JPS6040437B2 - Oxazolinoazetidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an oxazolinoazetidine compound (1) useful as an intermediate for the synthesis of antibiotics and a method for producing the same.

Compound (1) represented by formula (1) is produced by subjecting penicillin 1-oxide compound (0) represented by formula (0) to a ring-opening and closing reaction.

(In the formula, R is an aralkyl, phenoxymethyl or aryl group; B is a lower alkoxy, aralkoxy or nitroaralkoxy group; X is hydrogen, halogen or a lower alkanoyloxy group; respectively) Compound (1) is a compound (0) It can be produced by subjecting it to a ring-opening and closing reaction.

Compound (b) is described in J. Chem. Soc. Perkin
It can be manufactured according to l973932. This ring-opening/closing reaction can occur by heating alone as described in the examples (example in which benzene and N.N-dimethylacetamide (3:2) were refluxed in hawk liquor), so no particular reagent is essential. This reaction is carried out by producing sulfenic acid from compound (2) and subjecting it to a desulfurization reaction, so the conditions for producing deacetoxycephalosporanic acid from penicillin sulfoxide can be applied in the first stage, and in the second stage can be promoted by adding a desulfurization agent.

Here, as desulfurizing agents, trivalent phosphorus compounds (triarylphosphorane, trialkylphosphorane, trialkoxyphosphorane, etc.), sulfur compounds (sulfenic acid, sulfinic acid, sulfites, etc.), halogen compounds (molecular halogen, N-haloamide, N-haloimide, etc.), acids (organic acids, inorganic acids), acid anhydrides, and other compounds having an affinity for sulfur atoms are used. During the reaction, water that dissolves in the oxide is generated, but it can be removed by adding a molecule to the reaction solution or by drying the reflux solution. However, dehydration conditions are not essential for this reaction. Preferably, this reaction is carried out in a solvent.

The solvent is a hydrocarbon (benzene, toluene, hexane, etc.)
, halohydrocarbons (methylene chloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (dioxane, tetrahydrofuran, etc.), amides (N/N-
dimethylformamide, N/N-dimethylacetamide, hexamethylphosphorotriamide, etc.), esters (
Ethyl acetate, amyl acetate, etc.), alcohols (ethanol, butanol, t-butanol, etc.), and various other inert solvents can be used without significantly reducing the yield.

The reaction temperature is preferably 70°C to 130qo.

Although the reaction proceeds below 70°C, the reaction is slow and 13
Although the reaction proceeds at temperatures above 0 pm, the amount of decomposition products increases.

The reaction usually completes within a few minutes at high temperatures and several hours at low temperatures. The compound produced in this way can be easily purified by conventional methods such as removing it in an oven, washing it with water, drying it, concentrating it, and purifying it with silica gel chromatography if necessary. can be isolated to

Compound (1) thus produced can be used as a synthetic intermediate for antibiotics.

For example, by treating compound (1) with a base, compound (m) represented by the formula (blood) can be produced. (In the formula, COB
(R, This can be easily carried out by reacting at 0° C. to 7,000° C. for 1 minute to 5 hours.

Compounds (m) in which R is aryl are important because they promote the cleavage reaction of the oxazoline ring.

Compound (m) is hydrated after being treated with propargyl alcohol, and the side chain at position 1 of azetidinone is cleaved with ozone, reduced, and replaced with halogen, and then treated with triphenylphosphine to produce the Wittig reagent and ring-closed. In this way, 1-oxadethiacephalosporin can be produced. According to the method of the present invention, special face Sho 51-13580
The desired 1-oxadethiacephalosporin can be produced with a higher yield and fewer side reactions than the method described in No. 1. Compound (1) can be easily converted to 1-oxadethiacephyl by converting the exomethylene group into a diol with osmium tetroxide, then ring-closing with boron trifluoride, and dehydrating the product. Allosporin can be produced.

As mentioned above, the present invention provides a useful intermediate and a highly efficient method for producing the same.

Examples and manufacturing methods of the present invention will be described below with reference to Examples.

Example 1 Preparation of oxazo 1'' noazetidine compound (1) from penicillin 1-oxide (b) Table 1 illustrates the reaction conditions for the title ring opening and closing reaction.

Table 0 shows the physical constants of the products.

To show the details of the operation, Table 1 No. The reaction and post-treatment operations in step 8 are described below.

(No. 10) Dissolve 38.51 parts of 6Q-benzamidobenicillanic acid diphenylmethyl ester 1-oxide and 22.11 parts of triphenylphosphine into a mixed solution of 308 parts of toluene and 308 parts of 1,2-dichloroethane. 3. While dehydrating the distillate using a Dean-Stark type dehydrator packed with molecular nodes. Insect time reflux.

After cooling, the reaction solution was concentrated to 150% and purified by chromatography on 10% hydrated silica gel (500 ml). When crystallized, Q-(3-phenyl-7-oxo-4-oxer-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-Q-isoprobenylacetic acid diphenylmethyl ester 28.15
Get the evening. Yield: 81.2%. mPI16.5-118
00. Example 2 Production of double bond isomer (m) from compound (1) [1]
Q-(3-phenyl7-oxo4-oxer2.
6-diazapicyclo[3.2.0]heptoe-2-ene-
Dissolve 281-9 of p-nitrobenzyl isoprobenyl acetate in 2-2 of methylene chloride, add 48 of triethylamine, and let stand at room temperature for 15 minutes.

By concentrating the reaction solution under reduced pressure, Q-(3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0
] Hept-2-en-6-yl)-q-isopropylidene p-nitrobenzyl acetate 278-9 is obtained.

Yield: Quantitative. Foamy matter. NMR:6CDC131.96
3 days, 2.3$9 days, 5.0$IH, 5.1$IH, 5
．． 4 squares (3HZ) IH, 6.17d (3HZ) IH, 7
．． 3-7.6 7.9-8.4m. '21 In the same manner as in [1' above]
-en-6-yl)-Q-isoprobenylacetate 75M diphenylmethyl acetate is stirred with 0.03 triethylamine in methylene chloride 5' at room temperature for 1 hour, Q-(3-benzyl-7-oxo-4-oxer 2,6-diazabicyclo[3・2.0〕Hept-2-en-6-il)-
Q-isopropylidene diphenylmethyl acetate is obtained. m
pl04.5-106qo. Yield: 95%. Reference Example 1 Production of raw materials (Part 1) ×=CQCOO-

The residue was dissolved in a small amount of methylene chloride, and petroleum ether was added to crystallize it to obtain compound (2). mp8
3-8600. IR:〃Ascension CI33430, 3005
, 1785, 1745, 1700 skin 10NMR: 6
C0o13 1.9m3 days, 4.47s2 days
, 5.01s IH, 4.9-5.3h crime, 5,17d (
2 days 2) IH, 6.9$ IH, 6.8-8.1mlSH
.

(mouth) - Compound ■ 1.36 minutes, 400 parts of silver acetate and 1 part of acetic acid were stirred at room temperature for 3 hours in 21 parts of ethyl acetate.

The reaction solution from which the impurities have been removed is concentrated, and the resulting residue is 1
By chromatography on 0% diluted silica gel 15 ta, compound paste 460-9 is obtained from the fraction eluted with a mixture of benzene and decaacetate (95:5). IR: Reju SI3341
5.3005.1785.1745.1696.160
0C 110NMR: 6CDC131.21s group, 2.
1 melon group, 3.84d (11.5HZ) IH, 4.2 mother (
11.5 days 2) IH, 4.5 dollars 2 days, 4.8 dollars IH, 5
．． 2 red d (9; 2HZ) IH, 5.3 spots (2 days 2) IH
, 6.9$ IH, 6.8-7.8ml mark.

Compound (3) Dissolve 9 of 785 in 1.4 of a 20% solution of pyridine, add 1.4 of a solution of 760 of iodobenzene dichloride in pyridine, and stir at room temperature for 1.5 hours.

Add 50% of ethyl acetate to the reaction solution and remove the insoluble matter in an oven.
Concentrate the furnace liquid under reduced pressure. If the residue is purified by silica gel column chromatography, benzene + ethyl acetate (1:1)
Compound 09 Q is obtained from the fraction eluted with the mixed solution. IR
: Le thin 133420/3010/1795/1750
・1700・1600 arc-10NMR: 6 CDC
13 1.0 $9 days, 2.1 $3 days, 4,3 r
s is 4, 56 is 5, Old (2,3HZ) IH, 5
．． 62dd (2.3; 9HZ) IH, 6.9$ IH, 6
．． 9-7.7ml group, 7.8 Rainbow (9HZ) IH.

Q (×=CI)-Compound ■6.66 and cupric chloride 3
．． Dissolve 33% of dichloromethane in 100% methylene chloride and dissolve 33% of it at room temperature.
Stir the time.

The insoluble matter is removed in the furnace, the resulting furnace liquid is concentrated under reduced pressure, and purified by chromatography on 10% fused silica gel to form a compound lake (
×=CI) 2.72 evenings are obtained. Yield: 50%. IR: station connection o133415, 1790, 1750, 1700,
1605 Kayi 10NMR: 6CoCI31.27s 9 days, 3.47s 2 days, 4.4$2 days, 5.1$IH, 5.
12dd (8HZ; 1.5HZ) IH, 5.2 spots (1.
5HZ) IH, 6.8$IH, 6.5-7.5ml arc,
7.54d (8th day 2) IH.

(X=CI)-Compound (3'(X=CI)2.45
Dissolve the solution in 4.5 parts of 20% aqueous pyridine and add 2.45 parts of iodobenzene dichloride to 4.5 parts of the pyridine solution.
Add to the mixture under ice-cooling, bring to room temperature, and stir for 1 hour.

The reaction solution was diluted with 200 ml of ethyl acetate, and insoluble matter was removed in an oven. The residue was chromatographed on 45 ml of hydrous silica gel, and 1.23 g of compound '4-(X=CI) was obtained from fractionation with benzene-ethyl decacetate (4:1). Yield: 49%. IR:〃Sanai o133415, 1795, 1
755, 1700, 1600 skin 10NMR: 6C
DC13 1.07s 3 days, 3.70brs 2 days
, 4.47s 2 days, 4.90brsIH, 5.0melon IH
, 5.4&rd (8HZ) IH, 6.97sIH, 6.
8-7.5ml arc, 8.00brd (8HZ) IH.

Reference Example 2 Production of raw materials (Part 2) Compound '5} 1.0 in the same manner as Reference Example 1 [A]
Compound [6} is obtained by refluxing 0.35 mmol of 2-mercaptobenzothiazole and 0.35 mm of 2-mercaptobenzothiazole for 30 hours in toluene.

NMR: 6C. CI31.97s 3 days, 4.47s 2 days, 4.80-5.25h group, 5,4 red (I HZ
), 6.80-7.92h12 days, 8.1 (4HZ
)but. To) Add 5 parts of acetic acid and 0.7 parts of silver acetate to the reaction solution of [A] and treat it in the same manner as in Reference Example 2' to form the compound (710.54 parts and 7-phenoxyacetamide). A mixture of 0.18 g of p-nitrobenzyl 3-methyl-3-acetoxycepham-4-carboxylate is obtained.
MR:6C0CI31.3$, 1.8$, 1.9$, 3
．． 4 red (2HZ), 3.67 14.2 milk (6 days 2), 4
．． 5$, 4.87s, 5.3melon, 5.07-5.4h
, 6.83-7.73h, 8.3 (4 days 2).

In the same manner as in Reference Example 1H, 0.45 g of compound '7) was mixed with 1.5 g of a solution of 520 g of iodobenzene dichloride in pyridine of 2 g of pyridine and 0.4 g of water at room temperature. If you stir for a while, you will get a compound shelf of 0.39 minutes.

Foamy matter. IR: ReS connection 131800, 17551700
Skin-1.

NMR: 6 C0CI3 1.3$ milk day, 2.
1 melon 3 days, 4.10brs, 4.57s, 4.8
7sIH, 5.0 Mother (IHZ) IH, 5.3$, 5.
5 Beni d (1:4 day 2) IH, 6.83-7.42h group,
7.62 x 8.27q (4HZ) 4th, 7.9$ (4H
Z) IH. 2Q Fufune Satoshi S Befunekoi length 11 White short frog ＊ ll n ' entered L construction ^ Drum Y - Mi; Raw.

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Claims (1)

[Claims] A compound represented by a primary formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is an aralkyl, phenoxymethyl, or aryl group;
B represents a lower alkoxy, aralkoxy or nitroaralkoxy group; X represents hydrogen, halogen or a lower alkanoyloxy group, respectively)