JPS6040438B2 - Process for producing 1-oxadethiacephalosporin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention produces 1-oxadethiacephalosporin (R) by removing the leaving group at the 3-position of the 3-leaving group-substituted 1-1-oxadethiacepham compound (1). ).

(In the formula, A is aroylamino, phenylacetamide or phenoxyacetamide, B is aralkoxy, and X is hydrogen, halogen or 1-methyltetrazole-5
(Raw material production method) Raw material of this invention (1) can be synthesized, for example, by the method shown below.

(Reaction operation) This invention is carried out by producing target substance 0 by eliminating the leaving group Z of raw material 1 together with hydrogen.

The Δ2 and Δ3 isomers are produced depending on the position of the water level at which it is desorbed, but depending on the conditions, the produced double bond may move to produce positional isomers. When Z is hydroxy, a dehydrating agent (thionyl halide, phosphorus pentoxide, inorganic acid,
Organic acids, inorganic bases, organic bases, alumina, silica gel,
), halogenating agents (phosphorus pentahalides, phosphorus trihalides, phosphorus oxyhalides, sulfuryl halogenides, etc.), acylating agents (acid anhydrides, acid halides,
acid isocyanides, etc.), others, if necessary, bases (
(inorganic or organic base).

When Z is halogen or acyloxy, a deoxidizing agent (organic or inorganic base, silica gel, alumina, etc.) is used.

When the activity is high, HZ may be desorbed without the action of a specific deoxidizing agent. In the reagent, the halogen is preferably chlorine or bromine; the inorganic acid is mineral acid,
Lewis acids, etc.: Organic acids include strong acidic carboxylic acids, aliphatic or aromatic sulfonic acids, phosphonic acids, etc.; Inorganic bases include alkali metal hydroxides, bicarbonates, carbonates, weak acid salts, mercaptides, Alcoholates, alkali metal oxides, hydroxides, bicarbonates, carbonates, etc.; organic bases include aliphatic or aromatic amines, aromatic bases, salts of organic weak acids; acylating agents, such as acyl Examples of the group include acyl groups of inorganic acids or organic acids.

These reactions usually proceed in a solvent, at elevated temperatures, at room temperature, or at low temperatures.

Any solvent can be used here as long as it does not adversely affect the reaction, raw materials, and products.

For example, hydrocarbons (hexane, cyclohexane, benzene, toluene, etc.), halohydrocarbons (chloromethane,
methylene chloride, chloroform, dichloroethane, chlorobenzene, etc.), ethers (diethyl ether, dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, butyl acetate, methyl benzoate, etc.), ketones (
acetone, cyclohexane, etc.), alcohols (methanol, ethanol, benzyl alcohol, etc.), sulfoxides (dimethyl sulfoxide, etc.), nitriles (
acetonitrile, benzonitrile, etc.), bases (triethylamine, pyridine, quinoline, etc.), acids (acetic acid, propionic acid, etc.), acid anhydrides (acetic anhydride, trifluoroacetic anhydride, etc.), and other solvents or them. An example is a mixture of During the reaction, products may be obtained in which A, COB, X, Y, double bonds, steric coordination, etc. are different from the corresponding groups in the raw materials due to the action of de-HZing agents, solvents, etc. Such cases shall also be included within the scope of this invention.

Utilizing this, it is also possible to perform two or more reactions at the same time by appropriately selecting the deiriding Z agent and the solvent to achieve highly efficient synthesis. For example, in Examples 15 and 18, the X group can be substituted at the same time as the introduction of Δ3, and in Examples 17 and 18
Then, Y can be changed from hydrogen to methoxy at the same time as introducing Δ3. The compound (m) produced in this way is obtained by removing the solvent, unreacted substances, created substances, etc. by a conventional method such as concentration, extraction, washing, etc., and then purifying it by a conventional method such as reprecipitation, chromatography, recrystallization, etc. When △2 and △3 isomers are produced simultaneously, they can be separated by precise chromatography, fractional recrystallization, etc. In the compound (b) produced in this way, COB is Salts are useful as antibacterial agents, and those where COB is a protected carboxy can be deprotected to change A to the preferred acyl group, e.g. arylmalonamide, and X to 1-methyltetrazol-5-ylthio. By doing so, a highly potent antibacterial agent, 1-oxadethiacephalosporin, can be induced.

These reactions can also be carried out by applying methods commonly used in the chemistry of penicillins and cephalosporins. Examples are shown below to explain aspects of the invention.

Examples 1 to 22 The raw material compound (1) is dissolved in a solvent, a de-HX agent is added thereto, and the mixture is stirred while being maintained at a predetermined temperature for a predetermined period of time.

The reaction solution is poured into ice water, extracted with a water-immiscible solvent such as methylene chloride, and after drying, the solvent is distilled off. The desired substance (b) is obtained by recrystallizing the residue or purifying it by chromatography and solidifying it by adding an insoluble solvent. The reaction conditions are shown in Table 1, and the physical constants of the products are shown in Table 0.

During the reactions in Table 1, Examples 1, 10, 12, 21 and 2
The reaction operation in step 2 is detailed below.

Example 1 15.0 ml of 7a-benzamide 3f-hydroxy-3;-methyl-1-dethia-1-oxacephamo 4Q-diphenylmethyl carboxylate was suspended in 100 methylene chloride, and while stirring under ice-cooling, pyridine 6.8 chloride was added. Thionyl 3 skin was added and stirred for 75 minutes and at room temperature for 2 hours and 15 minutes. The reaction solution was poured into ice water, and the organic solvent layer was washed with water, dried, and the solvent was removed.

The residue was chromatographed on 10% hydrated silica gel 350 #, and the fractions eluted with a mixture of benzene and ethyl acetate (9:1) yielded 7Q-penzamido-3-methyl-1-dethia-1-oxa-3-cephemu-4-carboxylic acid. Diphenylmethyl 2.65% (yield: 25.2%; mp.144
~146oo) and 7Q-benzamido-3-methyl-1
-dethia 1-oxa-3-cephemu 4Q-carboxylic acid diphenylmethyl 1.05 mg (yield: 10.8%: I
R: Re common skin 133340, 1782, 1745, 167
6. Get 166$b skin-1). Note that a mixture of both isomers can also be obtained. Example 10 7Q-penzamide 3Q-hydroxy-38-chloromethyl-1-dethia-1-oxacefamo 4Q-carboxylic acid pendyl ester 1 to 0.905 thionyl chloride
Tetrahydrofuran 2 with m' and 0.825 pyridine
Dissolve in a 0M solution under ice cooling, return to room temperature, and stir for 6 hours.

The precipitated crystals are collected in a furnace, washed successively with ethyl acetate, water, methylene chloride, and acetone, and dried to obtain crystals of 452. The mother liquor was extracted with ethyl acetate, washed with water, combined with the washing solution of the crystals, extracted with ethyl acetate, dried over sodium sulfate, and the residue of 389-9 was obtained, which was recrystallized from acetone. 9 crystals of 236 were obtained. Both crystals are the target product, 7Q-penzamide-3-chloromethyl-dethia-1-oxa-3-cephem-4-carboxylic acid penzyl ester. mp. 187-18 Yo○(
Disassembly). Yield: 71.2%. Example 127Q-benzamide-3-exomethylene-1-dethia-1-oxacephaam 4Q-carboxylic acid diphenylmethyl ester 51
Dissolve 9 of 9 in 5 parts of methylene chloride, add 0.7 degrees of chlorine/1.6 degrees of carbon tetrachloride, and irradiate with a tungsten lamp for 40 minutes while cooling to 120 to 130 degrees.

Cyclobentene 15A was added to this and irradiated again, then 1,5-diazabicyclo[4.3.0]nonene-5
Add 140 tablespoons of water and stir at -20℃ for 10 minutes.
The reaction solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate, and the solvent was distilled off. Recrystallization of the residue from methanol yields 7Q-benzamide-3-chloromethyl-1-dethia-
1-oxer 3-cephem-4-carboxylic acid diphenylmethyl ester 484-9 is obtained. Yield: 86%. mp
．． 120-12800. Example 21 7Q-phenylacetamide 3-exomethylene-1
- Dithia 1-oxacephaam 4-carboxylic acid pendyl ester 205 9 is dissolved over methylene chloride 4,
1.34M chlorine/carbon tetrachloride solution kept at 0.
48' was added and irradiated for 20 minutes with a tungsten lamp, and then 0.11 m of 1.34M chlorine/carbon tetrachloride solution was added.
Irradiate for 8 minutes.

Add 32 parts of cyclobentene to the reaction mixture and stir for 15 minutes, add 59 parts of pyridine, and stir for 1 hour under ice cooling. Add 20 piveridine 2. React for an hour, dilute with ethyl acetate, and wash with ice water and hydrochloric acid. The organic layer was washed with water, dried, and the solvent was distilled off. Washing residue 9 of 221 with ether yields 7Q-phenylacetamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-
4-carboxylic acid pendyl ester 145-9 is obtained. m
p. 137-139.500. Yield: 65.3%. Example 22 [Production of raw materials] (1) 6Q-phenoxyacetamidobenicillanic acid diphenylmethyl ester 1-oxide 5.042 g,
A mixture of 2.73 hours of triphenylphosphine, 25.2 hours of 1,2-dichloroethane, and 25.2 hours of toluene was refluxed for 3 hours, ether was added to remove the precipitate, and the solution was chromatographed on silica gel. If you graph it, it will be (wave) -3-methyl-2-[(IR/station)-3-phenoxymethyl-7
-Oxo4-Oxor2,6-Diazabicyclo[3.
3.303 mg of 2.0]heptot-2-en-6-yl]-3-butenoic acid phenylmethyl ester are obtained.

Yield: 72.3%. [21 Product of m above 2.4699
Dissolve in 74.1 g of ethyl acetate and add 2. Add 1.1 equivalents of hydrogen chloride/ether solution to 1.3 molar solution at room temperature.
1.5 equivalents of 8M chlorine/carbon tetrachloride were added dropwise over 25 minutes,
After 10 minutes, the reaction solution was poured into a mixture of 74.1 parts of cold water, 1.51 parts of sodium bicarbonate, and 2.54 parts of sodium thiosulfate, and 74 parts of acetone was added, followed by stirring for 5 hours.

The mixture was extracted with ethyl acetate, the organic layer was washed with water, dried,
Concentrate. When the residue 2.808% is purified by chromatography, it becomes (Koi)-3-chloromethyl-2-[(IR・S
)-3-phenoxymethyl-7-oxo-4-oxer 2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-3-butenoic acid diphenylmethyl ester (1.664 g) is obtained. Yield: 62.9%. '3' A mixture of 9 of the product 749, 7.5 of acetone and 9 of sodium biodide 760 was stirred for 2 hours, and then extracted with ethyl acetate. Wash the organic layer with water, dry it,
Concentrate and dissolve the residue 818 in dimethyl sulfoxide 7.4
Mix with 9 parts of water, 1.87 parts of water, and 622 parts of cuprous oxide, and stir at 40 o'clock for 3 hours. Dilute the reaction solution with 50 parts of ethyl acetate. , the precipitate is removed from the furnace, and the furnace liquid is washed with water, dried, and concentrated. If the residue is chromatographed (wave) -3
-Hydroxymethyl-2-[(IR/Insect)-3-phenoxymethyl-7-oxo-4-oxa-2,6-diazabicyclo[3.210]hepto-2-en-6-yl]
218m9 of -3-butenoic acid phenylmethyl ester are obtained. Yield: 3o. 2%'4} 9 of the above products 169
Melt methylene chloride to 1.7 I, sulfuric acid steel to 169 to 9
Add 3. Song time reflux. Insoluble matter was removed in an oven, and the reaction solution was diluted with ethyl acetate, washed with water, dried, and concentrated. The residue is purified by chromatography to obtain phenylmethyl 7Q-phenoxyacetamido-3-methylene-1-dethia-1-oxacefam-4Q-carboxylate 78c.
Yield: 46.2%. [Reaction of Example 22] 68 mp of the above '4-' product was converted into 1.4 methylene chloride.
Comb it and heat it under irradiation with a tungsten lamp at 150 ohms.
Add 1.3 equivalents of 8M chlorine/carbon tetrachloride solution.

After 30 minutes, 0.4 equivalents of cyclobentene and 16 piberidine
Add Butsuji and chill on ice.

After 30 minutes, the reaction solution was diluted with ethyl acetate, washed with cold dilute hydrochloric acid, aqueous sodium bicarbonate, and water, and dried.
Concentrate.

Recrystallization of residue 70-9 from ether yields 7Q-phenoxyacetamide 3-chloromethyl-1-dethia-
1-Oxa-3-cephemu 4-carboxylic acid diphenylmethyl ester 63 females are obtained. Yield: 89%. mp16
2-I64°C. (The physical constants of the products of each process are as follows)'1) m:ReS 13178fu 17401651 佽-1.

NMR: 6 C0013 1.8 Monument 9th, 4.5
$2 days, 4.8 $IH, 4.9 $IH, 5.2-5.
1m2 days, 5.87d (4HZ) IH, 6.95 IH,
6.8-7.8ml thin [211R: Death bag 13178
317431658 arc-1. NMR: 6ooo13
4.1$2 days, 4.6$2 days, 5.15 IH,
5.2 (4HZ) IH, 5.2$IH, 5.5$IH
, 5.8 string (4 days 2) IH, 6.9 SI days, 6.8-7
．． 7ml 9 days. [31m: Les S bag CI33350, 17
82, 1750, 1662 arc-1.

NMR: 6 CoC13 4.1$2 days, 4.5
$2 days, 4.9 $IH, 5.1 $IH, 5.2 (4
Day 2) IH, 5.41sIH, 5.9 (4HZ) IH
, 6.9$IH, 6.6-7. Skin calm {4} m: Les S hair 1334101777, 1742, 1691 arc-1. N
MR: 60DC134.2 2 days, 4.5$ 2 days, 4.
9 red (8 days 2) IH, 5.1 $ IH, 5.262 days, 5
．． 3$IH, 6.8$IH, 6.6-7.8h18 days.
Application example 1 {1) 7Q-phenylacetamide 3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid diphenylmethyl 7 & tetrahydrofuran 3
Dissolve the solution in a mixture of 2 parts of sodium chloride and methylene chloride, and while stirring at 140 to 13 parts, add 26 parts of t-butylhypocrito and 10 parts of 2N lithium methoxide/methanol, and stir for 15 minutes.

The reaction solution to which 0.1M acetic acid was added was poured into ice-cold brine, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate, aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and the solvent was distilled off to give 73-phenylacetamide 7o-methoxy-3-chloromethyl-1-dethia-1-oxer-3-cefemu-4- Diphenylmethyl carboxylate 81 females were obtained. IR: 133410, 1788
1728 1695 Arc-INMR:6CDC133.4
$9 days, 3.6 $2 days, 4.4 $10s 4 days, 5.0 SI
day, 6.581 days, 6.9$ IH, 7.1-7.6ml
9th.

{2} Above m product 76 9, acetone 2, 1
- Sodium salt of tiltetrazole-5-thiol 2
Stir the two mixtures at room temperature.

After 35 minutes, the reaction solution is poured into ice water and extracted with ethyl acetate.

The organic layer was washed with brine, dried, and the solvent was removed. If the residue 88 o is recrystallized from methylene chloride ether, 7 is obtained.
6-phenylacetamido-7Q-methoxy-3-(1
-methyltetrazol-5-yl)-thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid diphenylmethyl 57 p is obtained. Total yield: 67.7%
. mP174-176q0. (3} 7Q-phenylacetamido-3-chloromethyl-1-dethia-1-oxa-3-cefemu-4-carboxylic acid diphenylmethyl 1
A mixture of 71 parts, 5 parts of acetone, and 51 parts of the sodium salt of 1-methyltetrazol-5-ylthiol is stirred at room temperature for 3 minutes.

The reaction solution was extracted with ethyl acetate, and the organic layer was washed with brine.
Drying over sodium sulfate and evaporation of the solvent yields 195 diphenylmethyl 7Q-phenylacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-1-dethia-1-oxa-3-cepheme-4-carboxylate. NMR: 6CDC133.6$2nd, 3-77S Mother's Day, 4.2$2nd, 4.57s, 4.6M (7HZ)
IH, 4.9 SI days, 6.2 lees (7HZ) IH, 6.9
Public IH, 7.2-7.6mlHH.

[4' 90 parts of the product from '3' above was dissolved in 2 parts of methylene chloride while stirring in a nitrogen stream, and 19 parts of t-butyl hypochlorite and 94 parts of a 2M lithium methoxide/methanol solution were added. Add.

After 5 minutes, add 50 grams of acetic acid.

Pour the reaction solution into ice water and extract with ethyl acetate. The organic layer was diluted with 10% sodium thiosulfate water, sodium bicarbonate water,
and brine, dry over sodium sulfate, and concentrate. When the residue 90-9 is crystallized from a mixture of chlorinated ethylene ether, 78-phenylacetamido-7Q-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4 is obtained.
- Diphenylmethyl carboxylate 54 was obtained. Yield 5
7.5%. mp176-177. yo. NMR: 8C.

CI33-47S Mother's Day, 3-67S 2nd, 3-8$SH
, 4.2 $2 days, 4.6 books 2 days, 5.0 SI days, 6.2
$IH, 6.9$IH, 7.2-7.8hl 9 days. IR
:Refuyode 13341u1792, 1700(br) skin-
1.

Usage example 2'1} Usage example 1 78-benzamide-7Q-methoxy-3-(chlor or bromo)methyl-1-dethia-1-oxa-3-cephem-4
-73-benzamide 7-methoxy 3-(1-methyltetrazole-5-
diphenylmethyl)thiomethyl-1-dethia-3-cephem-4-carboxylate is obtained.

IR: 133420, 2840, 1790, 17
25, 1 Iso 0 Ka■ Similarly to {1' above, (7Q-penzamide or 78-penzamide-7Q-methoxy)-3-koomethyl-1-dethia-1-oxer 3-
Penzyl (7Q-benzamide or 78-benzamide 7Q-methoxy)-1-3-(1-methyltetrazol-5-yl)thiomethyl-1-dethia-1-oxa-3-cephemu-4-carboxylate is obtained from penzyl cephemu-4-carboxylate.

(7Q-penzamide form) mp186-189pm ○. (
78-penzamide-7Q-methoxy form) mp189~
19100 (decomposition). Approximately striped rhombus false carp, carp, fin, fence, Sannomiya zafu; 1st place in the table subject.

・ Target ○ fever government army Length To board 1. ．． Up( Hue cover order ○) foundation vine

Claims (1)

[Claims] 1. A method for producing a cephalic compound represented by formula II, which comprises reacting a cephalic acid compound represented by formula I with a dehydrating agent or a dehydrohalogenating agent. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A is aroylamino, phenylacetamide, or phenoxyacetamide, B is aralkoxy, and X is hydrogen, halogen, or 1-methyltetrazole-5
-ylthio, Y is hydrogen or methoxy, Z is a hydroxyl group or halogen, the wavy line represents an α bond or a β bond, and the dotted line represents a double bond at the 2- or 3-position, respectively).