JPS60155182A - Penicillanic acid derivative and use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to beninolanoic acid derivatives and their uses.

Compounds of the invention have the formula [In the formula, X does not represent chlorine, bromine or iodine. Ko.

benicilanoic acid derivatives and salts thereof, easily Ju+
"hydrolyzable", including salts of stellates and their esters.

The increasing frequency of β-lactamase producing bacteria is a serious problem in the treatment of bacterial infections. These enzymes have been shown to inactivate various β-lactam antibiotics4'3 and to inactivate both Cram-positive and Clam-negative bacteria11.
The β-ratatamase produced is a β-lactam antibiotic acid 1
Resistance of 4-4 bacteria to 1, -41 Hatake! It is known that j, l-.

6β-1 Beninolanoic acid 111 was found to be a potent inhibitor of β-lactamase produced by a variety of Clam-positive and -negative bacteria. This property makes 6β-benisolanic acid and its salts and easily hydrolyzed esters useful as pharmaceuticals for humans and livestock.
It is assumed that there is an i value. This 41 study shows that when the compound is co-administered with the β-Lacta J1 antibiotic, it inhibits the latter.
This is to protect against 'iI'l'.

In addition to its inhibitory activity against β-lactamase, 6β-halobenine lanic acid has antibacterial properties (see Table 1).
Particularly active against the genus Neisseria.

With the exception of 6β-promopeninolanic acid, which has already been described in the literature (see below), the compounds of the invention are new and
None of them, including 6β-promopeninolanic acid, have hitherto been obtained in a pure state.

Until now, mixtures of 6β- and 6α-bu[1-moveninolanic acids have been prepared, either by shrimpification of the latter or by selective hydrogenation of 6,6-nopromobeny7lanic acid, so that the 6β-bromoepimer is present in the reaction mixture at approximately 5-15%. It has been reported that it can be obtained in the state of
) Vol. 43, pp. 3611-3613 (1978);
Off Science Is Gob The United States Stave Off America (Proc, Na11. Ac
ad, 5ciUSA) Vol. 75, pp. 4145-4149 (1978), U.S. Patent No. 4,180,506 (19
December 1979 Patent), The Biochemical Journal (13iocl+cm, , 1, ) No. 17
70365-36711 (+979)], the same document is
Such an epimer mixture has no activity as an inhibitor of β-lactamase (j), and since it has no effect on these enzymes, the inhibitory activity is 6.
It has been reported that this is due to the β-bromo isomer. After filing the application which is the basis of the priority right corresponding to the present application, 6.
Trimedylsolyl 6-nopromopenine lanate
Selective reduction with Pugildino hydride followed by hydrolysis to form salts to give 6β-buCJ mopeninolanoate containing up to 5% of 6α-bromo epimer in 3 yields.
However, it has been reported that penicillanic acid formation occurs as a main side reaction due to excessive reduction.
Tetrahedron Letters ('I'eLral+cdr
on LcLtcrs) No. 48, pp. 4631-4634, 1979, 11 JLI.

The same document further states that the corresponding 6-chloro-6-iodopenicillanate was similarly reduced to obtain a mixture of 6β and 6α chloropeninolanic acids containing about 25% of the 6α-epimer in a yield of 39%. It describes what will happen. However, neither 6β-bromo nor 6β-chloropenicillanic acid or its salts and easily hydrolyzable esters have so far been isolated in pure crystalline form.

Furthermore, 6β-iodopenicillanic acid or its salts and esters have not been reported in the literature.

That is, one object of the present invention is to provide 6β-halopenicillanic acid [+] and its salts in essentially pure crystalline form. These compounds are suitable as pharmaceuticals and have β-lactamase inhibitory activity, the potency of which increases in the order of Cz<13r<1. Additionally, these compounds have shown some fungal activity, especially activity against Neisseria spp.

Another object of the present invention is to provide easily hydrolyzable esters of benicilanoic acid [1] and salts of the esters useful as prodrugs and/or intermediates.

Yet another aspect of the present invention is to combine the compounds of the present invention with selected β-lactanoantibiotics, whereby the novel compounds combine β-lactanoantibiotics with various β-lactanoantibiotics. -Protects these enzymes from inactivation by lactamase-producing bacteria (acts linearly).

Another object of the present invention will become apparent from the following description.

The salt of 6β-halopenine lanoic acid is preferably a salt with a non-toxic base that can be used pharmacologically, and suitable salts include alkali metal salts and alkaline earth metal salts, such as Lidium J5, Natriuno, For potassium and magnesium, calcium salts can be mentioned. In some cases it may be preferable to use salts that are readily soluble in water (2), and for other purposes, such as to obtain a sustained effect or to prepare aqueous suspensions, salts that are only slightly soluble may be used. It is suitable to use salt.

''-The above statements are merely illustrative examples and are not intended to limit the invention.

The ester of 6β-ha[nopeninolanic acid of the present invention is preferably an ester that is easily hydrolyzed with inhohi or inhydro. In the formula for such an ester, X has the same meaning as above. [Engineering, hydrogen, stermaj
, represents ethyl, IN represents straight-chain or branched alkyl having 1 to 6 carbon atoms, and represents Al: J gino or aryl or aryl 1 quino;
-6 straight-chain or branched aminoalkyl, the alkyl radical optionally containing one or more]2 other groups, such as hydrogine, mercapto, alkoxy, algyldi1, carboalcoquine, carpooxamil', phenyl or Optionally substituted with hydroxyphenyl.

” is an alkyl, alkoxycarbonyloxyalkyl, or aminoanoloxyargyl esulfonyl or aminoanoloxyargyl fluorine. shows.

] Among the esters listed above, the following are preferred: 3 to 8 carbon atoms
Alkanoyloxyster, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, alkoxyloxymethyloxymethyl having 3 to 6 carbon atoms, 1-(alkoquinocarbonyl 1quino) having 4 to 7 carbon atoms, and α with 2 to 6 carbon atoms
-Aminoalkanoyl 1-quinomedyl'' - Stell.

(A preferred ester of lactonyl J.

Stel, such as 3-phthalicyl, 4-crotonolactonil or iJγ-butylorac!・No 4-Ill'' - Stealth is one example.

In addition, methkinoster, noazmedel ma)koha mono-
Preferred are noargyl-substituted aminoargyl esters such as 2-dimethylaminoethyl, 2-noethylaminoethyl or 3-thumedelaminopropyl esters.

In particular, esters that are well absorbed when administered orally and are hydrolyzed to the free acid [1] during or after absorption are preferred.

The ester containing an amino group in the ester residue can be prepared and used in the form of a pharmacologically acceptable, non-toxic salt with inorganic or organic boric acid. Suitable inorganic or organic acids include hydrohalonic acids (e.g. hydrochloric acid, hydrobromic acid and hydroiodic acid), phosphoric acid, sulfuric acid, nitric acid, p-1-luenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, Propionic acid, citric acid, tartaric acid, maleic acid, pamonic acid,
Examples include, but are not limited to, p-(dipropylsulfamyl)benzoic acid (Propenet) and phenoquinosterbeninoline or other acidic β-lactam antibiotics. As mentioned above, salts that are easily soluble or slightly soluble are preferred depending on the purpose.

The corresponding 6α- 4° may be present in the phase reaction mixture.
A method for preparing a compound of the invention, which involves separating the compound of the invention from a mixture containing epimers and/or 6,6-nohalo derivatives, is described below.

- According to the manufacturing method, the epimer mixture of 6-valopeninelanic acid can be measured by measuring the pH of the reaction mixture using an automatic titrator? By adding 1l14 of Koyoru flower basal aqueous solution llk, keep it constant, 30-4
0” C-(=slightly basic 1) II (8-10
) for 6 to 48 hours, preferably at 30 to 32°C, pH 9.

0-9 Ite 20-2411. ! For 1 hour, add the salt of 60-halopeninolanoic acid over P1 water (equ
ili-Lnation), J, +1
,,Made by IAI. In the resulting mixture, (f(]-4
The yield of 6β-halo”-pimer decreases in the order of I>l(r>CJ, or the yield of β-epimer increases as
41. The conversion of monobenolanoic acid into pyridine is described in the literature. )-accommodation'↓ corresponds to 4 6α-ri [7 mouth and 6α:? The yield is at least 62 times higher than the yield obtained by using the -1+ acid bicarbonation method.

Thus obtained 6-tacy(l,G-bromo'-
A bimer mixture of 6-iotobenylinolanic acid (J) can be separated by column chromatography on a glue gel.As a developing agent, a suitable mixture of solvents is used. - thiru petroleum ether, ethyl acetate petroleum ether, chloroform-henzeno or ethylnochlorohexine acetate are used; these solvent mixtures contain carboxylic acids such as formic acid or acetic acid in low proportions (0.1-0.05%). Preferably, the 1' developing agent is very effective in separating the above epimer mixtures using Norikakel's dry column chromatography.
For example, ether-petroleum ether-formic acid (70:30:
01). In this way, the more polar 6β-halobeninolanoic acid is completely separated from the less polar 6α-epimer and then processed throughout the field with an eluent to form the free form or the corresponding kaliuno, or sodium salt. It can be obtained by elongation in crystalline form. Obtained crystalline 6β
- The purity of halopeninolanic acid and the corresponding potassium chloride sodium salt is at least 99% according to thin layer and gas-linked solubility chromatography.

Other methods include converting 6,6-halopeninolanoic acid or its salts to alkali metal or te) sialkyl monoammonium boranonates, such as sodium hydride, potassium borohydride J3, noanoborohydride lithium hydride. , tetrabutylammonium boranate or cedyl tristellammonium hora→-1, can be selectively reduced to free 6β-halopeninolanic acid II in high yields (>50%)! , 1 to i. reaction (J appropriate (
0 to 8 in a single solvent such as trimethyl sulfoxide, trimethylformamide, ethyl acetate or methylene chloride.
f) carried out at a temperature of "C", preferably at room temperature.
-halobeninolanic acid [+1 corresponds to 4-6α-halo and/or 6,6-cyhalope! by chromatography or fractional crystallization as known in the art, as described above. -Separated from nolanic acid.

The new ester of 6β-haloacid [1] has the corresponding 4 6α-
A halopeninolanic acid ester is prepared in a suitable solvent (such as methylene chloride, di[Jroporum or disterformamide 1-) with a base (such as I).

-10°C to room 7j in the presence of 5-noazabintaro[4,3,0]non-5-eno or triethyl)'mino)
A can be epimerized and prepared. In this way, the epimeric mixture of 6-valopeninolanic acid ester obtained in step 9 was separated by Calano chromatography under the same conditions as in duplicate to give the pure 6β-halo isomer. .

The ester of the present invention can be obtained by selectively reducing 6,6-cyhalopenylinolanic acid ester with an alkali metal or tetraalkylammonium folanate in the same manner as in the method described in 11j. The resulting 6β-haloester is separated from small amounts of the corresponding 6α-epimer and/or unreacted starting material by column chromatography as described above.

6β-halopeninolanoic acid [1] or its salts can be converted to the corresponding A esters by known esterification methods, and vice versa, these ``-sters can be converted to the (ya part of the molecule or more or less without A1). It can be chemically or enzymatically decomposed under suitable conditions such as 1 to give the corresponding 4 free acid Lll.

As mentioned above, the 6β-ha[nopeninolanoic acid of the present invention is a synergist of antibiotics affected by β-lactamases, and is itself useful in the treatment of certain bacterial infections.
'It is for.

More specifically, the antibacterial spectrum of pure 6β-HaL1 peninolanoic acid of the present invention is revealed from Table 1.

i(4ga) Determined by sequential dilution in liquid base, 10
'CFUb) (Crum-positive bacteria) or 10'CFLJ (
Crumb positive bacteria) inoculation b) CFtJ=coio++1' forming
units (colony forming trophies) Table 2 shows that 4 units of 6β for β-ratatamase producing strains.
4-0 These results demonstrate that the inohydroactivity of 11 combinations of 6β-halobeninolanic acid, henozylbeninoline, and anopinoline with selected β-lactam antibiotics is Staphylococcus aureus
It can be seen that the activity is particularly high against resistant bacteria.

K. pneumoniae (K. pneumoniae)
iae), Proteus mirapilis
m1rab-ilis) and Escherichia coli (Escheri
A similar synergistic effect against Cbia coli 4' is also shown for the combination of anopinoline and menlinum with the 6β-haloacids of the present invention.

Furthermore, it provides a pharmaceutical composition that is used for the treatment of infectious diseases and contains at least one of the compounds of the present invention as an active ingredient.
This is one of the objectives of the present invention.

The composition can be administered orally, 1-1, in the milk organ (inLr).
am-ammal) or topical administration, and can be used to treat infections in mammals (including humans).

Free 6β-halopeninolanic acid [11 or its salt is
'', which can be used for parenteral or topical administration. However, for oral administration, it is advantageous to use easily hydrolyzable esters of the invention or salts thereof.

6β-halobeninolanic acid when needed to rapidly increase tissue health or when used in combination with parenterally administered β-lactam antibiotics as described below.
Peninolanic acid [1] is suitable for use in injectable or injectable compositions of its salts.

In the case of intra-organal administration of milk, it is preferable to use an alkylaminoalkyl ester or a salt thereof to give an appropriate local concentration and to remove the A-terminus.

The active ingredients can be used as such or in admixture with carriers and/or adjuvants.

In such compositions, the proportions of therapeutically active substance and carriers and adjuvants can vary between 1 and 95%.

The compositions can be made into a variety of pharmaceutical forms, including tablets, pills, capsules, powders, tablets, suspensions, solutions, and other forms suitable for injection or infusion.

Carriers and/or adjuvants include pharmacologically acceptable substances such as gelatin, lactose, starch, macanenium stearate, talc, vegetable and animal fats and oils, cum, polyalkylenes, glycols or other known Pharmaceutical carriers (such as diluents, binders, buffers, preservatives, disintegrants, coating materials, etc.) may be selected and formulated in accordance with pharmacological practice and in a manner well known to those skilled in the art to provide, e.g., a sustained release drug. ,
Suitable pharmaceutical forms, including tablets and enteric-coated tablets containing the therapeutically active ingredients in isolation from each other, are prepared.

The compounds of the invention are suitable for use in compositions, alone or in admixture with other therapeutic ingredients, particularly beta-lactam antibiotics. In addition to some β-lactam antibiotics that are considered to be non-sensitive to β-lactamase,
Good intrinsic resistance to β-lactamases (J4”
Also includes Rurano. Accordingly, preferred β-lacta J3 antibiotics for the compositions include henzilpeninoline, phenoquinomethylpeninoline, pJrubenoline, methicillin, pcrhinoline, anopinoline, anopinoline,
evinorin, dicarnolino, ncranolino, cephalolidine, cepha[J Chino, cefazolin, cephalequinone, cefaclor, cefacedryl, cefamandole, cephapirin, cefrazine, cefa[J grits, menolinano, and other well-known beninolinos, cephalosporins or acetoquine methyl, pinocyloyl oxymethyl, acetoquine carbonyloxyethyl and phthalinol esters of aminopenine lanoic acids or their drugs such as hetanoline, methanopinoline, benolbeninoline, ampinoline, amoxicillin or cephaloglycin. Or cal) carrots,
phenyl, tolyl and indanyl α-esters such as dicarnoline or 6β-amidinobenisolanic acid protolac or similar 7β-amidinocephalosporanic acid derivatives such as pibmenolinum or batamesolinam.

When present together with other β-lactam antibiotics in the pharmacological composition, the ratio of the compound of the invention to the other β-lactam antibiotic is between 101 and 10, preferably between 31 and 10, calculated in terms of free acid. 3 is preferred, but is not limited to this range.

Another object of the invention resides in the determination of the dosage of the compounds of the invention and the dosage unit of the compositions of the invention.

The dosages and dosage units can be adjusted to achieve the desired effect without side effects.

The composition of the present invention has an antibacterial agent of 0.02 in terms of free acid.
FT-4 containing 5-2.5g, preferably 0.1-1.0y
Preferably, it is administered as a single administration.

1-Antibacterial agent-1 refers to a single agent, one type, or more.
One or more compounds of the invention in combination with two known beta-lactam antibiotics, salts or prodrugs thereof, are combined. When used for veterinary therapy, throw +
8 units may contain up to 259 antimicrobial agents.

``E throwing unit'' is qi (which can be administered to a small child by 4゛).
-gamma, which can be easily replaced and packaged in physically stable units 911, containing active substances alone or in mixtures with pharmacological carriers. It has become.

Similarly, for injection, the compositions of the present invention can be administered as dosages containing up to 109 antimicrobial agents in aqueous solution.

For parenteral administration, e.g. injection, the compositions of the invention can be used together with pharmacologically acceptable excipients or at a concentration of O1 in terms of free acid previously dissolved or suspended.
It can be presented as a dosage unit containing ~1 g of antimicrobial agent, for example as an aqueous solution or aqueous suspension.

When in dosage unit form, the compound may be administered in 1 dose depending on the condition of the child.
It can be administered once a day or in divided doses at appropriate intervals.

Therefore, the daily dose of antibacterial agent in terms of free acid is 0.
1-309 (equivalent to 1-425 iy/ky body weight/day),
Preferably it is 02-67.

The compositions of the invention can be used to treat infections of the respiratory tract, urethra and soft tissues in humans, and can also be used to treat infections in animals, such as mastitis in bovines.

If the pharmaceutical composition contains other β-lactam antibiotics, the latter may be used in much the same way as traditionally used when used alone as a therapeutic agent, but in certain circumstances may their amount be reduced? Appropriate.

Particularly suitable formulation compositions include β-lactano antibiotics,
6β-halobeninolanic acid, a salt or protorug, more preferably a β-lactam antibiotic, a salt or prodrug thereof, in an amount of 200 to 500 ag, in the proportions described above, 1, Contains 25-250 mg of H6β H-V nopeninolanic acid, its salts or drug.

The compounds of the present invention can be used as pharmacologically acceptable non-toxic esters. The term 1-non-toxic regarding esters herein means that the J-ester is pharmacologically acceptable for the given dosage form. Generally, the compounds of the invention are used for oral administration,
One throw to the dead! ]Niwa 1! It is within the scope of the present invention.

The invention further encompasses a method of treating a human or other mammal comprising administering to a child suffering from an infection 111 an effective amount of a compound of the invention.

A compound of the invention may be administered as a pharmaceutical composition comprising a β-lactam antibiotic J- and a compound of the invention, preferably as a composition comprising a compound of the invention. In the latter case, the two active ingredients can include 6β-halopeninolanic acid and a β-lactam antibiotic in various proportions.

According to the invention, the antibacterial agent is administered at 01 to 800 μg per day of treatment, often 500 to 600 T1! ? /day administered.

However, the above dosages do not refer to the total amount of antimicrobial agent, i.e., the total amount of one or more compounds of the invention administered alone or in combination with other β-lactam antibiotics. Of course.

Next, examples will be shown to specifically explain the present invention.

Example 1 Preparation of potassium 6β-bromobenylanoate-6α-bromobenylanoic acid potassium z, 764y (24 mmol)
An 800 mQ solution of 004M disatium hydrogen phosphate aqueous solution was aged at 30°C for 72 hours. NMR-spectrum (ILO) analysis of a freeze-dried sample of i5mQ revealed that
The epimer mixture was impregnated with 6β-bromo compound at 10-12%.

After adding 160 g of sodium chloride, 250 g of ether
The mixture was stirred at 0°C under the (!) layer, and the aqueous phase 1)1) was adjusted to 3 with 4N hydrochloric acid. Separate the organic layer and dilute the aqueous phase with ether.
oII (i. Re-extracted with ether hlHl)
The mixture was washed with 1 TIQ of sodium chloride and 10 TIQ of a saturated aqueous solution, dried, and then concentrated to a temperature of 11 F to about 4 mL.

The concentrated solution was applied to Nori-Riki Gel (Nori-Riki, Woelm J, ・Cheese-Tsu, S.
C), Woelm Pharma
), West Germany, Eschwege
) I was interested in the dry column taromato taraphy in ). Column (straight tfJ), 6 CIR, length 46c+n) with ether-petroleum ether-formic acid (70:30:0.1) I2
Developed at 00ηρ, collected the a2cm fraction, suspended it in ethyl acetate (io*c/fraction), and poured the supernatant sample 1'1 into a thin layer [l matocraphy (the solvent system was the same as the multiplex). Analyzed by. The more polar pure 6β-promobeninolanic acid was combined and eluted with ethyl acetate. The obtained syneresis liquid was concentrated under reduced pressure to about 50 μm (!), and thoroughly washed with water (6 x 5 m) to remove most of the formic acid.

The four layers were added to 40 mQ of water and the apparent ft pH of the mixture was adjusted to 72 by addition of 0.5M aqueous potassium bicarbonate solution. Separate the aqueous layer and freeze-dry it to pure potassium 6β-promopeninolate 054? was obtained as a colorless amorphous powder, which was crystallized from n-butanol. [α]i)
=+240° (c=0.2, water) detailed FT proton N
The MR-spectrum (Fig. 1) shows δ-1,47(s,3
H: C1j32α), 159(s, 3H; C)(3
2β), 4.27 (s, IN+0113 3), 552
and 5, 58 (doublets.

, J =411z, 21 (; C1+-5α and C11-6α, see Figure 1a) ppm.

Equipment JEOL FX100o concentration 50TI2/Re.

All data are for tetrasternolane at 0.00 ppm and d-
was converted to the δ-scale.

Example 2 Preparation of potassium 6β-chlorobenynolanate - Potassium 6α-chlorobenynolate 13.149 (48 mmol)
0.04M disodium hydrogen phosphate aqueous solution 1600R
The Q solution was aged for 96 intercostals at 30°C, and a 5 mQ lyophilized sample was analyzed with N M II-Subeyotol (010), which revealed that approximately 5-6% of 6β-liloropeni7lanic acid was present in the mixture with the starting material. The reaction mixture obtained as
After adding 4N hydrochloric acid at 0° C. while stirring, the aqueous layer was adjusted to 1111 to 3. The six layers were separated, and the aqueous phase was extracted at 200 μσ.

Combine the ether extracts and add a saturated aqueous solution of sodium chloride 2
It was washed with aF at 0 mQ, dried, and concentrated under reduced pressure F to about 50 mO. The concentrate is dried by Norikakel's dry color J.
(Similar to Example 1 in which the corresponding 4 6-promobeninolanoic acid epimers were separated).

The fraction containing pure 6β-[1 peninolanoic acid] was eluted with ethyl acetate, and the resulting solution was treated as in Example 1 to obtain 6β-[J potassium peninolanoic acid 0689
was obtained as an amorphous powder.

Crystallize this from +1 butanol and no.

N M It-spectrum (D, O), δ-1,48 (
s, 311: 0 mountain - 2α), 1.58 (s, 311:
Cjj3-2β), 4.27(s, I II: C1
13), 543 and 563 (2d, J=4+1z,:
Hl: C1↓-5α and C1j-6α) ppm,
External enemy quasi-tetramethylnorane.

Example 3 Production of potassium 6β-iotopenicillanate 6α-
The same procedure as in Example 1 was repeated using potassium 6α-iodopenynolanate in place of potassium bromobenisolanate to obtain the amorphous title compound, which was crystallized from n-butanol.

Example 4 Preparation of potassium 6β-bromobenisolanate - Potassium 6α-bromobenisolanate 15.289 (48 mmol)
A 320% water solution was adjusted to pl+9.0 with IN aqueous sodium hydroxide solution and stirred at 30°C for 24 hours. During the reaction, IN hydroxide
The p I-1 of the solution was maintained at 90 by adding I+t+ to the aqueous solution. 1 mfl of solution! When it was freeze-dried and subjected to NMll-spectrum (opo) analysis, it was shown that the resulting epimer mixture contained about 25% of the 6β-bromo compound.

The mixture was treated as in Example 1 and purified by column chromatography to obtain crystalline potassium 6β-bu[J mopenine lanate. This was the same product as Example 1.

[α - +243° (C-05, 1M phosphate buffer,
pt17).

Original moisture 11ir, as Ce1leBrKNO3S,
Calculation value C930, 19%: H, 2, 85%; Br,
25.11%2N.

440%, S, 10.08%, actual value, C, 30,
16%; 11°295%, Iur, 25.28%, N,
4.33%: S, 10.07%0 Example 5 Production of potassium 6β-chlorobeny7ranoate - 6α-b [J potassium mopeninolanoate was replaced with 6α-[potassium J ropeninolate, Example 5] Repeat the same procedure as step 4 and add 15% of 6β chloro compounds.”-Bima
A mixture was obtained. This is the freeze-drying sample of the reaction mixture.
N M It-spectrum (D, 0) to a) to -7 to 3, which was treated in the same manner as in Example 1 [17 Tokurafi to be delivered] Title compound 6β-chloropeninolanic acid Potassium.

lα1201-243° (c-05, IM phosphate slow ■
] solution, pl, +7).

Example 6 Preparation of 6β-iodopenine potassium lanate, =A, 6-
-Production of acetoquinomethyl diazopeninelananate 577 g (
20 mmol) and 276 g (40 mmol) of sodium sulfate
mmol) of ditalolomethane 12011a and water 120m
Add 7 m of 4N sulfuric acid to the mixture solution of ρ at 0-3°C without stirring.
Q was added dropwise.

After stirring for a further 30 minutes at that low temperature, the organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure to about 3 On (l!).

This concentrate was immediately used in the next -L step.

B Production of 6α-iotopeninolanoic acid acetoquinoster A concentrated solution of 6-tazobeninolanoic acid acetoquinoster obtained in Step A was mixed with 180 uf of ice-cold acetone! 9. Add potassium iodide to this mixture at 0-3°C without stirring.
0y (60 mmol) and 57% hydroiodic acid 7,
4 m(l) of a 15 iC solution in water was added dropwise.

After stirring for a further 25 minutes at 0-3°C, the mixture was treated with solid Satorium bicarbonate 2, IOg and filtered. The filtrate was diluted with ethyl acetate 150ii7 and the acetone was reduced 11
-Remove to F/ko. The remaining organic layer was separated, washed with an aqueous solution of 05M diosulfate, dried over sodium sulfate, and concentrated under reduced pressure to about 10 mQ.

11 liters of concentrated wax (1 liter of dry column of Noriyoku Gel)
Ma) Kufufi ("-Furui, Ura", -Chiru, 46)
(*1) to obtain pure acetoquinomethyl 6α iodobeny7lanate in the form of a slightly yellow oil.

NMIt Supeta!・Le (CI) Ce 3), 61.
48 (s, 3 II: Cj-1-3-2cr), 1.
63 (s, 311: C1ja-2β), 2.11 (s
, 3H; COC! j-a), 45G (s, l II;
Cil 3), 4.99 (d, J=1.511z, l
H: Cjl-6) 5.45(d, , 1 = 1
．． 511z.

111, C member j-5) and 579 (Δ1.-(q2.
1 = 55 II Z, 2 II: O(E j
j-20) pp110 internal randomization/tetrastern run.

Production of C,6α-iotobeninolanoic acid, 6α-
A solution of 20 g (5 mmol) of acetoquine methyl iotopenine lanate in 50% 70% aqueous methanol and 1.5 ml of 4N hydrochloric acid was added.
After adding 5 mσ and excluding light, the mixture was stirred at room temperature for 3 days. The mixture was poured into 150 Rρ of water and diluted with ether l0
Extracted twice with 0iρ, combined ether extracts and diluted with water (2X
25 mρ).

Add 40mσ of fresh water to the 6th layer to bring the water phase PTL to 1M
Potassium bicarbonate was added with stirring to adjust the temperature to 6.8. The aqueous phase is branched and lyophilized to form an amorphous powder of 6α-
Potassium iodopenynolanate was obtained. This was crystallized from acetone.

NMR-spectrum (1), O), δ-1,46 (s.

311, cx+a -2α), l, 5 7(s, 3
11; CH3-2β), 4.30(s, IH: C
H-3), 5.24 (d.

J = 1.5 Hz, l HHC ratio −5) and 546
(d, J = 1.5 Hz, lH; (41-5)
ppm.

D Production of potassium 6β-iodopenynolate Potassium 6α-iodopenynolate 3.65y (10 mmol)
A 200 Rρ solution of water was stirred at 30°C for 20 hours. During this time, the pH of the reaction mixture was 0. IN sodium hydroxide was added via automatic titrator and maintained at 90. According to the NMR-spectrum (+), 0) of a freeze-dried sample of 1 cape, the epimeric mixture of 6-iotopeni7ranic acid contained about 30% of 6β-io1-compounds.

150 ml of ether was added to the mixture, 4N hydrochloric acid was added with stirring, and the aqueous phase was diluted to 30 ml for 1 week.

Separate the organic layer and add 50mf of ether to the aqueous phase! It was extracted with II. The ether extracts were combined, washed with sodium chloride, saturated aqueous solution (2X 20ml), dried over magnesium sulfate, and concentrated under reduced pressure to approximately 6-8 kg. Dry column chromatography ('', - on petroleum - on formic acid, 70,
30 0.1), the corresponding 6β and 6α-compounds were separated in the same manner as in Example 1, and the isolated crystalline 6β
Potassium iothopenylanate was obtained. [α]20 =
+260° (c=0.5, IM phosphate buffer, pl+
7).

NMlt-spectrum (Dto), δ-1,49 (s.

3H, Cdan, -2α), 1.65(s, 3H: C1-
1*-2β), 4.29(s, III: 011-3
), 542 and 5.80 (2d, J=3.5l-1z
, 2+4: qH-5 and Cl-1-6) ppm0 Elemental analysis, as Ce H91K N 03S, calculated values C, 26,31%, H, 2,48% l I, 34
．． 75%, N.

384%, S, 8.78%, actual value C, 26,5
1%, 1゜258%: 1.34.91%: N,
3.75%+S, 8.80%.

Example 7 Production of pivaloyl oxumedel 6β-promobeninolanate ~ Chloromethyl pivalate 0.27zQ (2,5 mmol),
The mixture was stirred at room temperature for 16 hours.

After diluting with 451 ml of ethyl acetate, the mixture was diluted with water (4×IO
The residue was washed with 70% magnesium sulfate, dried over magnesium sulfate, and evaporated under reduced pressure. The oily residue was crystallized from neunobrobyl ether to give the title compound. Melt=e4 Li7-68°C.

N N4I sheath vector (CI) C, ), δ f12
3(s, 911: C(Cjl3)3), 1.51(S
, 3) 1. C4+.

-2α), 1.68 (s, 311: Cll3 2β)
, 454 (s, III: C113), 532 and 557 (2d, J = 41-1z, 2H; C11-5
and C]↓-6) Onibi 5.82 (ABq, j =
=5.511z, 2+1; OCC2O4ppmo internal stalk quasi-tetramethylenran.

Example 8 Preparation of 6β-diO(J-beninolanic acid viva L1-yl oxtmedel) Using 6β-chloro[l-potassium beninolanoate in place of 6β-bu[1-potassium mopeninolanate, and repeating the same procedure as in Example 7. jllE [A crystal 6β-ri[Jlopeninlananic acid biha[Jyl1quinomenor] was obtained.

Melting point ('+8~69℃.

N M It-Svecyl ((-1) Ce 3), δ
== 1, 22(s, 9 II; C(CII3)
3), 1.51 (s, 3 II; Cjl-3-2α
), 1.68 (s, 3H: 01+3 2β), 453
(s, l II: co -3), 522 Nara Hini 56
0(2d,,1-411z,2+1: Ci, I-5 and C[l-6) and 5.82(AI3ft,,J
= 5, 511z.

21-1; OC-H40) pHm0 internal standard tetramethyl run.

Example 9 Production of pivaloyl oxmedel 6β-iothopeninolanate - Production of pivaloyl oxmedel 80-diazopeninolanate - Pivaloyl subquinoster 6β-aminopeninolanate 33
09 (1059 mol), sodium dinitrate 1.38ir
(20 mmol), 120 mfi of methylene chloride and 120 IIρ of water was cooled to 0°C without stirring,
It was treated with 2N sulfuric acid 7,5 vtQ for 40 minutes.

Several layers were separated, dried over sodium sulfate, and concentrated under reduced pressure to about 30 mQ. The concentrate was immediately used in the next reaction.

+3.Production of pivaloyl oxyester 6-diacibeninolanate obtained in step A of 120 uf of ace1-ene! dilute to 0
Cool to no. Then add 67% to the mixture with stirring.
Hydroiodic acid 3.5 iρ and thorium iodide 452
A cold solution of 20 iσ of water was added. After stirring for a further 20 minutes at low temperature, the mixture was treated with solid hydrogen carbonate, filtered and discharged.

The residue was washed with 10 liters of ethyl acetate (dissolved in 5% diosulfuric acid) and aqueous ff&(2×75zυ)C. The organic layer was separated, dried over 15 ml of sulfuric acid, and then evaporated under reduced pressure.The curved residue was purified by Norikaker's column chroma)/Cluffy (eluent: ether-petroleum), -chill, 30 ml. The pure 6α-iodopenynolanate pivaloyl 1-quinomethyl of colorless Bacillus subtilis was obtained by crystallization from nobile ethyl. Melting point 63-64°C.

Preparation of C6β-iodobenynolananoic acid pivaloyl sub-kinstel - 6α-iodopeninelananoic acid pivaloyl ocytumedel 0.
1.5-Noazahinokuro [4
,3,0]non-5-ene (1)IN) in dry methylene chloride 2Il+f! A 1M solution was added. Mixture at 0℃
Stir for 0 minutes, shake with 14i'l acid aqueous solution 2 times ρ, dilute with methylene chloride 2 (1 + ρ), dilute with water (2xlo
3111, dried over sodium sulfate and evaporated under reduced pressure to give a dark oil. The residue was purified by Norikakel column chromatography (eluent: ether-petroleum ether, 30 min. 0) to give piva c1yloxymedyl 6β-iotopeninolanate as a slightly yellow oil. This was crystallized from noisopropyl ether. Melting point 78-79°C.

NMR-spectrum (CI) C, e3), δ-12
3(s, 91-1, C(CLL, ), 3), 1.49(
S, 311. Cjl-3-2α), 1.70(s, 3
H; C, -2β), l155(s, I II; C
11-3), 538 Nara Hini 562 (2d, J=4Hz
, 211 C 6) and 5.81
(ABq,, 1-5.51-1z.

2H; OC1120) ppm. Internal tube: Tetramethylnorane.

Example 10 Preparation of acetogynoster 6β-b(J moveninolanate) 10 methyl O,IIzll!
9c (1 mmol) was added to a solution of 5 ml (1 mmol) of Tumedelformamide and the mixture was stirred in the dark at room temperature for 16 hours.

Needel 20J11! After diluting with water, the mixture was diluted with water (4x
The residue was washed with 5 ml of water, dried over Macnenoum sulfate, and evaporated under reduced pressure to give the title compound as a yellow curve.

N1viR spectrum ((shoulder) Cy 3), δ-1,
/19(s, 3H; C-j!1-2α), l,
68 (s, 3II; CLI-3-2β), 2.11
(s, 311: C:0CIjs), 4.54(s
, I II: Cj-j-3), 533 and 559 (
2+1. J = 4112.2111 Cjj-5α and C11-6α) and 5.82 (AI3q, J =
5.5II z, 2H; OCU-20) pp+n
0 Internal Fundamentals Tetramethylnorane.

Example 11 Preparation of 6β-iothopeninolanic acid acetogynoster. - The procedure of Example 10 was repeated using potassium 6β-iodopenicillanate instead of potassium 6β-bromopenicillanate to obtain the title compound as a yellow oil.

NMI spectrum (CDC poor), δ-1,50 (
s, 3HI GH32α), 1.70 (s, 3H;
cii. -2β), 2.12(s, 3+1: COC
l13), 4.55Cs, lH+ C bar3), 539
and 5.63 (2d, J=3.5Hz, 2H; C
11-5α and C-6α) and 5.83 (AB
q, J=5.5+lz, 2H; 0(2HtO)ppm
o Internal group degradation Tetramethyl 7ran.

Examples 12-14 Preparation of 6β-halopeninolanic acid - a) Acetic acid containing pure 6β-halo compound obtained after separation from the corresponding 6α-epimer by dry column chromatography on Nori gel (similar to Example I) The ethyl solution is concentrated under reduced pressure, b) liberated from the aqueous solution of the corresponding potassium salt under a layer of ether or ethyl acetate at pH 3, followed by separation of the child layer, dried and ether-
By crystallizing from diisopropyl ether or acid-resistant ethylhexane, crystalline 6β halopenine lanoic acid represented by formula 1, where X is as shown in Table 3, is obtained.

Table 3 The above acids decomposed at about 80-100°C, so no definite melting point could be determined.

Example 15 Production of sodium 6β-bromobeny7lanate-A 6.
Production of tetrabutylammonium 6-dipromopeninolanoate - Tetrabutylammonium hydrogen sulfate 34 @ (01 mol)
100 sO of methylene chloride in a solution of 50 Ilρ of water.

Subsequently, 2N sodium hydroxide 501117 was added. Add 6.6-bromopeninolanoic acid 36 to the mixture with stirring.
y (0.1 mol) was added and adjusted to p1170 with 2N sodium hydroxide J1. The organic layer was separated and the aqueous phase was re-extracted with methylene chloride (50 R). After the organic phases were combined and dried, 500 m (I) of ethyl acetate was added and the solution was concentrated under reduced pressure to approximately 300 mσ. ]child.

8.6β ~ Production of sodium bromobeninolanate - Add polarit 2 to the solution of tetrabutylammonium 6-dibromobenifuranate above.
4. J (0.1 mol) was added in one portion with stirring. 3
After 0 minutes, reduce the temperature of the mixture to 45-50°C.
After that, the temperature dropped.

After leaving it for a while, add 300g of solution (!
The mixture was diluted with water, 300 nρ of water was added, and the pH was adjusted to 3 with hydrochloric acid. f] Machine t[l was separated and washed with water.No. 50m+ of fresh water! Add to the scraping layer, add carbonated water, +; → Triuno aqueous solution 1) Change 11 to 68 and no. Separate the aqueous layer and reduce the water 1. iE'F with 11 butanol and 1(in)(
The solution was removed evaporatively to obtain a 65:25:101-4 crystalline mixture of potassium salt of mopeninolanoic acid (iβ) )child.

Ether layer 1 from aqueous solution of salt, pH 3 (S hydrochloric acid)
The free acid was liberated in d, and the resulting mixture was separated by column talomadography in the same manner as in Example 1, and 0.5 M
Crystalline sodium 6β-promopeninolate is obtained by forming a salt with sodium bicarbonate and removing water azeotropically with I-hibutanol. 1αl;=+26(io(
c=0.5, l lvl phosphate buffer, ptl7).

Elemental analysis, Cs H9B r N Na O3S, calculated value C13180%; l-1,3,00%:
Br, 26.45%.

N, 4.64%; S, 10.61%, actual value C,
31,,85%.

11, 3.04%; Br, 26.53%, N,
4.56%, 5.1072%.

Example I6 Preparation of 6β-promobeninolanic acid - Potassium 6,6-dipromobeninolate 11.919 (
114 g (30 mmol) of sodium borohydride was added to a suspension of 30 nQ (30 mmol) of trimethylformamide with stirring.
mmol) was added. During about 30 minutes, the temperature of the reaction mixture increased to about 50°C. Ta. After that, the temperature dropped to room temperature. After stirring at room temperature for 20 hours, 100 mC of water and 100 iQ of ether were added, and the mixture was diluted with dilute hydrochloric acid.
Adjusted 1 to 3. Separate the organic layer and dilute the aqueous layer with ether 2
Extracted with 5mQ. Combine the n extracts and add 25ti (I) of water.
I washed it. Add 25+ fresh water (!) to the organic layer, add i1 sodium bicarbonate while stirring, and reduce the ptl of the aqueous phase.
was adjusted to 7. The aqueous layer was separated, and the water was co-distilled off with n-butanol under reduced pressure ()β and 6α-
A crystalline mixture of potassium promopeninolate J was obtained.

The ratio between the two was approximately 55.45 according to N~11 man-hour tli.

1. Dissolve Kariuno and salt in water (5TIσ/W salt),
Under the acetic acid (5 u/g salt) layer, 4N hydrochloric acid was added to adjust the pH of the aqueous phase to 3. Separate the ladle layer,
After washing with water and drying, the mixture was diluted with an equal volume of hexadiene.

Add seed crystals to the resulting solution and reduce the pressure to 1/2! Concentration to 1 ml gave crystallized 16β-b(J mopeninolanoic acid).

This was collected by filtration, washed with J acetate and Tyl\Kirin (11), and then dried. Ether Recrystallized from neunobrovir ether to obtain a pure product.

Eαl;=1268° (c=-0,5, ClIC93)
.

Elemental analysis, Cs1l+nL3rNOsS as 1. ! f
H value c, 34.3Q%, Il, 3.6G%, Br
, 2P, , 53%, N, 500%; 3.11.45
%, actual value C, 34,47%, 11.381%: D
r, 28.66%, N, 4.99%: S, 1
1.43%.

Example 17 Preparation of 6β-promopeninelananoic acid - Preparation of Δ 6β-promopeninelanic acid zinc [nohexylammonium° - 6,6-dipromopeninelanolanic acid 10.89 (30 mmol) disster sulfoquinoto 75 shoulders ρ 21 g of sodium noanoborohydride (90% purity) was added to the solution and the mixture was stirred until a clear solution was obtained (approximately 30 minutes). After standing for 72 hours, the mixture was diluted with 7511μ of water to remove unreacted starting material from 7methylsulfoquinoto solvate (C
sH9Br2NO3S-02HaO3)
Ta. Pass the crystals through, wash with water, and dry. The filtrate was extracted with methylene chloride (4×25 mθ), the extracts were combined, washed with 50 mQ of water, and dried with sulfuric acid + thorium.
It was reduced to about half its volume under reduced pressure. After adding 2,5 i(v) of nonochlorohexylamine and 50 ml of hyacetone, the mixture was further condensed to approximately 25 mQ. After being rubbed to induce crystals and left at room temperature for 1 hour,
Pure 6β nonchlorohexylammonium bromobenifuranoate was collected by filtration, washed with acetone, and dried. The mixture shows a clear melting point, after turning black at about 170 °C, 28
Decomposed at 0-290°C.

Production of H,6β-bromobenyllanic acid -6β-bromobenyl7rananic acid
'1 acid'-1-l Water (1:1) (20z0/y salt) Add 4N hydrochloric acid to the suspension with stirring to adjust the pH to 3931
It was knotted. After filtering off the precipitated Nnotaroammonium chloride [Jsu1-], 9 layers were separated, washed twice with water, and dried.

The same volume of hegysan was added and then concentrated under reduced pressure F to give the same crystalline pure 6β-promopeninolanoic acid as obtained in Examples 12 and 16 ('J/g).

Example 18 Production of sodium 6β-iodobeny7lanate A 6,6
- Preparation of small phosphorus salt of diyotobeninolanoic acid - 2,5 M IJli nitric acid was added to a solution of 110 f/(approximately 0.5 mol) of 6-amizupeninolanoic acid in a mixture of 4001 mQ of 5N sulfuric acid and 1500 mQ of methylene chloride at 0°C with stirring. 340 ml of aqueous sodium chloride solution and 1000 ml of a 0.5 M iodine solution in methanol were simultaneously added dropwise. After the addition, the cooling bath was removed and the mixture was stirred for 1 hour and continued.
Ta. Separate the 1-1° phase, and add the aqueous phase to 200% methylene chloride.
i1! Extracted with. Combine the extracts and add 600 JIl of IM sodium diosulfate aqueous solution! and dried over sodium sulfate. After adding 32.0 mC0375 mol of morpholino, the resulting solution was heated to 200-250 mρ under reduced pressure.
The mixture was concentrated to 100% and cooled to give the title compound as colorless crystals, which were collected, washed with acetone, and then dried. Yield 162.61i.

Melting point 152-154°C (decomposed).

Elemental analysis, C+tH1sl, l”J, 04S,
Calculated values C, 26, 68%, H, 3, 36%, l,
46.99%, N.

5.19%+S', 5.94%, actual value C, 27
,01%, 11°344%: 1.46.70%; N
, 5111%, S, 5.64% 013.6 Preparation of β-iodobenylananic acid morpho-1J salt 54 g (
0.1 mol) of methylene chloride 500uf! Cedyl tristellammonium boranate 369 (0.12 mol) was added to the solution while stirring in the absence of light.

After stirring at room temperature for 15 minutes, the mixture was evaporated to vacuum F. The residue was treated with 250 μl of acetone, the insoluble salts were filtered off, and the filtrate was evaporated to dryness. The oily residue was dissolved in ethyl acetate 2
00 Il (dissolved in 1 l), added 200 z of water (with stirring, added 2N hydroxide, and dissolved 1111 l of the aqueous phase).
Adjust the water to 7, separate the human-0 water layer, and add the white water layer to 50Rρ of water.
The pH of the combined aqueous phases was adjusted with ether 200mQ layer 1.
・UAI section was adjusted to 3 by adding m hydrochloric acid. The organic phase was separated, the aqueous phase was re-extracted by chilling, and the ether extracts were combined, dried, and concentrated under reduced pressure of 1:1 to about 80-1001 RC. The concentrate consists of a mixture of 6β and α-yol peninolanoic acids and a small amount of peninolanoic acid (approximately 50%
40:I O), which were separated by dry chromatography as in Example 1.
child. The obtained A1 noni pure 6β-io1 acid was salted with a 0.5M aqueous solution of sulfur and lium hydrogen carbonate, and the water was distilled off azeotropically with 11-butanol to obtain crystalline sodium 6β-iotobeninolanate. .

[α': F = −+−274° (c = 0, 5.
1M phosphate buffer, pH 7).

As original moisture 1i, c, lon+ NNa03S, M+
, ) values, 27.52%, II, 2.60%, I
, 36.35%, N, 4.01%, S, 9.1
8%, actual value. C, 27,31%, H, 2,64%, l
, 36.12%, N, 3.92%: S, 9.34%.

Example 19 Production of 6β-iodobeny7lananic acid - A Production of 6,6-noyotopenynolanic acid trimethylsulfokite solvate - 6,6-noyotopenynolanic acid morpholino salt IO,8y
(20 mmol) of Tsumedel Sulfokit 20 mQ cold solution was added with 20 ml of IN hydrochloric acid and rubbed to initiate crystallization.Additionally, 20 mρ of water was added, the crystals were collected by filtration, washed with water, and dried to almost Quantitatively, the title compound was obtained, which showed indefinite melting and decomposed above 120-125°C.

Elemental analysis, C8H, 12NO3S, C2H, O5, old value C, 22, 61%, l-1, 2, 85%,
l, 47.78%; N, 2.64%; S
, 12.07%, actual value 0.2296%, H,2
,81%, l, 47.64%, N, 2.74%
, 8°1214%.

■3.Production of 6β-iotopeninelananic acid nonchlorhexa/ruammonium- ()16-diyotobenolanic acid dister sulfoquino I
・Noanoboron hydride → 1 in dimethylsulfo/l ・25Q solution of solvate 5.31 LI (l O mmol)
-Rium 079 (90% purity) was added and the mixture was stirred until a clear solution was formed (approximately 30 minutes).

After standing at room temperature for 40 hours, <5 omg of A was added and the mixture was cooled to 5° C. to precipitate unreacted starting material. The precipitate was collected, washed with water, and dried. li! The liquid was extracted with Medilenochloride (3 x 25 IIC), the extracts were combined and diluted with water (2
After washing with XIOmρ), it was dried with l1IC acid gotol, reduced to 1.0 depth under reduced pressure. After that, crystallization started. After standing for 1 hour, pure ()β-iotopeninelanic acid non-chloroheginol ammonium was filtered, washed with acetone, and dried. The melting point of the compound is not clear and is approximately 1
After turning black at 50"C, it gradually decomposed above this temperature.

Production of C6β-iodopeninolanoic acid In Example 1713, dinochlorohexylammonium 6β-iodopeninolanoate was used in place of the corresponding 6β-promobeninolate to obtain colorless crystalline 6β-iodopeninolanoic acid. A pure product is obtained by recrystallization from chirnoisopropyl ether. [α]2°−→ 2
78° (c=0.5, CHCp 3).

Elemental analysis, C, H,. Eyes 0. As S, old value C2
29,37%, I-1,3,08%; I, 38
．． 79%, N, 428%, S, 9.80%, actual value C, 29,46%, 1-1.313%: 1, 38
．． 96%, N, 4.27%, S, 9.81%.

Example 20 Production of pivaloyl ocytumedel 6β-promopeninolanate - 8 Production of pivaloyl subquinoster 6,6-dipromopeninolanate - 6,6-nopromoveninola/potassium acid 2.5.969 (
15 mmol) of Tumedel 71; Lumamimil” 30
= chloromethyl pivalate 2.22 times Q (1
5 mmol) was added and the mixture was stirred at room temperature for 16 hours. After diluting with 120 iij of ethyl acetate, the mixture was diluted with water (
It was washed with 4×30×ρ), dried, decolorized by stirring with charcoal and then evaporated to dryness to give the desired compound as a yellow Al+. This was crystallized from ether-hegysan. Melting point: 101-102°C.

136β-B "Preparation of bivaloyl oginstel nomopeninolanoic acid - 6,6-dibu
849 (90% purity) was added and the mixture was stirred in the dark at room temperature for 24 hours. After adding 75 mQ of water, the mixture was extracted with ethyl (1 x 25 iθ).

The extracts were combined, diluted with 6 L of water (3×25 μ), dried, and concentrated under reduced pressure to a concentration of about 20 μ. The concentrate was applied to a Norical column chromatography in the same order as in Example 9C to separate the 6[beta]-[J mole compound from unreacted starting material. Combine the two parts containing the more polar 6β-bromoester and reduce +1:
1: No evaporation. The ura-like residue M was crystallized from ether-noisopropyl ether to obtain pivaloyl 1-quinomethyl 6β-bu[Jmobeni7ranate.

Melting point 66-68°C. Same as the one obtained in Example 7.

Examples 21-23 Preparation of inorganic base salts of 6β-halopeninolanic acid - A knee-chill solution of 6β-halopeninolanic acid was treated with an equal volume of salt-turbid aqueous solution, then the aqueous phase was separated and lyophilized to give a colorless powder. In the formula 1, x, Z, and n are as shown in Table 4. ] was obtained.

Table 4 Example 24 Manufacture of tablets - Ingredients per tablet: 6β-iotobenino, lanonic acid sodium salt 250 ffli, microcrystalline cellulose + 10q1 h] loquinopropyl cellulose 5 miI, alkino acid 10 mg, talc 23 uii, stearic acid Maci・Noum 2ml? , total 400 mg.

The active ingredient and microcrystalline cellulose were mixed and granulated with 10% ink of human [J chinopropyl cellulose] in panol solution, dried at 40"C and passed through a 1 mm sieve.Alkynic acid, talc and stearic acid. Add makufunoum,
400η per mixture? It was compressed into tablets. This was coated with a coating of hydroquinopropyl methylcellulose to obtain tablets.

Example 25 Manufacture of tablets - Ingredients per tablet: 6β-b(J Moveninola/Acidus I
Lium salt 250mg, microcrystalline cellulose 110J19,
Hydroquinopropylcellulose 5R9, Alkynoic acid 10
So, gluta 23m stearic acid mataneno rshi),
2d, 4 0 0 yi 6° Tablets containing ζ (iβ-promopeninolanoic acid, i, riuno, l! A) were obtained in the same manner as in Example 24.

Example 26 J1 IJ injection, Preparation of agent) 2 Ingredients per vial: 6β-iodopenine lanic acid]
・Ryuuno, salt 125-7° Sterilized crystalline component is filled into a sterile vial, 1 piece per piece.
Sealed no. Eye Y1. After the first injection, 2 m0 of sterile physiological saline was added to the contents of the vial.

Example 27 Preparation of parenteral dosage form - Ingredient I per vial: 125 mg of 6β-bu [1 mopeninolanic acid sthorium salt].

Parenteral administration using the above active ingredient and treatment in the same manner as in Example 26! Agent J was obtained.

Example 28 Production of capsules 1 capsule 46β-iodopenine lanic acid potassium salt 125 mg, hydroquinopropylcellulose 3
mg, talc 6 mg, macanenium stearate l m
g, total 135ffll.

The active ingredient was granulated with an isopropanol solution of hydroquinopropylcellulose, dried at 40°C, and
passed through a sieve. Talc and magnesium stearate were added, and each component was thoroughly mixed. The resulting mixture was filled into 135 J19 capsules per No. 3 hard geladine capsule.

Example 29 Manufacture of tablets - Ingredients per tablet: 6β-iothobenine sodium lanate salt 125 m Kai Anovinolino 25 Or+y, Corn Star Def 5 mg, hydroxypropyl cellulose 10 scraps? , Alkynoic acid 10mg, Talc 201, Macnenoum stearate 5mg, combined jl1195 T:gc Among the above ingredients, the active ingredient and corn starch were mixed, and 10% of H.I. Roquinbrovil cellulose ('40 °C and passed through an I'm sieve. Alginic acid, talc and squaric acid were added and the mixture was compressed into 495 m!7 tablets. The tablets are made by coating with Kino rJ Bill Cell C7-su film.

Example 30 Manufacture of tablets - Ingredients per tablet: 6β-b [Jmobeninolanate potassium fM! 25R Gai Ampinolino 250 ~, cornstarch 75 o'clock, h) Lokinobu [l Bircel [) - SlO+
ag, alkino acid 10mg, gluta 20g, stearinoic acid Macunium 5m7, combined Wl' 495mg.

Using the ingredients listed above, the treatment was carried out in the same manner as in Example 29 (5) to obtain tablets containing 6β-bu (J mopenine lanic acid potassium salt and ampinoline) as active ingredients.

Example 31 Manufacture of tablets Ingredients per tablet: 200 TRy of 6β-iothobeninolanic acid potassium salt, 250 bibuampinoline (free basis)
tli, Conostade+00111@, Human [J King [l Vircel [1-su5Rg, Methylcell [J-su5
mg, alginic acid 15ml? , Talc 20m? , macnesium stearate 5 mg, aiguchi 6 (] Omg.

Among the above ingredients, 6β-iodopenylinolanoic acid potassium salt and half of corn starch were mixed, and human [noquinbrovir cellulose 10% isobutylene] was granulated with 1 panol solution.
It was dried at 0°C and passed through a No. 1 sieve.

Mix the remaining cornstarch and pibanvinlino, make granules with a paste of methylcellulose and water, dry at 50°C, and pass through a 11 tube through a 7 mm diameter tube. Both granules were mixed with alkino acid, talc OJ, histearic acid Macui, and Noum, and the mixture was made into 111600i@ tablets and coated with human quinomethylbu[l vircel[)-su film]. , Take the tablet.

Example 32 Manufacture of tablets - Ingredients per tablet: 150 mg of 6β-bu[lmoveninolanoic acid sodium salt, 25 mg of bibuambinolino (free base)]
0ay, cornstarch 100air, hydroxypropyl cellulose 5J1g, alginic acid 15iy, talc 20m? , magnesium stearate 5Rg, total 550 m9
.

4. Using the same ingredients as in Example 31 (・■), a nail agent containing 6β-promobeninofunoic acid salt 11 salt and bibuanovinolin (allltu people) as active ingredients was obtained. .

Example 33 Manufacture of tablets - 1 batch of tablets! 1 component 6β yo) Beni/sodium lanate J3 salt 125 sin, ampinoline 2 5 (I h
t Kaikonostadji8 (] brg, human [l chinozo [l vircell (1-suIOzy, alginic acid 10y+y
, talc 20η9, Ste)' Macunium phosphate 5 sins,
Combined A150 0 R@.

1- Mixing the active ingredient and cornstarch (7, human [J
Kinozo[l] Bircel[l] 10% Isopropanol solution-C granulate, dry at 40°C, and pass through a sieve. Add the alkino acids, talc and magnesium stearate and mix the mixture into one 500iy tablet.
! in'! Tablets (7) Take this tablet for human use.

Example 34 Manufacture of tablets - Ingredients per tablet: 6β-bu[l] mopeninolanoic acid potassium salt 125 mg, ampinoline 250 mg, corn starch 80 m? , 10 places of hydrogin propylcellulose?
, Alkynoic acid 10m9, Talc 20m9, Macunium stearate 5m9, total 500ig.

The above components were treated in the same manner as in Example 33, and 14
4° tablets were obtained.

Example; 35 Manufacture of tablets - Ingredients per tablet 6β-iotopenine lanic acid potassium salt 12F1+41, cephalequinone 250z@, corn starch 80 mg, human quinop [l pyrucellulose I]
Omg, alkyl/acid 10d1 talc 20 starvation Macnenoum stearate 5mg, combined it' 500 mkai The above ingredients were treated in the same manner as in Example 33, and the active ingredients were potassium 6β-iotopeninolanate J, salt and cephalequinone. Tablets containing the following were obtained.

Example 36 Manufacture of tablets - 1 tablet (1 household) Ingredients: 6β B (1mobeninolanic acid citric acid 13 salt 125y+y, Cefac [J-ru 250z)
y, cornstarch 80mg, human [J gimp [1 birsel [+-sl tlig], alginic acid 10uy, talc 20m? , Magnene Uno Stearate, 5+ag, total 500 mg.

- The ingredients listed above were treated in the same manner as in Example 33 to obtain tablets containing 6β mopeninolanic acid sodium salt and cefac as active ingredients.

Example 37 Manufacture of bilayer tablets containing 6β-iotopeninolanoic acid thorium salt/pibmenolinum hydrochloride - Manufacture of granules ■ - Ingredients per tablet: 6β-iotopeninolanoic acid sodium salt 100 mg, human [J Kinopropyl cell [I] -S2
mg, dicalcium phosphate dihydrate 86m9, starch glycolate l(]my, magnesium stearate 2m?.

The above 6β-iodopenine lanoic acid thorium salt was granulated with an isopropanol solution of hydroxypropyl cellulose, dried at 40° C., and passed through a 0.75 mm sieve. Dicalcium phosphate dihydrate, starch glycolate, and magnesium stearinoate were mixed into the granules.

Production of Granules 11 - Ingredients per tablet: 100 mg of pivmenolinum hydrochloride,
Hydroquinopropylcellulose 2mg, Microcrystalline cellulose 50119, Macnenoum stearate 1.5+++
9. Talc 3.5 mg.

Pivmenolinum hydrochloride was granulated with a solution of hydroquinopropylcellulose and dried at 40°C, and 075R1! passed through a sieve. Mix this granule with microcrystalline cellulose, magnesium stearate, and talc.

The above granules +200R9 as the bottom layer, granules ++1571g
A two-layered granule containing hydroxypropyl methyl cellulose as an upper layer was molded and coated with a solution of hydroxypropylmethylcellulose in ethanol-water (l 1) to obtain a two-layer tablet.

Example: 38 Manufacture of two-layer tablet containing 6β-promobeninolanic acid sodium salt/pivanobinoline with salt - Manufacture of granules I - Ingredients per tablet: 6β-promobeninolanic acid (sodium salt), lithium salt 100 mg, polyvinylpyrrolidone 5m9, Dicalcium phosphate aqua regia hydrate 85mg, starch glycolate 8IIg, stearate magnenowl,
2mg.

6β-Bromopenicillanic acid sodium salt was granulated with a solution of polyvinylpyrrolidone in isopropanol, dried at 40°C, and passed through a 075H sieve.

This was mixed with di-carnout phosphate hydrate, statriglycolate and macanenium stearate.

Manufacture of Granules II - Ingredients per tablet: 125 mg of Pibuanbinlin base
, starch 30mg, hydroquinopropyl cellulose 3
, 5 rig, Magnesium Stearate 15 mg.

Bivampinphosphorus base and 10 mg of starch were mixed, granulated with a deionized water solution of hydroxypropylcellulose, dried at 50°C, and 0.75-mI! passed through a sieve.

This was mixed with the remaining starch and magnesium stearate.

The above granules! 200iy as the bottom layer, 60mg of granules
Granules consisting of two layers containing as an upper layer were molded and coated with a solution of hydroxypropyl methylcellulose in deionized water and ethanol (11) to obtain two-layer tablets.

Example 39 Manufacture of bilayer tablets containing 6β-bromobenynolanic acid salt/amoginonoline - Manufacture of granules 1 Ingredients per tablet: 6β-bromobeny7ranic acid sodium salt 1100 u, polyvinylpyrrolidone 7vrg, lactose 50mg, dioxide Silicon 1.5119, Magnesium stearinoate l, 5 mg.

6β-Bromopenicillanic acid sodium salt was granulated with an isopropanol solution of polyvinylpyrrolidone, dried at 40° C., and passed through a 75R shoulder sieve.

The granules were mixed with lactose, silicon oxide, and macanenium linoate.

Production of granules 11 - Tablet 1 if! Ingredients per unit: Amoginonorin 200 m
Kai starch 30mg, polyhinyl vinyl LJ Ridone 6I! 9
, -4 silicon oxide 2TAg, stearic acid magneuno・
') rig.

Mix Amokinonorin and Stachi, and make Polyhealupi [l].
It was granulated with a deionized water solution of Lydone, dried at 50°C, and passed through a 0.7577x+ sieve. Mix this with 1 element of carbon dioxide, stearic acid, and make noni.

Upper 5 fortunes 1) By making 11 compressed tablets 4-, 1! I
F 11240 iy as the bottom layer, condyle ll71 l [i
91, J/-6 Example 40 Production of three-layer tablet containing 6β-iotopeninolanoic acid sodium salt/bibumenolinum hydrochloride/bibuanobinolino! l! Ingredients per tablet: 1001 g of 6β-iotopeninelanoic acid sodium salt, human [JGip C7 building cellulose 2]
mg, microcrystalline cellulose 50zy, starch licorate 6I! 9. Magnesium stearate 2m
g.

The 6β-iotopeninolanoic acid thorium salt was granulated with an isopropanol solution of hydroquinopropylcellulose, dried at 40°C, passed through a 075 sieve, and mixed with microcrystalline cellulose, sodium stardecrycolate, and macanenium stearate. did.

Production of Granules 11 - Ingredients per tablet: 100 mg of pivmenolinum hydrochloride;
Human [J Gynopropyl Cellulose 2q1 Microcrystalline Cellulose 50iy, Magnesium Stearate 1,5 m9
゜ Bibmenlinum hydrochloride was granulated with an isopropanol solution of hydroquinopropylcellulose and dried at 40°C.
It was passed through a 0.75 ynm sieve. The granules were mixed with microcrystalline cellulose and macanenium stearate.

Production of granules Il+ Ingredients per 1fl^J tablet Bicyanopinoline base I25
Il1g, Stade24 M9, Hydroxypropyl Cell [I-su 3.5 mg, Starch Glycolic Acid Triuno 7n9, Stearate Magnenow 1, l, 5
Mix 10 m9 of starch with m9° bicyanopinoline base, granulate it with a deionized water solution of human [1 chinopropyl cell], dry at 50°C, pass through a 0.75 am sieve, and then starch cream. The sulfuric acid powder, the remainder of the starch, and the stearic acid powder were mixed.

Add 1-1 J of the above granules for every 4 ゛ of the reduced preparation, and add granules I + 6.
0m9 as a layer in 1, granules II, +535xrg as a middle layer, and granules 111,161mg as an upper layer. - Three-layer tablets were obtained by film coating treatment with ethanol (II).

[Brief explanation of the drawing]

FIG. 1 is the NMIl spectrum of the compound prepared in Example I. Patent applicant Shisai Pharmaceutical Products Ltd., A/Nis (Lebens Chemiske Fabric Production Nosaczielskabu) Agent Patent attorney 2 people mentioned above First page Continued priority claim 6197 September 5th [phase] United Kingdom (G@
197CR-November 29 [phase] United Kingdom (G0198
February 27 [phase] United Kingdom (GB) [stock] 30819
/79 B) ■41252779 B) [Phase] 06681/80 ■Indication of the case 1982 Patent Application No.] -467 (No. 12, 2. Name of the invention, 1 penicillanic acid derivative 1 and its use 3. Amended party Limited)・A/Nis (Lebens Chemiske Fa7rique Productions Acti Selscuff) 4 Agent 5 Date of amendment order 1985] JJ 29th (shipment date)
7 Contents of amendment The following parts in the description have been amended - 4゜1 Drawing 1! j1 Simple explanation column (1) Page 75, line I, replace the text “It is a spectrum.” [
Spectrum, 1st al<1 is about 6 ppm from about 5 ppm in FIG.
It is an enlarged view of the N M It spectrum of m. ” and X + positive. that's all

Claims (1)

Claims: 1. Essentially pure formula. Compounds represented by the above, their salts and esters, and salts of their esters [wherein X represents chlorine, bromine or iodine]. ]. 2 Alkali metal'! The compound according to claim 1, which is A. 3. The compound according to claim 2, which is a potassium salt. 4. The compound according to claim 2, which is a sodium salt. 5. The compound according to claim 1, which is an alkaline earth metal salt. 6. The compound according to claim 1, which is in a crystalline form. The compound according to claim 3, which is potassium 7.6β-bromobenyptalanate. The compound according to claim 3, which is potassium 86β-chlorobeninolanoate. 3. The compound according to claim 3, which is potassium 96β-iotobenine lanate. 10. The compound according to claim 4, which is sodium 6β-promobenine lanate. 11. The compound according to claim 4, which is sodium 6β-chlorobenyptalanate. 5. The compound according to claim 4, which is sodium 126β-iothobenine lanate. 13. The compound according to claim 1, which is an alkanoyloxyalkyl or alkinocarbonyloxyalkyl ester. 14.6 The compound according to claim 13, which is pivaloyl 14.6-promopenine lanate. 156. The compound according to claim 13, which is bihaloyloxymedyl 156β-CI Cl penynolanate. The compound according to claim 13, which is pivaloyl diquinomedyl 166β-io1-peninlanoate. The compound according to claim 1, which is +7.6β-iotopeninolanic acid. The compound according to claim 6, which is 186β-iothopeninolanic acid. 19. The compound according to claim 6, which is 6β-promopeninolanoic acid. 206 β-Chlorobeninolanic acid (compound according to claim 1). 21 Compound shown as an active ingredient, a pharmacologically acceptable salt or ester thereof, or a salt of an ester thereof 0025-2.5 g
1 dosage intermediate form pharmacological preparation for the treatment of infectious disease mimics (including animals) comprising, if necessary, a pharmacologically acceptable carrier and/or adjuvant, where X is chlorine, bromine or iodine. Show the basics 4~. ]. 22. A pharmaceutical dosage unit form according to claim 21 containing 0.1-1.0 g of active ingredient. 23. The pharmaceutical preparation in dosage unit form according to claim 21, which contains an alkali metal salt of the compound as an active ingredient. 24. An intermediate-dosage pharmacological preparation according to claim 21, which contains as an active ingredient a β-lactam antibiotic containing the basal group of said compound or its salt with bucc nodolac. 25. The pharmaceutical preparation in dosage unit form according to any one of claims 21 to 24, which is a tablet, pill, capsule, or suspension. A compound represented by formula 26, a salt or ester thereof, preferably a salt of the ester together with a carrier and/or an adjuvant,
A pharmaceutical composition containing 1 to 95% of the active ingredient [wherein X represents chlorine, bromine or iodine, 1-o]. 27, one or more β-lactam antibiotics or prodrugs thereof together with the compound at Amane ratio 1.10
-IO:I, preferably 13-31. 28 A claim in which the active ingredient is an alkali metal salt of said compound and a β-lactam antibiotic selected from the group consisting of known peninolines, cephalosporins, substituted 6β-aminopenine lanic acid and protorogs thereof. The pharmaceutical composition according to item 27. 29. The pharmaceutical composition of claim 28, wherein the β-lactam antibiotic is selected from the group consisting of ampinolino, amoxicillin, cephalequinone, cefaclor, menolinum, and protorogs thereof.