JPS609514B2 - 7-amino-3'-norcephalosporanic acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to important synthetic intermediates to new analogues of cephalosporins with potent antibacterial activity, particularly 78-amino-1-oxadethiacephalosporins.

The compound of the present invention can be represented by the following general formula.

(In the formula, RI is a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkylsulfonyloxy group, an arylthio group or a methyltetrazolylthio group; R2 is a COO group or a (nitro or phenyl)penzyloxycarbonyl group: R
3 represents a hydrogen atom or a methoxy group; The compound of the present invention represented by the general formula (1) can be produced by the methods shown in the following reaction process diagrams 1 to 8.

In the general formula (1), the compound (la) in which RI is a halogen atom or a sulfonyloxy group is represented by reaction process diagram-1
It can be manufactured by the method shown in .

Reaction process diagram-1 (However, in the formula, R is an amino protecting group, R' is a carboxylic acid protecting group, and X is a halogen atom or a sulfonyloxy group, respectively: R2 has the same meaning as above) Raw material in the above step (n) is a known substance, and can be produced, for example, by the method described in Samurai Publication No. 51-41385.

Alternatively, it may be produced according to the following reaction process diagram-2 according to the method of the present inventors. Reaction process diagram-2 (However, in the formula, X' and X'' are each a halogen atom,
R'' each represents an ester residue; R and R' have the same meanings as described above) The reaction in the above reaction process diagram-2 can be carried out according to known reaction conditions that satisfy the reaction steps shown in each step. good.

The compound (l) obtained by the process shown in Reaction Process Diagram 1
a) corresponds to a compound of general formula (1) in which RI is a halogen atom or a sulfonyloxy group, R2 has the same meaning, and R3 is a hydrogen atom.

Reaction Steps The reaction conditions for each step shown in Figure 1 are explained in detail as follows. Step a (0→m) The hydroxyl group at the 3-position is replaced with a halogen atom or sulfonylated with a sulfonylating agent to obtain the desired 3-halogen or 3-sulfonyloxy compound.

The halogenation reaction of the 3-position hydroxyl group is carried out using a reaction method normally used for halogenation of a hydroxyl group (for example, phosphorus trihalide PX).
However, in the present invention, among known halogenation methods, oxalyl halides (e.g., oxalyl chloride),
A reaction method using phosphorus oxyhalide (eg, phosphorus oxychloride), halogen (eg, chlorine)-triphenylphosphine, etc. is applied as a preferred method.

The sulfonylation reaction of the 3-position hydroxyl group can be carried out in the same manner as the sulfonylation reaction of the hydroxyl group.

Specific examples of the sulfonylating agent include alkylsulfonyl halides (methylsulfonyl chloride, ethylsulfonyl chloride, etc.) and arylsulfonyl halides (benzenesulfonyl chloride, toluenesulfonyl chloride, etc.). The reaction is carried out under the usual conditions of a sulfonylation reaction, for example, by reacting the above-mentioned halogenating agent in the presence of a tertiary amine such as pyridine or triethiamine. Step b (m→la) In this step, the 7-position amino protecting group and, if necessary, the 4-position carboxylic acid protecting group are simultaneously or stepwise hydrolytically or reductively added depending on the nature of the protecting group. to be removed.

The 7-position amino protecting group and the 4-position carboxylic acid protecting group used in the present invention are commonly used in the synthetic chemistry of penicillin or cephalosporin, and can be easily removed by known methods. In general formula (1), when RI is other than a halogen atom or a sulfonyloxy group, it can be produced as shown in the reaction process diagram below.

Reaction Process Diagram-3 (However, in the formula, R, R1, R2 and X have the same meanings as above.

) Reaction process diagram-3 shows a process for producing a compound in which RI in general formula (1) is a hydrogen atom.

Step c (m→W) The halogen atom or sulfonyloxy group at the 3-position of the compound represented by the general formula (m) is reductively eliminated to prepare an unsubstituted oxadethiacephim skeleton at the 3-position.

The reduction reaction in this step is performed using a combination of metal and acid, especially zinc-acetic acid, as a method for specifically reducing and eliminating the 3-position halogen atom or sulfonyloxy group without damaging other substituents and functional groups. A combination of these methods is effective.
The reaction may be carried out according to known methods. Process d (W→l
b) This step is a hydrolysis/reduction step that has exactly the same purpose as the above-mentioned step b, and can be carried out according to methods frequently used in the synthetic chemistry of penicillin or cephalosporin.

Note that the target compound (lb) in this step may be produced according to the following reaction process diagram.

(However, in the formula, R and R' have the same meanings as described above.

)* The reaction in the above reaction process chart-4 may be carried out according to known reaction conditions that satisfy the reaction steps shown for each step.

A compound in which RI is an arylthio group or a monocyclic heterocyclic thio group in general formula (1) can be produced according to the following reaction scheme.

Reaction Process Diagram 15 (However, in the formula, R, R1, R2 and x have the same meanings as described above; Y represents an arylthio group or a monocyclic heterocyclic thio group.

) Step e (Machi→V) The 3-position halogen atom or sulfonyloxy group of the compound (plate) is substituted with a desired arylthio group or monocyclic heterocyclic thio group.

In this reaction, the starting compound (m) may be reacted with the corresponding aryl thiol or monocyclic heterocyclic thiol in the presence of a weak base, or with a salt of the corresponding thiol. As the weak base, organic bases such as pyridine and triethylamine are particularly preferred. The reaction usually proceeds easily at room temperature. Step f (V→lc) This step is a hydrolysis or reduction step having exactly the same purpose as the above-mentioned steps b and d, and the reaction can be carried out under the same conditions as these steps.

Moreover, the target compound (lc) of this step can be produced according to the following reaction process diagram.

Reaction Process Diagram-6 (However, in the formula, R, RI and Y have the same meanings as above.

)★ The reaction in the above self-reaction process diagram-6 may be carried out according to known reaction conditions that satisfy the reaction steps shown for each step.

A compound in which RI is a lower alkoxy group in general formula (1) can be produced according to the following reaction scheme.

Reaction Process Diagram-7 (However, in the formula, R, R' and R2 have the same meanings as described above: R... represents a lower alkyl group.

) Step g (0→W) The reaction in this step is carried out according to the conditions for the enol etherification reaction of ketones, or is carried out using a reagent such as diazoalkane that is usually used for esterification of carboxylic acids.

The phenol etherification reaction of a ketone includes, for example, a reaction using a trialkylorthoformate (eg, triethyl orthoformate), a reaction between an alcohol and p-toluenesulfonic acid, and the like. Furthermore, alkylation reactions using diazoalkanes (diazomethane, diazoethane, etc.) are also carried out in the present invention. These reactions may be carried out according to known reaction methods. Step h (W → ld) The reaction in this step is exactly the same as the above-mentioned steps b, d, and f, and the objective is a reduction reaction, and the reaction can be carried out under the same conditions as these steps. can.

A compound in which R3 is a methoxy group in general formula (1) can be produced according to the following reaction scheme.

Reaction Process Diagram-8 (However, in the formula, RI and R2 have the same meanings as those described above.) The process raw material compound (lf) corresponds to each compound obtained according to the reaction process diagrams 1 to 7 described above.

For the introduction of the methoxy group at the 7-position shown in Reaction Process Diagram-8, the 7-methoxy group introduction method commonly used in the chemistry of penicillin and cephalosporin can be applied as is. The details of these methods are as follows. Method 1 The 7-ami/group of the starting compound (lf) is acylated to give the corresponding 7-acylamino compound, which is then treated with methoxylithium (LiOCH3) and t-butyl hypochlorite (t-butyl hypochlorite).
-BuOCI) at low temperature in a boarding solvent (Belgium Patent No. 817836).

The 7-position acyl protecting group is then removed. Method 2 The 7-amino group of the raw material compound (lf) is reacted with sodium nitrite to form a 7-diazo compound {a), which is then treated with haloazide (prepared from sodium azide and the corresponding halogen) (e.g. BrN3, CIN3, IN3). ) is reacted to form the corresponding haloazide 'b-, which is then reacted with methanol to further reductively decompose the azide to obtain the desired 7-amino-7-methoxy form (le).

This process can be expressed as follows using a reaction formula. (Tokubatsu Showa 47-1931) (However, in the formula RI
and R2 have the same meanings as above; x''' represents a halogen atom.

) Method 3 The raw material compound (lf) is reacted with p-hydroxybenzaldehyde (particularly preferred is 3,5-di-tert-butyl-4-hydroxybenzaldehyde, which has a bulky substituent at the position adjacent to p-hydroxy) to form penzylidene molecule. The conductor [c' is oxidized with an appropriate oxidizing agent (e.g. nickel peroxide, lead tetraacetate) to form a quinoid derivative [d-], which is reacted with methanol to form a 7Q-methoxy derivative 'e-. After that, the benzylidene group is hydrolyzed (usually treated with a Girard reagent) to obtain the desired 78-amino-7Q-methoxy compound (le).

This process can be expressed as follows using a reaction formula. (Hakama Seki Sho 50-50394) (However, in the formula, RI and R2 have the same meanings as those mentioned above.) Method 4 As another method, a method such as the following reaction formula can also be used.

That is, the amino group at the 7-position of the starting compound (lf) is protected with an acyl group having at least one hydrogen atom at the Q-position, and this 7-acylamino derivative [fl] is treated with a halogenating agent to form an iminohalide derivative ( g), which is treated with a base to eliminate hydrogen halide, and the obtained keteneimine derivative (h) is halogenated to give a dihalogenoidine derivative (i), which is reacted with an alkali metal methoxide, and then subjected to appropriate hydrolysis. to remove the acyl group. (JP 50-126692) (However, in the formula RI and R2
have the same meanings as above; Q' and Q'' each represent a hydrogen atom or a suitable substituent, and X and X' each represent a halogen atom.

) The compound of the present invention represented by the general formula (1) serves as an important synthetic intermediate in the production of new types of 1-oxadethiacephalosporins, and the compound of the present invention (
By introducing various acyl groups commonly used in the field of penicillin or cephalosporin chemistry into the free amino group at position 7 of 1), compounds exhibiting strong antibacterial activity can be obtained.

The embodiments of the method of the present invention are shown below.

Example 1 78-amino-3-chloro-1-oxer-1-dethia-
3-cephem-4-carboxylic acid (la:RI=CI;R
2=COOH; R3=H) (la:R2:C〇〇H:X
=CI)'1' 78-penzyloxycarbonylamino-3-hydroxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid diphenylmethylester (
0:R:PhCH20C○;R'=CHPh2)1.5
Dimethylformamide (3 mol) was dissolved in 30 ml of dimethylformamide, and 0.03 M (0.3 mol) of pyridine was added to this under cooling with ice water.
6 mmole) and then 0.31 oxalyl chloride
(3.6 moles).

After stirring at room temperature for 3 hours, the reaction solution was poured into 5% phosphoric acid in ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, and the resulting residue was passed through a 2-fold volume silica gel column and eluted with benzene-ethyl acetate (5:1) to obtain the desired 3-chloro compound and 76-benzyl compound. Oxycarbonylamino-3-chloro-1-oxer-1-dethia-3-
Cephem-4-carboxylic acid diphenylmethyl ester (m:R=PhCQOCO;R'=CHPh2:X=C
I) 9 of 489 (yield 31.4%) is obtained. mp1
30-13100. IR:Hibuwashi〆3hada-・:3450
, 1805, 1725, 1620. NMR: 6(C
DCl3) Skin: 4,32 (s, 2H), 4,98 (d,
Jni 4.0HZ, IH), 5.10 (s, 2H), 5.
20-5.80 (m, general) "6.97 (s, IH), 7
．． 0 (m, aromatic ring proton). This product can also be manufactured by the following method.

Triphenylphosphine 1.62 mmole (6.2 mmole)
) was melted over 20 vessels of tetrahydrofuran, and 6.2 mmole of chlorine-carbon tetrachloride solution was added thereto under ice-water cooling.

Next, the 3-hydroxy form (R=Ph
A solution of 1.55 mol (3.1 mole) of CH20CO:R=CHPh2) and 10 mol of tetrahydrofuran is added, followed by 0.86 mol of triethylamine (6.2 mole). After the reaction solution was heated at room temperature for 1.5 hours, it was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off, and the resulting residue was passed through a silica gel column with a volume of 3 pips, and benzene-ethyl acetate (10
:1), the target 3-chloride (m:R=P
hCH20CO; R'=CHPh2; x=CI) 0.9
5 days (yield 59.0%) is obtained. '2' The above 3-chloride (dish: R=PhCH20CO; R'=CHPh2
Dissolve 9 (1.83 mmole) of CI) 950 in methylene chloride and add 1.78 mmole of anisole (16.5 mmole) to it. A solution consisting of 1.45 mmoles (11 mmoles) of aluminum chloride and 18 mmoles of nitromethane is added to this solution and allowed to stand at room temperature overnight. 15 parts of ice-cold 2% hydrochloric acid was added to the reaction mixture, and the aqueous layer was washed successively with methylene chloride and ethyl acetate, and the solvent was removed under reduced pressure. The residual liquid is Diaion HP20 (Mitsubishi Chemical trademark;
high porous polymer) through a column of 400 p
Elute with H3 water. When the eluate was concentrated to pH 4.4, the desired free 3-chloride (1:R'=CI; R2=C
OOH; R3=H) 9 of 175 (yield 43.8%) is obtained.・R: Rikkou Houka-1:3420・181816
30.1613 Example 278-amino-1-oxa-
1-Dethia 3-cephem-4-carboxylic acid (1:RI
=R3=H;R2=COOH)(lb:R2=COOH
) [1} 3-hydroxy form (0:R=PhCH20C
O; R=CHPh2)1. Madarayu (3.96mmole)
was dissolved in 20% dimethylformamide, 0.62% (2 equivalents) of methylsulfonyl chloride was added to this at -50%, then 0.83% (1.5 equivalents) of triethylamine was added, and the mixture was heated at the same temperature for 13 minutes. worship the hawk.

The reaction solution was poured into ice water and the precipitated crystals were collected in a furnace to obtain the desired 3-methylsulfonyloxy compound, 78-benzyloxycarbonylamino-3-methylsulfonyloxy-1-oxer-1-dethia-3-cephem-4-. Carboxylic acid diphenylmethyl ester (m:R-PhCH20
C0;R':CHPh2;X=OS02CH3)2.1
5 ml (yield 94.0%) is obtained. IR:Hinishikibukuro 3-1:3420, 1810, 1730, 1510, 13
65, 11650 NMR: 8 (CDCl3) Trace: 2.9
6 (s, wide), 4.46 (wide, 2H), 4,97 (d,
J: 4.0 days 2, IH), 5.07 (s, ga), 5.4
5 (dd., J=4.0HZ, IH). [2] 3 above
-Methylsulfonyloxy compound (m:R=PhCH20C
O;R'=CHPh2:X=OS02CH3)1.15
Dissolve 2 moles of dichloromethane in a mixture of 20 moles of methylene chloride and 40 moles of acetic acid, add 3 moles of activated zinc powder, and let stand overnight at room temperature. During this time, 3 doses of zinc powder were added at 2 and 3 hours after the start of the reaction. Zinc powder was removed from the reaction mixture in an oven, ethyl acetate was added, the organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to obtain the desired 3-deoxy compound, 78-penzyloxycarbonylamino-1-oxer-1. -dethia 3-cephemu 4-carboxylic acid diphenylmethyl ester (W:R=PhCH20CO;
R'=CHPh2)913 secretion (yield 94.2%) is obtained as a powdered material. IR:Re Tokuda 3-1:34
50, 1800, 1730, 1650. NMR: 6(C
DC13) Trace: 4.41 (m, wide), 4.95 (d, J
=4.0HZ, IH), 5.15 (s, ga), 5.53
(dd., J=4.0, 9.0HZ, IH), 6.51
(m, IH), 6.99 (S, IH). This product can also be manufactured by the following method. 3-chloride obtained in Example 1 (dish: R=PhCH2○C〇; R'=CHPh2; X=
CI) 240 of 9, methylene chloride 4 of [and acetic acid 8
Dissolve the mixture and add 0.72 g of activated zinc powder,
Serve at room temperature.

During the period from 4 to 9 hours after the start of the reaction, 0.72 g of zinc powder was added three times each time, and the mixture was left under a hawk bed overnight. The zinc powder was removed from the reaction mixture in an oven, the solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The resulting residue was passed through a silica gel column and eluted with benzene-ethyl acetate (5:1) to obtain the desired 3-deoxy form (N
:R=PhCH2-OCO;R'=CHPh2)215
Females (yield 96.0%) are obtained. The above 3-deoxy form (W:R=PhCH20C.

;R'CHPh2) 913 phosphorus (18,8 mole)
To this, add 1.85 ml of anisole (9 equivalents) to methylene chloride, add a solution consisting of 1.51 ml of aluminum chloride (6 equivalents) and 1 ml of nitromethane, and leave at room temperature. Leave it overnight. The reaction mixture was extracted with 2% hydrochloric acid under ice cooling, and the extracted aqueous layer was washed with methylene chloride and ethyl acetate. The organic solvent in the aqueous layer was evaporated under reduced pressure, and the eluate was passed through a column of Diaion HP20 (Mitsubishi Kasei trademark; No Bolus Polymer) and eluted with dilute hydrochloric acid (pH 3.0). Concentration under reduced pressure yields the desired 3-oxacephem (1:RI=R3=H; R2=
COOH) hydrochloride 291 of 9 (70.6% yield) is obtained. [Pa] Color 4.511. r 2.4 (c=0.2
10 meta/-le). IR: Re-fin skin-1:3500, 2
600, 1805, 1645, 1610, 1550. N
MR: 6 (CD30D) 5.37 (d, J = 4.0 days 2
, IH), 5.51 (d, J=4.0HZ, IH), 6
．． 70(m,IH)YanagiO Example 3 78-Amino-3-(1-methyltetrazol-5-yl)thio-1-oxa-1-decithia-3-cephem-4
-carboxylic acid (1:RI=1-methyltetrazole-5
-ylthio; R2=COOH:R3=H) (le:Y=
1-methyltetrazol-5-ylthio; R2=COO
H) [1-3-methylsulfonyloxy compound obtained in Example 2 (Rainbow: R=PhCH20CO; R'=CHPH
2:×=OS02CH3) 1.12 evening (1.94 mmo
le) in dimethylformamide, cooled to 0°C, 373 M (3.2 mmole) of 1-methyltetrazol-5-ylthiol and 0.42 M (3.0 mmole) of triethylamine were added thereto, and the mixture was stirred overnight at room temperature. to worship.

After the reaction is completed, the reaction solution is poured into ice water, and the resulting yellow precipitate is collected in an oven, washed, and dried to obtain the desired 3-tetrazolylthio derivative (V:R=PhC ratio OCO; R'=CHP
h2:Y21-methyltetrazol-5-ylthio)1
．． 007 (yield 86.7%) is obtained as a yellow powder. IR: Hi Monu *3 Skin-1:3450, 1805173
0. NMR: 6 (CDCl3) Skin: 3.93 (s, fine)
, 4.28 (ABq, J=18HZ, 2H), 5.00
(d, J = 4.0 days 2, IH), 5,17 (s, pan),
5.30-5.90 (m, 2H), 6,98 (S, IH
). (2} The above 3-tetrazolylthio derivative (V:P
hC ratio OCO; R=CHPh2:Y=1-methyltetrazol-15-ylthio) 137 to 8 (0.229 skin mo
le) in 4 parts of methylene chloride, add 0.223 parts of anisole (2.06 mmole), and then dissolve 190 parts of aluminum chloride (1.4 mmole).
and nitromethane 2' is added.

The reaction mixture was left at room temperature overnight and then diluted with 2%
Add 3 portions of hydrochloric acid. The aqueous layer is washed successively with methylene chloride and ethyl acetate, and then concentrated. When sodium carbonate is added to this concentrated solution and the pH is adjusted to 2.5, the desired 76
-Amino-3-tetrazo 1''ruthio derivative (1:RI:
1-methyltetrazol-5-ylthio; R2=COO
H:R3=H)2.4 fences are obtained as crystals.

mp>20000. IR:Himotodama, enemy-1:182o,
1630, 1620. Example 4 78-Amino-3-methoxy 1-oxa-1-dethia 3-cephemu 4-carboxylic acid (1:RI=OCH3
;R2=COOH;R3=H)(ld:R2=COOH
;R river=CH3)'1' 3-hydroxy body (ro:R=
PhCH20CO:R':CHPh2) 1.15 evening (2
．． 30 mmole) in 12 parts of methylene chloride,
A diazomethane-ether solution was added to this, and 10
Light up for a minute.

The reaction solution was concentrated under reduced pressure, and the resulting oily residue was passed through a silica gel column of 50 ml, and benzene-ethyl acetate (4:
If the elution and purification is performed in step 1), the desired 3-methoxy form, 78-benzyloxycarbonylamino-3-methoxy 1-oxer 1-dethia 3-cephimu 4-carboxylic acid.
Diphenyl methyl ester (River: R=PhCH20CO
; R = CHPh2: R river = CH3) 0.89 m (yield 7
5%) is obtained. IR: 3c-1:3495
, 1796, 1725, 1626, 15120NMR:
6 CDC13) Skin: 3.70 (s, thin), 4.23
and 4.54 (ABq, J=18HZ, 2H), 4.
96 (d, J = 4.0 Hz, IH), 5.18 (s, ga), 5.42 (dd, J = 10 and 4.0 days 2, IH
), 5.81 (d, J=10HZ, IH), 7.02 (
s, IH), ~7.4 (m, aromatic ring proton). ■The above 3-methoxy form (W: R=PhCH20CO; R'=C
HPh2; R'''=CH3) 1.06 evening (2.06m
mole) in 20 parts of methylene chloride, and when cold, add 3 parts of anisole and 3 parts of acetic acid trifluoride, and make 1 part of the solution.
Pray for 5 minutes.

Add 20% of toluene to the reaction solution and concentrate under reduced pressure. The resulting oily residue is dissolved in benzene and extracted with a 5% aqueous sodium bicarbonate solution. Wash the extract with benzene and
After making it acidic (pH 2) by adding 0% hydrochloric acid. Extract with ethyl acetate. This extract was washed successively with water and brine, and the solvent was removed under reduced pressure to free 4-carboxylic acid, 73
-penzyloxycarbonylamino-3-methoxy 1
0.6 M of -oxa-1-dethia-3-cefim-4-carboxylic acid is obtained. IR: Rinishikibukuro 3-1:3430
, 1793, 172fu 1630, 1510. '3'5
% palladium-carbon 100% is suspended in 20% ethyl acetate-methanol (1:1) mixture to absorb hydrogen gas in advance. 200 parts (0.934 mmole) of the above-mentioned free 4-carboxylic acid is added to this mixed solution, and hydrogen gas is absorbed while stirring vigorously. After standing at room temperature for 2 hours, the catalyst was removed from the furnace and the solvent was distilled off under reduced pressure.
8-amino body <1:RI=. CH3;R2=COOH;
9 with R3=H>65 (yield 53%) is obtained. IR
:Rekikyo 1: ~340~2900, 178fu16
791647. The catalyst removed from the furnace was washed several times with methanol-hydrochloric acid, and the washings were removed under reduced pressure to form a 78-amino compound (1:RI=OCH3:R2=COOH;R3=H).
Hydrochloride 65:9 (yield 45%) is obtained as white powdery crystals. IR:〃Foundation main arc-1: ~milk oo, ~300
0, 1787, 169mm 1619. Example 57 3-amino-3-chloro-7Q-methoxy-1-oxa-1-dethia-3-cephemu-4-carboxylic acid p-nitrobenzyl ester (1:RI=CI:R2=COOCH2
・C6 day 4・N02-p; R3=OCH3) (le:R
=CI;R2=COOCH2・C6B・N02-p) {
1} 78-amino-3-chloro-1-oxer-1-dethia-3-cephemu-4-caralboxylic acid p-nitrobenzyl ester (1: RI=CI; R2; COOCH2
・C6 day 4・N021p:R3=H) [free 3-chlor form obtained in Example 1 (1:RI=CI;R2=COO
Obtained by esterifying H; R3=H)]
Dissolve 141 females (0.399 mmole) in a concentrated solution of 7 parts of chloroform and 1 part of benzene, and add 3.5 parts to this.
-d-t-butyl-4-hydroxybenzaldehyde 1
9 of 12 (1.2 equivalents) is added, and the mixture is heated to reflux in a reaction vessel containing a monocular sieve and equipped with a dehydration tube.

Start of reaction 2. After the worm time, add 9 of 30 aldehydes, and then add 3. Continue the insect time reaction. The reaction mixture is then cooled to -15 qo and 65 parts of magnesium sulfate and 219 parts of nickel peroxide are added and stirred at the same temperature for 30 minutes and then at room temperature for 40 minutes. The reactants were placed in a furnace, 5 parts of methanol was added to the furnace solution, and the mixture was heated at room temperature for 1. The period of time is cicada. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column with 12 layers of silica gel and eluted with benzene-ethyl acetate (19:1) to obtain the desired 7-methoxy compound, 7B-(3.5
-di-t-butyl-4-hydroxybenzylidene)amino-3-chloro-7o-methoxy1-oxer1-dethia3-cephemu4-carboxylic acid p-nitrobenzyl ester (e: RI=CI; R2=COOCH2
C6 day 4・N02-p; 78 one side chain = 3.5-G t-
Butyl-4-hydroxybenzylidene amino) 125-9 (yield 52.2%) is obtained as a candy-like substance. IR
:〃Kinkan 3 arcs: 178o, 1735, 1680, 15
20, 1345. NMR: 6 (CDC13) Chest: 1.
48 (s, 1 group), 3.61 (s, thin), 4.49 (s
, is), 5.23 (s, IH), 5.44 (aromatic ring proton), 8.53 (s, IH). ■ The above 7-methoxy form (e: RI=CI; R2=COOCH2・C6day4・
N021p; 78 one side chain = 3,5-di-t-butyl-4
-Hydroxybenzylidene amino) 125 female was dissolved in a mixture of 2.5 parts of methanol and 0.5 parts of tetrahydrofuran, and added with Girard reagent (0jrard T).
Add 9 of 81 and stir at room temperature for 1 hour. The reaction mixture was poured into water, extracted with methylene chloride, and the methylene chloride extract was washed with water, dried, and evaporated under reduced pressure. The resulting residue was passed through a column of 3.5 mL of silica gel, and benzene-ethyl acetate (4:
1) After elution fractionation, the desired 7-amino compound (1:RI=
CI; R2=COOCH2・C65・N021p:R3
=OC) 35M (yield 43-8%) is obtained. IR
:Re Toen and 3 skins: 1790, 1740, 1520, 1
350. NMR: 6 (CDC13) Yanagi: 1.83 (戊, が), 3.53 (s, thin), 4.54 (s, ban), 5
．． 01 (s, IH), 5.47 (split, ga), 7
．． 67 (d, J = 9 days 2, IH), 8.28 (d, J:
9th day 2, IH), 8.28 (d, J=9HZ, IH).
Similarly, the following compounds can be obtained by any of the above methods.

78-amino-1-oxa-1-dethia-3-cephemu 4-carboxylic acid p-nitrobenzyl ester (1:
RI NiH; R2=COOCH2・C6 day・N02-p;
R3=H): (IR:Retokudan 3hada-1:3405, 17
72, 1726, 1633, 1605, 1517, 13
450NMR: 6 (CDCl3) Skin: 1.74 (b, 2
H), 4.61 (m, 2H), 5.05 (d, 1=4.
0HZ, IH), 5.42 (wide, 2H), 5.5 (m,
IH), 6.615 (m, IH), 7.67 and 8.
31 (q, J=9.0HZ, 4H).

73-Amino-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephemu-4-carboxylic acid p-nitrobenzyl ester 0 (1:RI=OS02CH
3:R2=COOCH2・C6day・N02-p;R3:
H):IR:Renabe Kankitsune-・:342o, 1790, 17
35, 16100NMR: 6 (CDC13) Skin: 2.1
5 (戊, が), 3.23 (s, thin), 4,52 (s, 2
H), 5.02 (d, J=4HZ, IH), 5.30 (
s, ga), 5.33 (m, IH), 7.48 and 81
0 (q, J=8.0HZ, 4H).

78-Amino-3-phenylthio-1-oxa-1-dethia-3-cefemu-4-carboxylic acid (1:RI=S.
Ph; R2=COOH; R3=H).

Example 6'1} 2-[2f-(2-propynyloxy)-38-amino-4-oxoazetidin-1-yl]-2-isopropylideneacetic acid diphenylmethyl ester (2:R'-CHPh2 )-2-(2f-chloro-38-amino-4-oxoazetidin-1-yl)-2
-isopropylidene acetic acid diphenylmethyl ester (
1:R=CHPh2:X'=CI) 0.95 moles were dissolved in a mixture of 3 parts of propargyl alcohol and 2 parts of tetrahydrofuran, and 0.79 parts of silver tetrafluorochloride (4 moles) was added to this. Stir for 3 hours at room temperature.

The reaction mixture was diluted with 50 parts of benzene, cooled to 0°C, and a mixture of 10 parts of 5% sodium bicarbonate and 5 parts of saturated saline was added thereto. This mixture is filtered through Celite to separate the furnace liquor. The benzene layer is dried with ramie and concentrated under reduced pressure to yield a brown oil. When this was purified by chromatography using 10% hydrous silica gel, the desired 2-propyloxy derivative (2:
R'=CHPh2) 268 9 (2Q-propynyloxy form 134 members 9 and 28-propynyloxy form 134
o) is obtained. - Propynyloxy form: IR: 3400, 3320, 2115, 1767
, 17230NMR: 6 (CDCl3) trace: 1.83 (
br-s, general), 1.98 (s, chichi), 2,22 (s
, Pan), 2.33 (t, J=2.5HZ, IH), 4,
07 (d, J = 2.5 days 2, ga), about 4.07 (m, I
H), 4.93 (d, J=1.0HZ, IH), 6.9
0 (s, IH), 7.32 (s, 1 order) 23-F.

o Pyroxy form IR: Hikinishiki Muga-,: 3410, 33
20, 2115, 1767, 1720. NMR: 6(C
DCl3) Chest: 1,77 (br-s, 2H), 2,00
(s, general), 2.23 (s, general), 2.27 (t, J=
2.5HZ, IH), 4.12(d, J=2.5HZ,
Pan), 4.23 (d, 1:4.0HZ, IH), 5.2
7 (d, J=4HZ, IH), 6.90 (s, IH),
7,32 (s, 1 female). {2) 2-[28-(2-propynyloxy)-38-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetic acid diphenylmethyl ester (3:R=
PhC ratio OCO; R'=CHPh2) - the above 28-propynyloxy derivative (2:R'=CHPh2) 30.0
0.074 mole of anhydrous methylene chloride was added to 250 moles of anhydrous methylene chloride, 14.07 mole of penzyloxycarbonyl chloride (0.0825 mole) was added under ice-cooling, and then 6.7 moles of pyridine was added to the solution of 6.7 mole of pyridine. 0.0828ho
A solution consisting of methylene chloride and methylene chloride was added dropwise, and the
Rope for a minute. The reaction mixture was poured into ice water and extracted with methylene chloride. The extract was washed with water and brine, dried, and the solvent was removed under reduced pressure. The resulting oily residue was chromatographed on silica gel 1000 ml and eluted with benzene-ethyl acetate (5:1) to yield 26.5 ml (66.5 ml).
3% yield) of the target product 38-benzyloxycarbonylamino derivative (3: R = PhC wide OCO; R' = CHPh
2) is obtained. IR:Re falling ball 〆3 skin-1:3440,
3300・2110・1774, 1720, 1630,
1507. NMR: 6 (CDC13) Skin: 2.00 and 2.25 (s, coarse x2), 2.17 (d, J=3HZ
, IH), 4.07 (d, J = 3 days 2, 2H), 5.1
0 (d, J=4HZ, IH), 5.17 (s, ga), 5
．． 33 (q, J=8 and 4HZ, IH), 5.55 (
d, J=8HZ, IH), 6.98 (s, IH). '3
'2-(28-allyloxy-38-penzyloxycarbonylamino-4-oxoazetidin-1yl)
12-isopropylidene acetic acid/diphenyl methyl ester (4:R=PhCH20CO;R'=CHPh2) 15% palladium-calcium carbonate was suspended in 170m' of methanol and hydrogenated under the ocean. absorb gas.

Then, the above 38-penzyloxycarbonylamino derivative (3:R=PhCH20CO:R'=CHPh2)2
Dissolve 0.049 holes in 100 ml of methanol and add to the palladium catalyst suspension. After standing in hydrogen gas for 50 minutes, the catalyst was removed from the furnace and the furnace liquid was concentrated under reduced pressure to obtain the desired 28-allyloxy derivative (4:R=P
hCH20CO; R'=CHPh2) 26.3 evening (98
．． 8% yield) is obtained. IR: Le Tokibukuro to 3hada-1: I 40, 1772, 172 stops 1628, 1505. N.M.
R: 6 (CDCl3) Trace: 2.00 and 2,25 (s
, is x2), 3-90 (m, 2H), 4.8-5-9 (
m, mother H), 5.17 (s, ga), 6.95 (s, IH
). ■2-[28-(2.3-epoxypropoxy)-
33-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isop. Pyrideneacetic acid/diphenylmethyl ester (5:R=PhC ratio OCO:R
'CHPh2) - the above 28-allyloxy derivative (4
:R=PhC&OCO;R'=CHPQ)25
．． 6 Add 0.047 mole of chloroform to 260
To this, 15.3 moles (0.071 mole) of m-chloroperbenzoic acid was gradually added, and the mixture was heated to room temperature (23 to 2 moles).
Leave 2 questions to yourself at 5q0).

The reaction solution is concentrated under reduced pressure, and the resulting residue is dissolved in ethyl acetate, washed successively with 5% aqueous sodium thiosulfate, 5% aqueous sodium bicarbonate, water, and brine, and the solvent is removed under reduced pressure. The resulting oily residue was chromatographed on silica gel 800 gel and benzene-ethyl acetate (
5:1), the desired epoxy derivative (5:R
=PhCH20CO; R=CHPh2) 21.25 evening (
81.2% yield) is obtained. IRI: Bitokura 3 Hada-1
:3445, 1778/1724/1632, 1508
. NMR: 6 (CDC13) Yanagi: 2.00 and 2.2
5 (s, thin x 2), about 2.2-3.9 (m, mottled), 5.
18 (s, ga), about 5.0-5.3 (m, 2H), 5.
58 (d, J = 10 days 2, IH), 6.83 (s, IH
). In addition, in this step, a small amount of jepoxy body (2.25 min; mpl 18-120 oo) is obtained as a by-product. ■ 2-[28-(2,3-dihydroxypropoxy)-3-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetic acid.
Diphenylmethyl ester (6:R=PhC ratio OCO;
R′=CHPh2) The above epoxy derivative (5:R=P
hC ratio OCO: R' = CHPh2) 21.25 evening (0.
038hole) is dissolved in 220M' of acetone, 66% of 30% perchloric acid and 44ml of water are added thereto under ice-cooling, and the mixture is heated at room temperature for 2 to 3 hours.

Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 5% aqueous sodium bicarbonate, water, and brine, and then the solvent was removed under reduced pressure. The resulting oily residue was dissolved in 200% methanol, added with 40% 10% hydrochloric acid, and stirred at room temperature for 30 minutes. Next, ethyl acetate was added, washed with 5% sodium bicarbonate solution, water, and brine, and after drying, the solvent was removed under reduced pressure to obtain the desired diol derivative (6:R=PhC ratio OCO;R
'=CHPh2) 20.6 hours (94.4% yield) are obtained.

IR: 36oo, 3445, 1778
, 1725, 1632, 1508. NMR: 6 (CDC
13) Chest: 1.97 and 2.22 (s, pan x2), 3
．． 47 (m, 4H), 4.9-5.3 (m, 2H), 5
．． 13 (s, ga), 6.07 (m, IH), 6.97 (
s, IH). Similarly, the above 28-propynyloxy compound (2:R=CHPh2) was reacted with phenylacetyl chloride to obtain a 33-phenylacetamide derivative (3:R=CHPh2).
=PhC is OCO; R'=CHPh2), and when this is sequentially subjected to hydrogenation, epoxidation, and epoxy ring process,
2-[26-(2,3-dihydroxypropoxy)-3
8-phenylacetamido-4-oxoazetidine-1
-yl]-2-isopropylideneacetic acid diphenylmethyl ester (6: R=PhCQCO; R'=CHPh2
) is obtained.

Example 7 {1'2-[28-(2,3-isopropylidenedioxypropoxy)-38-penzyloxycarponylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetic acid diphenyl Methyl ester (13:R=
PhCH20CO; R'-CHPh2)-28-(2,3-dihydroxypropoxy)-38-penzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetic acid diphenylmethylester (6: R=PhCH20CO; R=CHPh2
) Dissolve 2.5 liters in 50M acetone, add 5 parts 9 parts of p-toluene/sulfonic acid to this under ice cooling, and stir for 3 hours.

Next, a small amount of 5% aqueous sodium hydrogen carbonate is added to this, and the mixture is concentrated under reduced pressure. The remaining residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The obtained residue was subjected to chromatography on silica gel and eluted with benzene-ethyl acetate (2:1) to obtain the desired isopropylidene dioxy Conductor (
13: R = PhC ratio OCO: R' = CHPh2) 2.2
6 hours (84% yield) are obtained.

IR: Retotai 3hada-1:3450, 1780, 1725
, 1635, 1600. NMR: 6 (CDC13) legs; 1.28 (s, thin), 2.00 (s, wide), 2.25
(s, 3H), 3.25-4.20 (m, spots), 4.9
0-5.77 (m, spots), 6.95 (s, IH), 7.
Around 3 (m, 1 group). (2 hands 2-[28-(2,3-isopropylidenedioxypropoxy)-38-benzyloxycarbonylamino-4-oxoazetidine-1
-yl]-2-hydroxyacetic acid diphenylmethyl ester (15:RPhCH20CO;R';CHPh2
)-the above isopropylidene dioxy derivative (13:R=
PhC expansion OCO: R'=CHPh2) 2.2 evenings (3.5
8 mmole) was dissolved over 40 methylene chloride, and ozone was introduced therein under cooling with dry ice-acetone until the reaction solution took on a blue color.

After removing excess ozone, 2.2 g of methyl sulfide was added, and the mixture was cooled at the same temperature for 1 hour and then left at room temperature for 1 hour. After adding a small amount of acetic acid to the reaction solution, washing with water, drying, and concentrating, the intermediate 1-diphenylmethoxalyl-28-
(2,3-isopropylidenedioxypropoxy)-3
8-benzyloxycarbonylamino-4-oxoazetidine (14:R=PhC-OCO:R=CHPh2)
You get 2 evenings. Immediately dissolve this in a source solution of 20 parts methylene chloride and 20 parts acetic acid, add 2 parts activated zinc powder, and keep under ice for 2 hours. Remove the zinc powder in a furnace, wash with methylene chloride, combine the furnace liquid and washing liquid, wash with water, dry,
Upon concentration, the desired 2-hydroxy derivative (15:R=
PhCH20CO; R'=CHPh2) 2.0 evening (95
% yield) is obtained. IR: Shikaede Shizuhada 4: 350o, 3
43o・1780・1740・1720, 16000N
MR: 6 (CDC13) Skin: 1.47 (s, thin), 3.
17-4.30 (m, 5-thin), 5.16 (s, wide),
4.70-6.00 (m, 3-4H), 6.97 and 7.00 (each s, IH), 7. Close to the needle (m, aromatic ring proton). (3'2-[28-(2,3-isopropylidenedioxypropoxy)-38-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-
Triphenylphosphoranylidene acetic acid/diphenylmethyl ester (16: R=PhC ratio OCO; R'=CHPh
2)-The above 2-hydroxy transferor (15:R=PhCH
20CO; R'=CHPh2) 2.0 evening (3.4 mmo
Le) was dissolved in 60' of anhydrous methylene chloride, 1.3 mole of dimethylaniline (10.2 mole) was added thereto under ice cooling, and then 0.74 mole of thionyl chloride (10.2 mole) was dissolved.
mmole) was added dropwise and kept at the same temperature for 30 minutes.

The reaction solution was cooled with ice, and the methylene chloride layer was washed with water, dried, and concentrated to give 2-[23-(2,3-isopropylidenedioxypropoxy)-38-benzyloxy] as an intermediate. Carbonylamino-4-oxoazetidine-1
-Yel]-2-chloroacetic acid diphenylmethyl ester 2.3 times is obtained [IR:Renishikishio〆]2-1:343
01178F1750/1720/1595] Dissolve garlic in 40% methylene chloride, add 0.86 dimethylaniline (6.8 mole) and 1.89 (6.8 mmole) of triphenylphosphine, After heating under reflux for 6 hours, 1.8 hours of triphenylphosphine was added and the mixture was allowed to react for 12 hours. The reaction mixture was poured into 5% sodium bicarbonate water under cooling, washed with water, dried, and concentrated. The resulting residue was subjected to chromatography on silica gel to obtain the desired triphenylphosphorane derivative (1
6: REPhC expanded OCO: R'=CHPh2) 1.6 hours (56.6% yield) is obtained.

IR: Les Nishikibukuro 3-1: 3400, 1760, 1710
, 1620, 1590. {4-21 [231 (2.3
-dihydropropoxy)-38-penzyloxycarbonylamino-4-oxoazetidin-1-yl]-2 triphenylphosphoranylidene acetic acid diphenylmethyl ester (17: R=PhCH20CO; R'=CHP
h2) - the above triphenylphosphorane derivative (16:R
=PhCH20CO;R'=CHPh2)417m9(
Dissolve 0.5 mmole in 8 parts of methanol, add 1.6 parts of 10% hydrochloric acid, and stir at room temperature for 40 minutes. The reaction solution was poured into cooled 5% sodium hydrogen carbonate water,
Extract with ethyl acetate. The extract was washed with water, dried, and concentrated, and the resulting residual solution was subjected to chromatography on silica gel to obtain the desired deacetonide (17:R=PhC
CO:R'=CHPh2) 9 of 172 (43.3% yield) is obtained. IR Sanre Kinka 3 Hada-1:3450-32
00, 1770/1720/1630, 1600. '5
) 78-penzyloxycarbonylamino-1-oxa-1-dethia-3-cephem-4-carboxylic acid diphenylmethyl ester (W:RPhCH20CO;R'
=CHPh2)-the above deacetonide form (i7:R=Ph
CH20CO; R'=CHPh2) 139 female (0.17
5 mmole) in 4 parts of tetrahydrofuran,
This was added to periodic acid (9 of Nal0445 and IN-W).
S042.2 (consisting of) was added under ice cooling, and the mixture was incubated at the same temperature for 3 hours, and then further incubated at room temperature for 1 hour.

The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The resulting residue was separated and purified by silica gel chromatography to obtain the desired oxacephem protected substituted derivative (W:R=PhC Mountain OCO:R
'=CHPh2) 9 of 15 (17.7% yield) is obtained. This product completely matches the separately synthesized product obtained in Example 2 in thin layer chromatography, IR spectrum, and NM old spectrum, confirming that it is the same compound. Example 8 {1) 2-[28-(2-oxoethyloxy)-3
8-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetic acid diphenylmethylester (7:R=PhCH20CO;R
'=CHPh2)-2-[26-(2,3-dihydroxypropoxy)-38-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetic acid diphenylmethyl ester (6:R =P
hCH20CO; R'=CHPh2) 11.5 evening (0.
02hole) was dissolved in 200ml of ethanol, and to this was added 5.14ml of sodium periodate (0.024mol).
Add a solution consisting of e) and IN-sulfuric acid 210' and mix for 3 minutes at room temperature.

The reaction solution was poured into ice water, extracted with ethyl acetate, the extract was washed with water and brine, and after drying, the solvent was distilled off under reduced pressure to obtain the desired formyl conductor (7:R=PhC&OCO:R
' = C liver h2) lo. You can get 8 takami. IR:Res Tokimaimu 1:344fu1778172fu1632,150&
'2) 2-(28-methoxycarbonylmethoxy3
8-benzyloxycarbonylamino-4-oxoazetidin-1-yl)-2-isopropylideneacetic acid diphenylmethyl ester (8:R=PhCH20CO:R
'=-CHPh2;R''=C ratio) the above formyl derivative (
7:R=PhC ratio OCO:R'=1CHPh2) Dissolve 10.8 liters in 100 ml of acetone and add 14 M of Jones reagent at a temperature below 15 qo to an ice-cold drop.

After 30 minutes, i-propanol is added to the reaction solution to kill excess reagent, and insoluble matter is removed in an oven.

The furnace solution was poured into ice water, extracted with ethyl acetate, and the extract was poured into water. After washing with brine, the solvent was distilled off under reduced pressure to obtain the crude carboxylic acid (8: R=PhCH20CO; R'=CHP~
R″=H) 11.1 is obtained. This is dissolved in 150 methylene chloride and esterified by adding a diazomethane-ether solution. The solvent is distilled off and the resulting residue 11
The sample was passed through a silica gel 200 column and eluted with benzene monoethyl acetate (5:1) to obtain the desired methyl carboxylate (8: R = PhC; R' = CHPh2; R
″=C horse) 9.2 days (80.3% yield) is obtained.I
R: Shitoshio Sohada - 1: 344 1780, 172 Fu 16
35.15100NMR: 6 (CDC13) Chest: 2.0
0 and 2.25 (each s, pan x2), 3.58 (s,
ancestor), 3.97 (s, bait), 5.0-5.40 (m, ga), 5.13 (s, general), 5.57 (d, J=8HZ,
IH), 6.93 (s, IH). {3'1-diphenylmethoxalyl-28-methoxycarbonylmethoxy 3
8-penzyloxycarbonylamino-4-oxoazetidine (9:R=PhCQOCO:R'=CHPh2;
R″=C is)-the above methyl carboxylate (8:R:PhC
The ratio OCO: R'=CHPh2;R''=CH3) 9.2 holes (0.016 holes) is dissolved in methylene chloride 230', cooled to -78q C and ozone introduced therein.

After about 3 minutes, when the reaction solution turns blue, the reaction is stopped and nitrogen gas is introduced to drive out excess ozone. Then, the mixture was cooled to 178°C, 10°C of dimethyl sulfide was added, and the mixture was incubated at the same temperature for 1 hour and then at room temperature for 1 hour. 2 to 3 drops of methylene chloride and acetic acid were added to the reaction solution, washed successively with water and brine, dried, and the solvent was distilled off to obtain the desired methoxalyl derivative (9: R=PhCH20CO; R'=C
HPh2;R''=CH3) 8.99 is obtained as an oil.IR:Rekintai 3-1:3450, 1830.1
756, 1720, 1509. (4} 2-(28-methoxycarbonylmethoxy-38-benzyloxycarbonylamino-4-oxoazetidin-1-yl)-2
-Hydroxyacetic acid diphenylmethyl ester (10:
R=PhC uniform OCO; R′=CHPh2:R″=CH3
)-the above toxalyl derivative (9:R=PhCH20C
O:R'iCHPh2:R''=CH3) 8.9 hours was dissolved in a mixture of 90 parts of methylene chloride and 90 parts of acetic acid, and 9 parts of activated zinc powder was added to this under ice-cooled water.

After about 15 to 30 minutes, the zinc powder is removed from the furnace, methylene chloride is added to the furnace solution, and the mixture is washed successively with water and saline. After drying, the solvent was distilled off under reduced pressure to obtain the desired hydroxyacetic acid derivative (10:R=PhC ratio OCO; R'=CHPh2:R''
=CH3) 8.4 hours (95.2% yield) are obtained. I
R: Leskin hair 3 skin-1: 3500-360 or more 3445.1
790 1747, 1512. [5'2-(20-Methoxycarponylmethoxy-38-penzyloxycarponylamino-4-oxoazetidin-1-yl)-2-chloroacetic acid diphenylmethyl ester (il:R=P
hC ratio OCO: R'=CHPh2;R''=CH3;X'
'=CI) - the above hydroxyacetic acid transfer derivative (io:R=P
hC ratio OCO; R'=CHPh2:R''=CH3)8.
4 moles (0.015 mole) of anhydrous methylene chloride 100
of thionyl chloride, and add 3.34% of thionyl chloride (0.
046 moles) and 1.46 moles of pyridine [(0.0
18 mole) was dropped onto an ice-cold rope underwater.

After cooling on ice for 3 minutes, add an appropriate amount of methylene chloride to the reaction solution, and wash with water and brine. After drying, the solvent was distilled off under reduced pressure to obtain the desired monochloroacetic acid derivative (11:R
=PhC ratio OCO; R'=CHPh2:R''=CH3;
]''-CI) 8.9 minutes are obtained. rw chicken skin 3 skin-1:
3435, 1790, 1748, 1725 1502.
{6'2-(28-lupoxymethoxy-30-penzyloxycarbonylamino-4-oxoazetidine-1
-yl)-2-triphenylphosphoranylidene acetic acid diphenylmethyl ester (12:R=PhC&OCO;
R=CHPh2)-the above monochloroacetic acid derivative (11:
R=PhCH20CO; R=CHPh2:R″=C ratio:
Dissolve 0.015 mole of X''=CI) in 100 M methylene chloride to which 8.0 mole of triphenylphosphine (0.03 mole) is added.1. Heat to reflux for a period of time.

This was then treated with 2.0 tsp of triphenylphosphine (7.0 tsp).
5 mmole) and further heated under reflux for 1 hour. The reaction solution was poured into 5% aqueous sodium bicarbonate, neutralized, and extracted with methylene chloride. The extract was washed sequentially with water and brine, dried, and the solvent was distilled off under reduced pressure.
4:1 to 1:1), the desired triphenylphosphorane methyl ester, i.e., 2-(20-methoxycarbonylmethoxy-38-benzyloxycarbonylamino-4-oxoazetidin-1-yl) 10.2 times (84.1% yield) of 12-triphenylphosphoranylidene acetic acid/diphenylmether ester are obtained. I
R:〃Nishikami 3 enemies-1:3445・I790・I725・
I630/I5I20NMR: 6 (CDCl3) Skin: 3
．． 58 (s, thin), 3,6-5.2 (m, 4H), 5.
07(s,ga). 16.23 mmole (20.5 mmole) of the above triphenylphosphorane 1 methyl ester was dissolved in 240 mmole of tetrahydrofuran, and 118 mmole (2 mmole) of sodium hydroxide solution (0.19 mmole/similar) was added to this under ice cooling.
2.5 mmole) was added dropwise over 30 minutes at a temperature of 2-5°C. After pressing the reaction solution for 1 hour, add 2% hydrochloric acid
Neutralize by adding (23 mmole) of [(23 mmole), and extract with ethyl acetate. The extract was washed with water and brine, dried, and the solvent was distilled off under reduced pressure to obtain the desired triphenylphosphorane derivative (12:R=PhCH20CO:R=CHPh2).
15.8 evenings are obtained.

IR:Retokami 3 arc-1:3440, 177i17251
625.1510. [7] 70-penzyloxycarbonylamino-3-hydroxy-1-oxa-1-dethia-3-cephemu 4-carboxylic acid diphenylmethyl ester (R=PhCH20CO; R'=CHPh
2)-The above triphenylphosphorane conductor (12:R:
PhCH20CO; R'=CHPh2) 15.8 evening (2
0.3 mmole) in 300M anhydrous toluene,
This was combined with 41.4 mmoles (406 mmoles) of acetic anhydride and 8.87 mmoles (102 mmoles) of NON-dimethylacetamide.
ole) and 16 to 100-1050○ (normal temperature).
Heat for an hour.

After pouring, benzene was added to the reaction mixture, and the mixture was washed successively with water and brine, dried, and the solvent was distilled off under reduced pressure to obtain a residue of about 20 minutes. This was passed through a silica gel 600 column and a benzene-ethyl acetate-acetic acid (9:1:0.001)
Elution with falcon solution yields 3-acetoxy-78-benzyloxycarbonylamino-1-oxa-1-dethia-3-
Cephem-4-carboxylic acid/diphenylmethylester 5.08 g (48% yield) (hereinafter referred to as 3-acetoxy form) and 2-(2-penzyloxycarponyl-3,8-dioxo 5) as a by-product -oxa m2.7-diazabicyclo[4.2.0]octane-7-yl)-2
-Triphenylphosphoranylidene acetic acid/diphenylmethylester 3.25 hours (21.5% yield) are obtained.
3-Physics of acetoxy body teaching position: Le Qiandan 3 skin-1:34
45, 1800, 1785 172fu 1656, 15
08.

NMR: 6 (CDCl3) Yanagi: 2.00 (s, Chihito),
4,32 (s, ga), 5.05 (d, J=4HZ, IH
), 5.13 (s, ga), 5.38 (q, J = 4 and 10HZ, IH), 5.68 (d, J = 10HZ, IH
), 6.95 (s, IH). Physical constants of by-products IR: Les Kinkura 3-1: 179o, 177 & 1740, 162
80NMR: 6 (CDCl3) Chest: 3-4 (m, 2H)
, 4-5 (m, general), 5.27 (s, ga).

3.2 mmoles (5.9 mmole) of the above 3-acetoxy compound was dissolved in a mixture of 60 parts of pyridine and 12 parts of water,
Stir for 1.7 hours at room temperature.

Pour the reaction mixture into ice and extract with ethyl acetate. The ethyl acetate extract was washed successively with water, 10% phosphoric acid, water, and brine, dried, and the solvent was removed under reduced pressure to obtain the desired 3-hydroxy form (D:R:PhC ratio OCO; R'=CHPh2). 3
．． 05 is obtained as a white foam. IR:Reshi Higeshi〆3佽1: 3440, 1795, 1725, 1675,
1625, 15100NMR: 6 (CDCl3) Skin: 4
．． 37 (s, ga), 5.05 (d, J=4HZ, IH)
, 5.18 (s, 2H), 5.45 (q, J=loHZ
, IH), 5.72 (d, J=10HZ, IH), 7.
00 (s, IH), 10.83 (s, IH). This product can be used as a raw material compound in Example 1.

Claims (1)

[Claims] 1 7-amino-3'-nor-1-oxa-1 represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼
- dethiacephalosporanic acid compound (wherein R^1 is a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkylsulfonyloxy group, an arylthio group or a methyltetrazolylthio group; R^2 is COOH or (nitro or phenyl)benzyloxycarbonyl group; R^3 represents a hydrogen atom or a methoxy group; respectively).