JPS59196891A - Carbacephem compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R is (halogen-substituted) 1-5C alkyl, substituted silyl, benzyl, benzhydryl, or trityl (with the proviso that phenyl nucleus of the group may be replaced with methyl, methoxy, or nitro)]. EXAMPLE:(+ or -)-6,7-Cis-7-phthalimido-1-azabicyclo[4, 2, 0]oct-2-ene-3-formyl-3-oxo-2- carboxylic acid tertiary butyl ester. USE:An intermediate for antibacterial compound. PREPARATION:A nitro derivative shown by the formula III is reacted with titanium trichloride in a mixed system of an aqueous solution and an organic solvent such as methanol, THF, DMF, etc. at 0-30 deg.C, to give an aldehyde derivative shown by the formula IV. This compound is then treated with a halogenating agent such as pyrrolidone hydrotribromide, etc., and a halogen is introduced into the treated compound at alpha-position. The resultant compound is dehydrohalogenated with a base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel carbacephem compounds. More specifically, the present invention is based on the general formula [1] [wherein R is C1 to C5
a straight-chain or branched alkyl group (which may be substituted with halogen), a directly substituted silyl group, or a benzyl group, a benzhydryl group, or a trityl group (however, the phenyl nucleus of these groups is a methyl group, a methoxy group, or a nitro A novel carbacephem compound (hereinafter referred to as compound CD or simply [I
]. The same applies to compounds with other formula numbers).

Conventionally, carbacephem compounds having a substituent at the 3-position include those having a halogen atom at the 3-position (GB2.0419
23A, JP-A-55-87791), those having methyl groups, hydroxymethyl groups, etc. (U.S. Patent No. 4226,8
No. 66) etc. are known.

Thus, the compound CI having a formyl group at the 3-position
) is a new compound that has not been described in the literature, and is a useful intermediate that can be substituted for a compound with antibacterial activity, as described below.

In the general formula CI), for R, [self-C5(7) linear or branched alkyl group] is methyl, ethyl, ter
Examples include t-butyl. Examples of groups substituted with halogen for R include chloromethyl, chloroethyl, 2,2.
Examples include 2-11-chloroethyl, 42.2-)-fluoroethyl, and halogens include chlorine, fluorine, and bromine.

Examples of the substituted silyl group include trimethylsilyl and tert-butyldimethylsilyl.

Compound [1] is synthesized according to the following process using as a starting compound the compound described in Japanese Patent Application No. 1987-198, represented by the general formula [■] 02R (wherein R has the same meaning as above). Ru.

[I[:] (Uo2R CI) The conversion of the nitromethyl group into an aldehyde group from [■] to [■] is preferably performed by neck reaction (distillation treatment),
Examples include reaction with MoO2/pyridine/hexamethylphosphoramide after base treatment, ozone oxidation after base treatment, reaction with potassium permanganate after base treatment, reaction with titanium trichloride, etc., but the last method is particularly effective. Calm and desirable. The reaction method is described in J, Org, Chem
,.

□, Sha 26, 4367 (1973).

Particularly preferably, the nitro compound [L) is reacted at 06 to 30°C in a mixed system of an aqueous solution of titanium trichloride and an organic solvent such as methanol, ethanol, x,2-dimethoxyethane, tetrahydrofuran, dioxane, dimethylformamide, or dimethyl sulfoxide. Do the following. The yield is even better if the reaction is carried out under weakly acidic conditions by adding, for example, ammonium acetate to the reaction system. The amount of titanium trichloride used is 1 to 10 equivalents based on the substrate.

To create the equal size of the double bond from [U to [■], start [■] with an appropriate halide, introduce a halogen into the α-position of the aldehyde, that is, the 3-position, and then use an appropriate base. This is done by dehydrohalogenation. For halogenation at the 3-position, reagents used for halogenation at the α-position of 317i common aldehydes are used, preferably bromine, chlorine, N-bromosuccinimide, N-chlorosacdiimide, N-bromoacetamide, and sulfuryl. Chloride, rust bromide, cupric chloride, benzene dichloride iodide, pyrrolidone hydrotribromide, 5,5-dibromo-2
, 2-dimethyl-4°6-thioxo-1,3-dioxane and the like. In particular, the last two halogenating agents are preferred.

The solvent used is not particularly limited as long as it is inert and does not itself participate in the reaction, but tetrahydrofuran,
Dioxane, 1,2-dimethoxyethane, diethyl ether, methylene chloride, chloroform, toluene, acetoni)! Jk'J is exemplified. The reaction temperature is -20℃~
80℃1. ) The desired temperature depends on the halogenating agent used! The temperature ranges from 0°C to 60°C. In addition, halogen, a suitable acid, etc. are necessary for the reaction to proceed smoothly.
It is also possible to add a base. The reaction time varies depending on the halogenating agent, reaction temperature, solvent, etc. used, but is usually 10 minutes to 2 hours.

The generated halide can be treated with an appropriate base without isolation to obtain the desired compound [■]. The bases used at that time are triethylamine, diethyl ether, 1゜5-diazabicyclo(4,3
', 0]] Nonene-51.8-diazabicyclo(s
, 4.0] undecene-7, pibenzine, pyrrolidine, pyridine, N,N-hacarium, and calcium charcoal. The amount of base used is 1 to 5 equivalents, preferably 2 to 3 equivalents, based on the starting material [ll], and the reaction temperature at that time is -10' to 5.
The reaction time is 0°C, preferably water cooling, and the reaction time is 30 minutes to 6 minutes.
time, preferably 1 to 3 hours.

The compound (1) obtained here is a useful intermediate that can be converted into a compound having antibacterial activity, and the following is an example of the conversion to a vinylcarbacephalosporin compound. Also, is there any reference to the seventh embodiment? It is shown in lJ.

In the above process formula, Y is exemplified by ethoxycarbonyl group, cyan group, 1-methylyl-5-tetrazolyl group, etc., and R1 is selected from various acyl groups commonly used in the chemical field of penicillin and cephalosporin. be done.

Defthaloylation can be carried out by a method using a hydrazine compound described in JP-A-57-91991. In addition, the ester represented by C02R can be converted to carboxyl without damaging the substituents and functional groups in the molecule by selecting appropriate conditions and reagents using a method similar to that used in penicillin and cephalosporin chemistry. Can be converted to base.

Examples and reference examples of the present invention are shown below.

Example 1-1) (to)-6,7-cis-twophthalimide-
1-Azabicyclo(4,2,0)oct-3-formyl-8-oxo-2-carboxylic, tertiary butyl ester: (i)-6,7-cis-twophthalimide-1 obtained in Reference 9ij 6 - Azabicyclo [t2. c3. +cuto-3-nitromethyl-8-oxo-2-carboxylic branch, 3rd
Butyl ester 2.759 (6,4 mmol)' (i
-12-Dimethoxyethane 60m and methanol 40m dissolved in ammonium acetate 11.5F, 25
% aqueous titanium trichloride bath solution 15.5 ? A solution of 70d consisting of water and water was added in 7 portions over 1 hour, followed by stirring at room temperature for 1 hour. 200 grams of water and 200 grams of ethyl acetate are added to the reaction solution for extraction. The extract was washed twice with saturated brine, once with saturated deuterated water, twice with water, and once with saturated brine, dried over Glauber's salt, and the common solvent was distilled off, yielding the crude target product 1. 9 '29 (74,9%). This product can be used in the next step without purification.

The physical properties of the target compound obtained by purifying a portion of the crude target compound by silica gel chromatography (n-hexane-l':ethyl 1:1) are shown below.

<Highly polar compounds> ■R BrCcrA-li: 1795, 1780 (sh)
, 1775°ax 1740 (sh), 173O NMR (CDCta) δ: 9.90 (IH, s),
7.67-7.93 (4H, m), 5.43 (I
H, d, J = 4.5H2), 5.17 (IH, b
r, s), 3.90-4.20 (IH, m), 2
．． 77-2.9a (ta, m), 1.47-2.57
(4H, m), 1.50 (9H, s) <Low polar compound>
), 1775°ax 1740(sh), 173Q N1. AR (CDCta) δ: 9.80 (1, H, s)
, 7.70. -7.97 (4H,,m), 5.5
0(IH,a, J=4.51(z), 5.20(I
H.

d, J=5.5H2), 3.93-4.27(IH
,m), 2.93-3.13(1:E(,m),
1.23-2.43 (4H, m), 1.47 (9H,
s) 1-2) (to) -6,7-cis-tophthalimido-1-azabicyclo(4,2,013 oct-2-ene-3-formyl-8-oxo-2-carvone V, 3rd
Butyl ester: 1-1) -6,7-cis-
7-7 Thalimido 1-azabicyclo[4,2,0)octo-3-formyl-8-oxo-2-carboxylic acid, tertiary
10.2 F of butyl ester was dissolved in 200 d of anhydrous tetrahydrofuran, 12.8 f of pyrrolidone hydrotribromide was added thereto, and the mixture was stirred at 50° C. for 1 hour. Next, the reaction solution was cooled to 0 DEG C., 12.5 d of triethylamine was added thereto with stirring, and stirring was continued for 2 hours. The reaction solution was extracted with ethyl acetate in IN hydrochloric acid water under cooling. The organic layer was washed successively with water, sodium sulfite solution, water and saturated brine, dried over Glauber's salt, and then the solvent was distilled off under reduced pressure. The obtained residue is crystallized in a mixed solvent system consisting of ethyl acetate-dimethyl ether-n-hexane to obtain the target product 2.36'S' as a solid. The mother liquor was further purified using concentrated drra L and silica gel 100R (n-hexane/intoxicated ethyl 1:1) under reduced pressure to obtain 1.26f of the target product (yield: 3
6%).

The physical properties of this material are as follows.

NMR (CDCt3) δ: 9.97 (IH,S
), 7.70-8.00 (4H, m), 5.68 (
IH, (1, J=s, ong), 3.90-4.20 (
LH, m), 2.77-3.10 (IH, m).

1.33-1.67 (3H, m), 160 (9H, s)
.

IRν:H:Za (crn-ri:1810 (sh)
, 1800#1790, 1730.1725(ah)
, 1670.1600° Example 2. (To) -6,7-
cis-twophthalimido-1-azabicyclo[4,2,,
0.]]Octo-2-ene-3-formyl-8-oxo-
2-carbo/acid.

Tertiary butyl ester: ω-6,7-cis-twophthalimido-1-azabicyclo(t2.o)oct-3-nitromethyl-8-oxo-2-cal; 'r:/ Enemy, 7M3 butyl ester 2.75F (6,4 mmol) 1,2-
KM to dimethoxyethane 60d and methano-AI 40yd
To this, add 11.5SF of toric acid °f ammonium, 2
Add 70 J of a bath solution consisting of 5% aqueous titanium trichloride bath solution 15.5 F and water in 7 portions at 1 hour (1 hour).
After that, I perform the maintenance procedure based on the foot temperature. 200 nl of water and 200 nl of water were added to the reaction solution for extraction. Extract twice with saline, once with water, twice with water, and once with saturated saline. After washing, the solvent was distilled off. To the residue was added 35% of anhydrous tetrahydrofuran, and to this was added 2.49% of pyrrolidone hydrotribromide, and 50% C
At 1 o'clock 1'ijJ agitation was carried out. Next, the reaction solution was heated to 0°C.
2.4% of triethylamine was added to this mixture under stirring.
Add the ingredients and continue stirring for 2 hours.

The reaction solution was poured into aqueous IN hydrochloric acid under cooling, and extracted with ethyl acetate. The organic layer was washed successively with water, sodium sulfite water, and saturated brine, dried over Glauber's salt, and then the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate-diethyl ether-n
- When crystallization is carried out in a mixed solvent system consisting of hexane, the desired product 631 Kashi is obtained as a solid. Further purification of the mother liquor using silica gel zof (n-hexane/ethyl acetate 1:1) yields an additional 3035 g of the target product (yield 35%).
).

The physical properties of this product are exactly the same as those obtained in Example 1.

Reference example 1. (to)-6,7-cis-twophthalimide-1
-AzabicycloC4,2,0〕〕Octo2-En-3
-2-(1-methyl-IH-tetrazol-5-yl)
Vinyl2-8-oxo-12-carvone, tertiary butyl ester: ω-6,7-cis-twophthalimido-1-azabicyclo(4,2,0)oct-2-ene- obtained in Example 1
600q of 3-formyl-8-oxo-2-carboxylic acid, tert-butyl ester was dissolved in 20d of anhydrous tetrahydro 7 run, and (1-methyl-IH-tetrazol-5-yl)methylene triphenylphosphor was added to this solution. run 1,1
1 and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, and silica gel 1
oOM ethyl acetate:chloroform:n-hexane=3:
1:1) to obtain the target product of 520'IQ as a solid (yield 72%).

The physical properties of this material are given below.

NMR (cDcta) δ: 8.17 (IH, d,
J=16.5Hz).

7.70-7.93 (4H, m), 6.51 (IH, d
, J=16.5Hz),' 5.65(IH, cl,
J=6.0Hz), 407 (3H.

8), 3.90-4. L7 (IH, m), 1.90
-3.00 (4H.

m), 1.60 (9H, e).

I RQ max (cr++-li:1795.178
5.1775 (sh).

1730.1725 (sh), 1625° Reference Example 2. (
g)-6,7-cis-twophthalimido-1-azabicyclo[4,2,0]]octo-2-dyne-3-2-ethoxycarbonylvinyl)-8-oxo-2-carbonyl,
Tertiary butyl ester: CB-6 obtained in Example 1. 7sis, -7-
Phthalimido-1-azabicycloC4.2. O) Octo-
2-ene-3-formyl-8-oxo-2-carboxylic acid, tert-butyl ester 27319 was dissolved in toluene 14-, and to this was added carbethoxymethylenetriphenylphosphorane 32'lnfPQ, and heated to 60°C for 4 hours. Stir. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, and purified using silica gel 50f (n-hexane:ethyl acetate = 2:1) to obtain 190WI of the target product as a solid (yield: 59%).

The physical properties of this product are as follows.

NMR (cDcta)δ: 8.03 (IL
cl, , T=1 6.5Hz).

r. 6r ~7.90 (4) (, m), 5. c+s
(xa, a, J=16.5Hr;), 5.611
(LH, d, J=6.OIHz), 4.20(2
H.

q, J=7.5Hz), 3.83 ~ 4.1'0 (
IH, m), 1.77-2.90 (4H, m), 1
．． 60' (9H, 8), 1.27 (3H.

t, J=7.5 Hz) HCtB IRν (crn"'"door 1800 (sh), 1
795. 1785ax (sh), 1780. 173'0. 1725(s
h), 1710 (sh).

Reference example 3. cfl-6.7-cisfuphthalimide 1
-azabicyclo(4.2.0 3oct-2-e/-a-(2-cyanovinyl)-8-oxo-2-carboxylic acid, tert-butyl ester: ω- obtained in Example 1
6,7-cis-twophthalimido-1-azabicyclo(4
．． 2.0) Oct-2-ene-3-formyl-8-oxo-2-carboxylic acid. Tertiary butyl ester 12 was dissolved in anhydrous tetrahydro 79728yd, and cyanomethylenetriphenylphosborane 1,1f was added thereto, followed by stirring at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, and purified with H using silica gel 120F (n-hexane: ethyl acetate = 1:1).
8Mf of the target product was obtained as a solid (yield 67%).

The physical properties of this product are as follows.

NMR (CDC4) δ: 7.70 ~7. c+a(4
n, m), 7.5 (IH, d, J=13.5Hz)
, 5.67(IH, (1, J=55Hz), 5.30(
IH, d, J = 13.5Hz), 3.90-413 (I
H, m), 3.07-3.43 (if (, m), 2.3
7-2.90 (IH, m), 1.77-2.36 (2
H,m), i,s7(9H,5)IR)),,X(m+-'): 2225.1805
(sh), 1800°1790.1780 (sh),
x7as(sh), 1730 Reference Example 4. (a) -6,7
-cis-7-(2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamide) -3-(
2-, (1-methyl-IH-tetrazol-5-yl)
Vinyl]-8-oxo-2-carvone 1. I〆: (t)-6,7-cis-twophthalimide obtained in Reference Example 1
1-Azabicyclo[4,2,0)oct-2-ene-3
-(2-(1-Methyl-IH-tetrazol-5-yl)vinyl]-8-oxo-2-carboxylate, tertiary butyl ester 54011k) f Tetrahydrofuraf 15.
Dissolved in 6- and water z7- and cooled with water, sodium sulfide 9
Add 3.52 d of aqueous solution containing 375~ of aqueous salt,
Perform a minute weighing. Add IN@enemy to the reaction solution and adjust the pH'f
! f: adjusted to 1.5, extracted twice with ethyl acetate, and the organic layer was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was diluted with anhydrous tetrahydrofuran.
mt@ was added, N,N'-dicyclohexylcarbodiimide 28125 was added to this, and the mixture was stirred at room temperature for 2 hours. After separating the formed precipitate, the solution F was cooled to -78°C, 72 μt of methylhydrazine was added thereto, and the mixture was stirred for 20 minutes. Next, add 1.2-IN hydrochloric acid, bring it back to room temperature for 20 minutes, and leave it there! ! :Another 30
Do a minute's worth of alms. Add 50 d of water and 2 d of IN hydrochloric acid to the reaction solution, wash the aqueous layer three times with ethyl, adjust the pH of the aqueous layer to 8 with saturated deuterated water under cooling, and extract three times with ethyl acetate. .

The organic layer was washed with saturated brine and dried with sodium sulfate.

0.8 d of trifluoroacetic acid was added to the organic layer, and the solvent was distilled off under reduced pressure. Add anhydrous methylene chloride 7- to the residue,
Furthermore, 7 grams of trifluoroacetic acid was added and the mixture was left at room temperature for 1 hour. The solvent is distilled off under reduced pressure. Rev ethyl 5- was added to the residue and the solvent was distilled off again under reduced pressure. When the obtained residue was crushed with ether, a solidified product of 1357N! Get 7. This product was dissolved in a solution consisting of 37 g of water and 2.2 ynl of tetrahydrofuran, and the pH was adjusted to 7.7 with triethylamine.

On the other hand, 3#L of 2-(2-1lytylamino-4-thiazol-1)-2-synmethoxyimino vinegar
/ in anhydrous tetrahydrofuran, 84 μt under water cooling.
of triethylamine.

Next, 125 μl of phosphorus pentachloride was added and stirred at the same temperature for 1 hour to obtain an acid chloride solution. The acid chloride solution is added dropwise to the above bath number while maintaining the pH of the acid chloride bath at a total pH of 7.5 to 8.0 with triethylamine.

Thereafter, stirring was performed for 1 hour at the same temperature. After adjusting the pH to 1.5 with IN hydrochloric acid, saturated brine was added and extraction was performed twice with vinegar and ethyl. After washing the organic layer with saturated saline,
The solvent is distilled off under reduced pressure. Add 20 d of 50% aqueous oxalic acid to the residue and stir at 50°C for 1 hour. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in a small amount of dimethyl sulfoxide, passed through a column of Diaion HPIO (30 m/), and after washing the column with water, it was eluted with water-methanol (3:1). Both fractions containing the product were collected and the solvent was distilled off under reduced pressure to obtain the target product of 36 capes as a solid (yield 7%).

The physical properties of this material are as follows.

NMR (D20-CD30D-a6DMS○)
δ: s, 1o (LH, a.

J=16.5Hz), 7.92(IH,s), 6.73
(IH, a.

J = 16.5Hz), 5.52 (IH, d, J
=5.5H2).

4.10 (3H, s), 3.90-4.17 (IH,
m), 4.00 (3H, s), 1.67-3.10 (
4H, m) IR'9KBr(cln-"): t7'
5o (ah), 1770.1755ax (sh), 1660.1620 Reference example 5. -6,7-cis-7-C2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamide)-3-(2-ethoxycarbonylvinyl)
-8-oxo-2-carboxylic acid: -6,7-cis-7-fu8 obtained in Reference Example 2
-Oxo-2-carboxylic acid, tertiary butyl ester 390
Using 99, the debonding and acylation reactions were carried out in the same manner as in Reference Example 4 to obtain 40 of the target compound as a solid (
yield 14%).

The physical properties of this material are as follows.

NMR (D20-CD, 0D-d, DMSO) δ: 7
．． 95 (IH, a.

J=16.4Hz), 6.81 (LH, 8), 6.10
(IH, (1°J=16.4 H2), s, s 3
(I H, d, 'J=5.2H2).

4.19 (2H, q, J near, 0Hz), 3.94 (3
H,s).

1.27 (3H, t, J=7.0Hz) IR=H(=
-71-1): 1790(ah), 1780.1
7'l0(sh), 1760(sh), 167.0.1
630 Reference Example 6. (t)-6,7-cis-twophthalimido-1-azabicyclo[4,2,0]]octo-3-nitromethyl-8-oxo-2-carboxylic acid, tert-butyl ester: ω-cis-7-phthalimido-1 - Azabicyclo L 4.
2.0 :) Oct-2-ene-8-oxo-2-carboxylic acid, tertiary butyl ester 6f (16.3 mmol)
of 1,8-diazabicyclo(5,4,·0.]undecene-71,0 was suspended in nitromethane 60d.
5d and stirred at room temperature for 23 hours. The reaction solution was poured into 200 d of ice-cooled 0.5 N hydrochloric acid solution, and 20 d of ethyl acetate was added.
After washing with saturated brine three times, twice with saturated deuterated water, twice with water, and once with saturated brine, the extract was dried with a sieve and the solvent was distilled off. The obtained residue was dissolved in ethyl acetate-n
-4.55F (65N) when crystallized from hexane
Obtain the desired object.

The physical properties of this material are as follows.

NMR(CDCl3)δ: 7.63-7.97(
4H, m), 5.48 (IH, d, J=5.0H2)
, 5.03 (IH, act, J=10.5.7.5H2
), 4.85 (IH, aa, J=10.5.7.5
H2), 4.51 (IH, br, s), 3.93~
4.23 (IH.

m), 2.87-3.17 (IH, m), 1.43-1
．． 93 (4H.

m), 1.50 (9H, s) I R)) , x (crn-li: 1790 (sh),
1780 (ah).

1770.1730, 1560.1385ゞsu・n'
・;, - 1 Procedural amendment May 9, 1980 Commissioner of the Patent Office Mr. 2. Name of the invention: carbacephem compound 3. Relationship with the person making the amendment Patent applicant Postal code: 100 Address: Ote, Chiyoda-ku, Tokyo Town-chome 6-1 Name Name (102) Kyowa Hakko Kogyo Co., Ltd. Contents of the amendment (l) Change “Nonene-5, 1, 8J” to “Nonene-5, 1, 8” in the bottom three lines of page 6 I'll correct it.

(2) Correct the reaction scheme on page 7 as follows.

+3 Correct r55HzJ on page 1, line 1 to r5.5HzJ.

(Correct r7.92J in the bottom 7 lines of page 4122 to r6.92J.

Procedural amendment Commissioner of the Patent Office 1.Display of the incident 1981 Patent Application No. 72034 2. Name of the invention carbacephem compounds 3. Person who makes corrections Relationship to the case Patent applicant Postal code io.

Address: 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name
(102) Kyowa Hakko Kogyo Co., Ltd. (Location: 03-2
Inside 01-7211! 2751) The following reference example is added after the description of reference example 6 in column 5 of the detailed description of the invention in the specification, page 25 of the contents of the amendment.

Reference example 7. (e)-6,7-cis-twophthalimide-1
-Azabicyclo[4,2,0)oct-2-ene-3-
Cyano-8-oxo-2-carboxylic acid.

Tertiary butyl ester: (f) -6,7-cis-twophthalimido-1-azabicyclo[4,2,O]]octo2 obtained in Example 1
-en-3-formyl 8-oxo-2-carboxylic acid, tertiary butyl ester 800/·η to toluene 10 InI!
Suspend in Add to this pyridine 5soPAi and 0. N
-Bis-(trifluoroacetyl)-hydroxyamine 96077217 was added, and the mixture was heated and stirred at 85°C for 1 hour. After cooling the reaction solution, water and ethyl acetate are added, and the organic layer is separated. After washing the organic layer sequentially with water, aqueous sodium chloride, and saturated brine, the organic layer is dried over anhydrous sodium sulfate. The organic layer was distilled off under reduced pressure, and the resulting residue was crystallized from an ethyl acetate-chloroform-n-hexane system to obtain the desired cyano compound 596 ni9. Further loading of the mother liquor with 7 y of silica gel (chloroform-n-hexane-ethyl acetate, 1:1:1) yields 124 rti da of the desired product. (Yield: 91.5 cm) The physical properties of this product are as follows.

NMR (CDC4) li: 7.7-8.0 (4H
, m), 5,70 (1'H, a, J=5.5Hz)
, 3.83-4.23 (IH.

m), 2.37-2.73 (2H, m), 1.80
~417 (2H, m), i, 59 (9H, s) Engineering Rp (ff+-1): 2230, 1810 (a
h), 1805°aX 1795 (sh), 1780 (ah), 1
740 (ah ka 1735゜1725 (sh) zu 4 sales xiang 1 tun zhan - 1985/Q month 316, Patent Office J Administrative Officer 1, case report 1988 Special Jin'1 Application No. 72034" 2. Name of the invention: Carbacefueno Compound 3. Relationship with the amended item Iil Patent N applicant's mail &'9100 address Otemachi, Chiyoμm-ku, Tokyo--J River-161!i
1.3 Name (102) Kyowa Hakko Kouma Co., Ltd. (rE
l, : 03-20L7211 interior i + 2751) Light for details 1 y],, 1 darkness of E-sen tr explanation 5, contents of correction (1) Details "W 191' line 7 11 and page 23 line 3 1 = 8 Add 1--■-azabicyclo 11° 2.0] oct-2-ene to 11;S of ``-oxo''.

(2) No. 3 of the procedural amendment dated June 30, 1982
Add the following reference example after the description of reference example 7 on the page [Reference example 8 Mucl l(!+--11inton'lJ person(p
H7, 0) The final 1 according to the 411 interpretation method in 1: J state Hokuaimono resistance'l 14 life 1 no 1 is shown in the following table (841
Cμg/ml).

Claims (1)

[Scope of Claims] General Formula [I] [In the formula, R is a C1 to C5 linear or branched alkyl group (which may be substituted with ].logen), substituted silyl group, benzyl group, benzhydryl or trityl group (however, the phenyl nucleus of these groups is a methyl group,
A carba-fem compound represented by the formula (optionally substituted with a methoxy group or a nitro group).