JPS61200994A - 3-pyridinium methylcephem derivative - Google Patents

Abstract

NEW MATERIAL:(6R,7R)-7-Amino-3-(1-pyridinium methyl)-3-cephem-4-carboxylate borofluorate. USE:An intermediate for synthesizing cephalosporin antibiotic, having improved crystallinity, stability and improved reactivity at 7-position. PREPARATION:A neutral aqueous solution of (6R, 7R)-7-amino-3-(1-pyridinium methyl)-3-cephem-4-carboxylate is blended with preferably >=twice molar amounts of an aqueous solution (42wt% concentration) of borofluorate and then with preferably >=20 times as much as isopropyl alcohol by weight and the aimed substance is crystallized, or a hydrgen-chloride of the starting substance is dissolved in preferably 1-10 times water by weight and the same treatment is performed to crystallize the aimed substance.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel synthetic intermediate for cephalosporin antibiotics.

(Prior art) (6R,7R)-7-amino-3-(1-pyridiniummethyl)-3-cephem-4-calcexylene-1(1)
d is an important sweet acid intermediate, and its salts include, for example, dihydrochloride, dihydrochloride/dihydrate, and perchlorate in JP-A-56-12397; In Japanese Patent Publication No. 60-13793, -hydrochloride, -hydrate, etc. are known.

However, when producing cephalosporin antibiotics from these salts, Otsuki's reagent is required for neutralization, dehydration, and 7-position acylation of the salts, and the stability and reactivity of the salts may be affected. In some cases, the results were insufficient, and satisfactory results were not always obtained.

As a result of intensive studies to overcome the above-mentioned drawbacks, the inventors of the present invention have completed 4: Invention.

(6R,7R)-'/-amino-3-, which is uninvented, has excellent crystallinity, is stable, and has good reactivity at the 7-position.
(t-pyridinium methyl)-3-cephem-4-carboxylate -hydroborocytolate anhydride The compounds of the present invention may be prepared by any of the following methods: however, these themselves form another aspect of the invention.

(6R,7R)-7-amino-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate fI) by adding an excess aqueous solution of borohydrocranic acid, Then add inpropyl alcohol,
or (B) by a method comprising dissolving the hydrochloride salts of compound (I) in water, adding an excess of an aqueous solution of hydroboronic acid, then adding inpropyl alcohol, and crystallizing. Manufactured.

A commercially available 42% aqueous boroborohydric acid aqueous solution used in the above methods (Al and (B)) is sufficient, and can be used as it is or after being further diluted with water.

Such borosilicate water t, eI! The usability of the aqueous solution is sufficient if the mole is equal to or more than that of the compound I), but preferably 2
The amount of isopropyl alcohol to be used is not particularly limited, but is preferably 20 parts or more per liter of compound fI) 111i.

The amount of water used in the above method (B) is
The amount is not particularly limited as long as it dissolves the hydrochloride salts, and 1 to 10 times is usually suitable.

In the above methods CAJ and FB), crystallization occurs rapidly by adding an organic solvent or isopropyl alcohol. In this way, the precipitate is stored at room temperature or under cooling.
By filtration, the desired product can be obtained in high yield and with high purity (effects of the invention) The fluoroboric acid salt of the present invention is an extremely stable chemical compound. For example, this compound is heated at 60°C under close contact with a glass.
- Even after weeks of abuse, no decrease in content is observed.
However, the dihydrochloride described in JP-A-56-12397 almost decomposed under the same conditions.

The monoborohydroctate of the present invention is used as an intermediate in the production of cephalosporin antibiotics.

For example, -hydroborofluoride of compound <I) is a compound represented by the formula (wherein, R2 and R3Fi are the same or different and represent a hydrogen atom or a hydroxide group, and R4 represents a hydrogen atom or an alkali metal group) or The compound described in JP-A-58-174386 is prepared by reacting it with a corresponding acylating agent and subsequently removing the protective group if necessary.

Next, the present invention will be explained in detail with reference to Examples and Reference Examples.

Example 1 (a) 7β-CD-5-(inbutyloxycarbonyl)amino-5-carboxybarrel 7mi)')-3-(1
-pyridiniummethyl)-3-cepheme-4-carboxylic acid monosodium salt nia β-(D-5-(inbutyloxycarbonyl)amino-5-calgeki7noZ-relamide]-3-acetoxymethyl-3-cepheme To 35.4 g of -4-carboxylate were added water IS, 11.1 N of pyridine, 5.76 g of sodium hydrogen carbonate, and 51.4 g of sodium iocide, and the mixture was stirred for 5 hours on a 60°C water bath. Keep at the same temperature and acetone 60
117 to dissolve the reaction mixture, acetone 4.51
Pressure was applied. The precipitate was collected, washed with acetone, and dried under reduced pressure to obtain 41.1 g of the title compound.

This crude*Jtog was mixed with Diaion 5P-207 (
The mixture was subjected to column chromatography (manufactured by Mitsubishi Kasei), eluted with a water-acetonitrile mixture, and the main compartment was concentrated under reduced pressure. The residue was dissolved in a small amount of water and pressed into acetone 22 to give the title compound 4.
．． 9g was obtained.

'H-NMR(-DzO) 1.6~ZO(4H, rob r, -(C)!d,
-CHx-CONH-) 5.49 (2H, AB fathom, J=14.0Hz, cH at the 3rd position of the cephem ring,)N72 (IH, d, J=5.0
Hz, H at position 7 of cephem ring) m15 (zH, t, s
-7,01 (Z, viridi/a, H at s position) [24 (IH
, t, J-7,0Hz, H at position 4 of pyridine)9.
02 (2H, d, J-7,0Hz, pyridine 2.6
H) (b) (6R,7R)-7-amino-3
-(!-Pyridinicum methyl)-3-cephem-4-carloxylate--borohydrocytolate nia-β-CD-5-(inbutyloxycartyl)amino-5-carl Xyparel 7mi)')-3-(1-Hiry)niummethyl)-3-cephem-4-carboxylic acid monosodium salt 4.9g and dichloromethane 70*/N
1 and 5 g'17 of trimethylchlorosilane were added to 9.5 g of N-dimethylaniline, and the mixture was stirred at 30 to 34° C. for 1 hour. Then, it was cooled to -30°C and 6.1% of phosphorus pentachloride was added.
g and stirred at -25°C for 1 hour. Add this solution to 35
It was added to a mixture of 12 g of 1°3-buta/diol and 90 d of dichloromethane cooled to 1°C while maintaining the temperature at -30°C, and the temperature was raised at O''tit over 1 hour.The precipitate was collected by filtration.
Washed with dichloromethane. The obtained wet body is dissolved in 16M1 of a 14% aqueous fluoroboric acid solution at room temperature. Next, the mixture was cooled to 5°C, and an inopropyl alcohol bowl was slowly added dropwise. The precipitate was collected by filtration, washed with isopropyl alcohol, and dried over phosphorus pentoxide under reduced pressure overnight at room temperature to obtain 2.35 g of the title compound. λ50 (2H, AB@, J=1&OHz, Cephem42
C1 (,) Fs, 05 (IH, d, J=S, O
Hz, H at position 6 of cephem ring) 5.36 (II(, d,
J=5.0Hz, Cephem 337th H) m54 (
2H, AB! , J=140Hz, 3rd place C!
! ,)N16 (2H,t, J=7.0Hz, H at position 45 of pyridine)N65 (IH,t, J=7.0Hz
, H at position 4 of pyridine) 9.01 (2H, d, J =
7.0Hz, l:#H at the 2.6th position of lysine) IR (KB
r) 3400, 3100.1780.1630.1490.
14B0.1410.1340°1280.1060.
. -l Moisture content 1.2% (Karl Fischer moisture vaporization method)
CI3f (+4 N5O3S BF4-1-1,2 Calculated value as water C40,69, Hλ81. N10.9
5. Fl9.80. vdk O$6 1st straight α C40, 37, H3J9. N10.82. Fl m
59. -〇When this product was dried under reduced pressure at 50°C for 5 hours, the moisture content was 0.6% (Karl Fischer moisture vaporization method), and the melting point was 190-200° (br, deeompd).
) According to differential thermal analysis, the ice crystals are only diffracted at 190-200℃ as shown in Table 1 below! It showed ￥f characteristics.

Table 1 17.68 rn 153 vw1
1L8s vv 139 m7
．． 76 m m1
1 yd7.38 w 1
04 m6.01 w 193
vva41s λ81
Wd462s 171yd4
．． 53 md 158 w4.
40s m5
2 v4.04 m
141 v&87
vs 136 vw168
vw m29 vwd
(However, 3 in the table means [strong J, m means [moderate J, w means "weak J," v means "very," and d means "diffuse.") Implementation World 12 (a) 7β-(D-5-(Phenoxycarzenyl)amino-5-calgexi/2leramide]-3-(1-pyridiniummethyl)-3-cephem 1-carmenic acid monosodium salt niaβ-(D- s-(phenoxycarzenyl)amino-5
9 g of 3-7 setkin methyl-3-cephem 4-calcexylene) and 9 g of water
el and 1.4K sodium hydrogen carbonate were added to form a solution.

Then viridi 72.7*t and sodium iodide 25.
2 g was added, and the mixture was heated and stirred on a 60°C water bath for 2 hours and 40 minutes. At the same temperature, 20 Jll of acetone was added, and another 2 liters of acetone was filtered, and the precipitate was collected by filtration and washed with acetone to obtain 10.2 g of a crude product.

This crude product was mixed with Diaion 5 in the same manner as in Example 1 (1).
Chromatographic purification using P-207 yielded 6.1 g of the title compound.
H2CON! ()13~ZS (2H,br,C
H2C0NH) 3.36 (2H, AJ, J=1&OHz
, C)(,)5.21 (IH,d,
J=5.0Hz, H) at position 13.6 of cephem ring) 5.47 (2H, ARg, J=14.0Hz, Cq mushroom at position 3 of cephem ring) 5.71 (2H, d, J=5
．． 0Hz, H at position 7 of cephem ring) 7.2-7.5 (5H
,m, -oiD)8.10 (2H,t, J=7
．． 0Hz, H at position 3.5 of pyridine ring) 8.60 (I
H, t, Jw7.0Hz, pyridine term 4th H) &9
7 (2H, d, J=7.0Hz, pyridine 2,6
H) (b) <6rt, 7R) -7-amino-3-(1-pyri-cniummethyl)-3-cephem-
4-carboxylate -hydroborofluoride nia β-(D-5-(phenoxycargenyl)amino-5
-calgexi, l-relamide)-3-(1-e+)-)
715 ml of dichlormeth, N
, 72-66w1 of N-dimethylanili, and 2.65% of trimethylchlorosilane were added, stirred at room temperature for 1 hour, and then the clear yellow reaction solution was cooled to -30°C, 219g of phosphorus pentachloride was added, and the mixture was heated to -30~30°C. Stir at -25°C for 1 hour. This reaction solution was added to a mixture of 3.2 g of 1.3-butane fall and 20 d of dichloromethane cooled to 40°C.
Pressure was applied below 0°C, and the temperature was raised to 0°C over one hour. Add 7.51 L of 42-thioboric acid aqueous solution to the reaction mixture.
is added, the precipitate is stirred and dissolved, and the aqueous layer is separated. The organic layer was washed with a small amount of an aqueous solution of 42-hectonic hydrochloric acid. The aqueous layers were combined, and inopropyl alcohol Bow/ was slowly added dropwise to the mixture while cooling with water.

The precipitate was collected by filtration to obtain 0.74 g of the title compound.

Ice crystals are IR and powder XfJ! The diffraction pattern matched that of Example 1(b).

Example 3 (1) 7β-[D-5-(p-methoxylzenyl)benzamide-5-carboxylate-3-(1-pyridiniummethyl)-3-cepheme-4
-Carmenic acid monosodium salt = 7β-CD-5-(
p-Methoxycartyl)benz7mil-'-5-calcexino2leramito)-3-acetoxymethyl-3-
To 2 and 76 g of cefem-4-carmenic acid were added 15 ml of water, 4.2 g of sodium bicarbonate, pyridi:'al*/ and 37.4 g of sodium iodide, and the mixture was stirred at 60°C for 5.5 hours. The precipitate was removed and dried under reduced pressure to obtain a crude product.The crude product was subjected to activated carbon column chromatography, and water-acetonitrile? % solution @ town, main compartment Yone mark A bicompound t 7.41 g
I got it.

rL 1H-NMR(-Dlo) δ(ppM) 1.6~Z2 (4H, mbr, -(CH2)z
CH2C0NH)&11 (2H, t, J=7.0Hz
, H at position 3.5 of pyridine)8.63 (I H,t,
J=7.0Hz, H at position 4 of pyridine) &96 (2)(
, d, J=7.0H-bipyridine 46H) (bl
(6R,7R) -7-Amino-3-(l-pyridiniummethyl)-3-cephem-4-carboxylate -hydroborfluoride nia-β-CD-s-(p-methoxycarzenyl)benzamide- 5-carboxyvaleramide]-3-(1-pyridiniummethyl) 3 4% mu 4-cal 1y/eR
19.4 g of the monosodium salt was treated in the same manner as in Example 1(b) to obtain 7.6 g of the title compound.

The quartz crystal has an IR and powder X-ray diffraction pattern of Example 1 (b).
) was consistent with what was obtained.

Example 4 (a) 7β-(D-5-cyclohexylamide-5-carboxyvaleramide 3-<1-pyridiniummethyl)-3-7femu 4-cardianic acid monosodium salt nia β-(D -5-7 Chlorhecyclamide 5-carboxyvaleramide-3-acetoxymethyl-3-cephem-4-carmenic acid & 75g add 1Od of water, 4g of sodium bicarbonate, 2.71I7 of pyridine @ After dissolution, add 242g of sodium iodide. and stirred at 60°C for 3 hours.The reaction solution was separated into acetate/21. and the precipitate was collected by filtration.The obtained crude product was subjected to activated carbon column chromatography in the same manner as in Example 3 (al). Elution was carried out with 1 water and acetonitrile, and 6.6 g of the desired compound was obtained from the compartment containing the target compound.

5 H-NMR (→D20) δ (ppM) 3.4 + (zH, person B!, J = 18.0 Hz, C' H2 at the 2nd position of the cephem ring) 5.21 (II, d, J =
5.0Hz, Cephem fR6 position H) 5.50 (2H
,AB! , J==14. OHz, CH ranked 3rd in cephemyang
2) 5.69 (IH, d, J = 5.0Hz, H at the 7th position in cephemyang) 8.15 (2H, t, J = 7.0Hz
, H at position 45 of the pyridine ring) & 64 (LH, L, J=
7.0Hz, Pyridine Shin 4th H) 9.02 (2
H, d, J = 7.0 Hz, H at position 46 of pyridine ring) (
b) (6R,7R)-7-amino-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate -hydroborofluoride nia β-(D-5-cy'yohexylamide 5-ruboxinozeta-relamido-3-(X-pyridinium methyl)
-3-cephemu 4-carmenic acid monosodium salt a
5g was treated in the same manner as in Example 1(b) to obtain the title compound 18.
I got g. The IR and powder X-ray diffraction/C ratio of the crystals matched those obtained in Example 1(b).

Example 5 (8) 7β-propionylamino-3-(1-pyridiniummethyl)-3-7femu-4-cal-2-xylate niame-propionylamino-3-acetoxymethyl-3
- 7.5 wl of water to 15 g of cefem-4-carmenic acid,
Add 184 g of sodium hydrogen carbonate, 7.8 ml of pyridine and 34.2 g of sodium iodide, and heat at 60°C for 4 hours.
Stir for hours. Add 7 Y/ of water to the reaction solution, add 3 Y/ of acetone
After applying dK, 111 precipitates were collected. The obtained powder was purified by chromatography using Diaion 5P-207 to obtain the title compound I.
8g of Z was obtained.

; Le' H-NMR (ip$DMSO) δ (ppM) 0.98 (3H, L, J=&OH viscosity C small CT(,-)2
41 (2H,!, J-FtOHz, CT(scH
z −) 3.42 (2H, ABJ', J=1 'l
OHz, Cephem Tomb 2nd place C)1. )5.14 (
1 [, d, J=s, ou H at position 6 of the viscopheme ring)5.
54(2)1. AB! , J = 15.0 Hz, CI (,) a64 (IH, d, J = 5. OHE
, 77MjlI7th position H) &02 (2H,t, J
=7.0Hz, 3.5th position H) & 52[I
H, t, J = 7.0Hz, H at position 4 of pyridine) &87
(2H, d, J"7.0Hz, H at position 2.6 of pyridine) (b) (6R,yR) -7-amino-3-
02g
was treated in the same manner as in Example 1(b) to obtain 4.9 g of the title compound.
I got it. The IR and powder diffraction note patterns of the crystal were consistent with those obtained in Example 1(b).

Example 6 (a) 7β-acetylamino-3-(l-pyridiniummethyl)-3-cephem-4-carboxylate: 5.35 g of 7β-acetylamino-3-acetoxymethyl-3-cephem-4-carmenic acid Water 5 TRt.

Sodium hydrogen carbonate 1.43g, pyridine 15mk
Add 25.5 g of sodium iodide to 60℃ for 15 minutes.
Stir for an hour. The reaction solution was pressurized to A7Tone 31, one precipitated portion was taken, and 7.9 g of the obtained powder was purified by Diaion 5P-207 column chromatography in the same manner as in Example 1 (a) to obtain the title compound 4. .38g was obtained.

; Le' H-NMR (-020) δ (p pM) 1.95 (3M, S, CHJ-Co)
H turtle [6 (2H, ABf, J = 204. C at the 2nd position of the cephem ring
H, ) 5.13 (IH, d, J = 5) Tz, Sefe AJ 16th place H) 5.51 (2H, AB!, J = 1
4Hz, CH at position 3 of cephem ring, )5.64 (IH,
d, J=51(z, H at position 7 of cephem ring) &02(2
H, t, J = 8Hz, Piriji / also 5th place H) & S2 (
IH, t, J-8Hz, pyridine tomb 4th H) &87
(2H, d, J = 8Hz, H of pyridine tomb 46th) (b
) (6R,7R)-7-Amino-3-(1-pyridiniummethyl)-3-cephem-4-cal 2xylate -hydroboroptsinate Niamey-acetoxyamino-3-(1-pyridiniummethyl) )-3-cephem-4-cal 2-xylate x, <+g
was treated in the same manner as in Example 1 fb) to give the title compound 0.6
1) (obtained. The IR and powder X?s patterns of the crystal were consistent with the fc obtained in Example 1(b).

Example 7 (6R,7R)-7-amino-3-(1-pyridinillamethyl)-3-77emu 4-carboxylate-borohydrogen heptatide RR salt: (6R,7R)-7-amino- Dissolve 1.60 g of 3-(1-pyridinylmethyl)-3-cephem-4-cal 2 xylate dihydrochloride anhydride in 2 d of water,
Neutralize to pH 7 using Light IR-AS (manufactured by Rohm & Haas, USA). Filter off the resin and wash with a small amount of water. Add 42-thioboric acid aqueous solution &5 to the filtrate.
- and then add 50 t of isopropyl alcohol under water cooling. The precipitated part was collected by filtration and washed with inopropyl alcohol to obtain the title compound (197 g.
The IR and powder X-ray diffraction patterns were consistent with those obtained in ).

Example 8 (6R,7R)-7-amino-3-(1-pyridylate-hydroborofluoride: (6R,7R)-7-amino-de(1-pyridiniummethyl)-3-cephem-4 - Calxylate, dihydrochloride, anhydride isg 42 yen borohydrofluoric acid aqueous solution 6
Dissolve in 0m/3OaZK of water at ambient temperature. Next, 900 d of inopropyl alcohol was slowly added dropwise. The precipitated portion was collected by filtration, washed with inopropyl alcohol, and dried under reduced pressure.
12.1 g of the title compound was obtained.

The rR and powder X-ray diffraction pattern of the crystal matched those obtained in Example 1(b).

Example 9 (6R,7R) -7-amino-3-(1-pyridiniummethyl)-3-cephem-4-cal 2-xylate.
borohydrocytrate: (6R,,7R)-7-amino-3-(l-pyridiniummethyl)-3-cepheme-4-calcexylene-)14
An aqueous solution of 14 diborohydrocranic acid was added to the aqueous solution containing g, and the mixture was slowly added dropwise to 48-'' inopropyl alcohol under cooling with ice water. 46 g of compound ! was obtained. The IR and powder X-ray diffraction patterns of the crystals matched those obtained in run f111 (b).

[ximino]acetamide)-3-<1-pyridiny'7/
Chyl)-3-cephem-4-cal 2-xylate dihydrochloride (cy/isomer): N,N-dimethylacetamide 0.303d and phosphorus oxychloride α306d″4f: dichloromethane 0.5 under water cooling
Add dK dropwise and add Vilsmeier reagent to 1A.

2-(2-tritylaminothiazol-4-yyl)methoxyimino I vinegar #10.828r with acetonitrile &
At 3 aefC and cooled to -40' to -35°,
Add the above reagent and stir at the same temperature for 30 minutes. Next, bistrimethylsilylacetamide α was added dropwise at 732 dl-35° or less, and (6R,7R)-7-amino-3-(1-
453 g of H+)-)nium methyl)-3-cephem-4-carboxylate-hydroborofluoride α was added, and the temperature was raised to 0° C. over 1 hour. The reaction mixture was pressurized with 250 a/ml of cold water, and the precipitate was 11 ml. It was taken, washed with water, and dried to obtain 1.278 g of powder.

A mixture of 4 t/90 tise acid fi and 1.278 g of the obtained powder was dissolved at room temperature and stirred on a 40° C. water bath for 2 hours. Precipitated triphenyl carbinol t-a is removed,
The filtrate was subjected to Diaion 5P-207 column chromatography and eluted with a water-acetonitrile mixture.

The main fraction was adjusted to pH 2-3 with hydrochloric acid to obtain the title compound. n'H-NMR (-Dl 0 ) δ (p pM)

Claims (3)

[Claims] (1) (6R,7R)-7-amino-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate-hydroborfluoride. (2) Add excess hydroborofluoric acid aqueous solution to a neutral aqueous solution containing (6R,7R)-7-amino-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate, and then add isopropyl alcohol (6R,7R)-7-amino-3, characterized in that it is crystallized by adding
A method for producing -(1-pyridiniummethyl)-3-cephem-4-carboxylate-hydroborfluoride. (3) Add excess hydroborofluoric acid aqueous solution to an aqueous solution of (6R,7R)-7-amino-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate hydrochloride, and then add isopropyl alcohol. (6R,7R)-7-amino-
3-(1-pyridiniummethyl)-3-cephem-4-
Process for producing carboxylate-hydroborate.