JPS61249989A - 7-amino-3-propenylcephalosporanic acid and ester - 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] <Industrial Application Field> The present invention relates to novel cephalosporin intermediates, acid addition salts thereof and metal salts thereof ◇These compounds are used as intermediates for the production of orally active cephalosporins. It is useful for the body.

<Prior Art> U.S. Pat.
, 769°277 and 3,994.884) discloses the compound ■:ooon, but the process for its preparation involves the use of 7β
-amino-3-[(Z)-1-propen-1-yl]
There is no description of -3-cephem-4-carboxylic acid.

U.S. Patent No. 4,409,2, dated October 11, 1983.
No. 14 uses diphenylmethyl 7 in production methods 38 and 39.
- discloses a method for the preparation of compound ■: via Witzteig reaction with penzylideneamino-3-triphenylphosphoniomethylcef-3-em-4-carboxylate, but 7β-amino-3 [(Z
) -1-propen-1-yl]-3-cephem-4-
There is no description of carboxylic acids or other 3-(1-propen-1-yl)cephalosporin compounds.

U.S. Patent No. 4,110,53 dated April 29, 1978
No. 4 is particularly concerned with the production of various compounds of ■ and ■ by the Witteigh reaction.
1m! l (Example 21) Reference 0 H, O, House et al.; Journal of Organic Chemistry (Jou
r, Org, Chem,) Volume 29, No. 3327~
3333 Negative (1964) investigated the influence of solvents and additives including lithium salts on the ratio of cim- and trans-olefins produced in the Witzteich reaction using aldehydes. The present invention relates to cephalosporin intermediates having I, synthetically useful acid addition salts and metal salts thereof, and methods for their production.

OOR In compounds of formula I, the configuration of the 3-propenyl group is 2- or aim-. R is hydrogen or a conventional carboxylic acid protecting group. The expression "common carboxylic acid protecting group" refers to the type of protecting group commonly used for amino or carboxyl groups in the synthesis of cephalosporin compounds. Carboxylic acid protecting groups include aralkyl groups such as benzyl, p-methoxybenzyl, 0-nitrobenzyl, p-nitrobenzyl and hiscyphenylmethyl (benzhydryl); alkyl groups such as t-butyl; haloalkyl groups such as λ2,2
-) Likuloethyl; alkenyl group e.g. allyl, 2-
Chloroallyl; alkoxymethyl groups such as methoxymethyl, 2-(trimethylsilyl)ethyl, trimethylsilyl, tert-butyldimethylsilyl, tart-butyldiphenylsilyl, and in the literature, e.g. British Patent No. 1
, 399,086, 0% preferred carboxylic acid protecting groups are benzhydryl or t-butyl groups, which are easily removed by treatment with acid. Acid addition salts of the aforementioned substances and metal salts of substances in which R is hydrogen are also part of the invention.

The 2-1 or cia-configuration of the 3-propenyl group is the subject of the compounds of the invention. This is applicant's U.S. Patent Nos. 4 and 5.
Synthetically useful acid addition salts include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid. Included are salts of formula (2) with organic sulfonic acids such as p-toluenesulfonic acid and other acids known and used in the cephalosporin art.

Substances of formula (3) in which R is hydrogen also form metal salts. Synthetically suitable metal salts include sodium, potassium, magnesium, aluminum and zinc.

The most preferred compounds of the invention are: 1. diphenylmethyl 7β-amino-3-[(Z)-1
-propen-1-yl]-3-cephem-4-carboxylate, 2, diphenylmethyl 7β-amino-3-[(Z)-1
-propen-1-yl]-3-cephem-4-carboxylate-hydrochloride, 3, diphenylmethyl 7β-amino-3-((2)-1
-propen-1-yl]-3-cephem-4-carboxylate sulfate, 4.7β-amino-3-C(Z)-1-propene-1-
Sodium yl]-3-cephem-4-carboxylate, 5
゜ Potassium 7β-amino-34(Z)-1-propen-1-yl]-3-cephem-4-carboxylate, and 6
．． 7β-Amino-3-[(Z)-1-propen-1-ylcu-3-cephem-4-carboxylic acid.

DETAILED DESCRIPTION OF THE EMBODIMENTS In a second aspect, the present invention relates to a method for preparing a compound of formula I. Preferred production examples are shown in Reaction Schemes 1 and 2.

In Reaction Scheme 1, diphenylmethyl group is shown as a preferred carboxylic acid protecting group. It will be apparent to those skilled in the art that other carboxylic acid protecting groups well known in the art can be used.

In the Witzteig reaction of compound 2 with acetaldehyde, the addition of a suitable lithium halide, such as lithium chloride, lithium bromide or lithium iodide, increases the yield of the reaction product I[a and the isomer ratio Z/E. It was found that

This reaction is preferably carried out using 5 to 15 chemical equivalents of lithium bromide, preferably 10 equivalents.

Methylene chloride is the preferred reaction solvent, preferably containing a small proportion of a co-solvent such as dimethylformamide or isopropyl, about 1/10 to 3 parts by volume per part of methylene chloride. ℃
A range from 0°C to +25°C is suitable, with 0°C to 25°C being preferred. 1m of the Wittstein product is extracted into a suitable organic solvent such as ethyl acetate and the extract is treated with Girard's reagent T to give the dud 7-aminocef-3-em compound, la.

See Production Example 3. Then Ia was converted into trifluoroacetic acid (TFA)
7β-amino-3-[
(Z)-1-propene-1-ircu-3-cephem-4
-Acylation of Ib with p-hydroxyphenylglycine by conventional acid chloride method or activated ester method to obtain carboxylic acid (Ib, Preparation Example 7) of U.S. Pat. No. 4,520,022 orally. ■ Obtain effective wheat cephalosporin.

In the second reaction scheme, 7β-amino-3-propene-1-
Ilcephalosporin ester Ia woN-Boe
Cephalosporin is obtained.

The following abbreviations that appear in the Description of Specific Embodiments and Experimental Preparation Examples have the following meanings.

Ph=phenyl BOC= -COOC(CHs)s DCC=dicyclohexylcarbodiimide TFA=
) Rifluoroacetic acid EtOAc = ethyl acetate DMF = dimethylformamide 8 -... Production example 1 diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxy in monotochloride CH, C1, (940-) Rate hydrochloric acid! INNa (440 m) was added to a suspension of (200 f, 0.44 mol) at room temperature. mix 10
The organic layer was separated by shaking for a minute. MgS in this organic layer
O4 (75f) and benzaldehyde (519,0,
48 mol) was added and the mixture was allowed to stand at room temperature for 3 hours. The reaction mixture was filtered and the insoluble matter was removed by cn, cz snow (200-
). The combined fcP solution and washing solution nitriphenylphosphine (126f, 0.48 mol) were added. The mixture was concentrated to about 400 m under reduced pressure and allowed to stand for 4 days, and the resulting viscous oil was diluted with ethyl acetate (1 t) and triturated to separate the title compound, a pale yellow crystalline powder. This was collected by filtration and vacuum dried. Yield 3229 (96 chi)
. m, p, 185-190°C (decomposition).

IR: νKBrcm-” 1780.1720.
1630゜ax IJ■: 2"""nm (g) 260 (24100)
.

ax Production Example 2 Diphenylmethyl 7-penzylideneamino-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate chloride (3
229,0,42 mol) and 5 N NaICOs (
252fRt) was stirred vigorously for 15 minutes at room temperature. Separate the organic layer and dry with MgSO4 to about 500%
− was given # to the extreme. Acetone (1
t) to obtain a pale yellow crystalline powder, which was collected by filtration.1. m237 with melting point 195-198°C (decomposed)
t (78%) was obtained.

IR:l""r51-" 1770.1620..

ax Uv:λCH1c” nm (g) 254 (230
00), 389ax (22000).

NMR: δcDc's ppm z, s6 and 3.1
6 (2H, ABq), 5.00 (IH, d, J = 4
Hz), 5.23 (IH%d.

J=4Hz), 5.47 (IH%d, J=22Hz
), 6.95 (IH%g), 7.2-7.8 (3
0H,m), 8.55 (IH,s).

Production Example 3 Hydrochloride (hydrochloride of Ia) Anhydrous dimethylformamide (100xg) and CH!
LiBr (
Acetaldehyde (2 (ld, 360 mmol)) and diphenylmethyl 7
-penzylideneamino-3-(()liphenylphosphoranylidene)methyl)-3-cephem-4-carboxyle) ([1) (14M, 20 mmol) was added at -5<0>C. The mixture was left at -5°C to -10°C for 20 hours and then at room temperature for 5 hours. The resulting light brown solution was heated to about 100-
It was concentrated in vacuo to a volume of 200 ml and added to a two-layer solvent of ethyl acetate (400 d) and H snow 0 (400 d). The upper layer was separated and 0 silica gel (Wako Gel C-XAO, 40t) diluted with isopropyl ether (400d) was added to the mixture. The mixture was shaken for 5 minutes and filtered through a diatomaceous earth filter aid pad. Insoluble matter was washed with a mixed solvent of ethyl acetate-isopropyl ether (1/1.200 m). The combined P solution and wash solution were concentrated to a volume of approximately 400-mL. 0.
5M Girard reagent T in methanol (60mj) and acetic acid (6-) were added to the above concentrate and the mixture was stirred for 15 minutes at room temperature. The mixture was evaporated to a volume of approximately 200 m, H snow 0 (200 m), saturated NaHCOs aqueous solution (3
x 20m) and brine (20d), dried over MgSO, treated with activated carbon,
- Concentrated to -. 1N HCj in methanol (60-) was added to the concentrate at room temperature and allowed to stand for 15 minutes.

The mixture was evaporated to about 30 m
) was added to dilute it. P for precipitation? 4, p.
Drying over O.G. gave a pale yellow powder of 7.99%. A solution of the powder (7,3f) in a mixed solvent of methanol (80+d) and ethyl acetate (80m) was treated with activated carbon to give about 10
The crystalline hydrochloride of the title compound was added as seed crystals, slowly diluted with ether (80d), and stirred for 1 hour. Collect the separated crystals by filtration, p.
6. Vacuum dry on O. :1 liter (71%) of the title compound was obtained. This product tube is a mixture of isomers 2 and E for the propenyl moiety in the 3 position. (Z by HPLC
/E=9/1) (Lichrosorb
]RP-18,80qb methanol-pH 7,2 phosphate buffer, 254 nm, 1 dlwk).

IR: v KBrctm-” 2850.178
5.1725. .

m&X UR:λmaxn m (E”r 2) 287 (1
73).

EtO)l NMR: δDMSO-” ppm 1.47 (27/
IOH, dd, J=7.2Hz, =CHCH3, ci
s), 1.74 (3/10H%d, J=7Hz, =
CHCHs, trans ), 3.47 and 3,8 (
Each IH%d%J=16Hz), 5.13(IH.

d, J=4.5Hz, 6-H), 5.23(1)(
, d, J=4.5Hz, 7-H), 5.62(IH,
d-q, , T-10 and 7Hz, 3-CH=CH),
6.24 (IH, d-d.

J=10 and 2Hz, 3-CH), 6.81 (IH
,s.

CHPH), 7.35 (IOH%m%Ph H
).

Preparation Example 4 Diphenylmethyl 7-amino-3-[(Z)-1-propene- in H2O (20d) and ethyl vinegar (40m)
To a stirred suspension of the hydrochloride salt of 1-yl)-3-cephem-4-carboxylate (5f, 11.31 mol) was added NaHCOs until the pH of the mixture was 8. The organic layer was washed with saturated NaCj aqueous solution (5-) and MgSO4
and concentrated to a volume of approximately 20 cm. The resulting solution was diluted with isopropyl ether (10 m), seeded with 1 m of the crystalline compound, and further diluted with isopropyl ether (3 m).
After 15 minutes, the separated colorless crystals were collected by F'' filtration, washed with isopropyl ether (10d), and vacuum dried over P2O6 to give 4.3f (94%). ) title compound (Z by HPLC)
/E=9/1) was obtained. (Licrosolve RP-18,
80 timetanol pH 7,2 phosphate buffer, 254n
m,lsd/”).

IR: uKB'ear-" 3450.1765
．． 1730°ax Uv:λF't0Hnm (E:ri 289 (185)
.

ax NMR: δCDCt” ppm 1.43 (3H%
dd, J=2 and 7Hz, CH==cl(CHs)
, 1.66 (2H1br, s, disappeared by D!O, NMR), 3.23 and 3.55 (each IH, d, J
=17Hz, 2-H), 4.73(IHld, J=4
．． 5Hz, 6-H), 4.96 (IH, d, J
=4.5Hz, 7-H), 5.46 (IH, ci-
q, J=10 and 7Hz, 3-CH=CH), 6.0
6 (IH, br.

d%J-10Hz, 3=CJH, 6,94(IH, a,
Cdanph, ), 7.3 (IOHlm, Ph H)
.

Preparation Example 5 Diphenylmethyl 7-amino-3-[(Z)-1-propen-1-yl)-3-cephem-4-carboxylene) (Ia) (4.2 g, 1
0.4 mmol), (D)-α-(t-butoxycarbonylamino)-α-(4-hydroxyphenyl) vinegar @
(3,3f, 12.5 mmol) and DCC (2,6t
, 12.5 mmol) was stirred for 1.5 hours at room temperature. The mixture was filtered and the insoluble matter was removed with ethyl acetate (20 d
)r Washed. The P solution and washing solution were combined and saturated NaHC
Os aqueous solution (3X5m), brine (5-), lO-H
Washed with Ct (5 m) and brine, MgSO
4, treated with activated carbon and filtered. Approximately 10% V liquid
- and diluted with n-hebutane (20 gg). The precipitate was collected by filtration and vacuum dried over P, Os.

Yield 7.8F (90% purity, heavy weight quantitative) (') as a colorless powder (Z/E=971 based on HPLC)
lo Fulv RP-18, 80% methanol-pH 7,2
phosphate buffer, 254 nm·1−/sb).

@ KBr -1 1R0ν cs 3400, 1790. 172
0,1690゜ax tOH Uv: λm, xn m (E-h!) 278
(113), 289(115), 295(95).

NMR: δCD” ppm 1.3-1.45 (12
H1m, BOC-H and =CH-CH), 3.08
and 3.33 (each IH1d, J=18Hz, 2-H),
4.92 (IH, d, J=4.5Hz, 6-H
), 5.06 (IH%d, J=51(z, D2
0 addition, 8, CHN), 5.5 (IH%d-q%J
=10 and 7Hz, 3-CH=CH), 5.68 (
IH, d-d.

J = 4.5 and 8 Hz with % DBO addition, d s J
” 4-5 Hz.

6.71 (IH%d, J=8Hz, disappears at 010, 7-
NH), 6°88 (IHLs, CHPh, ), 7.3
(IOHlIn.

ph- and).

Production Example 6 Diphenylmethyl produced in Production Example 5? -((t))-
α-(t-butoxycarbonylamino)-α-(4-hydroxyphenyl)acetamide)-a-((z)-x
-propen-1-yl)-3-cephem-4-carboxylate (IV) (90% purity, 7.7 f, 10.
6 mmol), anisole (7.7m) and trifluoroacetic acid (77d) was stirred for 1 hour at room temperature.

The mixture was concentrated in vacuo. Toluene (50d) was added to the concentrate and the mixture was evaporated in vacuo. Ether (200m
) was added to the residual oil. The separated solid was collected by filtration, washed with ether (20 mg), and dried in vacuo over KOH to yield 5.3 t of the trifluoroacetic acid (TFA) salt of BMY-28100. This salt (5,:l) is H,0
Diaion HP-20 (0,6 t) was dissolved in H, 10 (ld) and treated with activated carbon and loaded onto a nine column. The column was washed with H,0 (4 t);
Eluted with 409G aqueous M@OH. The methanolic fraction (1,71) containing the desired product was collected and evaporated to a volume of approximately 20 cm. The concentrate was slowly diluted with acetone (100+sg). The separated colorless crystalline powder was collected by filtration, washed with acetone (20 m), and dried under vacuum over P,O, to give 4 t (97 m) of BM.
0 production example yielding Y-28100 (ZE=9/1, zwitterion) (Licrosolve RP-18, 20% methanol-PH7,2 phosphate buffer, 254 nm, 1-7m)
7. To a stirred solution of fc260-anisole and 1.381 trifluoroacetic acid (TFA) cooled to
0,338 mol) of diphenylmethyl 7-amino-3-
[(Z)-1-flopen-1-yl]-3-cephem-
4-carboxylate hydrochloride (0,338 mol, Preparation Example 3 or 11) was added. Most of the excess TFA was removed in vacuum on a rotary evaporator. The remaining supernatant solution was decanted and the remaining slurry was triturated with 1.5 t of anhydrous ether for 1 hour.

The crystalline product was 2i, P, 0. Dry with 87.24
The trifluoroacetate of Ib of 9 was obtained. This 87.24
The trifluoroacetate of No. 9 was suspended in 900 d of water and stirred (pH approximately 2.5). The mixture was cooled to +5°C and adjusted to pH 0.6 using 12NHct. The yellow solution was treated with activated carbon and the slurry was filtered through a diatomaceous earth filter aid pad. The resulting solution was cooled to +5°C and 20% N
The pH was adjusted to 2.0 using aOH. The suspension was kept in the refrigerator for 1 hour to promote crystallization. The crystals were collected, washed with 800% water and 800% acetone, and dried under vacuum at room temperature. Yield 69.4f (85.5%) (column RP18 Merck [:MERCK); 0. IM Hz (
N) Cut PO495d+CH3CN 5d; 290n
Contains 9.7% trans isomer (according to HPLC detected at m).

Production example 8 7-amino-3-[(Z)-1-propen-1-yl)
A solution of the phosphoranyl compound III prepared in Preparation Example 2 (50, Of, 68.7 mmol) in -CH2C4 (500 m) was brominated in anhydrous DMF (170++ l) containing a small amount of CH,C1, (10d). Lithium (2
9,8F, 343 mmol) and then (N.
Elle Drake and G.B. Cook, Organic Synthesis Collective Volume (N, L,
Drake and G, B, Cooke, O
rg, Syn, Cot.

Vol.) Volume 1, No. 407 Negative method) was mixed with anhydrous acetaldehyde (39m, 687 mmol) prepared by distillation from paraaldehyde and toluenesulfonic acid according to the negative method.

The mixture was placed in a sealed container and kept at 20°C for 2 days. The reaction mixture was evaporated and the remaining liquid was diluted with EtOAe (8
Diluted with 00sO, water (3X300m) and saturated Na
The 3-propenyl derivative 1 was washed with CL bath solution 300d) and evaporated as a foamy solid (34?).
1a was obtained and used in the next reaction without further purification.

The crude ITa obtained above was treated with 98% formic acid (35%
d) and concentrated HCt (17d, 206 mmol). Water (350m) was added to the reaction mixture to separate the oily layer, which was washed away with EtOAe (3X100m). adjusting the pH of the aqueous layer to about 3 using 4N NaOH (about 65 wIt) under stirring to produce a crystalline solid;
This was collected by filtration and washed with water (50d) to obtain the title compound (Ib, 9.72.59%). HPLC (
Licrosolve RP-18, 4X300■, Me OH:
Phosphate buffer (pH 7) = 15:85)tj, indicating that the product was an 83:17 mixture of 2 and E isomers for the double bond of the 3-propenyl group.

m, p, 200℃ (decomposition) 0 I R: v (KBr) cm 3420
, 1085, ax 1620°Uv:λ (pH 7 phosphate buffer) nm (Li 28
3ax (8900).

NMR: δ(DzO+NaHCOs) pprn 1
．． 69 and 1.88 (3H1 each d, J = 6.0Hz, -
CH=CH-CH3 Z and E), 3.38 and 3.
72 (2H%Abq, J=17Hz, H-2), 5.
18 (IH, d, J, , ==5.0Hz,
H-6), 5.51 (IHld, H-7), approx.
8 (IHlm, -CH=CH-CH3) and
6.06 (IHldlJ"11Hz, -CH=CHCH
3).

Elemental analysis: Calculated value as C16HBN203 S:
C149,99;H,5,03;N,11.66:S
, 13.34%.

Actual value: C, 50, 20; H14, 94; N, 10.9
3;S, 12,82ch.

Production Example 9 7((D)-2-amino-2-(4-hydroxyphenyl) Compound Ib (1,58f, 6.
56 mmol) of CH2Cl2 (16 mj
) dimethylaniline (1.7 m, 13.1 mmol), trimethylsilyl chloride (2.1 td, 1
6.4 mmol) and triethylamine (TEA, 2.
3d, 16.4 mmol) were added in this order.

The mixture was stirred at room temperature for 30 minutes. To this mixture was added a small amount of D-p-hydroxyphenylglycyl chloride hydrochloride (1,46f, 6.56 mmol) under stirring,
The reaction was analyzed by HPLC (Licrosorb RP-18,4X3
Monitored by 00m MeOH:phosphate buffer (pH 7) = 25 nia 5). Additional amounts of glycyl chloride were added to the mixture three times at 15 minute intervals (to 291 Cape) to complete the acylation. The resulting clear solution was neutralized to pH 6 using TEA (3,2d) and then diluted with CH*C4 (30ttt) to produce a precipitate, which was collected by filtration and CH*C1z ( 10
m) to obtain the title compound as a dimethylformamide solvate. (2,39f, yield 94%; purity about 50%; HPLCKJZ/E = 47:12).

Production example 10 Rate (K) MW = 758.8 18t CC1a, 1.8t methanol and 12f
A stirred solution of p-benzoylbenzoic acid was cooled to 8°C,
970-g of acetaldehyde was added. The temperature of the resulting solution rose to +14°C. After 5 minutes, 588t (0.7
749 mol) of diphenylmethyl 7-phenylacetamido-3-(()liphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate was added. The O cooling bath was removed and the mixture was exposed to light and N3 atmosphere. The mixture was stirred vigorously at 35° C. for 4 hours until complete dissolution of the phosphorane occurred. The resulting solution was concentrated in vacuo, the residue was dissolved in 2 t of ethanol, the solution was concentrated in vacuo to a semi-crystalline residue, which was slurried with 3 t of ethanol. The mixture was stirred for 2 hours at +5° C., stored overnight, and the crystals were collected twice, washed with ethanol, and dried under vacuum at room temperature. Yield 191t (47%) a m-P.

124-128℃,? , containing 5% trans isomer (
='Glue Closolv Si 60 5μmHPL manufactured by Luk Co., Ltd.
P column was eluted with 85%) toluene and 15% ethyl acetate.Production Example 11゜(1a)
pct, of 280- CH=C2
56.7m (0,700 mol) of pyridine in m is 20
Added over a period of minutes. Slurry under nitrogen atmosphere
256t of ■ produced in Production Example 10 while cooling to °C (
0,488 mol) was added.

The mixture was stirred for 40 minutes and the resulting slurry was
1.4t CH Goose Ct snow and 209td (2,3
3 mol) of 1,3-butanediol was added rapidly to a vigorously stirred solution without allowing the temperature to rise above -5°C. The cooling bath was removed, and after 45 minutes, the temperature was raised to 10 °C and kept at this temperature for 35 minutes. Water (1, (1)) was added and stirring was continued for 5 minutes to separate into two layers. The organic layer was separated into two layers. 6
Washed with 00-2N HCL and then 400-saturated brine. The combined aqueous extracts (washes) were backwashed with 2×600 − CH,Ct, and the CH,CL, was combined with the original CH,Ct, extract.

The solution was dried with anhydrous Mg SO. Mg S 04
The slurry was filtered and the MgSO was washed with 2×500 ml of cn2cz.

The combined fcP liquids were vacuum concentrated on a rotary evaporator to a volume of 2.4 t and diluted with 2.5 t of ethyl acetate.

The solution was concentrated to a volume of approximately 1.3 t. The resulting crystalline slurry was filtered and washed with 3×300 ethyl acetate. Air and p, vacuum drying above 0°, 149
．． 8t of the title compound was obtained as beige crystals. Yield 69.3%.

Claims (1)

[Claims] 1. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, the 3-propenyl group has a Z-configuration, and R
is hydrogen or a conventional carboxylic acid protecting group,
and acid addition salts thereof and metal salts of said substances, wherein R is hydrogen. 2, R is hydrogen, methoxymethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, t-butyl, benzyl, diphenylmethyl, o-nitrobenzyl, p-nitrobenzyl, trimethylsilyl, t-butyldimethyl The compound according to claim 1 and its acid addition salt, which is selected from the group consisting of silyl, t-butyldiphenylsilyl, allyl and 2-chloroallyl. 3. The compound according to claim 2, wherein the acid addition salt is selected from the group consisting of hydrochloride, sulfate, p-toluenesulfonate and phosphate. 4. The compound according to claim 1, wherein the metal salt is a sodium, potassium, calcium, or aluminum salt. 5, diphenylmethyl 7β-amino-3-[(Z)-1
-propen-1-yl]-3-cephem-4-carboxylate and its hydrochloride. 6,7β-amino-3-[(Z)-1-propene-1-
yl]-3-cephem-4-carboxylic acid and its hydrochloride. 7,7β-amino-3-[(Z)-1-propene-1-
5. The compound according to claim 4, which is sodium [yl]-3-cephem-4-carboxylate. 8. Formulas: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [However, the 3-propenyl group has a Z-configuration, and R
is hydrogen or a conventional carboxylic acid protecting group,
and its acid addition salts, and the method for producing metal salts of the above substances in which R is hydrogen: Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [However, R is hydrogen or a normal carboxylic acid protecting group. ,
Ph is a phenyl group] with acetaldehyde in an inert organic solvent consisting of dichloromethane, N,N'-dimethylformamide, isopropanol or mixtures thereof at a reaction temperature of 0°C to 25°C. Formula: ▲Mathical formula, chemical formula, table, etc.▼ and then remove the benzylidene group or both the benzylidene group and the carboxylic acid protecting group, and optionally convert 3-(Z) and 3-(E ) Formulas characterized by separating isomers: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Methods for producing compounds. 9. The method according to claim 8, wherein the reaction with acetaldehyde is carried out in the coexistence of lithium halide. 10. The method according to claim 9, wherein the lithium halide is lithium chloride, lithium bromide, or lithium iodide. 11. The method according to claim 9, wherein the lithium halide is lithium bromide.