ^) ^ i ^ and L ^ ^(l ^ oy sulfate :.

NMR (D 2 O) δ: 1.5-2.3 (4H, m), 3.0-3.4 (2H, m), 3.4-3.6 (2H, m), 3.90 (3H) , m), 4.0

4.0-4.2 (2H, m, 5.03 (1H, d, J = 5Hz), 5.63 (1H, d, J = 5Hz), 5.85 (1H, s).

7th Natrum ^m (6R, 7R) -7 - {(Z) -2- ^(2-i aminoth Alol --- y1)) · ² - | [Up ^ roHUM- ³ · - ¹⁾ ^ tx ^yi m ^and a-4, and ^C et ^am idoo-3- ^(l-t IEE ^1-H-L tetrlzz 5-y ^{1) i} t il> Me ^{d 434} cdfdm ^4-yl ^ - ^ l ^ i ^] ^ l (^ ty ¹ ί ^ t:.

NMR (DMSO-d6): 2.1-2.5 (2H, m), 3.1-3.5 (2H, m), 3.94 (3H, s), 4.2-4.5 ( 2H, m)

4.6-4.8 (1H, m, 5.03 (1H, d, J = 5 Hz), 5.5-5.8 (1H, m), 6.76 (1H, s), 3 (2H, broad s), 8.00 (1H, s), 9.55 (1H, broad).

8th Natri.im (6R, 7R) -7 - {(2) -2- (2-ат1поЬ ⁰ 1аго1-4-у1) -2- [1-methyl j-22py rlidoo _rr 3 ^3-yl) ~ oxylmino ] tcettmido-- ³ - ^{[(1-MT s} ^ ¹⁾ .H ^{^,} ^ yeyr tz ^{^]), 45 s).)} ^ iometyl] ⁴³ cephem (l- ^(t ^ e ^ ^r ^ ¹ⁱ Ooy ^ t.

NMR (D-O) δ: 2.1-2.7 (2H, s), 2.89 (3H, s), 3.2-3.8 (-H, m), -, 05 (3H, s), s), -,? -?, 3 (2H, m, -, 9-5.3 (2H, m, 5.73 (1H, d, J = 5Hz)), 7.00 (1H, s).

EXAMPLE 9 (1) 3.0 g of 7-trifluoro-phthlosyoranic acid are suspended in 30 ml of N-dimetritetetamide, and 9 g of sulfuric acid are added to 6.6 ml of pyridine. After micht yři temperature ⁵ to ¹⁵ ° C to give TZ RE ^{H or alkyl,} a solution ^{of p} era t ^to nt ocHlttdí - TZ ²⁵ - ² 0 ° C.

^{(2) 2,} 7 ^{g of} (Z) 42 - ((- atinоthiaтo ^of L4-yl) - ⁴⁴⁴¹⁾ 4 ² "[((ЗS)" 2 "pyrrolidoо43 ⁴ RL) oxyimino] acetic acid are suspended in 80 ml nzn Dimethylcetamide was added to the suspension to obtain 1.1 g of yyrylnitrine. ^The suspension was stirred for 65 t s ⁷⁰ ° C ^for TZ to ignite at ^or RE ^{H y} on the solution of ^the extended ut ^{k y} o ^d I nt ochlt temperature MESNA-book. To the solution 20 ml of chloroform yřidt t PTK him přilctpe flicker zt ^y te s ^{y of} Oy -30 t ^f - ² 1 0 ° C, ^{65 g} ^ s ^ rox-Chloro chloride. ^MES ball ^ht s ^y s ^{y s} publicly ye ^{s Ye} lo ^y o to ^{about 10} minuted at t t ^{p k p k} t s ^s s ^p e ^-25 t ^{F -15} ° C ^{to a} solution of zísltanému odsttvci (1 ).

The mixture was stirred for 40 minutes. The retkání smměi yřidt to 100 ml in a ^dy t ² 0 ⁰ ml eyjtce yu ^ t ^ht mixture MIC ³⁰ minutes yři ^y e ^{y 0} llУ ^of TZ ¹⁰ ° C. Organic ^kt vrsyvt was collected, washed with water YTK t exyrthuje 5% aqueous Uydro ^{lhličitоnei-g} en sulfate. The extract was introduced into a cation untyped with 400 ml of Dition HP-20, and the product was eluted with water. The elutt was reconstituted from the reduced rate to dryness. The residue is separated from the residue by distillation. Hatrbum ^{2.9 g} of (6R 7R) - ^{-7 ({(Z)} - ^- -тm nо ^{i l} h ^{l l} ATO - ^4-41) - ^- - ^[((3 S ^-2 - ^y4 rrllidl - 3 - ⁴ 1) ox ^y IIIn] acetii ^d d (y ^ CE ^ u losportn.

NMR (D 2 O) δ: 2.12 (3H, s), 2.3-2.6- (2H, m), 3.2-3.9 (-H, m), -, 75 '(1H, d, J = 13 Hz), 4.95 (1H, d, J = 13 Hz), 5.10 (1H, t, J = 7 Hz), 5.25 (1H, d, J = 5 Hz), 5.85 (1H, d, J = 5Hz), 7.08 (1H, s).

PPíkltd 10^{1,35 g} () -2- (²⁴т_Γ^^andlо^-t^laтz^{-) 4--}^¹)^4-4 [((ЗS) -²-^pprroli^dl- ·^зЗ--^yl)o) x^yii^andоl] ocyov^{é k}yse Dilute to 40 ml with Ν, Ν-diethyl ether^ytiidu t 1.85 g Уr0buryтamiоuт mixture to heat nt^{60 tž} 70 [deg.] C. until the solution is heated. Rozyo^to chills nt ye^ployu misynosbi t^yadd ytk to 20 ml mee^ylenchlordd solution containing 1.65 g yerc.Ouyyl (6R, 7R) ~ 47⁴тiinoce^Ftloy^p<lrтоáУu.^TOe may mix^yři^{dt y}ři^yE^yloy⁰ tž⁵ ° C 0.8^{8 g} l-^Uydrox^ybon-z^lanus⁴The mixture was stirred for 5 hours^por yУejоé Уeylltě. Water (50 ml) was added to the retention mixture, and the mixture was stirred with 100 ml. The insoluble elements are removed by filtration and the organic layer is separated off, dried and then concentrated to dryness. To the residue was added 30 ml of tartaric acid and 1 ml of toluene, the mixture was stirred at room temperature for 20 minutes, then reduced from the reduced pressure to dryness. bases Uydro^Genоlhličitоnei sodným. The non-drying lines are inoculated and the filters are loaded onto a column untyped with 150 ml of Dition HP-20. The desired products are eluted with water. The elutes are terminated from reduced vacuum to dryness. Z £ s^kt se 1^,2^G nahruum (6R 7R) -7- (Z) -2-^[(^--aminnlh^laтz^l44-4¹)^4-- [⁽⁽3S H 4 pyrro lidon-3-yl) oxyimino] acetamide orcephalosporanate.

The physicochemical properties of the products are identical to those of the product obtained in Example 9.

Example 11 (1) 2.5 g of benzhydryl (6R, 7R) -7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate is dissolved in 3 ml of tetrahydrofuran and the solution is cooled to a temperature

-20 to -15 ° C.

(2) 2.0 g of (Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidin-3-yl) oxyimino] acetic acid is added to a mixture of 60. ml of Ν, Ν-dimethylacetamide and 0.8 g of triethylamine and the mixture is heated to 65-75 ° C until a clear solution is obtained. The solution is cooled to -20 to -15 ° C, and 1.1 g of isobutyl chlorocarbonate is added dropwise at -20 to -15 ° C. The mixture was stirred at the same temperature for 30 minutes. The mixture is added at -20 to -15 ° C to the solution obtained in (1) and the resulting mixture is stirred at the same temperature for 2 hours and then further stirred at -5 to 0 ° C for 1 hour. 50 ml of cold water and 100 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred. The organic layer was collected, washed with water and concentrated to dryness under reduced pressure. 1 g of anisole and 30 ml of trifluoroacetic acid were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated to dryness under reduced pressure and 20 ml of water were added to the residue. The aqueous mixture was made basic with sodium bicarbonate and loaded onto a column packed with 300 ml of Diaion HP-20. The column was washed with water and the desired product eluted with 10% aqueous methanol. The eluate was concentrated to dryness under reduced pressure. Acetone was added to the residue and the precipitate thus obtained was filtered off. 1.1 g of sodium (6R, 7R) -7- (Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) oxyimino] acetamidoyl is obtained. 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

NMR (DMSO-d6) d 2.0 - 2.5 (2H, m), 3.1 - 3.5 (2H, m), 3.93 (3H, m), 4.1 - 4.5 (2H-m)

4.6-4.8 (1H, m), 5.04 (1H, d, J = 5 Hz), 5.5-5.7 (1H, m), 6.76 (1H, s), 7 3 (2H, broad, s), 7.98 (1H, s), 9.57 (1H, broad).

Example 12 (1) 1.65 g of (6R, 7R) -7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is suspended in a mixture of 15 ml Of Ν, Ν-dimethylacetamide and 5 ml of chloroform, and 3.0 g of Ν, Ο-bis (trimethylsilyl) acetamide are added. The mixture is stirred at 10 to 20 ° C until a clear solution is obtained. The solution is cooled to -30 to -20 ° C.

(2) 440 mg of dimethylformamide are dissolved in 10 ml of chloroform and 820 mg of oxalyl chloride are added dropwise at 0 to 5 ° C. The mixture was then stirred at the same temperature for 30 minutes and cooled to -30 to -25 ° C.

(3) 1.35 g of (Z) -2- (2-aminothiazol-4-yl) -2- [S (3S) -2-pyrrolidon-3-yl) oxyimino acetic acid] are suspended in 40 ml Ν, 5-Dimethylacetamide and 0.55 g of triethylamine are added to the suspension.

The mixture is heated to 65-70 ° C until a clear solution is formed and the solution is cooled to room temperature. 10 ml of chloroform are then added to the solution and the mixture is cooled to -30 to -20 ° C. To this mixture was added dropwise the solution obtained in paragraph (2) stirring at -30 to -20 C, ^D, and stirring at the same temperature was continued for 15 minutes. The reaction mixture was added dropwise at -25 to -15 ° C to the solution obtained in (1) and the mixture was stirred at the same temperature for 30 minutes. 50 ml of water and 150 ml of chloroform were added to the reaction mixture, and the mixture was made slightly alkaline with sodium bicarbonate. The aqueous layer was separated and concentrated under reduced pressure to remove the chloroform and then loaded onto a column packed with 300 mL of Diaion HP-20. The column was washed with water and the desired product eluted with 10% aqueous methanol. The eluate was concentrated to dryness under reduced pressure. Acetone was added to the residue and the resulting precipitate was filtered off. 1.8 g of (6R, 7R) -7-Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) oxyimino] acetamido are obtained | 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

The physical-chemical properties of this product are identical to those of the product obtained in Example 11.

(Preparation of starting compounds)

Preparation 1 (1) 31.8 g of ethyl 2-hydroxyimino-3-oxo-on-butyrate are dissolved in 150 ml of acetone and 83 g of anhydrous potassium carbonate are added to the solution. To the mixture was added g of 3-bromo-2-pyrrolidone at 20-25 ° C, and the mixture was stirred at this temperature for one hour. To the resulting mixture was added 1 liter of ice-water and extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure to remove the solvent. The residue is crystallized using diisopropyl ether and the crystals are filtered off. The crystals were recrystallized from ethyl acetate. 32 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxyimino] -3-oxo-n-butyrate are obtained in the form of colorless needles.

Mp 92-93 ^e C.

(2) 14.5 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxyimino] -3-oxo-n-butyrate are dissolved in 60 ml of methylene chloride and 9.6 ml is added to the solution. g of sulfuryl chloride. The mixture was stirred at 15-25 ° C for hours and then concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water. The chloroform solution was dried and concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water. The chloroform solution was dried and concentrated to dryness under reduced pressure. The residue was recrystallized from ether and the crystals were filtered off. The crystals were recrystallized from ethyl acetate. 6.5 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxoimino] 3-oxo-4-chloro-n-butyrate are obtained.

Mp 102-103 ° C.

(3) 27.7 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxyimino] -3-oxo-4-chloro-n-butyrate and 7.6 g of thiourea are added to 200 ml of methanol, and 20 g of N, N-dimethylaniline are added to the mixture. The mixture was stirred at 20-25 ° C for 2 hours and then concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and washed successively with water and aqueous sodium bicarbonate solution. The chloroform solution was dried and concentrated under reduced pressure to remove the solvent. The residue is crystallized from isopropanol, and the crystals are filtered off. 17.5 g of ethyl (Z) -2- (2-aminothiazol-4-yl) -2- [1,2-pyrrolidone-3-oxyimino] acetate are obtained.

M.p. 156-158 ° C.

(4) 3.0 g of ethyl (Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] acetate is suspended in 60 ml of methanol and 10 ml of 2N sodium hydroxide are added. The mixture was refluxed for 30 minutes. After cooling, the mixture was neutralized with 20 ml

1N hydrochloric acid and then concentrated to dryness under reduced pressure. The residue is crystallized from 10 ml of ice-water and the crystals are filtered off and dried under reduced pressure at 70 ° C. 2.2 g of (Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] acetic acid are obtained in the form of colorless prisms.

M.p. 158-159 ° C.

Preparation 2 (1) 2 g of (R) -3-hydroxy-2-pyrrolidone [Tetrahedron Letters, 2617 (1971)] is suspended in 30 ml of acetone and 15 ml of 2N aqueous sodium hydroxide is added at room temperature to form clear solution.

The solution was cooled to -3 to -5 ° C and 5.7 g of p-toluenesulfonyl chloride was added. The mixture was stirred at the same temperature for 1 hour and then overnight at 10-15 ° C. The pH is adjusted to 2 with about 10 ml of 2N hydrochloric acid and the mixture is concentrated under reduced pressure to remove acetone. The mixture thus obtained was extracted with chloroform and the extract was washed with saturated sodium chloride solution. The chloroform solution was dried and concentrated under reduced pressure to remove the solvent. The residue was crystallized from ether and the crystals were recrystallized from ntslsentate. 3.5 g of (R) -4- (p-tosyloxy) -4-pyrrolidone are obtained.

M.p. 148-149 ° C.

[.alpha.] D + 17.7 DEG (C = 1, MeOH) (2) 1.07 g of ntsl- (Z) -2- (2-amino-thiazol-4-yl) -2- (hydroxy-amino) -acetate was dissolved in 5 ml of sulfonyl sulfoxide and 1 g of potassium carbonate and 1.53 g of (R) -3- (p-trifluoromethyl) -2-pyrrolidine are added to the solution. The mixture was stirred at room temperature overnight and water was added to the reaction mixture. The mixture was extracted with chloroform, the chloroform extract was washed with water, dried and then concentrated to dryness under reduced pressure. The residue was crystallized from propyl ether and the crystals were recrystallized from aq. M.p. to give 0.86 g of ethyl (Z) -2- (2-amino-thiazol-4-yl) -2 - [(( 3S) -2-pyrimidin-3-yloxyimino] acetate.

Melting point 160-163 ° C.

[Α] D -15.9 ° (C = 1, MeOH).

(3) Dissolve 0.27 g of sodium hydroxide in 3 ml of methanol and 1 ml of water, and add 1 g of the ester obtained according to (2) to the mixture. The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was adjusted to pH 5 with 10% hydrochloric acid and concentrated under reduced pressure to remove the pH of the residue with 3% hydrochloric acid, and the mixture was cooled with ice. The precipitated crystals are filtered and then washed with methanol and blown. 730 mg of (Z) -2- (2-amino-thiazol-4-yl) -2-Q ((3S) -2-pyrrolidin-3-yl) -oxyl-amino-acetic acid are obtained.

Melting point 199 až to 200 ° C (decomposition)

H 2 ⁵ -50.8 ° (C - 1 H ₂ O)

Preparation 3 (S) -3-hydroxys2-pysrolidine was treated in the same manner as described in Preparation 2 to give (Z) -2- (2-amino-thiazz-4-yl) -2-Q ((3R)). -2-pyrrolidon-3-yl) oxyirin] acetic acid.

Melting point 198-200 ° C (decomposition) [α] D 5 + 50.5 ° (C = 1, H ₂ O).

P rep a rá't 4

250 g of sodium iodide and 32.5 g of pyridine are dissolved in 85 ml of water and the mixture is heated to 70 ° C. 50 g of 7-formamidooephthalosporic acid are added and the mixture is stirred at 70 ° C for 1 hour. After cooling, 250 ml of methanol are added to the mixture. Then, 250 ml of 22% methanolic hydrogen chloride was added dropwise at 18-20 ° C. The mixture is stirred at the same temperature for 1.5 hours. The precipitated sodium chloride is filtered off and 80 ml of water are added to the filtrate. The pH of the filtrate was adjusted to 3.5-3.7 with pyridine. The precipitated crystals are filtered off, washed with water and methanol and then dried. 33 g of (6R, 7R) -7-amino-3- (1-pyridinoethyl) -3- (1-pyridinomethyl) -azephthimim-4-carboxylate-H2O.H2O are obtained.

Mp 160-163 ° C (dec.).

Claims (3)

OBJECT OF THE INVENTION ' 1. A process for the preparation of (6R, 7R) - (Z) -2- (2-amino-thiazol-4-yl) -2- (oxy-amino) -acetic acid (6H-eephem-4-carboxylic acid) of formula I (I) is hydrogen or lower alkyl having 1 to 4 carbon atoms, is acetoxy or (1-ethyl-1H-etrazo-5-yl) thio and is carboxy, or is ## STR6 ## R is -COO and Y is hydrogen, hydroxymineyl or carbamoyl; and n is an integer of 2 or 3, or a pharmaceutically acceptable salt thereof, characterized in that the derivative (Z (-2-amino) -zoyl-2- (substituted oxyimino) acetic acid of formula II (II) wherein R ¹ and n have the aforementioned meaning that this reactate is condensed with 8 (6R, 7R) -7-amino-3-cephe-4-carboxylic acid derivative of the general formula III (III) 4 2 where R represents a protected carboxy karbtxysktpint or ^Y, if R is 4 or acetoxy- ^(lH-7 l7meUtl tutrazzt-5- ^yl) tiiosktpint · or R is -COO, Υ, and Y has the above 2. A process according to claim 1, wherein the condensation of (Z, N-aminothiazole) (a substituted oxyimino acetic acid of formula II in aqueous form with a derivative of (6R, 7R-7-amino-37Cufum-4) is carried out. karbtxyltvé acid of formula III or a SOH ^p rov ^UNG in přítomnooti (hyárata ^ ^ í ^ ni ^ and in a solvent at a temperature of - ^{3 * * *} 0 and ^from + 20 ° C and the condensation of a reactive derivative of compound II with compound formula III or a salt thereof is carried out either in or příoomnossi nepřítomnooti acceptor ^ky ^ l ^ ^t) and ^y ^ n ^ extended mouth le ^ ^p ^ s te otzě ^{-30 z} + ²⁰ ° C. 3. The method of claim 1 vyznaautící in that starting from compounds of the above formulas for ^H obecnýc ignites at ^the (6R, 7R) ^-7-7- (Z) -2- (2-aminnthiaaol-4-yl) - 2- [j ((3S) -2-pyrrolidone ') When R is a group of the formula —N, or with a salt thereof. where R represents a protected carboxy ^y sktpiit, it is removed from the resulting product the protecting group, and thereafter optionally converting the product into a pharmaceutically acceptable salt thereof. 3-yl) oxyimino <3 ^i-acetamide 3- ^(l - ^d pyridine in ^t Omet ^{l) з} 3 ^c uf EM ^--7k arboxylá ^{u t} t ^b o is not ^H by ^f armaceut. ^ ^Y ck suitable soOi .